Two-dimensional optical beam deflector operated by wavelength tuning.
A new method based on an optical delay line structure is proposed for two-dimensional raster optical beam steering. For one-dimensional beam steering, the laser beam to be deflected is split into N co-directional sub-beams of equal intensity with the aid of a plane-parallel plate. These sub-beams experience a relative time delay, which translates into a phase difference, thus forming a phased array. When the laser wavelength is tuned, the relative phase varies and the far-field interference footprint can be steered across a receive plane. By employing two plane-parallel plates in series, the described scheme can be extended to produce a two-dimensional N x N array of sub-beams, allowing two-dimensional beam steering via wavelength tuning. In this case, wavelength tuning over a larger range leads to a linear deflection which repeats itself in a raster-like fashion. One direction of deflection repeats itself multiple times as wavelength is scanned over larger range, that is, a raster effect. In this paper, the principle is theoretically derived and formulated, and the preliminary experimental results with four sub-beams are presented.


Comprehensive analysis of NAC transcription factors uncovers their roles during fiber development and stress response in cotton.
Transcription factors operate as important switches of transcription networks, and NAC (NAM, ATAF, and CUC) transcription factors are a plant-specific family involved in multiple biological processes. However, this gene family has not been systematically characterized in cotton. Here we identify a large number of genes with conservative NAC domains in four cotton species, with 147 found in Gossypium arboreum, 149 in G. raimondii, 267 in G. barbadense and 283 in G. hirsutum. Predicted membrane-bound NAC genes were also identified. Phylogenetic analysis showed that cotton NAC proteins clustered into seven subfamilies and homologous protein pairs showed similar characteristics. Evolutionary property analysis revealed that purifying selection of NAC genes occurred between diploid and polyploid cotton species, and variation analysis showed GhNAC genes may have been subjected to selection and domestication. NAC proteins showed extensive transactivation and this was dependent on the C-terminus. Some development and stress related cis-elements were enriched in the promoters of GhNAC genes. Comprehensive expression analysis indicated that 38 GhNAC genes were candidates for involvement in fiber development, and 120 in stress responses. Gene co-expression network analysis revealed relationships between fiber-associated NAC genes and secondary cell wall (SCW) biosynthesis genes. NAC genes were identified in diploid and tetraploid cotton, revealing new insights into their evolution, variation and homology relationships. Transcriptome analysis and co-expression network indicated roles for GhNAC genes in cotton fiber development and stress response, and NAC genes may prove useful in molecular breeding programmes.


Variation within the gene encoding the upstream stimulatory factor 1 does not influence susceptibility to type 2 diabetes in samples from populations with replicated evidence of linkage to chromosome 1q.
The gene encoding the transcription factor upstream stimulatory factor (USF)1 influences susceptibility to familial combined hyperlipidemia (FCHL) and triglyceride levels. Phenotypic overlap between FCHL and type 2 diabetes makes USF1 a compelling positional candidate for the widely replicated type 2 diabetes linkage signal on chromosome 1q. We typed 22 variants in the F11R/USF1 region (1 per 3 kb), including those previously implicated in FCHL-susceptibility (or proxies thereof) in 3,726 samples preferentially enriched for 1q linkage. We also examined glucose- and lipid-related continuous traits in an overlapping set of 1,215 subjects of European descent. There was no convincing evidence for association with type 2 diabetes in any of seven case-control comparisons, individually or combined. Family-based association analyses in 832 Pima subjects were similarly negative. At rs3737787 (the variant most strongly associated with FCHL), the combined odds ratio, per copy of the rarer A-allele, was 1.10 (95% CI 0.97-1.24, P = 0.13). In 124 Utah subjects, rs3737787 was significantly associated (P = 0.002) with triglyceride levels, but direction of this association was opposite to previous reports, and there was no corroboration in three other samples. These data exclude USF1 as a major contributor to type 2 diabetes susceptibility and the basis for the chromosome 1q linkage. They reveal only limited evidence for replication of USF1 effects on continuous metabolic traits.


