In vitro antimicrobial susceptibility of Staphylococcus aureus strains from dairy herds in KwaZulu-Natal.
Staphylococcus aureus is 1 of the most important causes of bovine mastitis and is responsible for significant economic losses to the dairy industry worldwide. One of the principal approaches used in treating intramammary infections is the administration of antimicrobials. Due to the propensity of S. aureus to develop resistance, antimicrobial susceptibility monitoring is necessary to ensure that treatment regimens are effective. As part of this investigation, 90 S. aureus strains isolated from mastitis cases submitted to Allerton Provincial Veterinary Laboratory during 2008 and 2009 were evaluated for their susceptibility to a panel of 10 antimicrobials. Only 8 of the 90 S. aureus isolates tested (8.9%) were found to be susceptible to all of the antimicrobials evaluated. A very high level of resistance to the beta-lactam antibiotics was noted: 47.8% of the isolates were resistant to penicillin and 65.6% were resistant to ampicillin. Minimal resistance to oxacillin, cephalothin and trimethoprim-sulfamethoxazole (1.1%) was found. Seventeen (18.9%) of the isolates tested were found to be resistant to 3 or more antimicrobials. The need for vigilant monitoring of bacterial resistance trends in the dairy industry is warranted as the potential public health implications are significant.


Seizure sensitivity is ameliorated by targeted expression of K+-Cl- cotransporter function in the mushroom body of the Drosophila brain.
The kcc(DHS1) allele of kazachoc (kcc) was identified as a seizure-enhancer mutation exacerbating the bang-sensitive (BS) paralytic behavioral phenotypes of several seizure-sensitive Drosophila mutants. On their own, young kcc(DHS1) flies also display seizure-like behavior and demonstrate a reduced threshold for seizures induced by electroconvulsive shock. The product of kcc shows substantial homology to KCC2, the mammalian neuronal K(+)-Cl(-) cotransporter. The kcc(DHS1) allele is a hypomorph, and its seizure-like phenotype reflects reduced expression of the kcc gene. We report here that kcc functions as a K(+)-Cl(-) cotransporter when expressed heterologously in Xenopus laevis oocytes: under hypotonic conditions that induce oocyte swelling, oocytes that express Drosophila kcc display robust ion transport activity observed as a Cl(-)-dependent uptake of the K(+) congener (86)Rb(+). Ectopic, spatially restricted expression of a UAS-kcc(+) transgene was used to determine where cotransporter function is required in order to rescue the kcc(DHS1) BS paralytic phenotype. Interestingly, phenotypic rescue is largely accounted for by targeted, circumscribed expression in the mushroom bodies (MBs) and the ellipsoid body (EB) of the central complex. Intriguingly, we observed that MB induction of kcc(+) functioned as a general seizure suppressor in Drosophila. Drosophila MBs have generated considerable interest especially for their role as the neural substrate for olfactory learning and memory; they have not been previously implicated in seizure susceptibility. We show that kcc(DHS1) seizure sensitivity in MB neurons acts via a weakening of chemical synaptic inhibition by GABAergic transmission and suggest that this is due to disruption of intracellular Cl(-) gradients in MB neurons.


The evolutionary ecology of seed germination of Arabidopsis thaliana: variable natural selection on germination timing.
Germination timing of Arabidopsis thaliana displays strong plasticity to geographic location and seasonal conditions experienced by seeds. We identified which plastic responses were adaptive using recombinant inbred lines in a field manipulation of geographic location (Kentucky, KY; Rhode Island, RI), maternal photoperiod (14-h and 10-h days), and season of dispersal (June and November). Transgressive segregation created novel genotypes that had either higher fitness or lower fitness in certain environments than either parent. Natural selection on germination timing and its variation explained 72% of the variance in fitness among genotypes in KY, 30% in June-dispersed seeds in RI, but only 4% in November-dispersed seeds in RI. Therefore, natural selection on germination timing is an extremely efficient sieve that can determine which genotypes can persist in some locations, and its efficiency is geographically variable and depends on other aspects of life history. We found no evidence for adaptive responses to maternal photoperiod during seed maturation. We did find adaptive plasticity to season of seed dispersal in RI. Seeds dispersed in June postponed germination, which was adaptive, while seeds dispersed in November accelerated germination, which was also adaptive. We also found maladaptive plasticity to geographic location for seeds dispersed in June, such that seeds dispersed in KY germinated much sooner than the optimum time. Consequently, bet hedging in germination timing was favorable in KY; genotypes with more variation in germination timing had higher fitness because greater variation was associated with postponed germination. Selection on germination timing varied across geographic location, indicating that germination timing can be a critical stage in the establishment of genotypes in new locations. The rate of evolution of germination timing may therefore strongly influence the rate at which species can expand their range.


Drosophila TRF2 and TAF9 regulate lipid droplet size and phospholipid fatty acid composition.
The general transcription factor TBP (TATA-box binding protein) and its associated factors (TAFs) together form the TFIID complex, which directs transcription initiation. Through RNAi and mutant analysis, we identified a specific TBP family protein, TRF2, and a set of TAFs that regulate lipid droplet (LD) size in the Drosophila larval fat body. Among the three Drosophila TBP genes, trf2, tbp and trf1, only loss of function of trf2 results in increased LD size. Moreover, TRF2 and TAF9 regulate fatty acid composition of several classes of phospholipids. Through RNA profiling, we found that TRF2 and TAF9 affects the transcription of a common set of genes, including peroxisomal fatty acid β-oxidation-related genes that affect phospholipid fatty acid composition. We also found that knockdown of several TRF2 and TAF9 target genes results in large LDs, a phenotype which is similar to that of trf2 mutants. Together, these findings provide new insights into the specific role of the general transcription machinery in lipid homeostasis.


Validation of nonradioactive chemiluminescent immunoassay methods for the analysis of thyroxine and cortisol in blood samples obtained from dogs, cats, and horses.
The performances of a radioimmunoassay method, a chemiluminescent immunoassay method, and a chemiluminescent-enzyme immunoassay method were evaluated for the analysis of cortisol and total thyroxine in blood samples obtained from dogs, cats, horses, and humans (reference samples). The analysis of cortisol in human and animal samples exhibited good precision, linearity, and recovery. The 3 methods gave comparable values for the ACTH-induced increase and the dexamethasone-induced decrease in cortisol concentrations in animal samples. The recoveries of total thyroxine from human samples, analyzed by the 3 methods, were comparable. However, the basal total thyroxine concentrations determined by the chemiluminescent immunoassay method were 30-40% lower than those determined by the radioimmunoassay and the chemiluminescent-enzyme immunoassay methods in animal samples. In both human and animal samples, the plot of thyroxine values obtained by the radioimmunoassay method against those obtained by the chemiluminescent immunoassay method or the chemiluminescent-enzyme immunoassay method was linear. However, although the slope of the radioimmunoassay versus chemiluminescent-enzyme immunoassay curve was close to unity, the slope of the radioimmunoassay versus chemiluminescent immunoassay curve was 0.6. This result suggests that, compared with the radioimmunoassay method, the chemiluminescent immunoassay method underestimated thyroxine values in animal samples but not in human samples. Although all 3 methods yielded comparable changes in thyroxine concentrations in response to thyroid stimulating hormone, they did not yield comparable thyroxine concentrations in response to T3 suppression in dogs and cats.


Whole Exome Sequencing Identifies a Rare Mutation in NACAD as a Possible Cause of COVID Orchitis in Brothers.
COVID orchitis (testicular pain) is reported in 10-15% of men with long COVID. We identified 2 siblings with COVID orchitis and hypothesized that genetic mutations are associated with susceptibility. Blood samples from 5 COVID-19 (+) men, three of whom had orchitis were evaluated by whole-exome-sequencing. A rare deletion on chromosome 7 was found in NACAD among the 3 men with orchitis. Interestingly, circulating ACE2 levels was decreased in men with COVID orchitis. This pilot study generated the hypothesis that men who develop COVID orchitis could have underlying genetic variants and altered levels in circulating ACE2 that may increase their risk.


Online interprofessional health sciences education: From theory to practice.
Online learning (e-learning) has a nascent but established history. Its application to interprofessional education (IPE), however, is relatively new. Over the past 2 decades the Internet has been used increasingly to mediate education. We have come past the point of "should we use the Internet for education" to "how should we use the Internet for education." Research has begun on the optimal development of online learning environments to support IPE. Developing online IPE should follow best practices in e-learning generally, though there are some special considerations for acknowledging the interprofessional context and clinical environments that online IPE is designed to support. The design, development, and deployment of effective online IPE must therefore pay special attention to the particular constraints of the health care worker educational matrix, both pre- and postlicensure. In this article we outline the design of online, interprofessional health sciences education. Our work has involved 4 educational and 4 clinical service institutions. We establish the context in which we situate our development activities that created learning modules designed to support IPE and its transfer into new interprofessional health care practices. We illustrate some best practices for the design of effective online IPE, and show how this design can create effective learning for IPE. Challenges exist regarding the full implementation of interprofessional clinical practice that are beginning to be met by coordinated efforts of multiple health care education silos.


Pteropods are excellent recorders of surface temperature and carbonate ion concentration.
Pteropods are among the first responders to ocean acidification and warming, but have not yet been widely explored as carriers of marine paleoenvironmental signals. In order to characterize the stable isotopic composition of aragonitic pteropod shells and their variation in response to climate change parameters, such as seawater temperature, pteropod shells (Heliconoides inflatus) were collected along a latitudinal transect in the Atlantic Ocean (31° N to 38° S). Comparison of shell oxygen isotopic composition to depth changes in the calculated aragonite equilibrium oxygen isotope values implies shallow calcification depths for H. inflatus (75 m). This species is therefore a good potential proxy carrier for past variations in surface ocean properties. Furthermore, we identified pteropod shells to be excellent recorders of climate change, as carbonate ion concentration and temperature in the upper water column have dominant influences on pteropod shell carbon and oxygen isotopic composition. These results, in combination with a broad distribution and high abundance, make the pteropod species studied here, H. inflatus, a promising new proxy carrier in paleoceanography.


