Discrepancies in meta-analyses answering the same clinical question were hard to explain: a meta-epidemiological study.
To systematically explore the methodological factors underpinning discrepancies in the pooled effect estimates from Cochrane reviews (CRs) and non-Cochrane reviews (NCRs) systematic reviews, answering the same clinical question. Quantitative and qualitative analysis of concordance in effect estimates between meta-analyses from CR and NCR matched on population, intervention, condition, and outcome. We identified 24 matched meta-analyses from 24 CR to 20 NCR reviews (545 randomized controlled trials [RCTs]). Compared to their CR matched-pair, pooled effects from NCR were the same in only one pair, were on average 0.12 log units (13%) higher (P = 0.012), and had a greater than twofold larger effect size in four matched-pairs. Two-thirds of CR (15/24, 70.8%) and 0/20 (0%) NCR were rated to have moderate to high confidence in their results (AMSTAR 2). Differences in pre-defined methods, including search strategy, eligibility criteria, and performance of dual screening, could explain mismatches in included studies. Disagreements in the interpretation of eligibility criteria were identified as reasons underpinning discrepant findings in 14 pairs. 23/24 meta-analyses included at least one study of its match. Only two pairs agreed on the numerical data presented for the same studies. An assessment of 50% of discrepant studies (n = 45) showed that reasons for differences in extracted data could be identified in 15 studies. On average, meta-analyses from NCR reported higher effect estimates compared with meta-analyses from CR answering the same clinical question. Methodological and author judgments and performance are key aspects underpinning poor overlap of included studies and discrepancies in reported effect estimates. The potential impacts on health care policy and clinical practice are far-reaching but still remain unknown. Reinforcing awareness and scrutiny of application of reporting guidelines and improvements in protocol registration are needed.


Preparation of 17β-estradiol-imprinted material by surface-initiated atom transfer radical polymerization and its application.
A novel 17β-estradiol molecularly imprinted polymer was grafted onto the surface of initiator-immobilized silica by surface-initiated atom transfer radical polymerization. The resulting molecularly imprinted polymer was characterized by elemental analysis and thermogravimetric analysis. The binding property of molecularly imprinted polymer for 17β-estradiol was also studied with both static and dynamic methods. The results showed that the molecularly imprinted polymer possessed excellent recognition capacity for 17β-estradiol (180.65 mg/g at 298 K), and also exhibited outstanding selectivity for 17β-estradiol over the other competitive compounds (such as testosterone and progesterone). Then, the determination of trace 17β-estradiol in beef samples was successfully developed by using molecularly imprinted polymer solid-phase extraction coupled with high-performance liquid chromatography. The limit of detection was 0.25 ng/mL, and the amount of 17β-estradiol in beef samples was detected at 2.83 ng/g. This work proposed a sensitive, rapid, reliable, and convenient approach for the determination of trace 17β-estradiol in complicated beef samples.


Overall Structural Model of NS5A Protein from Hepatitis C Virus and Modulation by Mutations Confering Resistance of Virus Replication to Cyclosporin A.
Hepatitis C virus (HCV) nonstructural protein 5A (NS5A) is a RNA-binding phosphoprotein composed of a N-terminal membrane anchor (AH), a structured domain 1 (D1), and two intrinsically disordered domains (D2 and D3). The knowledge of the functional architecture of this multifunctional protein remains limited. We report here that NS5A-D1D2D3 produced in a wheat germ cell-free system is obtained under a highly phosphorylated state. Its NMR analysis revealed that these phosphorylations do not change the disordered nature of D2 and D3 domains but increase the number of conformers due to partial phosphorylations. By combining NMR and small angle X-ray scattering, we performed a comparative structural characterization of unphosphorylated recombinant D2 domains of JFH1 (genotype 2a) and the Con1 (genotype 1b) strains produced in Escherichia coli. These analyses highlighted a higher intrinsic folding of the latter, revealing the variability of intrinsic conformations in HCV genotypes. We also investigated the effect of D2 mutations conferring resistance of HCV replication to cyclophilin A (CypA) inhibitors on the structure of the recombinant D2 Con1 mutants and their binding to CypA. Although resistance mutations D320E and R318W could induce some local and/or global folding perturbation, which could thus affect the kinetics of conformer interconversions, they do not significantly affect the kinetics of CypA/D2 interaction measured by surface plasmon resonance (SPR). The combination of all our data led us to build a model of the overall structure of NS5A, which provides a useful template for further investigations of the structural and functional features of this enigmatic protein.


Persistence of fertility despite semen alterations in a pinealectomised patient treated with melatonin.
Little is known about the effect of chronic melatonin treatment on human reproductive function. We report here on the effect of 10 months treatment with a controlled-release melatonin preparation (Circadin®, 2 mg) on spermatogenesis and gonadotropic hormone status in a pinealectomised patient whose melatonin secretion was abolished. Semen analysis, hormone (Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH), inhibin B, prolactin, testosterone and estradiol) and Sex Hormone-Binding Globulin (SHB G) concentrations were determined before and at the end of 4 and 10 months of, treatment. At the end of treatment, testosterone, sex hormone-binding globulin, prolactin and inhibin B levels did not display significant variation with time, whereas FSH and LH levels showed a tendency to a decrease, but remained in the normal range. Sperm concentration and total spermatozoa count dropped below the lower limit of the reference range during melatonin treatment, whereas motility and normal form percentages remained in the normal range. Fertility was preserved, since the patient's wife became pregnant during month 10 of melatonin treatment and gave birth to a healthy female baby. this isolated clinical observation shows that more investigations in large patient series are needed to document possible side-effects of melatonin administration on male reproductive function. One should therefore be cautious about melatonin prescription for circadian rhythm sleep disorders in young males.


Substrate clamping effects on irreversible domain wall dynamics in lead zirconate titanate thin films.
The role of long-range strain interactions on domain wall dynamics is explored through macroscopic and local measurements of nonlinear behavior in mechanically clamped and released polycrystalline lead zirconate-titanate (PZT) films. Released films show a dramatic change in the global dielectric nonlinearity and its frequency dependence as a function of mechanical clamping. Furthermore, we observe a transition from strong clustering of the nonlinear response for the clamped case to almost uniform nonlinearity for the released film. This behavior is ascribed to increased mobility of domain walls. These results suggest the dominant role of collective strain interactions mediated by the local and global mechanical boundary conditions on the domain wall dynamics. The work presented in this Letter demonstrates that measurements on clamped films may considerably underestimate the piezoelectric coefficients and coupling constants of released structures used in microelectromechanical systems, energy harvesting systems, and microrobots.


Ant-like Traits in Wingless Parasitoids Repel Attack from Wolf Spiders.
A recent study showed that a wingless parasitoid, Gelis agilis, exhibits a suite of ant-like traits that repels attack from wolf spiders. When agitated, G. agilis secreted 6-methyl-5-hepten-2-one (sulcatone), which a small number of ant species produce as an alarm/panic pheromone. Here, we tested four Gelis parasitoid species, occurring in the same food chain and microhabitats, for the presence of sulcatone and conducted two-species choice bioassays with wolf spiders to determine their degree of susceptibility to attack. All four Gelis species, including both winged and wingless species, produced sulcatone, whereas a closely related species, Acrolyta nens, and the more distantly related Cotesia glomerata, did not. In two-choice bioassays, spiders overwhelmingly rejected the wingless Gelis species, preferring A. nens and C. glomerata. However, spiders exhibited no preference for either A. nens or G. areator, both of which are winged. Wingless gelines exhibited several ant-like traits, perhaps accounting for the reluctance of spiders to attack them. On the other hand, despite producing sulcatone, the winged G. areator more closely resembles other winged cryptines like A. nens, making it harder for spiders to distinguish between these two species. C. glomerata was also preferred by spiders over A. nens, suggesting that other non-sulcatone producing cryptines nevertheless possess traits that make them less attractive as prey. Phylogenetic reconstruction of the Cryptinae reveals that G. hortensis and G. proximus are 'sister'species, with G. agilis, and G.areator in particular evolving along more distant trajectories. We discuss the possibility that wingless Gelis species have evolved a suite of ant-like traits as a form, of mimicry to repel predators on the ground.


Three-dimensional linear system analysis for breast tomosynthesis.
The optimization of digital breast tomosynthesis (DBT) geometry and reconstruction is crucial for the clinical translation of this exciting new imaging technique. In the present work, the authors developed a three-dimensional (3D) cascaded linear system model for DBT to investigate the effects of detector performance, imaging geometry, and image reconstruction algorithm on the reconstructed image quality. The characteristics of a prototype DBT system equipped with an amorphous selenium flat-panel detector and filtered backprojection reconstruction were used as an example in the implementation of the linear system model. The propagation of signal and noise in the frequency domain was divided into six cascaded stages incorporating the detector performance, imaging geometry, and reconstruction filters. The reconstructed tomosynthesis imaging quality was characterized by spatial frequency dependent presampling modulation transfer function (MTF), noise power spectrum (NPS), and detective quantum efficiency (DQE) in 3D. The results showed that both MTF and NPS were affected by the angular range of the tomosynthesis scan and the reconstruction filters. For image planes parallel to the detector (in-plane), MTF at low frequencies was improved with increase in angular range. The shape of the NPS was affected by the reconstruction filters. Noise aliasing in 3D could be introduced by insufficient voxel sampling, especially in the z (slice-thickness) direction where the sampling distance (slice thickness) could be more than ten times that for in-plane images. Aliasing increases the noise at high frequencies, which causes degradation in DQE. Application of a reconstruction filter that limits the frequency components beyond the Nyquist frequency in the z direction, referred to as the slice thickness filter, eliminates noise aliasing and improves 3D DQE. The focal spot blur, which arises from continuous tube travel during tomosynthesis acquisition, could degrade DQE significantly because it introduces correlation in signal only, not NPS.


Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor-related protein.
The regulation of cerebrovascular permeability is critical for normal brain homeostasis, and the "breakdown" of the blood-brain barrier (BBB) is associated with the development of vasogenic edema and intracranial hypertension in a number of neurological disorders. In this study we demonstrate that an increase in endogenous tissue-type plasminogen activator (tPA) activity in the perivascular tissue following cerebral ischemia induces opening of the BBB via a mechanism that is independent of both plasminogen (Plg) and MMP-9. We also show that injection of tPA into the cerebrospinal fluid in the absence of ischemia results in a rapid dose-dependent increase in vascular permeability. This activity is not seen with urokinase-type Plg activator (uPA) but is induced in Plg-/- mice, confirming that the effect is Plg-independent. However, the activity is blocked by antibodies to the LDL receptor-related protein (LRP) and by the LRP antagonist, receptor-associated protein (RAP), suggesting a receptor-mediated process. Together these studies demonstrate that tPA is both necessary and sufficient to directly increase vascular permeability in the early stages of BBB opening, and suggest that this occurs through a receptor-mediated cell signaling event and not through generalized degradation of the vascular basement membrane.


Electronic circular dichroism of disulphide bridge: ab initio quantum-chemical calculations.
Electronic circular dichroism (ECD) parameters of the disulphide chromophore have been calculated for dihydrogen disulphide, dimethyl disulphide, and cystine using density-functional theory, coupled-cluster theory, and multiconfigurational self-consistent field theory. The objective is twofold: first, to examine the performance of the Coulomb-attenuated CAM-B3LYP functional for the calculation of ECD spectra; second, to investigate the dependence of the ECD parameters on the conformation around the disulphide bridge. The CAM-B3LYP functional improves considerably on the B3LYP functional, giving results comparable to CCSD theory and to MCSCF theory in an extended active space. The conformational dependence of the ECD parameters does not change much upon substitution, which is promising for the application of ECD in structural investigations of proteins containing disulphide bridges.


Psychostimulant-induced neuroadaptations in nucleus accumbens AMPA receptor transmission.
Medium spiny neurons of the nucleus accumbens serve as the interface between corticolimbic regions that elicit and modulate motivated behaviors, including those related to drugs of abuse, and motor regions responsible for their execution. Medium spiny neurons are excited primarily by AMPA-type glutamate receptors, making AMPA receptor transmission in the accumbens a key regulatory point for addictive behaviors. In animal models of cocaine addiction, changes in the strength of AMPA receptor transmission onto accumbens medium spiny neurons have been shown to underlie cocaine-induced behavioral adaptations related to cocaine seeking. Here we review changes in AMPA receptor levels and subunit composition that occur after discontinuing different types of cocaine exposure, as well as changes elicited by cocaine reexposure following abstinence or extinction. Signaling pathways that regulate these cocaine-induced adaptations will also be considered, as they represent potential targets for addiction pharmacotherapies.


Density dependence, spatial scale and patterning in sessile biota.
Sessile biota can compete with or facilitate each other, and the interaction of facilitation and competition at different spatial scales is key to developing spatial patchiness and patterning. We examined density and scale dependence in a patterned, soft sediment mussel bed. We followed mussel growth and density at two spatial scales separated by four orders of magnitude. In summer, competition was important at both scales. In winter, there was net facilitation at the small scale with no evidence of density dependence at the large scale. The mechanism for facilitation is probably density dependent protection from wave dislodgement. Intraspecific interactions in soft sediment mussel beds thus vary both temporally and spatially. Our data support the idea that pattern formation in ecological systems arises from competition at large scales and facilitation at smaller scales, so far only shown in vegetation systems. The data, and a simple, heuristic model, also suggest that facilitative interactions in sessile biota are mediated by physical stress, and that interactions change in strength and sign along a spatial or temporal gradient of physical stress.


Air pollutants cause release of hydrogen peroxide and interleukin-8 in a human primary nasal tissue culture model.
A component of primary innate defense of the nasal mucosa against inhaled pathogens includes continuous, low-level release of hydrogen peroxide (H2 O2 ) into luminal secretions. Epidemiologically, an association exists between poor air quality and increased prevalence of sinonasal disease. To understand the effects of particulate matter (PM) in nasal mucosa, we studied the release of H2 O2 and interleukin 8 (IL-8) after PM exposure. Human nasal specimens were collected from surgery and cultured in serum-free growth medium. Cell integrity and recovery during culture was monitored by lactate dehydrogenase (LDH) release into the medium. Cultures were exposed to PM for 24 hours in the presence/absence of diphenyleneiodonium sulfate (DPI; a nicotinamide adenine dinucleotide phosphate [NADPH] oxidase inhibitor). Luminex cytokine and Amplex-Red H2 O2 assays were performed. LDH levels dropped rapidly within 2 days, indicative of stabilization and cell recovery after harvest. All cultures released H2 O2 into the medium. Exposure to PM (20 μg/cm(2) ) increased H2 O2 levels significantly (94.6 ± 7.7 nM) compared to untreated controls (55.8 ± 4.0 nM; p = 0.001). PM-induced H2 O2 production was partially inhibited by DPI (80.1 ± 3.8nM), indicating that cellular NADPH oxidase may be a primary source of H2 O2 production. Exposure to PM increased IL-8 levels in a dose-dependent fashion (control = 2301 ± 412 MFI; 20 μg/cm(2) = 5002 ± 1327 MFI; 40 μg/cm(2) = 8219 ± 1090 MFI; p = 0.022). PM increases the quantity of H2 O2 released by nasal epithelial cells, indicating that PM can contribute to oxidative stress in part by activating a normal cellular defense mechanism. Exposure to PM resulted in elevated IL-8 levels and mucin production in explants. Efforts to reduce airborne PM may lead to reduced H2 O2 and mucin production in sinonasal epithelium.


Interactions between neurofilaments and microtubule-associated proteins: a possible mechanism for intraorganellar bridging.
Mammalian neurofilaments prepared from brain and spinal cord by either of two methods partially inhibit the in vitro assembly of microtubules. This inhibition is shown to be due to the association of a complex of high molecular weight microtubule-associated proteins (MAP1 and MAP2) and tubulin with the neurofilament. Further analysis of the association reveals a saturable binding of purified brain MAPs to purified neurofilaments with a Kd of 10(-7) M. Purified astroglial filaments neither inhibit microtubule assembly nor show significant binding of MAPs. It is proposed that the MAPs might function as one element in a network of intraorganellar links in the cytoplasm.


Two congenital cases of pigmented epithelioid melanocytoma studied by fluorescent in situ hybridization for melanocytic tumors: case reports and review of these recent topics.
The term 'pigmented epithelioid melanocytoma' (PEM) has recently been proposed as a nosological framework grouping lesions formerly known as animal-type melanomas, sporadic epithelioid blue nevi and Carney complex-associated epithelioid blue nevi. Congenital PEMs have been reported extremely rarely and their prognosis is poorly known. Four-color fluorescent in situ hybridization (FISH) for melanocytic lesions is a recent method developed to assess the malignant potential of ambiguous melanocytic lesions. Here we describe 2 cases of congenital epithelioid and strongly pigmented melanocytic lesions consistent with PEM. No BRAF gene mutation was found in the 2 cases. FISH for melanocytic lesions was also performed. The first case proved entirely negative, whereas the second one showed a positive zone with an extra copy of chromosome 6. The prognosis and management of PEM are discussed, with a review of the available data on the history, demographics, molecular alterations and histopathological aspects of this entity. PEM seems to represent a unique low-grade melanocytic tumor with a limited potential of metastasis to lymph nodes, but a favorable long-term clinical course. The published data about FISH for melanocytic tumors, and especially PEM, are reviewed. Four-color FISH may be a useful tool to assess more accurately the prognosis of these tumors.


WE-G-BRCD-02: Speed Up Standard Optimization of IMPT Treatment Planning Through the Application of GPUs.
While intensity-modulated proton therapy (IMPT) has great potential to deliver highly conformal tumoricidal dose to targets whilst minimizing dose to nearby organs-at-risk, IMPT optimization is very time consuming and memory extensive due to finer dose grids and a large number of energy layers used compared to intensity-modulated radiation therapy (IMRT). In this presentation, for the first time, a new approach is introduced to speed up the IMPT treatment planning through application of parallel computing with Graphic Processor Units (GPUs). Parallel computation with GPUs, which are affordable and can be plugged in a workstation easily, is potentially a good way to improve the computation efficiency. In our approach, we used the standard quadratic objective function to optimize the intensity map of beamlets. The objective function and gradient equations, which are the most time consuming parts of the optimization, were calculated with GPUs. We compared the computation time of optimization done by an Intel ® Core™ i7 CPU and that by the same CPU accelerated by GPUs (TESLA C1060). The influence matrix was pre- calculated before optimization with an in-house proton pencil beam dose calculation engine. Two clinical cases were studied: one base-of-skull (BOS) case (clivus chordoma) and one prostate case (adenocarcinoma). The dose volume histogram (DVH) data for the tumor and critical organs were derived for comparison of optimization results generated by CPU and GPUs. For the BOS case, application of GPUs for the optimization and overall gained 54 and 36.5 times speedup. For the prostate case, application of GPUs for the optimization and overall gained 69 and 28.5 times speedup. The application of GPUs for the parallel computing of IMPT treatment plan optimization can dramatically improve the computation efficiency. The optimization time can be reduced from typically half to one hour to only several minutes.


Loss of SLC45A3 protein (prostein) expression in prostate cancer is associated with SLC45A3-ERG gene rearrangement and an unfavorable clinical course.
The majority of prostate cancer harbors recurrent gene fusions involving ETS transcription factors, most commonly ERG. The second most common 5' fusion partner after TMPRSS2 is SLC45A3. The aim of our study was to quantify the protein expression of ERG, TMPRSS2 and SLC45A3 in prostate cancer to assess for diagnostic or prognostic utility. Six hundred and forty consecutive prostate cancer cases in tissue microarray format were immunohistochemically analyzed for ERG, TMPRSS2 and SLC45A3 protein. Resultant protein expression data was correlated to the respective gene rearrangement status and clinico-pathological parameters including PSA follow up times. ERG showed no expression in benign prostate glands. In cancer tissue, ERG protein expression showed a high rate of concordance with an underlying ERG rearrangement (91.5%). SLC45A3 showed a weaker expression in cancer as compared to benign tissue, which was pronounced in cases with SLC45A3-ERG fusion. Importantly, SLC45A3 down regulation was significantly associated with shorter PSA-free survival times. In contrast, TMPRSS2 was neither differentially expressed nor did it show a correlation between protein expression and rearrangement status. This study provides first evidence that the expression of SLC45A3 protein is down regulated through SLC45A3-ERG fusion in prostate cancer. Moreover, these cases may represent a distinct molecular subclass of ERG rearranged prostate cancer with distinct clinical features. This study also confirms that ERG protein expression is predominantly found in prostate carcinomas with ERG gene rearrangement and does not occur in benign glands.