Pain Experience in Dementia Subtypes: A Systematic Review.
Recently, the number of studies focusing on pain in dementia has increased considerably. Still, little attention has been paid to the influence of the neuropathology of different dementia subtypes on pain experience. In 2003, a review identified several studies that indicated a relation between dementia subtype and pain experience. Now, ten years later, an update is warranted. We conducted a systematic review to identify studies that assessed pain experience and dementia subtypes by searching PubMed, Embase, PsycINFO, CINAHL, and Cochrane Library. Inclusion criteria were: (1) major dementia subtype diagnosis i.e. Alzheimer's dementia (AD), vascular dementia (VaD), frontotemporal dementia (FTD), dementia with Lewy Bodies (DLB); (2) age ≥60 years; and (3) pain experience. We identified twelve studies that addressed AD, three studies VaD, one study FTD, and no studies DLB. In AD, studies on clinical pain indicate a reduced pain experience compared to controls, whereas experimental studies show inconsistent findings. In VaD, clinical studies found that primary caregivers rated pain equal to cognitively intact controls, although more painful locations were reported. During self-report, elderly with VaD reported higher pain levels than cognitively intact controls. In FTD, a significantly lower pain sensitivity to experimental pain was found. Considering the limited number of studies, these findings should be considered with caution. Existing literature provides some evidence that dementia subtype affects pain experience. Further research is needed to clarify the relation between dementia subtype and pain experience as it could serve as basis for improving the assessment and management of pain in people with dementia.


[Errors in hospital prescriptions of high-alert medications].
Medication errors are currently a worldwide public health issue and it is one of the most serious prescription errors. The objective of the study was to evaluate the practice of prescribing high-alert medications and its association with the prevalence of medication errors in hospital settings. A retrospective cross-sectional study was conducted including 4,026 prescription order forms of high-alert medications. There were evaluated all prescriptions received at the pharmacy of a reference hospital in the state of Minas Gerais, southeastern Brazil, over a 30-day period in 2001. Prescription were checked for legibility, patient name, type of prescription, date, handwriting or writing, prescriber identification, drug prescribed, and use of abbreviations. Prescription errors were classified as writing or decision errors and how the type of prescription affected the occurrence of errors was assessed. Most prescriptions were handwritten (45.7%). In 47.0% of handwritten, mixed and pre-typed prescriptions had patient name errors; the prescriber name was difficult to identify in 33.7%; 19.3% of them were hardly legible or illegible. Of a total of 7,148 high-alert drugs prescribed, 3,177 errors were found, and the most frequent one was missing information (86.5%). Errors occurred mostly in prescriptions of heparin, phentanyl, and midazolam. Intensive care and neurology units had the highest number of errors per prescription. Non-standard abbreviations were frequent and widespread. Overall it was estimated 3.3 errors per prescription order form. Pre-typed prescriptions were less likely to have errors compared to mixed or handwritten prescriptions. The study results show there is a need for standardizing the prescription process and eliminating handwritten prescriptions. The use of pre-typed or edited prescriptions may reduce errors associated to high-alert medications.


Withdrawing from research: a rethink in the context of research biobanks.
It is generally assumed in research ethics that research participants have an unconditional right to withdraw from research without any detriment or reprisal. This paper analyses this right in the context of biobank research and argues that the traditional shape of the right in clinical research can be modified in biobank research without incurring significant ethical cost. The paper falls in three parts. The first part is a brief explication of the philosophical justification of the right to withdraw. The second part presents a number of extant criticisms of the right. And the third and final part argues that although a right to withdraw is crucial in relation to biobank research, such a right has to be specified in a different way to the similar right in relation to clinical research.


Simultaneous multi-determination and transfer of eight pesticide residues from green tea leaves to infusion using gas chromatography.
A method for determining eight pesticide (cyhalothrin, flufenoxuron, fenitrothion, EPN, bifenthrin, difenoconazole, triflumizole, and azoxystrobin) residues in made green tea as well as a tea infusion (under various brewing water temperatures; 60, 80, and 100°C) using gas chromatography (GC) micro-electron capture detector (μECD) was developed and validated. The extraction method adopted the relatively commonly used approach of solid sample hydration, with the green tea hydrated before being extracted through salting out with acetonitrile followed by a cleanup procedure. The analytes were confirmed using GC-coupled to tandem mass spectrometry (GC/MS/MS) with a triple quadrupole. The linearity of the calibration curves yielded determination coefficients (R(2)) >0.995. Recoveries were carried out using blank samples spiked with all analytes at two levels. The results demonstrated that all pesticides were recovered within the range of 77-116% with a relative standard deviation (RSD) ⩽14%. The quantification limits of 0.015-0.03 mg/kg were lower than the maximum residue limits (MRLs) set by the Korea Food and Drug Administration (KFDA) for all analytes (0.05-10mg/kg). The infusion study indicated that cyhalothrin, flufenoxuron, and bifenthrin did not infuse into the tea brew from the made tea. Increases in brewing time resulted in increased transfer of azoxystrobin, fenitrothion, and difenoconazole from the made tea to the brew; however, this was not the case with triflumizole or EPN. We conclude that transfer of pesticides appeared to be dependent on their water solubilities and drinking a cup of tea is recommended to be at a water temperature of 60°C.