Value of routine voiding cystourethrography after renal transplantation.
The impact of vesicoureteral reflux (VUR) on renal allograft outcomes is debatable, with small cohort studies reporting controversial results. The objective of this retrospective study was to evaluate long-term clinical effects of early VUR in a large cohort of kidney transplant patients. Posttransplantation voiding cystourethrography was used to evaluate 646 consecutive kidney transplant recipients before discharge. The study endpoints included VUR grade, death-censored graft or patient survival, renal function, proteinuria and occurrence of urinary tract infections (UTIs). Of the 646 recipients, 263 (40.7%) were diagnosed with VUR. VUR grade II was most common (19.8%), followed by grades III (10.2%), I (7.9%) and IV (2.8%). VUR was less common in transplantations performed by experienced compared to inexperienced surgeons (36% vs. 48%; p = 0.004). VUR did not affect death-censored graft or patient survival and was not associated with proteinuria or occurrence of UTIs. Patients with VUR had a lower eGFR at 1 year after transplantation than did patients without VUR (60 vs. 52 mL/min/1.73 m(2) ; p = 0.02), although this difference was not observed at 3 and 5 years after transplantation. We conclude that early VUR, a common finding among renal transplant patients, may not have a meaningful impact on long-term transplant outcomes.


T cell sensitivity to HLA class I-mediated apoptosis is dependent on interleukin-2 and interleukin-4.
Antibody interaction with a specific epitope of the HLA class I alpha1 domain triggers apoptosis of activated but not resting T and B cells by a pathway which involves neither Fas ligand nor tumor necrosis factor-alpha. We have investigated at which stage of activation and proliferation T cells become sensitive to HLA class I-mediated apoptosis, using two monoclonal antibodies (mAb) which recognize the same monomorphic epitope of the HLA class I alpha1 domain (mAb9O, mouse IgG1, and YTH862, rat IgG2b) and can induce apoptosis of phytohemagglutinin (PHA)-activated peripheral blood lymphocytes. Sensitivity to apoptosis develops after the expression of G1 markers (CD69 expression) but it is accelerated by addition of recombinant interleukin-2 (rIL-2). Blocking the IL-2 pathway by cyclosporin A, FK506, rapamycin, anti-IL-2 or CD25 antibodies, prevented the development of sensitivity to apoptosis. Addition of IL-2 and, to a lesser extent, IL-4, reversed the inhibitory effect of cyclosporin A. Conversely, rIL-7 and recombinant interferon-gamma restored proliferation of peripheral blood lymphocytes stimulated by PHA in the presence of cyclosporin A but did not restore sensitivity to class I-mediated apoptosis. Finally cells stimulated in the presence of the DNA polymerase inhibitor aphidicolin did not enter into S phase of the cell cycle but secreted IL-2 and underwent apoptosis when exposed to mAb90 or YTH862. Together, the data indicate that sensitivity of peripheral T cells to HLA class I-mediated apoptosis depends on both activation signals and IL-2 or IL-4, but does not require cell proliferation. These data suggest that YTH862 and mAb90 might be used for achieving clonal deletion of antigen-activated peripheral T cells in vivo, provided that the IL-2 pathway is not blocked by other immunosuppressive agents.


Multiple ways of silencing E-cadherin gene expression in lobular carcinoma of the breast.
The cell-cell adhesion receptor gene E-cadherin (CDH1) is expressed by epithelial cells, in which it mediates adhesion and morphogenesis. Invasive lobular carcinoma (ILC) characteristically infiltrates diffusely as single cells; by immunohistochemistry, many of these tumours lack E-cadherin expression. In the present study we investigated various ways in which loss of function of the E-cadherin gene could occur in ILCs, namely, promoter methylation, mutation and allelic loss. We analysed 22 ILCs and found 12 (55%) E-cadherin-negative samples by immunohistochemical analysis. Methylation-specific polymerase chain reaction (PCR) showed that 17/22 (77%) of these tumours had methylation of the CDH1 promoter, including 11/12 (91%) of the E-cadherin-negative tumours. All 16 exons of E-cadherin (including intron-exon boundaries) were amplified from chromosomal DNA and screened for mutations by conformation-sensitive gel electrophoresis (CSGE). Bands with altered mobility were analysed by direct sequencing. We identified five frameshift mutations, which resulted in downstream stop codons and one splice site mutation in six different tumours (29%). Loss of heterozygosity (LOH) was assessed using microsatellite markers, and 9/18 (50%) informative tumours showed LOH. We conclude that most ILCs show genetic or epigenetic changes affecting the E-cadherin gene and that many of these tumours lack E-cadherin expression. In all cases in which there was loss of expression, this was consistent with biallelic inactivation of CDH1 by promoter methylation, mutation or allelic loss in any combination.


Normal pathogen-specific immune responses mounted by CTLA-4-deficient T cells: a paradigm reconsidered.
CTLA-4 is a critical negative regulator of T cell responses and CTLA-4-deficient (CTLA-4(-/-)) mice die of a lymphproliferative disease. Nevertheless, RAG-2-deficient mice reconstituted with a mixture of CTLA-4(-/-) and normal (CTLA-4(+/+)) bone marrow survive in the absence of any signs of disease, although 50% of their T cells do not express CTLA-4. Using such mixed chimeras, we analyzed the role of CTLA-4 in specific T cell responses to lymphocytic choriomeningitis virus, Leishmania major and mouse mammary tumor virus, which cause acute, chronic and persistent infections, respectively. The populations of antigen-specific CTLA-4(-/-)CD4(+) and CTLA-4(-/-)CD8(+) T cells became activated, expanded and contracted indistinguishably from CTLA-4(+/+)CD4(+) and CTLA-4(+/+)CD8(+) T cells after infection with all three pathogens. Thus, CTLA-4 is not involved in the down-regulation of specific T cell responses and peripheral deletion in a T cell-autonomous fashion.


The Aggression Observation Short Form identified episodes not reported on the Staff Observation Aggression Scale--Revised.
The purpose of this study is to evaluate the underreporting of violence and aggression on the Staff Observation Aggression Scale-Revised (SOAS-R) when compared to a simpler assessment: the Aggression Observation Short Form (AOS). During a period of one year, two open and two closed wards gathered data on both the SOAS-R and the AOS for all of their patients. The 22-item SOAS-R is to be filled out after each violent episode. The 3-item AOS is to be filled out during each shift and should also record the absence of violence. The SOAS-R registered 703 incidents and the AOS registered 1,281 incidents. The agreement between the SOAS-R and the AOS was good (kappa = 0.65, 95% CI = 0.62-0.67). Among the 1,281 AOS episodes, 51% were also registered on the SOAS-R. For the 176 AOS episodes with harm, 42% were also registered on the SOAS-R. We found 44% missing registrations on the AOS, primarily for open wards and for patients with short admission lengths. Standard instruments such as the SOAS-R underreport aggressive episodes by 45% or more. Underreporting can be reduced by introducing shorter instruments, but it cannot be completely eliminated.


Mysterious Ca(2+)-independent muscular contraction: déjà vu.
The permeabilized cells and muscle fibres technique allows one to study the functional properties of mitochondria without their isolation, thus preserving all of the contacts with cellular structures, mostly the cytoskeleton, to study the whole mitochondrial population in the cell in their natural surroundings and it is increasingly being used in both experimental and clinical studies. The functional parameters (affinity for ADP in regulation of respiration) of mitochondria in permeabilized myocytes or myocardial fibres are very different from those in isolated mitochondria in vitro. In the present study, we have analysed the data showing the dependence of this parameter upon the muscle contractile state. Most remarkable is the effect of recently described Ca(2+)-independent contraction of permeabilized muscle fibres induced by elevated temperatures (30-37°C). We show that very similar strong spontaneous Ca(2+)-independent contraction can be produced by proteolytic treatment of permeabilized muscle fibres that result in a disorganization of mitochondrial arrangement, leading to a significant increase in affinity for ADP. These data show that Ca(2+)-insensitive contraction may be related to the destruction of cytoskeleton structures by intracellular proteases. Therefore the use of their inhibitors is strongly advised at the permeabilization step with careful washing of fibres or cells afterwards. A possible physiologically relevant relationship between Ca(2+)-regulated ATP-dependent contraction and mitochondrial functional parameters is also discussed.


Ornithine decarboxylase gene of Neurospora crassa: isolation, sequence, and polyamine-mediated regulation of its mRNA.
Ornithine decarboxylase (ODC), which initiates the biosynthesis of the polyamines putrescine, spermidine, and spermine, is encoded by the spe-1 gene of the fungus Neurospora crassa. This gene and its cDNA have been cloned and sequenced. The gene has a single 70-nucleotide intron in the coding sequence. The cDNA, comprising the entire coding region, recognizes a single 2.4-kb mRNA in Northern (RNA) blots. The mRNA transcript, defined by S1 mapping, has an extremely long, 535-base leader without strong secondary-structure features or an upstream reading frame. The translational start of the protein is ambiguous: a Met-Val-Met sequence precedes the Pro known to be the N terminus of the ODC polypeptide. The polypeptide encoded by the N. crassa spe-1 gene (484 amino acids) has 46% amino acid identity with that of Saccharomyces cerevisiae (466 amino acids) and 42% with that of mouse (461 amino acids). Alignment of the longer N. crassa sequence with S. cerevisiae and mouse sequences creates gaps in different sites in the S. cerevisiae and mouse sequences, suggesting that N. crassa ODC is closer to an ancestral form of the enzyme than that of either yeast or mouse ODC. N. crassa ODC, which turns over rapidly in vivo in the presence of polyamines, has two PEST sequences, found in most ODCs and other proteins with rapid turnover. In striking contrast to other eucaryotic organisms, the variation in the rate of ODC synthesis in response to polyamines in N. crassa is largely correlated with proportional changes in the abundance of ODC mRNA. Spermidine is the main effector of repression, while putrescine has a weaker effect. However, putrescine accumulation appears to increase the amount of active ODC that is made from a given amount of ODC mRNA, possibly by improving its translatability. Conversely, prolonged starvation for both putrescine and spermidine leads to the differentially impaired translation of ODC mRNA.


Cell-Penetrating Peptide Conjugates of Steric Blocking Oligonucleotides as Therapeutics for Neuromuscular Diseases from a Historical Perspective to Current Prospects of Treatment.
The review starts with a historical perspective of the achievements of the Gait group in synthesis of oligonucleotides (ONs) and their peptide conjugates toward the award of the 2017 Oligonucleotide Therapeutic Society Lifetime Achievement Award. This acts as a prelude to the rewarding collaborative studies in the Gait and Wood research groups aimed toward the enhanced delivery of charge neutral ON drugs and the development of a series of Arg-rich cell-penetrating peptides called Pip (peptide nucleic acid/phosphorodiamidate morpholino oligonucleotide [PNA/PMO] internalization peptides) as conjugates of such ONs. In this review we concentrate on these developments toward the treatment of the neuromuscular diseases Duchenne muscular dystrophy and spinal muscular atrophy toward a platform technology for the enhancement of cellular and in vivo delivery suitable for widespread use as neuromuscular and neurodegenerative ON drugs.