Ecological speciation in postglacial European whitefish: rapid adaptive radiations into the littoral, pelagic, and profundal lake habitats.
Understanding how a monophyletic lineage of a species diverges into several adaptive forms has received increased attention in recent years, but the underlying mechanisms in this process are still under debate. Postglacial fishes are excellent model organisms for exploring this process, especially the initial stages of ecological speciation, as postglacial lakes represent replicated discrete environments with variation in available niches. Here, we combine data of niche utilization, trophic morphology, and 17 microsatellite loci to investigate the diversification process of three sympatric European whitefish morphs from three northern Fennoscandian lakes. The morphological divergence in the gill raker number among the whitefish morphs was related to the utilization of different trophic niches and was associated with reproductive isolation within and across lakes. The intralacustrine comparison of whitefish morphs showed that these systems represent two levels of adaptive divergence: (1) a consistent littoral-pelagic resource axis; and (2) a more variable littoral-profundal resource axis. The results also indicate that the profundal whitefish morph has diverged repeatedly from the ancestral littoral whitefish morph in sympatry in two different watercourses. In contrast, all the analyses performed revealed clustering of the pelagic whitefish morphs across lakes suggesting parallel postglacial immigration with the littoral whitefish morph into each lake. Finally, the analyses strongly suggested that the trophic adaptive trait, number of gill rakers, was under diversifying selection in the different whitefish morphs. Together, the results support a complex evolutionary scenario where ecological speciation acts, but where both allopatric (colonization history) and sympatric (within watercourse divergence) processes are involved.


A bioinformatics survey for conotoxin-like sequences in three turrid snail venom duct transcriptomes.
The repertoire of venom peptides produced by Conoidean snails has shown to be useful for therapeutic and neuropharmacologic applications. Despite their dominance in terms of species number, the Family Turridae is the least studied among their other Conoidean counterparts. They provide a vast resource of pharmacological material only hindered by the inaccessibility of their deep water habitat for sample collection and their small size that allows only a limited amount of material from their venom duct amenable for analysis. Using high-throughput transcriptome sequencing, toxin transcripts can be extracted bioinformatically to fast-track toxin discovery. This approach was utilized on the venom duct transcriptomes of three species of turrids: Unedogemmula bisaya, Crassispira cerithina, and Gemmula speciosa and resulted in the discovery of 41, 22, and 74 putative turrid toxin genes, respectively. Comparisons among these turrid toxin genes to conotoxins show (i) similar superfamily precursors between conotoxins and turrid toxins for the classes D, I2, L, M, O1, O2, and P, (ii) a wider range of peptide lengths of up to 190 amino acids long for mature turritoxin, and (iii) nondisulfide-rich turritoxins with the B2 signal sequence. Novel superfamilies and cysteine frameworks including a novel 14-cysteine residue framework were also obtained.


The human papillomavirus infection in men study: human papillomavirus prevalence and type distribution among men residing in Brazil, Mexico, and the United States.
Male sexual behavior influences the rates of cervical dysplasia and invasive cervical cancer, as well as male human papillomavirus (HPV) infection and disease. Unfortunately, little is known regarding male HPV type distribution by age and across countries. In samples combined from the coronal sulcus, glans penis, shaft, and scrotum of 1,160 men from Brazil, Mexico, and the United States, overall HPV prevalence was 65.2%, with 12.0% oncogenic types only, 20.7% nononcogenic types only, 17.8% both oncogenic and nononcogenic, and 14.7% unclassified infections. Multiple HPV types were detected in 25.7% of study participants. HPV prevalence was higher in Brazil (72.3%) than in the United States (61.3%) and Mexico (61.9%). HPV16 (6.5%), HPV51 (5.3%), and HPV59 (5.3%) were the most commonly detected oncogenic infections, and HPV84 (7.7%), HPV62 (7.3%), and HPV6 (6.6%) were the most commonly detected nononcogenic infections. Overall HPV prevalence was not associated with age. However, significant associations with age were observed when specific categories of HPV, nononcogenic, and unclassified HPV infections were considered. Studies of HPV type distribution among a broad age range of men from multiple countries is needed to fill the information gap internationally with respect to our knowledge of HPV infection in men.


Prolactin and lactation as modifiers of diabetes risk in gestational diabetes.
Pregnancy and puerperium are periods of intense hormonal changes. Maternal metabolism adapts to spare the mother from harm on behalf of her developing offspring and major alterations maintain normal glucose tolerance. Insulin secretion increases during a normal pregnancy to compensate for pregnancy-induced insulin resistance and maintain euglycemia. Women at risk for gestational diabetes have insulin resistance before conception. Gestational diabetes develops when a woman at risk is unable to meet the insulin secretory demands imposed by the additional insulin resistance characteristic of pregnancy. The lactogens, human placental lactogen and prolactin, are major stimuli for the adaptation of the endocrine pancreas during gestation. This review discusses the role of lactogens on glucose homeostasis during pregnancy and proposes a mechanism by which the hormonal control of lactation, led by prolactin, may regulate adipocyte biology, glucose and lipid metabolism, and guard postpartum women against type 2 diabetes.


Absencing/presencing risk: Rethinking proximity and the experience of living with major technological hazards.
There is now a substantial body of sociocultural research that has investigated the ways in which specific communities living in physical proximity with a variety of polluting or hazardous technological installations experience and respond to their exposure to the associated risk. Much of this research has sought to understand the apparent acceptance or acquiescence displayed by local populations towards established hazards of the kind that are typically resisted when the subject of siting proposals. However, recent theoretical contributions, produced largely outside the field of risk research, have problematised the objective distinction between proximity and distance. In this paper we explore the potential of some of these ideas for furthering our understanding of the relationship between place and the constitution of risk subjectivities. To do this we re-examine a number of existing sociocultural studies that are predicated on a localised approach and conceptualise the relationship of physically proximate sources of risk to everyday experience in terms of practices of 'presencing' and 'absencing'. We conclude with some thoughts on the methodological and substantive implications of this reworking of proximity for future research into risk subjectivities.


Inheritance of low-level resistance to penicillin, tetracycline, and chloramphenicol in Neisseria gonorrhoeae.
The genetics of low-level resistance to penicillin and other antibiotics in a clinical isolate and a multistep laboratory mutant of Neisseria gonorrhoea was studied by transformation. Mutations at three loci affected sensitivity to penicillin. Mutation at penA resulted in an eightfold increase in resistance to penicillin without affecting response to other antimicrobial agents. Mutation at ery resulted in a two- to fourfold increase in resistance to penicillin and similar increases in resistance to many other antibiotics, dyes, and detergents. Mutation at penB resulted in a fourfold increase in resistance to penicillin and tetracycline, the phenotypic expression of which was dependent on the presence of mutation at ery. The cumulative effect of mutations at penA, ery, and penB was an approximate 128-fold increase in penicillin resistance, to a minimum inhibitory concentration of 1.0 mug/ml. Low-level resistance to tetracycline or chloramphenicol was due to similar additive effects between mutations at the nonspecific ery and penB loci and a locus specific for resistance to each drug (tet and chl, respectively). No evidence was found for penicillinases or other drug-inactivating enzymes.


Comparison of different coating techniques on the properties of FucoPol films.
Plasma deposition, liquid flame spray (LFS) and atomic layer deposition (ALD) were used to form inorganic coatings in new exopolysaccharide (FucoPol) biodegradable films. Coated films were characterised in terms of surface, optical and barrier properties in order to evaluate their potential use in food packaging. FucoPol films presented dense and homogeneous surface with instant water contact angle of 95̊. Plasma deposition of perfluorohexane (PFH) on FucoPol surface has not shown significant improvement in the hydrophobic behaviour over the time. The FucoPol coating of SiO2 nanoparticles deposited by LFS and plasma deposition of PFH have shown higher instant water contact angle (135°) caused by coating surface roughness, but this hydrophobic behaviour was not stable over time. FucoPol films coated only with TiO2 deposited by ALD and combination of that with plasma deposition of PFH have shown stable water contact angle during time (90̊ and 115̊, respectively), transparency in the same order of magnitude and significantly lower permeability to water vapour (3.45×10-11mol/m s Pa and 3.45×10-11mol/m s Pa when compared to uncoated films with 5.32×10-11mol/m s Pa). Moreover, films coated with TiO2-PFH have also shown a permeability to oxygen of 1.70×10-16molm/m2sPa which is 67% lower than uncoated films.


Adaptive radiotherapy for NSCLC patients: utilizing the principle of energy conservation to evaluate dose mapping operations.
Tumor regression during the course of fractionated radiotherapy confounds the ability to accurately estimate the total dose delivered to tumor targets. Here we present a new criterion to improve the accuracy of image intensity-based dose mapping operations for adaptive radiotherapy for patients with non-small cell lung cancer (NSCLC). Six NSCLC patients were retrospectively investigated in this study. An image intensity-based B-spline registration algorithm was used for deformable image registration (DIR) of weekly CBCT images to a reference image. The resultant displacement vector fields were employed to map the doses calculated on weekly images to the reference image. The concept of energy conservation was introduced as a criterion to evaluate the accuracy of the dose mapping operations. A finite element method (FEM)-based mechanical model was implemented to improve the performance of the B-Spline-based registration algorithm in regions involving tumor regression. For the six patients, deformed tumor volumes changed by 21.2 ± 15.0% and 4.1 ± 3.7% on average for the B-Spline and the FEM-based registrations performed from fraction 1 to fraction 21, respectively. The energy deposited in the gross tumor volume (GTV) was 0.66 Joules (J) per fraction on average. The energy derived from the fractional dose reconstructed by the B-spline and FEM-based DIR algorithms in the deformed GTV's was 0.51 J and 0.64 J, respectively. Based on landmark comparisons for the 6 patients, mean error for the FEM-based DIR algorithm was 2.5 ± 1.9 mm. The cross-correlation coefficient between the landmark-measured displacement error and the loss of radiation energy was -0.16 for the FEM-based algorithm. To avoid uncertainties in measuring distorted landmarks, the B-Spline-based registrations were compared to the FEM registrations, and their displacement differences equal 4.2 ± 4.7 mm on average. The displacement differences were correlated to their relative loss of radiation energy with a cross-correlation coefficient equal to 0.68. Based on the principle of energy conservation, the FEM-based mechanical model has a better performance than the B-Spline-based DIR algorithm. It is recommended that the principle of energy conservation be incorporated into a comprehensive QA protocol for adaptive radiotherapy.