Computational Modeling Analysis of Generation of Reactive Oxygen Species by Mitochondrial Assembled and Disintegrated Complex II.
Reactive oxygen species (ROS) function as critical mediators in a broad range of cellular signaling processes. The mitochondrial electron transport chain is one of the major contributors to ROS formation in most cells. Increasing evidence indicates that the respiratory Complex II (CII) can be the predominant ROS generator under certain conditions. A computational, mechanistic model of electron transfer and ROS formation in CII was developed in the present study to facilitate quantitative analysis of mitochondrial ROS production. The model was calibrated by fitting the computer simulated results to experimental data obtained on submitochondrial particles (SMP) prepared from bovine and rat heart mitochondria upon inhibition of the ubiquinone (Q)-binding site by atpenin A5 (AA5) and Complex III by myxothiazol, respectively. The model predicts that only reduced flavin adenine dinucleotide (FADH2) in the unoccupied dicarboxylate state and flavin semiquinone radical (FADH•) feature the experimentally observed bell-shaped dependence of the rate of ROS production on the succinate concentration upon inhibition of respiratory Complex III (CIII) or Q-binding site of CII, i.e., suppression of succinate-Q reductase (SQR) activity. The other redox centers of CII such as Fe-S clusters and Q-binding site have a hyperbolic dependence of ROS formation on the succinate concentration with very small maximal rate under any condition and cannot be considered as substantial ROS generators in CII. Computer simulation results show that CII disintegration (which results in dissociation of the hydrophilic SDHA/SDHB subunits from the inner membrane to the mitochondrial matrix) causes crucial changes in the kinetics of ROS production by CII that are qualitatively and quantitatively close to changes in the kinetics of ROS production by assembled CII upon inhibition of CIII or Q-binding site of CII. Thus, the main conclusions from the present computational modeling study are the following: (i) the impairment of the SQR activity of CII resulting from inhibition of CIII or Q-binding site of CII and (ii) CII disintegration causes a transition in the succinate-dependence of ROS production from a small-amplitude sigmoid (hyperbolic) shape, determined by Q-binding site or [3Fe-4S] cluster to a high-amplitude bell-shaped kinetics with a shift to small subsaturated concentrations of succinate, determined by the flavin site.


Individual differences in the learning potential of human beings.
To the best of our knowledge, the genetic foundations that guide human brain development have not changed fundamentally during the past 50,000 years. However, because of their cognitive potential, humans have changed the world tremendously in the past centuries. They have invented technical devices, institutions that regulate cooperation and competition, and symbol systems, such as script and mathematics, that serve as reasoning tools. The exceptional learning ability of humans allows newborns to adapt to the world they are born into; however, there are tremendous individual differences in learning ability among humans that become obvious in school at the latest. Cognitive psychology has developed models of memory and information processing that attempt to explain how humans learn (general perspective), while the variation among individuals (differential perspective) has been the focus of psychometric intelligence research. Although both lines of research have been proceeding independently, they increasingly converge, as both investigate the concepts of working memory and knowledge construction. This review begins with presenting state-of-the-art research on human information processing and its potential in academic learning. Then, a brief overview of the history of psychometric intelligence research is combined with presenting recent work on the role of intelligence in modern societies and on the nature-nurture debate. Finally, promising approaches to integrating the general and differential perspective will be discussed in the conclusion of this review.


Differential activation of mTOR complex 1 signaling in human brain with mild to severe Alzheimer's disease.
Mammalian target of rapamycin (mTOR) signaling has been suggested to be effective in modifying cognitive status in animal models of Alzheimer's disease (AD), but little is known about its role in AD patients. We hereby tested whether mTOR signaling was activated and whether activated mTOR signaling was related to the degree of cognitive deficits in patients with AD. Autopsy brain hippocampal tissues were obtained from controls and patients with AD and Western blots were performed using antibodies against mTOR signaling molecules and RagC, an upstream component of mTOR complex 1 (mTORC1) signaling. We found that expression of mTOR/p-mTOR and its downstream targets S6/p-S6 and Raptor/p-Raptor were expressed in the control and AD hippocampus. The expression levels of these signaling molecules were significantly increased in the hippocampus at the severe stages of AD, compared to controls and other stages of AD. Interestingly, Rictor expression level was unaltered. In addition, RagC was increased in the hippocampus at the early, moderate, and severe stages of AD. Our data indicate that mTORC1, but not mTORC2, was activated in the AD brains and that the level of mTOR signaling activation was correlated with cognitive severity of AD patients.


Arabidopsis plants grown in the field and climate chambers significantly differ in leaf morphology and photosystem components.
Plants exhibit phenotypic plasticity and respond to differences in environmental conditions by acclimation. We have systematically compared leaves of Arabidopsis thaliana plants grown in the field and under controlled low, normal and high light conditions in the laboratory to determine their most prominent phenotypic differences. Compared to plants grown under field conditions, the "indoor plants" had larger leaves, modified leaf shapes and longer petioles. Their pigment composition also significantly differed; indoor plants had reduced levels of xanthophyll pigments. In addition, Lhcb1 and Lhcb2 levels were up to three times higher in the indoor plants, but differences in the PSI antenna were much smaller, with only the low-abundance Lhca5 protein showing altered levels. Both isoforms of early-light-induced protein (ELIP) were absent in the indoor plants, and they had less non-photochemical quenching (NPQ). The field-grown plants had a high capacity to perform state transitions. Plants lacking ELIPs did not have reduced growth or seed set rates, but their mortality rates were sometimes higher. NPQ levels between natural accessions grown under different conditions were not correlated. Our results indicate that comparative analysis of field-grown plants with those grown under artificial conditions is important for a full understanding of plant plasticity and adaptation.


Patenting human pluripotent cells: balancing commercial, academic and ethical interests.
The article addresses the issue of the ethics of patenting in human embryonic stem (hES) cells. The current stance of the European Patent Office in citing moral objections to patents on hES cells and the monopolistic scope of the Wisconsin Research Alumni Fund/Geron patents granted by the United States Patent and Trademark Office represent twin obstacles to achieving an ethical balance in patent rights in this field. The particular issues and strategies around granting patents on hES cells can be better understood by placing them in the context of the biotechnology industry and its role in the global bioeconomy. Some possible avenues of redress are considered based on the potential to open up cell pluripotency as new terrain for intellectual property offered by new technological breakthroughs such as induced pluripotent cells. Any changes in patent law should be accompanied by increased collaboration through devices such as patent pools.


Molecular phylogenetic evaluation of classification and scenarios of character evolution in calcareous sponges (Porifera, Class Calcarea).
Calcareous sponges (Phylum Porifera, Class Calcarea) are known to be taxonomically difficult. Previous molecular studies have revealed many discrepancies between classically recognized taxa and the observed relationships at the order, family and genus levels; these inconsistencies question underlying hypotheses regarding the evolution of certain morphological characters. Therefore, we extended the available taxa and character set by sequencing the complete small subunit (SSU) rDNA and the almost complete large subunit (LSU) rDNA of additional key species and complemented this dataset by substantially increasing the length of available LSU sequences. Phylogenetic analyses provided new hypotheses about the relationships of Calcarea and about the evolution of certain morphological characters. We tested our phylogeny against competing phylogenetic hypotheses presented by previous classification systems. Our data reject the current order-level classification by again finding non-monophyletic Leucosolenida, Clathrinida and Murrayonida. In the subclass Calcinea, we recovered a clade that includes all species with a cortex, which is largely consistent with the previously proposed order Leucettida. Other orders that had been rejected in the current system were not found, but could not be rejected in our tests either. We found several additional families and genera polyphyletic: the families Leucascidae and Leucaltidae and the genus Leucetta in Calcinea, and in Calcaronea the family Amphoriscidae and the genus Ute. Our phylogeny also provided support for the vaguely suspected close relationship of several members of Grantiidae with giantortical diactines to members of Heteropiidae. Similarly, our analyses revealed several unexpected affinities, such as a sister group relationship between Leucettusa (Leucaltidae) and Leucettidae and between Leucascandra (Jenkinidae) and Sycon carteri (Sycettidae). According to our results, the taxonomy of Calcarea is in desperate need of a thorough revision, which cannot be achieved by considering morphology alone or relying on a taxon sampling based on the current classification below the subclass level.


Maxillomandibular Fixation by Plastic Surgeons: Cost Analysis and Utilization of Resources.
Maxillomandibular fixation (MMF) can be performed using various techniques. Two common approaches used are arch bars and bone screws. Arch bars are the gold standard and inexpensive, but often require increased procedure time. Bone screws with wire fixation is a popular alternative, but more expensive than arch bars. The differences in costs of care, complications, and operative times between these 2 techniques are analyzed. A chart review was conducted on patients treated over the last 12 years at our institution. Forty-four patients with CPT code 21453 (closed reduction of mandible fracture with interdental fixation) with an isolated mandible fracture were used in our data collection. The operating room (OR) costs, procedure duration, and complications for these patients were analyzed. Operative times were significantly shorter for patients treated with bone screws (P < 0.002). The costs for one trip to the OR for either method of fixation did not show any significant differences (P < 0.840). More patients with arch bar fixation (62%) required a second trip to the OR for removal in comparison to those with screw fixation (31%) (P < 0.068). This additional trip to the OR added significant cost. There were no differences in patient complications between these 2 fixation techniques. The MMF with bone screws represents an attractive alternative to fixation with arch bars in appropriate scenarios. Screw fixation offers reduced costs, fewer trips to the OR, and decreased operative duration without a difference in complications. Cost savings were noted most significantly in a decreased need for secondary procedures in patients who were treated with MMF screws. Screw fixation offers potential for reducing the costs of care in treating patients with minimally displaced or favorable mandible fractures.


Meta-analysis of continuous outcome data from individual patients.
Meta-analyses using individual patient data are becoming increasingly common and have several advantages over meta-analyses of summary statistics. We explore the use of multilevel or hierarchical models for the meta-analysis of continuous individual patient outcome data from clinical trials. A general framework is developed which encompasses traditional meta-analysis, as well as meta-regression and the inclusion of patient-level covariates for investigation of heterogeneity. Unexplained variation in treatment differences between trials is considered as random. We focus on models with fixed trial effects, although an extension to a random effect for trial is described. The methods are illustrated on an example in Alzheimer's disease in a classical framework using SAS PROC MIXED and MLwiN, and in a Bayesian framework using BUGS. Relative merits of the three software packages for such meta-analyses are discussed, as are the assessment of model assumptions and extensions to incorporate more than two treatments.