Impact of upstream oil extraction and environmental public health: A review of the evidence.
Upstream oil extraction, which includes exploration and operation to bring crude oil to the surface, frequently occurs near human populations. There are approximately 40,000 oil fields globally and 6 million people that live or work nearby. Oil extraction can impact local soil, water, and air, which in turn can influence community health. As oil resources are increasingly being extracted near human populations, we highlight the current scope of scientific knowledge regarding potential community health impacts with the aim to help identify scientific gaps and inform policy discussions surrounding oil drilling operations. In this review, we assess the wide range of both direct and indirect impacts that oil drilling operations can have on human health, with specific emphasis on understanding the body of scientific literature to assess potential environmental and health risks to residents living near active onshore oil extraction sites. From an initial literature search capturing 2236 studies, we identified 22 human studies, including 5 occupational studies, 5 animal studies, 6 experimental studies and 31 oil drilling-related exposure studies relevant to the scope of this review. The current evidence suggests potential health impacts due to exposure to upstream oil extraction, such as cancer, liver damage, immunodeficiency, and neurological symptoms. Adverse impacts to soil, air, and water quality in oil drilling regions were also identified. Improved characterization of exposures by community health studies and further study of the chemical mixtures associated with oil extraction will be critical to determining the full range of health risks to communities living near oil extraction.


Heparan Sulfate Proteoglycan Synthesis Is Dysregulated in Human Osteoarthritic Cartilage.
Osteoarthritis (OA) is a common degenerative joint disease, characterized by cartilage loss and subchondral bone remodeling in response to abnormal mechanical load. Heparan sulfate (HS) proteoglycans bind to many proteins that regulate cartilage homeostasis, including growth factors, morphogens, proteases, and their inhibitors, and modulate their localization, retention, and biological activity. Changes in HS expression and structure may thus have important consequences for joint health. We analyzed normal and osteoarthritic human knee cartilage, and found HS biosynthesis was markedly disrupted in OA, with 45% of the 38 genes analyzed differentially regulated in diseased cartilage. The expression of several HS core proteins, biosynthesis, and modification enzymes was increased in OA cartilage, whereas the expression of the HS proteoglycans syndecan 4 and betaglycan was reduced. The structure of HS was also altered, with increased levels of 6-O-sulfation in osteoarthritic samples, which correlated with increased expression of HS6ST1, a 6-O-sulfotransferase, and GLCE, an epimerase that promotes 6-O-sulfation. siRNA silencing of HS6ST1 expression in primary OA chondrocytes inhibited extracellular signal-regulated kinase phosphorylation in response to fibroblast growth factor 2, showing that changes in 6-O-sulfation impact a key cartilage signaling pathway. Given the broad range of homeostatic and repair pathways that HS regulates, these changes in proteoglycan expression and HS structure are likely to have significant effects on joint health and progression of OA.


Computer generated holograms from three dimensional meshes using an analytic light transport model.
We present a method to analytically compute the light distribution of triangles directly in frequency space. This allows for fast evaluation, shading, and propagation of light from 3D mesh objects using angular spectrum methods. The algorithm complexity is only dependent on the hologram resolution and the polygon count of the 3D model. In contrast to other polygon based computer generated holography methods we do not need to perform a Fourier transform per surface. The theory behind the approach is derived, and a suitable algorithm to compute a digital hologram from a general triangle mesh is presented. We review some first results rendered on a spatial-light-modulator-based display by our proof-of-concept software.


Associations between neighborhood availability and individual consumption of dark-green and orange vegetables among ethnically diverse adults in Detroit.
Diets rich in dark-green and orange vegetables have been associated with a reduction in chronic diseases. However, most Americans do not consume the number of daily servings recommended by the 2005 Dietary Guidelines for Americans. An increasing number of studies suggest that changes to the neighborhood food environment may be critical to achieving population-wide improvements in eating. The objective of this study was to examine the relationship between observed neighborhood availability and individual consumption of dark-green and orange vegetables among low- to moderate-income and ethnically diverse adults in Detroit. This study used a cross-sectional design that drew upon a 2002-2003 community survey and 2002 in-person audit of food stores. A total of 919 adults (mean age 46.3 years, 52.2% female) including African Americans (56.7 %), Latinos (22.2%), and whites (18.7%) residing in three Detroit communities participated in the survey. Two-level weighted, hierarchical linear regression was used to analyze the data. On average, survey respondents ate 0.61 daily servings of dark-green and orange vegetables. Residents of neighborhoods with no stores carrying five or more varieties of dark-green and orange vegetables were associated with an average of 0.17 fewer daily servings of these foods compared with residents of neighborhoods with two stores carrying five or more varieties of dark-green and orange vegetables (P=0.047). These findings suggest that living in a neighborhood with multiple opportunities to purchase dark-green and orange vegetables may make an important contribution toward meeting recommended intakes.


Plastins regulate ectoplasmic specialization via its actin bundling activity on microfilaments in the rat testis.
Plastins are a family of actin binding proteins (ABPs) known to cross-link actin microfilaments in mammalian cells, creating actin microfilament bundles necessary to confer cell polarity and cell shape. Plastins also support cell movement in response to changes in environment, involved in cell/tissue growth and development. They also confer plasticity to cells and tissues in response to infection or other pathological conditions (e.g., inflammation). In the testis, the cell-cell anchoring junction unique to the testis that is found at the Sertoli cell-cell interface at the blood-testis barrier (BTB) and at the Sertoli-spermatid (e.g., 8-19 spermatids in the rat testis) is the basal and the apical ectoplasmic specialization (ES), respectively. The ES is an F-actin-rich anchoring junction constituted most notably by actin microfilament bundles. A recent report using RNAi that specifically knocks down plastin 3 has yielded some insightful information regarding the mechanism by which plastin 3 regulates the status of actin microfilament bundles at the ES via its intrinsic actin filament bundling activity. Herein, we provide a brief review on the role of plastins in the testis in light of this report, which together with recent findings in the field, we propose a likely model by which plastins regulate ES function during the epithelial cycle of spermatogenesis via their intrinsic activity on actin microfilament organization in the rat testis.


Combined in situ quartz crystal microbalance with dissipation monitoring, indirect nanoplasmonic sensing, and vibrational sum frequency spectroscopic monitoring of alkanethiol-protected copper corrosion.
In this study, we have applied three techniques to simultaneously and in situ study the initial stage of corrosion of copper protected by a self-assembled monolayer of octadecanethiol (ODT). We combined quartz crystal microbalance with dissipation monitoring (QCM-D), indirect nanoplasmonic sensing (INPS), and vibrational sum frequency spectroscopy (VSFS) and obtained complementary information about mass uptake and optical and spectroscopic changes taking place during the initial corrosion phase. All three techniques are very sensitive to the formation of a corrosion film (thickness in the range 0-0.41 nm) under mildly corrosive conditions (dry air, <0.5% relative humidity). The three techniques yield information about the viscoelasticity of the corrosion film (QCM-D), the homogeneity of the corrosion reaction on the surface (INPS), and the stability of the ODT protection layer (VSFS). Furthermore, by also studying the corrosion process in humid air (ca. 70% relative humidity), we illustrate how the combination of these techniques can be used to differentiate between simultaneously occurring processes, such as water adsorption and corrosion product formation.


Immune-glutamatergic dysfunction as a central mechanism of the autism spectrum disorders.
Despite the great number of observations being made concerning cellular and the molecular dysfunctions associated with autism spectrum disorders (ASD), the basic central mechanism of these disorders has not been proposed in the major scientific literature. Our review brings evidence that most heterogeneous symptoms of ASD have a common set of events closely connected with dysregulation of glutamatergic neurotransmission in the brain with enhancement of excitatory receptor function by pro-inflammatory immune cytokines as the underlying mechanism. We suggest that environmental and dietary excitotoxins, mercury, fluoride, and aluminum can exacerbate the pathological and clinical problems by worsening excitotoxicity and by microglial priming. In addition, each has effects on cell signaling that can affect neurodevelopment and neuronal function. Our hypothesis opens the door to a number of new treatment modes, including the nutritional factors that naturally reduce excitotoxicity and brain inflammation.


Community Protection Policies and Repeat Sexual Offenses in Florida.
The purpose of this study was to investigate the impact of sexual offender management policies on sex crime repeat arrest rates in Florida. Aggregate data for the period 1990 to 2010 were provided by the Florida Department of Law Enforcement. The repeat offense rate was defined as the proportion of arrests each year that were committed by individuals with a previous conviction in the same crime category. The average yearly repeat offense rate for sex crimes was 6.5%, which was consistently and significantly lower than rates for other crimes: 8.3% for non-sex assaults, 15.1% for robbery, 29.8% for drug offenses, and 11.6% for DUI. The average annual sexual repeat arrest rate prior to and after the implementation of sexual offender registration laws in 1997 was 4.9% and 7.5%, respectively, indicating a statistically significant increase. The average annual repeat arrest rates for non-sex assaults, robberies, drug crimes, and DUIs also increased after 1997. No significant differences were found when comparing the average annual percent change for sexual re-arrest (+3.47%) with non-sexual assault (+3.93%), robbery (-.73%), drug offenses (+1.59%), and DUI (+1.14). Sex crime repeat arrests in Florida do not appear to show a decline attributable to sex offender management policies implemented since 1997.


The Acute and Chronic Cognitive Effects of a Sage Extract: A Randomized, Placebo Controlled Study in Healthy Humans.
The sage (Salvia) plant contains a host of terpenes and phenolics which interact with mechanisms pertinent to brain function and improve aspects of cognitive performance. However, previous studies in humans have looked at these phytochemicals in isolation and following acute consumption only. A preclinical in vivo study in rodents, however, has demonstrated improved cognitive outcomes following 2-week consumption of CogniviaTM, a proprietary extract of both Salvia officinalis polyphenols and Salvia lavandulaefolia terpenoids, suggesting that a combination of phytochemicals from sage might be more efficacious over a longer period of time. The current study investigated the impact of this sage combination on cognitive functions in humans with acute and chronic outcomes. Participants (n = 94, 25 M, 69 F, 30-60 years old) took part in this randomised, double-blind, placebo-controlled, parallel groups design where a comprehensive array of cognitions were assessed 120- and 240-min post-dose acutely and following 29-day supplementation with either 600 mg of the sage combination or placebo. A consistent, significant benefit of the sage combination was observed throughout working memory and accuracy task outcome measures (specifically on the Corsi Blocks, Numeric Working Memory, and Name to Face Recall tasks) both acutely (i.e., changes within day 1 and day 29) and chronically (i.e., changes between day 1 to day 29). These results fall slightly outside of those reported previously with single Salvia administration, and therefore, a follow-up study with the single and combined extracts is required to confirm how these effects differ within the same cohort.


Effect of aging on coordinated eye and hand movements with two-segment sequence.
This study examined how aging compromises coordinative eye-hand movements with multiple segments. Older adults and young controls performed two-segment movements with the eyes only or with the eyes and hand together. The results showed minimal age-related changes on the initiation and execution of primary saccade during the first segment. However, the older adults showed a scaling problem of saccade velocity when hand movements were included. They were also slow in stabilizing gaze fixation to the first target. Regarding hand movements, the older adults pronouncedly increased the deceleration phase compared with the controls while fixating their gazes to the target. They also increased the intersegment interval for both eye and hand movements. Taken together, aging differentially affects various components of movements, which contributes to the slowness of overall performance.


Vitamin A supplementation for extremely low birth weight infants: outcome at 18 to 22 months.
A National Institute of Child Health and Human Development Neonatal Research Network randomized trial showed that vitamin A supplementation reduced bronchopulmonary dysplasia (O2 at 36 weeks' postmenstrual age) or death in extremely low birth weight (ELBW) neonates (relative risk [RR]: 0.89). As with postnatal steroids or other interventions, it is important to ensure that there are no longer-term adverse effects that outweigh neonatal benefits. To determine if vitamin A supplementation in ELBW infants during the first month after birth affects survival without neurodevelopmental impairment at a corrected age of 18 to 22 months. Infants enrolled in the National Institute of Child Health and Human Development vitamin A trial were evaluated at 18 to 22 months by carefully standardized assessments: Bayley Mental Index (MDI) and Psychomotor Index (PDI), visual and hearing screens, and physical examination for cerebral palsy (CP). The medical history was also obtained. Neurodevelopmental impairment (NDI) was predefined as > or =1 of MDI <70, PDI <70, CP, blind in both eyes, or hearing aids in both ears. Of 807 enrolled infants, 133 died before and 16 died after discharge. Five hundred seventy-nine (88%) of the 658 remaining infants were followed up. The primary outcome of NDI or death could be determined for 687 of 807 randomized infants (85%). Baseline characteristics and predischarge and postdischarge mortality were comparable in both study groups. NDI or death by 18 to 22 months occurred in 190 of 345 (55%) infants in the vitamin A group and in 204 of 342 (60%) of the control group (RR: 0.94; 95% confidence interval: 0.80-1.07). RRs for low MDI, low PDI, and CP were also <1.0. We found no evidence that neonatal vitamin A supplementation reduces hospitalizations or pulmonary problems after discharge. Vitamin A supplementation for ELBW infants reduces bronchopulmonary dysplasia without increasing mortality or neurodevelopmental impairment at 18 to 22 months. However, this study was not powered to evaluate small magnitudes of change in long-term outcomes.


SNP interaction detection with Random Forests in high-dimensional genetic data.
Identifying variants associated with complex human traits in high-dimensional data is a central goal of genome-wide association studies. However, complicated etiologies such as gene-gene interactions are ignored by the univariate analysis usually applied in these studies. Random Forests (RF) are a popular data-mining technique that can accommodate a large number of predictor variables and allow for complex models with interactions. RF analysis produces measures of variable importance that can be used to rank the predictor variables. Thus, single nucleotide polymorphism (SNP) analysis using RFs is gaining popularity as a potential filter approach that considers interactions in high-dimensional data. However, the impact of data dimensionality on the power of RF to identify interactions has not been thoroughly explored. We investigate the ability of rankings from variable importance measures to detect gene-gene interaction effects and their potential effectiveness as filters compared to p-values from univariate logistic regression, particularly as the data becomes increasingly high-dimensional. RF effectively identifies interactions in low dimensional data. As the total number of predictor variables increases, probability of detection declines more rapidly for interacting SNPs than for non-interacting SNPs, indicating that in high-dimensional data the RF variable importance measures are capturing marginal effects rather than capturing the effects of interactions. While RF remains a promising data-mining technique that extends univariate methods to condition on multiple variables simultaneously, RF variable importance measures fail to detect interaction effects in high-dimensional data in the absence of a strong marginal component, and therefore may not be useful as a filter technique that allows for interaction effects in genome-wide data.


Recommendations to improve the usability of drug-drug interaction clinical decision support alerts.
To establish preferred strategies for presenting drug-drug interaction (DDI) clinical decision support alerts. A DDI Clinical Decision Support Conference Series included a workgroup consisting of 24 clinical, usability, and informatics experts representing academia, health information technology (IT) vendors, healthcare organizations, and the Office of the National Coordinator for Health IT. Workgroup members met via web-based meetings 12 times from January 2013 to February 2014, and two in-person meetings to reach consensus on recommendations to improve decision support for DDIs. We addressed three key questions: (1) what, how, where, and when do we display DDI decision support? (2) should presentation of DDI decision support vary by clinicians? and (3) how should effectiveness of DDI decision support be measured? Our recommendations include the consistent use of terminology, visual cues, minimal text, formatting, content, and reporting standards to facilitate usability. All clinicians involved in the medication use process should be able to view DDI alerts and actions by other clinicians. Override rates are common but may not be a good measure of effectiveness. Seven core elements should be included with DDI decision support. DDI information should be presented to all clinicians. Finally, in their current form, override rates have limited capability to evaluate alert effectiveness. DDI clinical decision support alerts need major improvements. We provide recommendations for healthcare organizations and IT vendors to improve the clinician interface of DDI alerts, with the aim of reducing alert fatigue and improving patient safety.


Plasmonic band gap structures for surface-enhanced Raman scattering.
Surface-enhanced Raman Scattering (SERS) of rhodamine 6G (R6G) adsorbed on biharmonic metallic grating structures was studied. Biharmonic metallic gratings include two different grating components, one acting as a coupler to excite surface plasmon polaritons (SPP), and the other forming a plasmonic band gap for the propagating SPPs. In the vicinity of the band edges, localized surface plasmons are formed. These localized plasmons strongly enhance the scattering efficiency of the Raman signal emitted on the metallic grating surfaces. It was shown that reproducible Raman scattering enhancement factors of over 10(5) can be achieved by fabricating biharmonic SERS templates using soft nano-imprint technique. We have shown that the SERS activities from these templates are tunable as a function of plasmonic resonance conditions. Similar enhancement factors were also measured for directional emission of photoluminescence. At the wavelengths of the plasmonic absorption peak, directional enhancement by a factor of 30 was deduced for photoluminescence measurements.


Deception studies manipulating centrally acting performance modifiers: a review.
Athletes anticipatorily set and continuously adjust pacing strategies before and during events to produce optimal performance. Self-regulation ensures maximal effort is exerted in correspondence with the end point of exercise, while preventing physiological changes that are detrimental and disruptive to homeostatic control. The integration of feedforward and feedback information, together with the proposed brain's performance modifiers is said to be fundamental to this anticipatory and continuous regulation of exercise. The manipulation of central, regulatory internal and external stimuli has been a key focus within deception research, attempting to influence the self-regulation of exercise and induce improvements in performance. Methods of manipulating performance modifiers such as unknown task end point, deceived duration or intensity feedback, self-belief, or previous experience create a challenge within research, as although they contextualize theoretical propositions, there are few ecological and practical approaches which integrate theory with practice. In addition, the different methods and measures demonstrated in manipulation studies have produced inconsistent results. This review examines and critically evaluates the current methods of how specific centrally controlled performance modifiers have been manipulated, within previous deception studies. From the 31 studies reviewed, 10 reported positive effects on performance, encouraging future investigations to explore the mechanisms responsible for influencing pacing and consequently how deceptive approaches can further facilitate performance. The review acts to discuss the use of expectation manipulation not only to examine which methods of deception are successful in facilitating performance but also to understand further the key components used in the regulation of exercise and performance.


Immune activation and HIV-specific T cell responses are modulated by a cyclooxygenase-2 inhibitor in untreated HIV-infected individuals: An exploratory clinical trial.
Pathologically elevated immune activation and inflammation contribute to HIV disease progression and immunodeficiency, potentially mediated by elevated levels of prostaglandin E2, which suppress HIV-specific T cell responses. We have previously shown that a high dose of the cyclooxygenase-2 inhibitor celecoxib can reduce HIV-associated immune activation and improve IgG responses to T cell-dependent vaccines. In this follow-up study, we included 56 HIV-infected adults, 28 antiretroviral therapy (ART)-naïve and 28 on ART with undetectable plasma viremia but CD4 counts below 500 cells/μL. Patients in each of the two study groups were randomized to receive 90 mg qd of the cyclooxygenase-2 inhibitor etoricoxib for six months, two weeks or to a control arm, respectively. T cell activation status, HIV Gag-specific T cell responses and plasma inflammatory markers, tryptophan metabolism and thrombin generation were analyzed at baseline and after four months. In addition, patients received tetanus toxoid, conjugated pneumococcal and seasonal influenza vaccines, to which IgG responses were determined after four weeks. In ART-naïve patients, etoricoxib reduced the density of the activation marker CD38 in multiple CD8+ T cell subsets, improved Gag-specific T cell responses, and reduced in vitro plasma thrombin generation, while no effects were seen on plasma markers of inflammation or tryptophan metabolism. No significant immunological effects of etoricoxib were observed in ART-treated patients. Patients receiving long-term etoricoxib treatment had poorer tetanus toxoid and conjugated pneumococcal vaccine responses than those receiving short-course etoricoxib. Cyclooxygenase-2 inhibitors may attenuate harmful immune activation in HIV-infected patients without access to ART.