Microcompartmentation of cytosolic aldolase by interaction with the actin cytoskeleton in Arabidopsis.
Evidence is accumulating for molecular microcompartments formed when proteins interact in localized domains with the cytoskeleton, organelle surfaces, and intracellular membranes. To understand the potential functional significance of protein microcompartmentation in plants, we studied the interaction of the glycolytic enzyme fructose bisphosphate aldolase with actin in Arabidopsis thaliana. Homology modelling of a major cytosolic isozyme of aldolase, FBA8, suggested that the tetrameric holoenzyme has two actin binding sites and could therefore act as an actin-bundling protein, as was reported for animal aldolases. This was confirmed by in vitro measurements of an increase in viscosity of F-actin polymerized in the presence of recombinant FBA8. Simultaneously, interaction with F-actin caused non-competitive inhibition of aldolase activity. We did not detect co-localization of an FBA8-RFP fusion protein, expressed in an fba8-knockout background, with the actin cytoskeleton using confocal laser-scanning microscopy. However, we did find evidence for a low level of interaction using FRET-FLIM analysis of FBA8-RFP co-expressed with the actin-binding protein GFP-Lifeact. Furthermore, knockout of FBA8 caused minor alterations of guard cell actin cytoskeleton morphology and resulted in a reduced rate of stomatal closure in response to decreased humidity. We conclude that cytosolic aldolase can be microcompartmented in vivo by interaction with the actin cytoskeleton and may subtly modulate guard cell behaviour as a result.


'Without ultrasound you can't reach the best decision' - Midwives' experiences and views of the role of ultrasound in maternity care in Dar Es Salaam, Tanzania.
To explore Tanzanian midwives' experiences and views of the role of obstetric ultrasound in relation to clinical management of pregnancy, and in situations where maternal and fetal health interests conflict. In 2015, five focus group discussions were conducted with midwives (N = 31) at three public referral hospitals in the Dar es Salaam region as part of the CROss Country Ultrasound Study (CROCUS). Ultrasound was described as decisive for proper management of pregnancy complications. Midwives noted an increasing interest in ultrasound among pregnant women. However, concerns were expressed about the lack of ultrasound equipment and staff capable of skilful operation. Further, counselling regarding medical management was perceived as difficult due to low levels of education among pregnant women. Ultrasound has an important role in management of pregnancy complications. However, lack of equipment and shortage of skilled healthcare professionals seem to hamper use of obstetric ultrasound in this particular low-resource setting. Increased availability of obstetric ultrasound seems warranted, but further investments need to be balanced with advanced clinical skills' training as barriers, including power outages and lack of functioning equipment, are likely to continue to limit the provision of pregnancy ultrasound in this setting.


Primary acute stroke thrombectomy within 3 h for large artery occlusion (PAST3-LAO): a pilot study.
In recent trials, acute ischemic stroke (AIS) from large artery occlusion (LAO) was resistant to intravenous thrombolysis and adjunctive stent retriever thrombectomy (SRT) was associated with better perfusion and outcomes. Despite benefit, 39-68% of patients had poor outcomes. Thrombectomy in AIS with LAO within 3 h is performed secondary to intravenous thrombolysis, which may be associated with delay. The purpose of our study is to evaluate the safety, feasibility, recanalization rate, and outcome of primary SRT within 3 h without intravenous thrombolysis in AIS from LAO. Based on an institutionally approved protocol, stroke patients with LAO within 3 h were offered primary SRT as an alternative to intravenous recombinant tissue plasminogen activator. Consecutive patients who underwent primary SRT for LAO within 3 h from 2012 to 2014 were enrolled. Outcomes were measured using the modified Rankin Scale (mRS). 18 patients with LAO of mean age 62.83±15.32 years and median NIH Stroke Scale (NIHSS) score 16 (10-23) chose primary SRT after giving informed consent. Near complete (TICI 2b in 1 patient) or complete (TICI 3 in 17 patients) recanalization was observed in all patients. Time to recanalization from symptom onset and groin puncture was 188.5±82.7 and 64.61±40.14 min, respectively. NIHSS scores immediately after thrombectomy, at 24 h and 30 days were 4 (0-12), 1 (0-12), and 0 (0-4), respectively. Asymptomatic perfusion-related hemorrhage developed in four patients (22%). 90-day outcomes were mRS 0 in 50%, mRS 1 in 44.4%, and mRS 2 in 5.6%. Our study demonstrates that primary SRT in AIS from LAO is safe and feasible and is associated with complete recanalization and good outcome. Further study is required.


Cardiovascular function following reduced aerobic activity.
The aim of this study was to test the hypothesis that a sustained reduction of physical activity (deconditioning) would alter the cardiovascular regulatory function. Nineteen young, healthy volunteers participated in physical deconditioning for a period of 8 wk. Before (pre) and following (post) physical deconditioning, the responses of heart rate (HR), mean arterial pressure (MAP, measured by Finapres), central venous pressure (CVP), stroke volume (SV, Doppler), and forearm blood flow (FBF, plethysmography) were determined during lower body negative pressure (LBNP). The carotid baroreflex (CBR) function was assessed using a train of pulsatile neck pressure (NP) and suction, and the aortic baroreflex control of HR was assessed during steady-state phenylephrine (PE) infusion superimposed by LBNP and NP to counteract the PE increased CVP and carotid sinus pressure, respectively. Active physical deconditioning significantly decreased maximal oxygen uptake (-7%) and LBNP tolerance (-13%) without a change in baseline hemodynamics. Plasma volume (-3% at P = 0.135), determined by Evans Blue dilution, and blood volume (-4% at P = 0.107) were not significantly altered. During LBNP -20 to -50 torr, there was a significantly greater drop of SV per unit decrease in CVP in the post- (14.7 +/- 1.6%/mm Hg) than predeconditioning (11.2 +/- 0.7%/mm Hg) test accompanied by a greater tachycardia. Deconditioning increased the aortic baroreflex sensitivity (pre vs post: -0.61 +/- 0.12 vs -0.84 +/- 0.14 bpm.mm-1 Hg, P = 0.009) and the slope of forearm vascular resistance (calculated from [MAP-CVP]/FBF) to CVP (-2.75 +/- 0.26 vs -4.94 +/- 0.97 PRU/mm Hg, P = 0.086). However, neither the CBR-HR (-0.28 +/- 0.03 VS -0.39 +/- 0.10 bpm.mm-1 Hg) nor the CBR-MAP (-0.37 +/- 0.16 vs -0.25 +/- 0.07 mm Hg/mm Hg) gains were statistically different between pre- and postdeconditioning. We concluded that the functional modification of the cardiac pressure-volume relationship resulted in the reduced LBNP tolerance, despite the accentuated aortic and cardiopulmonary baroreflex function following deconditioning.


Distinct lower visual field preference for object shape.
Humans manipulate objects chiefly within their lower visual field, a consequence of upright posture and the anatomical position of hands and arms.This study tested the hypothesis of enhanced sensitivity to a range of stimuli within the lower visual field. Following current models of hierarchical processing within the ventral steam, discrimination sensitivity was measured for orientation, curvature, shape (radial frequency patterns), and faces at various para-central locations (horizontal, vertical, and main diagonal meridians) and eccentricities (5° and 10°). Peripheral sensitivity was isotropic for orientation and curvature. By contrast, observers were significantly better at discriminating shapes throughout the lower visual field compared to elsewhere. For faces, however, peak sensitivity was found in the left visual field, corresponding to the right hemispheric localization of human face processing. Presenting head outlines without any internal features (e.g., eyes, mouth) recovered the lower visual field advantage found for simple shapes. A lower visual field preference for the shape of an object, which is absent for more localized information (orientation and curvature) but also for more complex objects (faces), is inconsistent with a strictly feed-forward model and poses a challenge for multistage models of object perception. The distinct lower visual field preference for contour shapes is, however, consistent with an asymmetry at intermediate stages of visual processing, which may play a key role in representing object characteristics that are particularly relevant to visually guided actions.


The choice of response alternatives in COVID-19 social science surveys.
Social science research is key for understanding and for predicting compliance with COVID-19 guidelines, and this research relies on survey data. While much focus is on the survey question stems, less is on the response alternatives presented that both constrain responses and convey information about the assumed expectations of the survey designers. The focus here is on the choice of response alternatives for the types of behavioral frequency questions used in many COVID-19 and other health surveys. We examine issues with two types of response alternatives. The first are vague quantifiers, like "rarely" and "frequently." Using data from 30 countries from the Imperial COVID data hub, we show that the interpretation of these vague quantifiers (and their translations) depends on the norms in that country. If the mean amount of hand washing in a country is high, it is likely "frequently" corresponds to a higher numeric value for hand washing than if the mean in the country is low. The second type are sets of numeric alternatives and they can also be problematic. Using a US survey, respondents were randomly allocated to receive either response alternatives where most of the scale corresponds to low frequencies or where most of the scale corresponds to high frequencies. Those given the low frequency set provided lower estimates of the health behaviors. The choice of response alternatives for behavioral frequency questions can affect the estimates of health behaviors. How the response alternatives mold the responses should be taken into account for epidemiological modeling. We conclude with some recommendations for response alternatives for behavioral frequency questions in surveys.


Glycolysis inhibitors suppress renal interstitial fibrosis via divergent effects on fibroblasts and tubular cells.
Renal interstitial fibrosis is a common pathological feature of chronic kidney disease that may involve changes of metabolism in kidney cells. In the present study, we first showed that blockade of glycolysis with either dichloroacetate (DCA) or shikonin to target different glycolytic enzymes reduced renal fibrosis in a mouse model of unilateral ureteral obstruction (UUO). Both inhibitors evidently suppressed the induction of fibronectin and collagen type I in obstructed kidneys, with DCA also showing inhibitory effects on collagen type IV and α-smooth muscle actin (α-SMA). Histological examination also confirmed less collagen deposition in DCA-treated kidneys. Both DCA and shikonin significantly inhibited renal tubular apoptosis but not interstitial apoptosis in UUO. Macrophage infiltration after UUO injury was also suppressed. Shikonin, but not DCA, caused obvious animal weight loss during UUO. To determine whether shikonin and DCA worked on tubular cells and/or fibroblasts, we tested their effects on cultured renal proximal tubular BUMPT cells and renal NRK-49F fibroblasts during hypoxia or transforming growth factor-β1 treatment. Although both inhibitors reduced fibronectin and α-SMA production in NRK-49F cells during hypoxia or transforming growth factor-β1 treatment, they did not suppress fibronectin and α-SMA expression in BUMPT cells. Altogether, these results demonstrate the inhibitory effect of glycolysis inhibitors on renal interstitial fibrosis. In this regard, DCA is more potent for fibrosis inhibition and less toxic to animals than shikonin.