Cramer-Rao analysis of steady-state and time-domain fluorescence diffuse optical imaging.
Using a Cramer-Rao analysis, we study the theoretical performances of a time and spatially resolved fDOT imaging system for jointly estimating the position and the concentration of a point-wide fluorescent volume in a diffusive sample. We show that the fluorescence lifetime is a critical parameter for the precision of the technique. A time resolved fDOT system that does not use spatial information is also considered. In certain cases, a simple steady-state configuration may be as efficient as this time resolved fDOT system.


A and B utrophin in human muscle and sarcolemmal A-utrophin associated with tumours.
Utrophin is an autosomal homologue of dystrophin, abnormal expression of which is responsible for X-linked Duchenne and Becker muscular dystrophy. In normal mature muscle utrophin is confined to blood vessels, nerves and myotendinous and neuromuscular junctions. When dystrophin is absent utrophin is abundant on the sarcolemma. This has raised the possibility that up-regulation of utrophin may be of therapeutic benefit. Two full-length transcripts of utrophin, A and B, have been identified, which are regulated by alternatively spliced 5' promoters. In dystrophic mouse muscle, the A isoform is present on the sarcolemma, whereas the B form is confined to blood vessels. We show here using immunohistochemistry and human isoform-specific antibodies that A- and B-utrophin localisation is the same in human muscle. The A isoform is present on the sarcolemma of foetal human muscle fibres, regenerating fibres, fibres deficient in dystrophin and on blood vessels and neuromuscular junctions. B-utrophin is only detected on blood vessels. We also show that muscle adjacent to some soft tissue tumours shows increased sarcolemmal utrophin-A, showing that utrophin and dystrophin can simultaneously localise to the sarcolemma and raising the possibility that factor(s) from the tumour cells or accompanying inflammatory cells may have a role in regulating utrophin.


Elevated plasma urokinase receptor predicts low birth weight in maternal malaria.
The blood level of soluble urokinase receptor (suPAR) is increased and associated with a poor clinical or fatal outcome in children with acute malaria. This study hypothesized that the suPAR level would be associated with foetal outcome in maternal malaria. suPAR was measured by ELISA in maternal and cord plasma samples taken during delivery in 253 pregnant Kenyan women stratified according to placental histology: no malaria infection (non-infected), active or active-chronic infection (actively infected) or past-chronic infection (past-infected). Maternal-suPAR was higher in actively infected women (median 3.93 (IQR 2.92-5.29) ng/mL) compared with non-infected (median 2.78 (IQR 1.86-3.87) ng/mL, P = 0.001) and past-infected (median 2.67 (IQR 1.94-3.7) ng/mL, P = 0.012) women. Cord-suPAR was comparable across the groups (median 2.98 (IQR 2.38-3.77) ng/mL). In actively infected women, maternal-suPAR and gestational age were the only independent predictors of birth weight in multivariate linear regression adjusted for maternal-suPAR, HIV-1 infection, age, BMI, haemoglobin, peripheral parasitaemia, parity and gestational age; 1 ng/mL higher maternal-suPAR predicted -56 g (95% CI -100 to -12, P = 0.016) reduced birth weight. Cord-suPAR could not predict birth weight after adjusting for gestational age. Future studies are warranted to investigate whether the maternal suPAR level is increased earlier in pregnancy in women with active placental malaria infection and whether early maternal suPAR measurements can predict birth weight. If so, measurements of maternal suPAR early in pregnancy might then potentially identify women with increased needs for antenatal care and intervention.


Distal-less homeobox transcription factors regulate development and maturation of natural killer cells.
Natural killer (NK) cells constitute a subpopulation of lymphocytes that develop from precursors in the bone marrow (BM), but the transcriptional regulation of their development and maturation is only beginning to be understood, in part due to their relatively rare abundance, especially of developmental subsets. Using a mouse model in which NK cells are arrested at an immature stage of development, and a gene expression profiling approach, we uncovered transient normal NK cell expression of a homeobox transcription factor (TF) family, called Distal-less (Dlx), which had been primarily implicated in murine CNS, craniofacial, limb, and skin development. Our studies demonstrate that Dlx1, Dlx2, and Dlx3 are transiently expressed in immature Mac-1(lo) NK cells within the BM, with Dlx3 being the predominantly expressed member. These genes are expressed in a temporally regulated pattern with overlapping waves of expression, and they display functional redundancy. Expression is extinguished in fully mature splenic NK cells, and persistent expression of Dlx genes leads to functionally immature NK cells arrested at the Mac-1(lo) stage. Whereas conventional splenic NK cells develop but are arrested at an immature stage, there appears to be a complete failure to develop CD127(+) thymic NK cells when Dlx genes are persistently expressed. We also observed that T and B cells fail to develop in the context of persistent Dlx1 expression. Thus, these studies indicate that Dlx TFs play a functional role in lymphocyte development.


Medical students' early expectations and later opinions of aspects of their first year.
A survey of medical students on their first day of medical school and again near the end of their first year measured the discrepancy between their expectations of various aspects of the first year and their retrospective opinions about these aspects. The entering students had specific, detailed expectations about numerous aspects, many of which were not confirmed by their subsequent experience. The same students were reminded, one year later, of their unfulfilled expectations about the first year and were asked to describe any effects these expectations had had on class emotional climate and morale. They recalled both serious disappointments and pleasant surprises but no general change of class morale. A serendipitous finding was the profound indifference of the second-year students to their first-year emotional responses. Our results challenge the general practice of basing curriculum renewal programs on cross-sectional student surveys with no consideration of baseline expectations, and of relying on students to initiate improvements in educational programs.


Macrophage differentiation from embryoid bodies derived from human embryonic stem cells.
Human embryonic stem cells can differentiate into CD34+ hematopoietic progenitors by co-culture on murine feeders such as OP9 and S17. These CD34+ progenitors can be further differentiated into several cells of the hematopoietic lineage including macrophages. However, co-culture on murine feeders is time consuming and involves extensive manipulations. Furthermore, CD45 expression is low on hematopoietic cultures derived from stromal co-cultures. In this study we describe a novel and highly efficient system of generating differentiated macrophages from hematopoietic progenitors generated from embryoid body cultures of human embryonic stem cells. The hematopoietic progenitors generated from these embryoid bodies express higher numbers of CD45+ cells and are able to differentiate to macrophages when cultured in presence of cytokines. Using this system we were able to generate higher yields of CD14+ macrophages compared to traditional stromal cell culture methods. The embryoid body derived macrophages are phagocytic, respond to Toll-like receptor stimulation and express phenotypic markers of mature macrophages. Importantly, the embryoid body system generates hematopoietic progenitors suitable for clinical use by eliminating the need for murine feeder cells. Furthermore, this system is amenable to genetic manipulation and may thus be used to study important mechanisms of macrophage differentiation and function.


Fourier finite element modeling of light emission in waveguides: 2.5-dimensional FEM approach.
We present a Fourier finite element modeling of light emission of dipolar emitters coupled to infinitely long waveguides. Due to the translational symmetry, the three-dimensional (3D) coupled waveguide-emitter system can be decomposed into a series of independent 2D problems (2.5D), which reduces the computational cost. Moreover, the reduced 2D problems can be extremely accurate, compared to its 3D counterpart. Our method can precisely quantify the total emission rates, as well as the fraction of emission rates into different modal channels for waveguides with arbitrary cross-sections. We compare our method with dyadic Green's function for the light emission in single mode metallic nanowire, which yields an excellent agreement. This method is applied in multi-mode waveguides, as well as multi-core waveguides. We further show that our method has the full capability of including dipole orientations, as illustrated via a rotating dipole, which leads to unidirectional excitation of guide modes. The 2.5D Finite Element Method (FEM) approach proposed here can be applied for various waveguides, thus it is useful to interface single-photon single-emitter in nano-structures, as well as for other scenarios involving coupled waveguide-emitters.


Erythropoietin response to post-liver transplantation anemia.
Anemia frequently accompanies end-stage liver disease. Erythropoietin has recently been shown to be of benefit in a number of diseases complicated by anemia. We studied erythropoietin levels before and after orthotopic liver transplantation (OLT) and correlated these with the degree of anemia. Twenty-seven patients with end-stage cirrhosis who underwent OLT had preoperative and weekly postoperative serum erythropoietin levels determined by a highly sensitive radioimmunoassay. The relation of erythropoietin level to the values for hematocrit, serum creatinine, and cyclosporine and other biochemical test results was evaluated. Before transplantation, 23 patients were anemic; erythropoietin levels were appropriately elevated (72.7 +/- 37 mU/mL; normal, 10 to 15 mU/mL) for the degree of anemia (hematocrit, 33.1% +/- 1%) in 16 patients (70%). A blunted erythropoietin response to anemia was found in 7 of the anemic patients with cirrhosis (30%). After OLT, the hematocrit decreased to 29.5% +/- 0.6% at 4 weeks, with a reciprocal increase in serum erythropoietin levels to 36 +/- 5 mU/mL. Erythropoietin response appeared appropriate to the degree of anemia in 82% of the liver transplant recipients and blunted in 18%. We conclude that the ability to secrete erythropoietin in response to anemia is defective in many patients with end-stage liver disease, and a normal response may be restored after OLT. The results suggest that exogenous erythropoietin administration may be beneficial in anemic patients with cirrhosis and liver transplant recipients who have inappropriately low serum erythropoietin levels.


Update on dexmedetomidine: use in nonintubated patients requiring sedation for surgical procedures.
Dexmedetomidine was introduced two decades ago as a sedative and supplement to sedation in the intensive care unit for patients whose trachea was intubated. However, since that time dexmedetomidine has been commonly used as a sedative and hypnotic for patients undergoing procedures without the need for tracheal intubation. This review focuses on the application of dexmedetomidine as a sedative and/or total anesthetic in patients undergoing procedures without the need for tracheal intubation. Dexmedetomidine was used for sedation in monitored anesthesia care (MAC), airway procedures including fiberoptic bronchoscopy, dental procedures, ophthalmological procedures, head and neck procedures, neurosurgery, and vascular surgery. Additionally, dexmedetomidine was used for the sedation of pediatric patients undergoing different type of procedures such as cardiac catheterization and magnetic resonance imaging. Dexmedetomidine loading dose ranged from 0.5 to 5 mug kg(-1), and infusion dose ranged from 0.2 to 10 mug kg(-1) h(-1). Dexmedetomidine was administered in conjunction with local anesthesia and/or other sedatives. Ketamine was administered with dexmedetomidine and opposed its bradycardiac effects. Dexmedetomidine may by useful in patients needing sedation without tracheal intubation. The literature suggests potential use of dexmedetomidine solely or as an adjunctive agent to other sedation agents. Dexmedetomidine was especially useful when spontaneous breathing was essential such as in procedures on the airway, or when sudden awakening from sedation was required such as for cooperative clinical examination during craniotomies.


Immunoreactants in rheumatoid synovial effusions.
Measurements were made of the IgG in synovial fluid which is synthesized by the intact rheumatoid synovium. In five rheumatoid subjects 12-24% of the IgG present in their synovial fluid was derived from local production. No evidence for local production was found in patients with degenerative arthritis or Reiter's syndrome. It was estimated that as much as 95 mg of IgG was produced by the synovium of a single knee joint daily. Rheumatoid inflammation is associated with the presence of large numbers of white blood cells, predominantly polymorphonuclear, in the articular cavity. Each day as many as one billion white cells enter the articular cavity to participate in this inflammatory response. Factors causing the directed migration of polymorphonuclear leukocytes were found in the majority of rheumatoid effusions studied. The chemotactic activity is, in large part, related to the fifth (C5) and sixth (C6) components of human complement. Physical-chemical techniques indicate that the activity is attributable to C 567 and C5a, a cleavage product of C5. In addition to the presence of preformed chemotactic factors, more than half of the rheumatoid fluids contain an enzyme capable of generating chemotactic activity from the fifth component (C5) of human complement. This information supports the concept that rheumatoid joint inflammation is an example of immune complex disease in which a significant proportion of the immunoreactants are derived from local production.


High expression of the inhibitory receptor BTLA in T-follicular helper cells and in B-cell small lymphocytic lymphoma/chronic lymphocytic leukemia.
B- and T-lymphocyte attenuator (BTLA) is a lymphoid receptor that inhibits lymphocyte activation on interaction with its ligand, herpesvirus entry mediator (HVEM). We developed monoclonal antibodies against BTLA and HVEM to study their expression using immunohistochemical and flow cytometric analyses in human tissues. In reactive lymph nodes, they were both expressed in interfollicular T cells and in B cells from mantle and marginal zones. Within germinal centers, B cells were negative, whereas T follicular helper (TFH) cells were BTLA+ and follicular dendritic cells were HVEM+. BTLA was strongly expressed in chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL, 19 of 19 positive) when compared with other small B-cell lymphomas, including follicular lymphoma (0 of 24 positive), mantle cell lymphoma (0 of 10 positive), and marginal zone lymphoma (0 of 5 positive). Our results suggest that down-regulation of the BTLA-HVEM pathway may be involved in germinal center B-cell activation. The specific high expression of BTLA in B-CLL/SLL represents a new potential diagnostic tool. The BTLA positivity of TFH cells may be a basis for designing future immunotherapies.


India's rainfed sorghum improvement: Three decades of genetic gain assessment for yield, grain quality, grain mold and shoot fly resistance.
Sorghum is a climate-resilient cereal and staple food crop for more than 200 million people in arid and semi-arid countries of Asia and Africa. Despite the economic importance, the productivity of sorghum in India is constrained by biotic and abiotic stresses such as incidences of shoot fly, grain mold and drought. Indian sorghum breeding focused on dual-purpose (grain and fodder), short-duration varieties with multiple resistance/tolerance to pests and diseases and improved nutritional quality (high protein, iron and zinc and low fat). In this context, it is important to ascertain the genetic progress made over 30 years by assessing the efficiency of past achievements in genetic yield potential and to facilitate future genetic improvement. The current study determined the genetic gain in 24 sorghum varieties developed by the national and state level research systems during 1990-2020. The 24 varieties were evaluated for three years (2018-2020) at six locations in Telangana state for yield, nutritional characteristics and tolerance to shoot fly and grain mold. The absolute grain yield genetic gain from the base year 1990 is 44.93 kg/ha/yr over the first released variety CSV 15. The realized mean yield increased from 2658 kg/ha of the variety CSV 15 in 1990s to 4069 kg/ha of SPV 2579 developed in 2020s. The absolute genetic gain for grain mold resistance is -0.11 per year with an overall relative gain of 1.46% over CSV 15. The top varieties for grain yield (SPV 2579, SPV 2678 and SPV 2578), fodder yield (PYPS 2, SPV 2769 and SPV 2679), shoot fly tolerance (PYPS 8, PYPS 2 and SPV 2179), mold tolerance (PYPS 8, PYPS 2 and SPV 2579) and high protein (PYPS 8, PYPS 2 and SPV 2769) were identified for possible scale up and further use in breeding program diversification. The study revealed that sorghum varieties bred with diverse genetic backgrounds such as landraces and with tolerance to pests and diseases had stable yield performance. Application of genomics and other precision tools can double genetic gains for these traits to strengthen sorghum cultivation in rainfed areas serving food and nutrition security.


Characteristics of ultraviolet scattering and turbulent channels.
The nonline of sight (NLOS) ultraviolet (UV) scattering communication channel and atmospheric optical turbulent channel have been extensively but independently studied in the rich literature. However, the new characteristics of NLOS UV scattering and turbulent channels have not been comprehensively investigated. We propose a configurable framework, unifying the traditional line of sight turbulence theory and the Monte Carlo simulation framework for random scattering of photons. Results show that the scattering link geometry can significantly alter the received signal distribution. Irradiance fluctuations at the receiver may become much weaker due to the smoothing effect of impinging photons from different scattering paths, even though each scattering path undergoes strong turbulence.


3D Printed Microtransporters: Compound Micromachines for Spatiotemporally Controlled Delivery of Therapeutic Agents.
Functional compound micromachines are fabricated by a design methodology using 3D direct laser writing and selective physical vapor deposition of magnetic materials. Microtransporters with a wirelessly controlled Archimedes screw pumping mechanism are engineered. Spatiotemporally controlled collection, transport, and delivery of micro particles, as well as magnetic nanohelices inside microfluidic channels are demonstrated.


Impaired structural motor connectome in amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease selectively affecting upper and lower motor neurons. Patients with ALS suffer from progressive paralysis and eventually die on average after three years. The underlying neurobiology of upper motor neuron degeneration and its effects on the complex network of the brain are, however, largely unknown. Here, we examined the effects of ALS on the structural brain network topology in 35 patients with ALS and 19 healthy controls. Using diffusion tensor imaging (DTI), the brain network was reconstructed for each individual participant. The connectivity of this reconstructed brain network was compared between patients and controls using complexity theory without--a priori selected--regions of interest. Patients with ALS showed an impaired sub-network of regions with reduced white matter connectivity (p = 0.0108, permutation testing). This impaired sub-network was strongly centered around primary motor regions (bilateral precentral gyrus and right paracentral lobule), including secondary motor regions (bilateral caudal middle frontal gyrus and pallidum) as well as high-order hub regions (right posterior cingulate and precuneus). In addition, we found a significant reduction in overall efficiency (p = 0.0095) and clustering (p = 0.0415). From our findings, we conclude that upper motor neuron degeneration in ALS affects both primary motor connections as well as secondary motor connections, together composing an impaired sub-network. The degenerative process in ALS was found to be widespread, but interlinked and targeted to the motor connectome.


Analysis of risk factors for central venous port failure in cancer patients.
To analyze the risk factors for central port failure in cancer patients administered chemotherapy, using univariate and multivariate analyses. A total of 1348 totally implantable venous access devices (TIVADs) were implanted into 1280 cancer patients in this cohort study. A Cox proportional hazard model was applied to analyze risk factors for failure of TIVADs. Log-rank test was used to compare actuarial survival rates. Infection, thrombosis, and surgical complication rates (chi(2) test or Fisher's exact test) were compared in relation to the risk factors. Increasing age, male gender and open-ended catheter use were significant risk factors reducing survival of TIVADs as determined by univariate and multivariate analyses. Hematogenous malignancy decreased the survival time of TIVADs; this reduction was not statistically significant by univariate analysis [hazard ratio (HR) = 1.336, 95% CI: 0.966-1.849, P = 0.080)]. However, it became a significant risk factor by multivariate analysis (HR = 1.499, 95% CI: 1.079-2.083, P = 0.016) when correlated with variables of age, sex and catheter type. Close-ended (Groshong) catheters had a lower thrombosis rate than open-ended catheters (2.5% vs 5%, P = 0.015). Hematogenous malignancy had higher infection rates than solid malignancy (10.5% vs 2.5%, P < 0.001). Increasing age, male gender, open-ended catheters and hematogenous malignancy were risk factors for TIVAD failure. Close-ended catheters had lower thrombosis rates and hematogenous malignancy had higher infection rates.