Prostaglandin E2 receptors are differentially expressed in subpopulations of granulosa cells from primate periovulatory follicles.
Prostaglandin E2 (PGE2) mediates many effects of the midcycle luteinizing hormone (LH) surge within the periovulatory follicle. Differential expression of the four PGE2 (EP) receptors may contribute to the specialized functions of each granulosa cell subpopulation. To determine if EP receptors are differentially expressed in granulosa cells, monkeys received gonadotropins to stimulate ovarian follicular development. Periovulatory events were initiated with human chorionic gonadotropin (hCG); granulosa cells and whole ovaries were collected before (0 h) and after (24-36 h) hCG to span the 40-h primate periovulatory interval. EP receptor mRNA and protein levels were quantified in granulosa cell subpopulations. Cumulus cells expressed higher levels of EP2 and EP3 mRNA compared with mural cells 36 h after hCG. Cumulus cell EP2 and EP3 protein levels also increased between 0 and 36 h after hCG. Overall, mural granulosa cells expressed low levels of EP1 protein at 0 h and higher levels 24-36 h after hCG. However, EP1 protein levels were higher in granulosa cells away from the follicle apex compared with apex cells 36 h after hCG. Higher levels of PAI-1 protein were measured in nonapex cells, consistent with a previous study showing EP1-stimulated PAI-1 protein expression in monkey granulosa cells. EP4 protein levels were low in all subpopulations. In summary, cumulus cells likely respond to PGE2 via EP2 and EP3, whereas PGE2 controls rupture of a specific region of the follicle via EP1. Therefore, differential expression of EP receptors may permit each granulosa cell subpopulation to generate a unique response to PGE2 during the process of ovulation.


Comparative evaluation of the VITEK 2, disk diffusion, etest, broth microdilution, and agar dilution susceptibility testing methods for colistin in clinical isolates, including heteroresistant Enterobacter cloacae and Acinetobacter baumannii strains.
Increasing antibiotic resistance in gram-negative bacteria has recently renewed interest in colistin as a therapeutic option. The increasing use of colistin necessitates the availability of rapid and reliable methods for colistin susceptibility testing. We compared seven methods of colistin susceptibility testing (disk diffusion, agar dilution on Mueller-Hinton [MH] and Isosensitest agar, Etest on MH and Isosensitest agar, broth microdilution, and VITEK 2) on 102 clinical isolates collected from patient materials during a selective digestive decontamination or selective oral decontamination trial in an intensive-care unit. Disk diffusion is an unreliable method to measure susceptibility to colistin. High error rates and low levels of reproducibility were observed in the disk diffusion test. The colistin Etest, agar dilution, and the VITEK 2 showed a high level of agreement with the broth microdilution reference method. Heteroresistance for colistin was observed in six Enterobacter cloacae isolates and in one Acinetobacter baumannii isolate. This is the first report of heteroresistance to colistin in E. cloacae isolates. Resistance to colistin in these isolates seemed to be induced upon exposure to colistin rather than being caused by stable mutations. Heteroresistant isolates could be detected in the broth microdilution, agar dilution, Etest, or disk diffusion test. The VITEK 2 displayed low sensitivity in the detection of heteroresistant subpopulations of E. cloacae. The VITEK 2 colistin susceptibility test can therefore be considered to be a reliable tool to determine susceptibility to colistin in isolates of genera that are known not to exhibit resistant subpopulations. In isolates of genera known to (occasionally) exhibit heteroresistance, an alternative susceptibility testing method capable of detecting heteroresistance should be used.


Inflammatory response following in vitro exposure to methylmercury with and without n-3 long chain polyunsaturated fatty acids in peripheral blood mononuclear cells from systemic lupus erythematosus patients compared to healthy controls.
Methylmercury (MeHg) is a proposed environmental stimulus in systemic lupus erythematosus (SLE). Humans are primarily exposed to MeHg through fish consumption. Fish are also important sources of n-3 long chain polyunsaturated fatty acids (n-3 LCPUFA). This in vitro study investigated the inflammatory response of isolated peripheral blood mononuclear cells (PBMCs), when exposed to either MeHg alone or with added n-3 LCPUFA, from SLE patients (N = 12) compared to healthy sex matched controls (N = 12). The PBMCs were isolated and exposed to 200 nM of MeHg for 24 h with or without pre-exposure to eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) at a concentration of 100 μM each. Supernatants were analyzed for the inflammatory markers. Following exposure to MeHg, mean TNF-α concentrations were significantly higher in SLE patients (2226.01 ± 348.98pg/ml) compared to controls (701.40 ± 680.65 pg/ml) (P = .008). Pre-exposure of cells with MeHg and EPA resulted in a significantly higher concentration of IL-8 in supernatants from SLE patients (2137.83 ± 1559.01 pg/ml) compared to that of the controls (879.26 ± 979.49 pg/ml) (P = .030). EPA and DHA attenuated the pro-inflammatory inducing effects of MeHg in SLE and control cells. In summary, exposure to MeHg stimulated a higher TNF-α response in SLE patients compared with healthy controls; nevertheless the presence of n-3 LCPUFA reduced the overall inflammatory response, albeit to a lesser degree in SLE patients.


Focal adhesion kinase plays a role in osteoblast mechanotransduction in vitro but does not affect load-induced bone formation in vivo.
A healthy skeleton relies on bone's ability to respond to external mechanical forces. The molecular mechanisms by which bone cells sense and convert mechanical stimuli into biochemical signals, a process known as mechanotransduction, are unclear. Focal adhesions play a critical role in cell survival, migration and sensing physical force. Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase that controls focal adhesion dynamics and can mediate reparative bone formation in vivo and osteoblast mechanotransduction in vitro. Based on these data, we hypothesized that FAK plays a role in load-induced bone formation. To test this hypothesis, we performed in vitro fluid flow experiments and in vivo bone loading studies in FAK-/- clonal lines and conditional FAK knockout mice, respectively. FAK-/- osteoblasts showed an ablated prostaglandin E(2) (PGE(2)) response to fluid flow shear. This effect was reversed with the re-expression of wild-type FAK. Re-expression of FAK containing site-specific mutations at Tyr-397 and Tyr-925 phosphorylation sites did not rescue the phenotype, suggesting that these sites are important in osteoblast mechanotransduction. Interestingly, mice in which FAK was conditionally deleted in osteoblasts and osteocytes did not exhibit altered load-induced periosteal bone formation. Together these data suggest that although FAK is important in mechanically-induced signaling in osteoblasts in vitro, it is not required for an adaptive response in vivo, possibly due to a compensatory mechanism that does not exist in the cell culture system.


Clinical Importance of FNDC-5 and Selectin-E mRNA Expression Among Type 2 Diabetics with and without Obesity.
Type 2 diabetes mellitus (T2DM) is growing illnesses associated with metabolic dysregulation such as obesity affecting a large population become leading causes of death worldwide. Fibronectin type III domain-containing protein 5 (FNDC-5) and selectin-E were suggested to have effects on metabolism and diabetes, therefore present study aimed to evaluate the clinical importance of FNDC-5 and selectin-E among the T2DM patients with and without obesity. Study included cohort of 200 T2DM patients with and without obesity. We evaluated FNDC-5, selectin-E mRNA expression as well as vitamin-D, and vitamin-B12 levels in among the T2DM patients with and without obesity. Study observed significant difference in biochemical parameters included in study. T2DM patients with obesity had significantly higher fasting blood glucose levels (p<0.0001) and HbA1c (glycated hemoglobin) (p<0.0001) compared to those T2DM patients without obesity. T2DM patients with obesity also had higher systolic blood pressure (p=0.001), LDL (low density lipoprotein) (p=0.02), TG (triglycerides) (p=0.02) and cholesterol (p=0.01) compared to T2DM patients without obesity. The mRNA expression of FNDC-5 (p<0.0001) was lower in T2DM patients with obesity compared to T2DM patients without obesity. It was observed that the T2DM patients with vitamin-D deficiency had significantly lower FNDC-5 mRNA expression (p=0.03) when compared with those with sufficient vitamin-D level. T2DM patients with clinically normal vitamin-B12 level expressed 0.60 fold FNDC-5 mRNA expression while B12 deficient T2DM patients had 0.28 fold FNDC-5 mRNA expression (p=0.005). No as such significant association was was observed with selectin-E. A negative correlation of FNDC-5 mRNA expression with Post prandial glucose (mg/dl) (p=0.04) and TG (mg/dl) (p=0.02) was observed. FNDC-5 down regulation was observed with T2DM with obesity, vitamin-D and vitamin-B12 deficiency suggesting obesity, vitamin-D and vitamin-B12 deficiency could be the factor for FNDC-5 down-regulation leading to worseness or progression of disease. We suggest that FNDC-5 down-regulation could be used as an indicator for T2DM worseness and development of other associated complications.


Optimizing feature representation for automated systematic review work prioritization.
Automated document classification can be a valuable tool for enhancing the efficiency of creating and updating systematic reviews (SRs) for evidence-based medicine. One way document classification can help is in performing work prioritization: given a set of documents, order them such that the most likely useful documents appear first. We evaluated several alternate classification feature systems including unigram, n-gram, MeSH, and natural language processing (NLP) feature sets for their usefulness on 15 SR tasks, using the area under the receiver operating curve as a measure of goodness. We also examined the impact of topic-specific training data compared to general SR inclusion data. The best feature set used a combination of n-gram and MeSH features. NLP-based features were not found to improve performance. Furthermore, topic-specific training data usually provides a significant performance gain over more general SR training.


Young Children with ASD Use Lexical and Referential Information During On-line Sentence Processing.
Research with adults and older children indicates that verb biases are strong influences on listeners' interpretations when processing sentences, but they can be overruled. In this paper, we ask two questions: (i) are children with Autism Spectrum Disorder (ASD) who are high functioning sensitive to verb biases like their same age typically developing peers?, and (ii) do young children with ASD and young children with typical development (TD) override strong verb biases to consider alternative interpretations of ambiguous sentences? Participants were aged 5-9 years (mean age 6.65 years): children with ASD who were high functioning and children with TD. In task 1, biasing and neutral verbs were included (e.g., eat cake versus move cake). In task 2, the focus was on whether the prepositional phrase occurring with an instrument biasing verb (e.g., 'Chop the tree with the axe') was interpreted as an instrument even if the named item was an implausible instrument (e.g., candle in 'Cut the cake with the candle'). Overall, the results showed similarities between groups but the ASD group was generally slower. In task 1, both groups looked at the named object faster in the biasing than the non-biasing condition, and in the biasing condition the ASD group looked away from the target more quickly than the TD group. In task 2, both groups identified the target in the prepositional phrase. They were more likely to override the verb instrument bias and consider the alternative (modification) interpretation in the implausible condition (e.g., looking at the picture of a cake with a candle on it'). Our findings indicate that children of age 5 years and above can use context to override verb biases. Additionally, an important component of the sentence processing mechanism is largely intact for young children with ASD who are high functioning. Like children with TD, they draw on verb semantics and plausibility in integrating information. However, they are likely to be slower in processing the language they hear. Based on previous findings of associations between processing speed and cognitive functioning, the implication is that their understanding will be negatively affected, as will their academic outcomes.


Attitudes of suburban Western Australians to proposed cat control legislation.
To determine the knowledge, attitudes and practices of cat-owners and non-owners in suburban Perth, Western Australia, on issues relating to proposed local government regulation of cat-ownership. The 1,261 respondents to a mailed survey were ranked on issues regarding restrictions on cat-ownership and cat roaming (control scale), attitudes to wildlife in suburbia and putative impacts of cats on wildlife (wildlife scale), knowledge of cat behaviour and husbandry (knowledge scale) and attitudes and practices regarding cat sterilisation (sterilisation scale). Age, gender and cat-ownership status of the survey respondents were explored to see if any of these factors influenced the position of respondents on the scales. Cat-owners, particularly female owners, scored significantly higher on the knowledge scale than non-owners, whilst non-owners scored significantly higher than cat-owners on the control and wildlife scales. Women were more likely to favour compulsory sterilisation of pet cats than men, but men were more willing to implement controls on cat-ownership. Age was also a significant factor, with older people more willing to implement controls. Analysis of specific questions showed that both cat-owners and non-owners agreed that there was a need for cat control legislation and supported measures such as compulsory sterilisation, registering of cats, restricting cats' ability to roam and stipulating a maximum number of cats per property. Nevertheless, both groups rejected the idea that local governments should enforce cat-free zones. Cat legislation that avoids or educates about the contentious issue of cat-free zones should receive solid community support.


Excess carrier-envelope phase noise generation in saturable absorbers.
Attosecond spectroscopy and precision frequency metrology depend on the stabilization of the carrier-envelope phase (CEP) of mode-locked lasers. Unfortunately, the phase of only a few types of lasers can be stabilized to jitters in the few-hundred millirad range. In a comparative experimental study, we analyze a femtosecond Ti:sapphire laser and three mode-locked fiber lasers. We numerically demodulate recorded time series of the free-running carrier-envelope beat note. Our analysis indicates a correlation between amplitude and frequency fluctuations at low Fourier frequencies for essentially all lasers investigated. While this correlation typically rolls off at frequencies beyond 100 kHz, we see clear indications for a broadband coupling mechanism in one of the fiber lasers. We suspect that the observed coupling mechanism acts to transfer intracavity power fluctuations into excess phase noise. This coupling mechanism is related to the mode-locking mechanism employed and not to the gain medium itself. We further verify this hypothesis by numerical simulations, which identify resonances of the saturable absorber mirror as a possible explanation for the coupling mechanism. Finally, we discuss how to avoid a detrimental influence of such resonances.


National hospital discharge survey: annual summary, 1998.
This report presents 1998 national estimates and selected trend data on the use of non-Federal short-stay hospitals in the United States. Estimates are provided by demographic characteristics of patients discharged, geographic region of hospitals, conditions diagnosed, and surgical and nonsurgical procedures performed. Measurements of hospital use include number and rate of discharges and days of care, and the average length of stay. Estimates of first-listed diagnoses, days of care, all-listed diagnoses, and all-listed procedures are presented according to their code number in the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). The estimates are based on data collected through the National Hospital Discharge Survey. The survey has been conducted annually by the National Center for Health Statistics since 1965. In 1998, data were collected for approximately 307,000 discharges. Of the 495 eligible non-Federal short-stay hospitals in the sample, 478 (97 percent) responded to the survey. An estimated 31.8 million inpatients were discharged from non-Federal short-stay hospitals in 1998. These patients used an estimated 160.9 million days of care. Patients 65 years of age and over accounted for 39 percent of discharges and used 48 percent of days of care. Heart disease and deliveries made up 26 percent of first-listed diagnoses. One or more procedures were reported for 63 percent of discharges. The cesarean rate per 100 deliveries increased from 20.8 in 1995 to 22.5 in 1998. An estimated 3.8 million newborn infants were discharged from short-stay hospitals after average stays of 3.2 days.


Preventive effect of pre-warming, hot compress, and pH adjustment in oxaliplatin-induced venous pain.
Background Venous pain induced by peripheral intravenous administration of oxaliplatin remains clinically unresolved. Objective The aim of this study was to determine the efficacy of comprehensive intervention care for venous pain in colorectal cancer patients receiving oxaliplatin. Setting A Japanese tertiary hospital. Method We treated all outpatients after April 2012 with comprehensive intervention care including pre-warming of the oxaliplatin solution, use of a hot compress, and pH adjustment by combination with dexamethasone. We retrospectively reviewed the electronic medical records from colorectal cancer patients who had received oxaliplatin via a peripheral vein between December 2009 and June 2014. Main outcome measures The primary endpoint of this study was the incidence of venous pain at the administration site during oxaliplatin infusion, according to injection site reaction grade ≥ 2. Results We evaluated 271 treatment courses in 59 patients. Venous pain occurred in 42 courses (15.5%) among 26 patients. Multivariate logistic regression analysis revealed that female gender and body mass index ≥ 25 kg/m2 were significantly associated with an increased risk of venous pain during all courses (adjusted odds ratio [OR]: 3.18, 95% confidence interval [CI] 1.35-7.92; P < 0.01; and adjusted OR: 3.37, 95% CI 1.26-9.40; P = 0.02, respectively), whereas comprehensive intervention care were significantly associated with reduced risk of venous pain during all courses (adjusted OR: 0.10, 95% CI 0.02-0.44; P < 0.01). Conclusion Comprehensive intervention care is a clinical treatment option for oxaliplatin-induced peripheral venous pain in patients with colorectal cancer, especially females with obesity.


Redescription of Heterodera fici (Nematoda: Heteroderidae) with SEM Observations.
Heterodera fici is redescribed and illustrated with comparative details and revised measurements and diagnostic characters of the females, males, cysts, and juveniles from Maryland and Pakistan. This species is in the "schachtii group" (cysts lemon shaped, with bullae, and ambifenestrate) but the fenestrae in some cysts, presumab!y young ones, are small and widely spaced, appearing bifenestrate. It is most closely related to H. schachtii, H. glycines, and H. cajani but differs from these species especially in having cysts with small, scattered bullae and weakly developed underbridge; and males with four small nipples on tail tip. Scanning electron microscopy (SEM) observations of the specimens are also presented. The relationship of this species to closely related forms is discussed.


Physical Literacy, Physical Activity and Health: Toward an Evidence-Informed Conceptual Model.
Physical literacy (PL) provides a powerful lens for examining movement in relation to physical activity (PA) and motor skill outcomes, environmental context, and broader social and affective learning processes. To date, limited consideration has been given to the role PL plays in promoting positive health behaviours. There is no clear conceptual framework based on existing empirical evidence that links PL to health, nor has an evidence-informed case been made for such a position. The purpose of this paper is to (1) present a conceptual model positioning PL as a health determinant, and (2) present evidence in support of PL as a health determinant, drawing on research largely from outside physical education. Viewing PL from the perspective of a multidimensional, experiential convergence process enables it to be differentiated from other models. However, parallels between our model and existing models that focus on movement competence are also drawn. Arguing from a pragmatic perspective on PL, we present evidence for positioning PL as a determinant of health from two literature sources: research on motor coordination disorders in children, and associations between motor competence, PA and health in typically developing children. Statistical modelling approaches consistent with the concept of PL are discussed. Results from these approaches-confirmatory factor analysis and cluster analysis-support the idea that measures related to motor competence, motivation and positive affect work in an integrative manner to produce differences in PA and subsequent health outcomes in children. There is increasing interest in PL, particularly in the field of public health. Presenting a model that explicitly links PL to health can lead to the generation of new research questions and the possibility of broadening impact beyond the context of physical education alone. To date, there has been little conceptual attention to what positioning PL as a determinant of health means. By providing an evidence-based model of PL as a determinant of health, we hope to further the discussion and stimulate increased empirical research in the field.


AID-ing Signaling in Toxoplasma gondii.
The cyclic GMP-dependent protein kinase (PKG) of apicomplexan parasites is essential for secretion of micronemes and host cell invasion and egress. Both kinase specificity and localization can determine which substrates are phosphorylated. The functions of plasma membrane and cytosolic PKG isoforms of Toxoplasma gondii were unknown because of difficulties precisely manipulating expression of essential genes. Brown et al. (K. M. Brown, S. Long, and L. D. Sibley, mBio 8:e00375-17, https://doi.org/10.1128/mBio.00375-17) adapted the auxin-inducible degron (AID) system for conditional expression of T. gondii proteins. AID, in combination with clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 gene editing, facilitated creation of a panel of PKG mutants to demonstrate that the membrane association via acylation of PKG is critical for its essential functions in tachyzoites. The cytosolic form of PKG is not sufficient for viability and is dispensable. These studies illuminate a critical role for targeting of kinase complexes for parasite viability. The AID system enables rapid, conditional regulation of protein expression that expands the molecular toolbox of T. gondii.