Bacterial- and fungal-positive cultures in organ donors: clinical impact in liver transplantation.
Infection transmission from donor to recipient is a dreadful complication in transplantation. Although bacteremia was previously detected in 5% of donors without negative impact on recipient outcome, the current expansion of graft pool requires consideration of the infectious risk associated with suboptimal donors. This study aims to evaluate the incidence and risk factors of infection in unselected cadaveric liver donors, the occurrence of microorganism transmission to recipient and its influence on patient survival. Results of microbiologic cultures obtained before harvesting in intensive care unit (ICU) and routinely at harvesting from 610 consecutive liver donors were retrospectively analyzed. Evidence for bacterial and fungal transmission to the recipient was searched for in each culture-positive donor. One or more cultures were positive in 293 donors (48%), while bacteremia was present in 128 (21%). Culture-positive and bacteremic donors were of significantly older age and had longer ICU stays. At multivariate analysis, an ICU stay of 3 or more days was the only significant predictor of donor infection. Although 1-year patient/graft survival rates were not influenced by donor culture positivity, pathogen transmission occurred in 11 cases with high recipient 1-year mortality (45%). In those 11 cases, median donor age was 74 years, significantly much older than that of the other culture-positive donors. In conclusion, donors with a prolonged ICU stay are at increased risk of infection, while older donor age is associated with pathogen transmission to the recipient. Adequate donor maintenance and careful microbiologic surveillance and treatment, especially of elderly donors, may limit transmission of donor infection.


Role of Postdeposition Thermal Annealing on Intracrystallite and Intercrystallite Structuring and Charge Transport in Poly(3-hexylthiophene).
The performance of electronic devices comprising conjugated polymers as the active layer depends not only on the intrinsic characteristics of the materials but also on the details of the extrinsic processing conditions. In this study, we examine the effect of postdeposition thermal treatments on the microstructure of poly(3-hexylthiophene) (P3HT) thin films and its impact on their electrical properties. Unsurprisingly, we find thermal annealing of P3HT thin films to generally increase their crystallinity and crystallite coherence length while retaining the same crystal structure. Despite such favorable structural improvements of the polymer active layers, however, thermal annealing at high temperatures can lead to a net reduction in the mobility of transistors, implicating structural changes in the intercrystallite amorphous regions of these semicrystalline active layers take place on annealing, and the simplistic picture that crystallinity governs charge transport is not always valid. Our results instead suggest tie-chain pullout, which occurs during crystal growth and perfection upon thermal annealing to govern charge transport, particularly in low-molecular-weight systems in which the tie-chain fraction is low. By demonstrating the interplay between intracrystallite and intercrystallite structuring in determining the macroscopic charge transport, we shed light on how structural evolution and charge-transport properties of nominally the same polymer can vary depending on the details of processing.


Phase contrast tomography at lab on chip scale by digital holography.
High-throughput single-cell analysis is a challenging target for implementing advanced biomedical applications. An excellent candidate for this aim is label-free tomographic phase microscopy (TPM). In this paper, some of the methods used to obtain TPM are reviewed, analyzing advantages and disadvantages of each of them. Moreover, an alternative tomographic technique is described for live cells analysis, and future trends of the method are foreseen. In particular, by exploiting random rolling of cells while they are flowing along a microfluidic channel, it is possible to obtain phase-contrast tomography thus obtaining complete retrieval of both 3D-position and orientation of rotating cells. Thus, a priori knowledge of such information is no longer needed. This approach extremely simplifies the optical system avoiding any mechanical/optical scanning of light source. The proof is given for different classes of biosamples, red-blood-cells (RBCs) and diatom algae. Accurate characterization of each type of cells is reported and compared to that obtained by other tomographic techniques.


Modelling the effect of the antimicrobial tylosin on the performance of an anaerobic sequencing batch reactor.
A laboratory-scale anaerobic sequencing batch reactor (ASBR) was fed a synthetic wastewater containing glucose to study the effects of the antimicrobial tylosin on treatment performance. Measurements of methane, volatile fatty acids, and COD concentrations suggested that the addition of 1.67 mg/L and 167 mg/l of tylosin to the synthetic wastewater inhibited propionate oxidizing syntrophic bacteria and aceticlastic methanogens. The latter is presumed to be an indirect effect. A modified version of the IWA Anaerobic Digestion Model No. 1 (ADM1) with extensions for microbial storage and hydrolysis of reserve carbohydrates, and tylosin liquid-solid mass transfer and inhibition adequately described the dynamic profiles observed in the ASBR.


Structures of SAS-6 suggest its organization in centrioles.
Centrioles are cylindrical, ninefold symmetrical structures with peripheral triplet microtubules strictly required to template cilia and flagella. The highly conserved protein SAS-6 constitutes the center of the cartwheel assembly that scaffolds centrioles early in their biogenesis. We determined the x-ray structure of the amino-terminal domain of SAS-6 from zebrafish, and we show that recombinant SAS-6 self-associates in vitro into assemblies that resemble cartwheel centers. Point mutations are consistent with the notion that centriole formation in vivo depends on the interactions that define the self-assemblies observed here. Thus, these interactions are probably essential to the structural organization of cartwheel centers.


Discovery of the first telemid spider (Araneae, Telemidae) from South America, and the first member of the family bearing a stridulatory organ.
The genus Kinku n. gen. is established for the first telemid spider found in South America. The new species, Kinku turumanya n. sp. is characterized by the unique conformation of the male palp and the presence of an abdominal anterioventral stridulatory organ.


Myocyte Dedifferentiation Drives Extraocular Muscle Regeneration in Adult Zebrafish.
The purpose of this study was to characterize the injury response of extraocular muscles (EOMs) in adult zebrafish. Adult zebrafish underwent lateral rectus (LR) muscle myectomy surgery to remove 50% of the muscle, followed by molecular and cellular characterization of the tissue response to the injury. Following myectomy, the LR muscle regenerated an anatomically correct and functional muscle within 7 to 10 days post injury (DPI). Following injury, the residual muscle stump was replaced by a mesenchymal cell population that lost cell polarity and expressed mesenchymal markers. Next, a robust proliferative burst repopulated the area of the regenerating muscle. Regenerating cells expressed myod, identifying them as myoblasts. However, both immunofluorescence and electron microscopy failed to identify classic Pax7-positive satellite cells in control or injured EOMs. Instead, some proliferating nuclei were noted to express mef2c at the very earliest point in the proliferative burst, suggesting myonuclear reprogramming and dedifferentiation. Bromodeoxyuridine (BrdU) labeling of regenerating cells followed by a second myectomy without repeat labeling resulted in a twice-regenerated muscle broadly populated by BrdU-labeled nuclei with minimal apparent dilution of the BrdU signal. A double-pulse experiment using BrdU and 5-ethynyl-2'-deoxyuridine (EdU) identified double-labeled nuclei, confirming the shared progenitor lineage. Rapid regeneration occurred despite a cell cycle length of 19.1 hours, whereas 72% of the regenerating muscle nuclei entered the cell cycle by 48 hours post injury (HPI). Dextran lineage tracing revealed that residual myocytes were responsible for muscle regeneration. EOM regeneration in adult zebrafish occurs by dedifferentiation of residual myocytes involving a muscle-to-mesenchyme transition. A mechanistic understanding of myocyte reprogramming may facilitate novel approaches to the development of molecular tools for targeted therapeutic regeneration in skeletal muscle disorders and beyond.


SLC2A9 Genotype Is Associated with SLC2A9 Gene Expression and Urinary Uric Acid Concentration.
SLC2A9 gene variants have been associated with urinary uric acid (UA) concentration, but little is known about the functional mechanism linking these gene variants with UA. SLC2A9 encodes a UA transporter present in the proximal tubule of the kidney, and gene expression levels of SLC2A9 and other genes in the uricosuric pathway (ABCG2, SLC17A1, SLC17A3, and SLC22A12) could potentially mediate the relationship between SLC2A9 gene variants and urinary UA excretion. The association between urinary UA concentrations and single nucleotide polymorphisms (SNPs) within the SLC2A9 gene region, expression levels of genes in the uricosuric pathway, and dietary protein intake were analyzed for a sample of non-Hispanic white participants from the Genetic Epidemiology Network of Arteriopathy (GENOA) cohort. The SLC2A9 SNP most significantly associated with urinary UA concentration was then tested for associations with gene expression levels from uric acid absorption/secretion associated genes. Models including interactions between dietary protein (total, animal, and vegetable) and genetic factors were also assessed. The most significant SLC2A9 SNP associated with urinary UA (rs12509955, corrected p = 0.001) was also associated with SLC2A9 gene expression levels (corrected p = 0.0084); however, SLC2A9 gene expression levels were not significantly associated with urinary UA concentrations (p = 0.509). The interactions between rs12509955 and total dietary protein, and SLC2A9 gene-level gene expression and dietary vegetable protein on the outcome of urinary UA were marginally significant (p = 0.11 and p = 0.07, respectively). Gene expression level of one SLC2A9 transcript had a significant interaction with dietary animal protein (SLC2A9-001 ENST00000506583, p = 0.01) and a marginally significant interaction with total dietary protein (p = 0.07) on urinary UA. Our results illustrate that SNPs in the SLC2A9 gene influence SLC2A9 gene expression as well as urinary UA excretion. Evidence is also suggestive that gene-by-diet interactions may disproportionately increase urinary UA in genetically susceptible individuals that consume higher amounts of protein.


Internists' practices in health promotion and disease prevention. A survey.
To estimate internists' use of disease prevention and health promotion activities, and to explore demographic, professional, behavioral, psychological, cognitive, and organizational factors associated with the use of such practices. Mail survey. A sample of 2610 members and fellows of the American College of Physicians (ACP) participated in the study. They engaged in patient care activities more than 20 hours per week and were stratified by gender and region. They lived in four geographic areas of the United States (Northeast, Southeast, Central, and West), comprising 21 ACP regions. A questionnaire requesting background information as well as information about personal health; record keeping; use of immunizations (pneumococcal, influenza, tetanus, hepatitis B); use of screening tests and procedures for detecting cancer (breast examination, Papanicolaou smear, stool occult blood test) and other diseases (electrocardiograms, cholesterol level tests, chest radiographs); and behavioral counseling to promote health (in the areas of smoking, exercise, and alcohol and seat belt use). Internists used effective preventive interventions less frequently and ineffective practices more frequently than experts recommend. Internists' use of health promotion and disease prevention activities is associated with habit, attitude, and a lack of adequate knowledge. Younger physician age, general internal medicine practice, and personal health promotion and disease prevention practices were strongly associated with more appropriate use of recommended practices (P less than 0.01). Internists' use of disease prevention and health promotion activities falls short of expert recommendations. Programs to improve the delivery of preventive services might be aimed at improving physicians' personal health practices, might be directed toward patients, and might include the development of effective systems to remind physicians.