Virtual reality job interview training in adults with autism spectrum disorder.
The feasibility and efficacy of virtual reality job interview training (VR-JIT) was assessed in a single-blinded randomized controlled trial. Adults with autism spectrum disorder were randomized to VR-JIT (n = 16) or treatment-as-usual (TAU) (n = 10) groups. VR-JIT consisted of simulated job interviews with a virtual character and didactic training. Participants attended 90 % of laboratory-based training sessions, found VR-JIT easy to use and enjoyable, and they felt prepared for future interviews. VR-JIT participants had greater improvement during live standardized job interview role-play performances than TAU participants (p = 0.046). A similar pattern was observed for self-reported self-confidence at a trend level (p = 0.060). VR-JIT simulation performance scores increased over time (R(2) = 0.83). Results indicate preliminary support for the feasibility and efficacy of VR-JIT, which can be administered using computer software or via the internet.


Anti-inflammatory effects of essential oils extracted from Chamaecyparis obtusa on murine models of inflammation and RAW 264.7 cells.
Antimicrobial, antifungal and anti-inflammatory effects of essential oils extracted from Chamaecyparis obtusa (EOCO) have previously been reported. In the present study, the anti-inflammatory effects of EOCO were investigated in two murine models of inflammation: Carrageenan-induced paw edema and thioglycollate-induced peritonitis, and in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. The expression levels of proinflammatory cytokines were analyzed by ELISA, the expression of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were determined by western blotting, and nitrite concentration was measured using Griess reagent. In mice with carrageenan-induced edema, paw thickness and the expression levels of interleukin (IL)‑1β and IL-6 in paw homogenates were significantly decreased in the EOCO (5 and 10 mg/kg) group, as compared with the control group. In mice with thioglycollate-induced peritonitis, treatment with EOCO (5 and 10 mg/kg) reduced the number of total cells and suppressed tumor necrosis factor‑α (TNF‑α), IL‑1β and IL‑6 levels in peritoneal fluid. In addition, EOCO reduced nitric oxide, TNF‑α and IL‑6 production, and suppressed iNOS and COX‑2 expression in LPS‑stimulated RAW 264.7 cells. These results suggest that EOCO may exert anti‑inflammatory effects in vivo and in vitro, and that these effects may be associated with the inhibition of inflammatory mediators. Therefore, EOCO may be considered an effective therapeutic agent for the treatment of inflammatory diseases.


Characterization of glioma-cells derived from human polyomavirus-induced brain-tumors in hamsters.
Intracerebral injection of human polyomavirus, JCV, into neonatal hamsters causes tumors of,glial origin. HJC is an established cell Line derived from a JCV-induced mixed hamster brain tumor with astrocytic and ependymal components. Flow cytometric and immunohistochemical analysis of HJC suggests that it is comprised of a mixed population of cells all of which contain the JCV early protein, T-antigen, in the nuclei. Five individual clonal lines, called HJC-15a to HJC-15e, were isolated by limiting dilution and were found to exhibit distinct morphological characteristics with 25-30% variation in their sizes. It was evident that each clone has unique growth rates, doubling times, and cell cycle parameters with different G(1), S, and G(2) phase times. All clonal cells showed the presence of the JCV early protein in the nucleus. Of interest was the observation from immunoprecipitation and Western analysis indicating qualitative and quantitative differences in the T-antigen isoforms produced in these cells. Similar to the parental clone, HJC-15b produced two distinct forms of JCV T-antigen isoforms, 88 kDa and 92 kDa proteins. In addition, HJC-15c was able to produce a 23-25 kDa protein which was recognized by anti-T-antigen antibody. The activity of cyclin-dependent kinases, in particular cdc2, was higher in HJC-15c than in the other cell lines. The data presented herein indicates that glioblastomas induced by viral T-antigen expression are composed of a multitude of distinct cells that possess a variety of different characteristics.


Venous thrombosis of pancreatic transplants: diagnosis by duplex sonography.
Our objective was to determine whether elevated pancreatic transplant arterial resistive index (RI) and absence of venous flow correlate with pancreatic transplant venous thrombosis. Thirteen episodes of surgically documented pancreatic venous thrombosis occurred in 175 pancreases that had been transplanted over a 3-year period. Duplex sonography was performed before surgical exploration in 11 cases. We retrospectively reviewed these 11 sonograms to determine whether blood was flowing in the veins and arteries of the graft. The RI was calculated from all pancreatic artery waveforms. We compared these arterial RIs and the presence or absence of venous flow with those of pancreatic grafts without venous thrombosis to determine sensitivity and specificity. In the venous thrombosis group, thrombosis occurred within 12 days of transplantation (mean, 3.5 days) in all 11 cases. Six cases of thrombosis (55%) occurred within 1 day. Arterial flow was detected within the graft in nine cases (82%) and in the stump of the donor artery between the graft and the recipient iliac artery in the two remaining cases. Antegrade diastolic flow was absent in all arterial tracings. Diastolic flow reversal was present in seven (78%) of nine grafts with detectable intrapancreatic arterial flow. Arterial RIs ranged from 1.00 to 2.00 (mean +/- SD, 1.27 +/- 0.29). Intrapancreatic venous flow was absent in all 11 cases. In the control group (43 examinations in 34 patients) RIs ranged from 0.46 to 1.29 (mean +/- SD, 0.72 +/- 0.18). Two of 43 arterial tracings had diastolic flow reversal (RI > 1.0). Venous flow was present in all examinations in the control group. A statistically significant difference existed between the RIs in the thrombosis group and the RIs in the control group (p = .0001). Reversal of diastolic flow in pancreatic transplant arteries is highly specific for detection of graft venous thrombosis during the first 12 days after transplantation. Our findings suggest that an RI greater than or equal to 1.00 and absence of venous flow, in combination, are highly sensitive and specific for the diagnosis of pancreatic graft venous thrombosis.


Boolean Modeling of Cellular and Molecular Pathways Involved in Influenza Infection.
Systems virology integrates host-directed approaches with molecular profiling to understand viral pathogenesis. Self-contained statistical approaches that combine expression profiles of genes with the available databases defining the genes involved in the pathways (gene-sets) have allowed characterization of predictive gene-signatures associated with outcome of the influenza virus (IV) infection. However, such enrichment techniques do not take into account interactions among pathways that are responsible for the IV infection pathogenesis. We investigate dendritic cell response to seasonal H1N1 influenza A/New Caledonia/20/1999 (NC) infection and infer the Boolean logic rules underlying the interaction network of ligand induced signaling pathways and transcription factors. The model reveals several novel regulatory modes and provides insights into mechanism of cross talk between NFκB and IRF mediated signaling. Additionally, the logic rule underlying the regulation of IL2 pathway that was predicted by the Boolean model was experimentally validated. Thus, the model developed in this paper integrates pathway analysis tools with the dynamic modeling approaches to reveal the regulation between signaling pathways and transcription factors using genome-wide transcriptional profiles measured upon influenza infection.


Protocol for the development of guidance for stakeholder engagement in health and healthcare guideline development and implementation.
Stakeholder engagement has become widely accepted as a necessary component of guideline development and implementation. While frameworks for developing guidelines express the need for those potentially affected by guideline recommendations to be involved in their development, there is a lack of consensus on how this should be done in practice. Further, there is a lack of guidance on how to equitably and meaningfully engage multiple stakeholders. We aim to develop guidance for the meaningful and equitable engagement of multiple stakeholders in guideline development and implementation. This will be a multi-stage project. The first stage is to conduct a series of four systematic reviews. These will (1) describe existing guidance and methods for stakeholder engagement in guideline development and implementation, (2) characterize barriers and facilitators to stakeholder engagement in guideline development and implementation, (3) explore the impact of stakeholder engagement on guideline development and implementation, and (4) identify issues related to conflicts of interest when engaging multiple stakeholders in guideline development and implementation. We will collaborate with our multiple and diverse stakeholders to develop guidance for multi-stakeholder engagement in guideline development and implementation. We will use the results of the systematic reviews to develop a candidate list of draft guidance recommendations and will seek broad feedback on the draft guidance via an online survey of guideline developers and external stakeholders. An invited group of representatives from all stakeholder groups will discuss the results of the survey at a consensus meeting which will inform the development of the final guidance papers. Our overall goal is to improve the development of guidelines through meaningful and equitable multi-stakeholder engagement, and subsequently to improve health outcomes and reduce inequities in health.


Brain Training Games Enhance Cognitive Function in Healthy Subjects.
BACKGROUND Brain training games (BTG) are believed to play a major role in improving cognitive functions. The current study evaluated if BTG showed positive impact on attention and memory functions compared with baseline visit in healthy subjects. MATERIAL AND METHODS The study was carried out from October 2015 until April 2016 in the Department of Physiology, College of Medicine, King Saud University and in King Khalid University Hospital (KKUH), Riyadh, Saudi Arabia. We enrolled 51 normal healthy subjects to use a computerized cognitive training game (Lumosity) for exercises that target a range of cognitive functions, including attention, processing speed, visual memory, and executive functions for about 15 min per day, at least 7 days per week, for 3 weeks. The control (n=21) group did not perform the training. Both groups took the CANTAB test before and 3 weeks after training for various cognitive functions (flexibility, memory, attention, speed, and problem solving). Serum samples were used to study the brain-derived growth factor (BDNF) and apolipoprotein (Apo) E (APOE) levels. RESULTS A significant improvement in Lumosity performance index was observed in the active group compared to the control group by the end of training (p-value 0.001). After the training, a statistically significant difference in most of the CANTAB measures, such as attention-switching task (AST), mean correct latency, AST switching cost, AST mean correct latency (congruent), AST mean correct latency (incongruent), AST mean correct latency (blocks 3 and 5) [non-switching blocks], AST mean correct latency (block 7) [switching block], and MOT mean correct latency (all P=0.000). However, in the control group, significant improvements were not observed. A positive correlation between pattern recognition memory (PRM) and APOE was found and people who had higher ApoE levels had faster response. CONCLUSIONS An improvement in different cognitive domains was noted, including attention and motor speed. However, this study warrants further research to determine the long-term effect on other cognitive functions and in different groups (e.g., elderly vs. adults).


Use of deep whole-genome sequencing data to identify structure risk variants in breast cancer susceptibility genes.
Functional disruptions of susceptibility genes by large genomic structure variant (SV) deletions in germlines are known to be associated with cancer risk. However, few studies have been conducted to systematically search for SV deletions in breast cancer susceptibility genes. We analysed deep (> 30x) whole-genome sequencing (WGS) data generated in blood samples from 128 breast cancer patients of Asian and European descent with either a strong family history of breast cancer or early cancer onset disease. To identify SV deletions in known or suspected breast cancer susceptibility genes, we used multiple SV calling tools including Genome STRiP, Delly, Manta, BreakDancer and Pindel. SV deletions were detected by at least three of these bioinformatics tools in five genes. Specifically, we identified heterozygous deletions covering a fraction of the coding regions of BRCA1 (with approximately 80kb in two patients), and TP53 genes (with ∼1.6 kb in two patients), and of intronic regions (∼1 kb) of the PALB2 (one patient), PTEN (three patients) and RAD51C genes (one patient). We confirmed the presence of these deletions using real-time quantitative PCR (qPCR). Our study identified novel SV deletions in breast cancer susceptibility genes and the identification of such SV deletions may improve clinical testing.


The effect of group-based exercise on cognitive performance and mood in seniors residing in intermediate care and self-care retirement facilities: a randomised controlled trial.
To determine the effect of a general group-based exercise programme on cognitive performance and mood among seniors without dementia living in retirement villages. Randomised controlled trial. Four intermediate care and four self-care retirement village sites in Sydney, Australia. 154 seniors (19 men, 135 women; age range 62 to 95 years), who were residents of intermediate care and self-care retirement facilities. Participants were randomised to one of three experimental groups: (1) a general group-based exercise (GE) programme composed of resistance training and balance training exercises; (2) a flexibility exercise and relaxation technique (FR) programme; or (3) no-exercise control (NEC). The intervention groups (GE and FR) participated in 1-hour exercise classes twice a week for a total period of 6 months. Using standard neuropsychological tests, we assessed cognitive performance at baseline and at 6-month re-test in three domains: (1) fluid intelligence; (2) visual, verbal and working memory; and (3) executive functioning. We also assessed mood using the Geriatric Depression Scale (GDS) and the Positive and Negative Affect Schedule (PANAS). The GE programme significantly improved cognitive performance of fluid intelligence compared with FR or NEC. There were also significant improvements in the positive PANAS scale within both the GE and FR groups and an indication that the two exercise programmes reduced depression in those with initially high GDS scores. Our GE programme significantly improved cognitive performance of fluid intelligence in seniors residing in retirement villages compared with our FR programme and the NEC group. Furthermore, both group-based exercise programmes were beneficial for certain aspects of mood within the 6-month intervention period.


Staging and functional characterization of pheochromocytoma and paraganglioma by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography.
Pheochromocytomas and paragangliomas (PPGLs) are rare tumors of the adrenal medulla and extra-adrenal sympathetic chromaffin tissues; their anatomical and functional imaging are critical to guiding treatment decisions. This study aimed to compare the sensitivity and specificity of (18)F-fluorodeoxyglucose positron emission tomography with computed tomography ((18)F-FDG PET/CT) for tumor localization and staging of PPGLs with that of conventional imaging by [(123)I]-metaiodobenzylguanidine single photon emission CT ((123)I-MIBG SPECT), CT, and magnetic resonance imaging (MRI). A total of 216 patients (106 men, 110 women, aged 45.2 ± 14.9 years) with suspected PPGL underwent CT or MRI, (18)F-FDG PET/CT, and (123)I-MIBG SPECT/CT. Sensitivity and specificity were measured as endpoints and compared by the McNemar test, using two-sided P values only. Sixty (28%) of patients had nonmetastatic PPGL, 95 (44%) had metastatic PPGL, and 61 (28%) were PPGL negative. For nonmetastatic tumors, the sensitivity of (18)F-FDG was similar to that of (123)I-MIBG but less than that of CT/MRI (sensitivity of (18)F-FDG = 76.8%; of (123)I-MIBG = 75.0%; of CT/MRI = 95.7%; (18)F-FDG vs (123)I-MIBG: difference = 1.8%, 95% confidence interval [CI] = -14.8% to 14.8%, P = .210; (18)F-FDG vs CT/MRI: difference = 18.9%, 95% CI = 9.4% to 28.3%, P < .001). The specificity was 90.2% for (18)F-FDG, 91.8% for (123)I-MIBG, and 90.2% for CT/MRI. (18)F-FDG uptake was higher in succinate dehydrogenase complex- and von Hippel-Lindau syndrome-related tumors than in multiple endocrine neoplasia type 2 (MEN2) related tumors. For metastases, sensitivity was greater for (18)F-FDG and CT/MRI than for (123)I-MIBG (sensitivity of (18)F-FDG = 82.5%; of (123)I-MIBG = 50.0%; of CT/MRI = 74.4%; (18)F-FDG vs (123)I-MIBG: difference = 32.5%, 95% CI = 22.3% to 42.5%, P < .001; CT/MRI vs (123)I-MIBG: difference = 24.4%, 95% CI = 11.3% to 31.6%, P < .001). For bone metastases, (18)F-FDG was more sensitive than CT/MRI (sensitivity of (18)F-FDG = 93.7%; of CT/MRI = 76.7%; difference = 17.0%, 95% CI = 4.9% to 28.5%, P = .013). Compared with (123)I-MIBG SPECT and CT/MRI, both considered gold standards for PPGL imaging, metastases were better detected by (18)F-FDG PET. (18)F-FDG PET provides a high specificity in patients with a biochemically established diagnosis of PPGL.


Ether- and alcohol-functionalized task-specific ionic liquids: attractive properties and applications.
In recent years, the designer nature of ionic liquids (ILs) has driven their exploration and exploitation in countless fields among the physical and chemical sciences. A fair measure of the tremendous attention placed on these fluids has been attributed to their inherent designer nature. And yet, there are relatively few examples of reviews that emphasize this vital aspect in an exhaustive or meaningful way. In this critical review, we systematically survey the physicochemical properties of the collective library of ether- and alcohol-functionalized ILs, highlighting the impact of ionic structure on features such as viscosity, phase behavior/transitions, density, thermostability, electrochemical properties, and polarity (e.g. hydrophilicity, hydrogen bonding capability). In the latter portions of this review, we emphasize the attractive applications of these functionalized ILs across a range of disciplines, including their use as electrolytes or functional fluids for electrochemistry, extractions, biphasic systems, gas separations, carbon capture, carbohydrate dissolution (particularly, the (ligno)celluloses), polymer chemistry, antimicrobial and antielectrostatic agents, organic synthesis, biomolecular stabilization and activation, and nanoscience. Finally, this review discusses anion-functionalized ILs, including sulfur- and oxygen-functionalized analogs, as well as choline-based deep eutectic solvents (DESs), an emerging class of fluids which can be sensibly categorized as semi-molecular cousins to the IL. Finally, the toxicity and biodegradability of ether- and alcohol-functionalized ILs are discussed and cautiously evaluated in light of recent reports. By carefully summarizing literature examples on the properties and applications of oxy-functional designer ILs up till now, it is our intent that this review offers a barometer for gauging future advances in the field as well as a trigger to spur further contemplation of these seemingly inexhaustible and--relative to their potential--virtually untouched fluids. It is abundantly clear that these remarkable fluidic materials are here to stay, just as certain design rules are slowly beginning to emerge. However, in fairness, serendipity also still plays an undeniable role, highlighting the need for both expanded in silico studies and a beacon to attract bright, young researchers to the field (406 references).


Family and occupational functioning following military trauma exposure and moral injury.
Evidence is growing regarding the impact of potentially morally injurious events (PMIEs) on mental health; yet how moral injury may affect an individual's occupational and familial functioning remains poorly understood. Thirty male veterans who reported exposure to either traumatic or morally injurious events and 15 clinicians were recruited for semi-structured qualitative interviews. While many veterans experienced psychological distress postevent, those who experienced PMIEs especially reported social withdrawal and engagement in aggressive, risk-taking behaviours. This was highly distressing for family members and created a tense, volatile home and workplace environment that was difficult for others to navigate. Following PMIEs, employment could be used as a cognitive avoidance strategy or as a means to atone for transgressive acts. In cases of moral injury, clinicians considered that targeted support for spouses and accessible guidance to help children to better understand how their military parent may be feeling would be beneficial. This study provides some of the first evidence of the pervasive negative impact of PMIEs on veterans' familial and occupational functioning. These findings highlight the need to comprehensively screen for the impact of moral injury on daily functioning in future studies that goes beyond just an assessment of psychological symptoms.


Commitment of neural crest cells to the sensory neuron lineage.
Clonal cultures and monoclonal antibodies against a lineage-specific epitope, stage-specific embryonic antigen-1 (SSEA-1) were used to analyze the commitment of quail neural crest cells to the sensory neuron pathway. There were two distinct populations of sensory cells at the time of gangliogenesis. Postmitotic neuroblasts that remained in close association with the neural tube coexisted with a large number of pluripotent cells that formed the leading edge of the emigrating cells and gave rise to sensory and autonomic neuroblasts and to melanocytes. The data suggest a dual origin of spinal sensory neuroblasts and a predominantly late divergence of the autonomic and sensory lineages.


Relationship between the chest radiograph, regional lung function studies, exercise tolerance, and clinical condition in cystic fibrosis.
This study evaluated the accuracy of the interpretation of the chest film in delineating localised abnormalities of ventilation and perfusion, as well as the overall severity of airways obstruction, exercise tolerance, and clinical condition in children with cystic fibrosis. Radiographic findings in various regions of the chest film were compared with the functional values obtained with regional lung function tests which evaluated the arrival and disappearance of boluses of radioactive nitrogen given by inhalation and infusion. While the more severely affected areas on the chest radiograph were found to correlate with similar regions on the lung function tests, as did overall scores, errors occurred in some cases if the x-ray film alone was used as a judge of regional physiological derangement. In addition the degree of airways obstruction, the exercise tolerance on a cycle ergometer, and clinical grading, each correlated significantly with the radiographic score. We conclude that the chest radiograph is a good indicator of the overall severity of the lung disease and that it correlates well with exercise tolerance and clinical condition in cystic fibrosis.


Complications following hamstring anterior cruciate ligament reconstruction with femoral cross-pin fixation.
Cross-pin fixation of hamstring grafts for anterior cruciate ligament reconstruction was developed with hopes of improving on potential problems associated with interference screw and button fixation methods. However, cross-pins are a relatively new method of graft fixation and there are limited data on this technique. We report 2 cases in which reoperation was necessary after complications associated with cross-pin fixation. In one case, the cross-pin was left too proud and in the other it penetrated the medial side of the femur and was prominent. Surgeons who use cross-pin fixation should pay close attention so as not to leave the cross-pin proud laterally or medially to avoid the necessity of reoperation for hardware removal.