Mapping ergonomics application to improve SMEs working condition in industrially developing countries: a critical review.
In industrially developing countries (IDC), small and medium enterprises (SMEs) account for the highest proprotion of employment. Unfortunately, the working conditions in SMEs are often very poor and expose employees to a potentially wide range of health and safety risks. This paper presents a comprehensive review of 161 articles related to ergonomics application in SMEs, using Indonesia as a case study. The aim of this paper is to investigate the extent of ergonomics application and identify areas that can be improved to promote effective ergonomics for SMEs in IDC. The most urgent issue found is the need for adopting participatory approach in contrast to the commonly implemented top-down approach. Some good practices in ergonomics application were also revealed from the review, e.g. a multidisciplinary approach, unsophisticated and low-cost solutions, and recognising the importance of productivity. The review also found that more work is still required to achieve appropriate cross-cultural adaptation of ergonomics application.


Thermal stress reduces pocilloporid coral resilience to ocean acidification by impairing control over calcifying fluid chemistry.
The combination of thermal stress and ocean acidification (OA) can more negatively affect coral calcification than an individual stressors, but the mechanism behind this interaction is unknown. We used two independent methods (microelectrode and boron geochemistry) to measure calcifying fluid pH (pHcf) and carbonate chemistry of the corals Pocillopora damicornis and Stylophora pistillata grown under various temperature and pCO2 conditions. Although these approaches demonstrate that they record pHcf over different time scales, they reveal that both species can cope with OA under optimal temperatures (28°C) by elevating pHcf and aragonite saturation state (Ωcf) in support of calcification. At 31°C, neither species elevated these parameters as they did at 28°C and, likewise, could not maintain substantially positive calcification rates under any pH treatment. These results reveal a previously uncharacterized influence of temperature on coral pHcf regulation-the apparent mechanism behind the negative interaction between thermal stress and OA on coral calcification.


Gene x environment interactions in conduct disorder: Implications for future treatments.
Conduct disorder (CD) causes high financial and social costs, not only in affected families but across society, with only moderately effective treatments so far. There is consensus that CD is likely caused by the convergence of many different factors, including genetic and adverse environmental factors. There is ample evidence of gene-environment interactions in the etiology of CD on a behavioral level regarding genetically sensitive designs and candidate gene-driven approaches, most prominently and consistently represented by MAOA. However, conclusive indications of causal GxE patterns are largely lacking. Inconsistent findings, lack of replication and methodological limitations remain a major challenge. Likewise, research addressing the identification of affected brain pathways which reflect plausible biological mechanisms underlying GxE is still very sparse. Future research will have to take multilevel approaches into account, which combine genetic, environmental, epigenetic, personality, neural and hormone perspectives. A better understanding of relevant GxE patterns in the etiology of CD might enable researchers to design customized treatment options (e.g. biofeedback interventions) for specific subgroups of patients.


Stress hormones: a link between maternal condition and sex-biased reproductive investment.
In species where offspring fitness is sex-specifically influenced by maternal reproductive condition, sex allocation theory predicts that poor-quality mothers should invest in the evolutionarily less expensive sex. Despite an accumulation of evidence that mothers can sex-specifically modulate investment in offspring in relation to maternal quality, few mechanisms have been proposed as to how this is achieved. We explored a hormonal mechanism for sex-biased maternal investment by measuring and experimentally manipulating baseline levels of the stress hormone corticosterone in laying wild female European starlings (Sturnus vulgaris) and examining effects on sex ratio and sex-specific offspring phenotype adjustment. Here we show that baseline plasma corticosterone is negatively correlated with energetic body condition in laying starlings, and subsequent experimental elevation of maternal baseline plasma corticosterone increased yolk corticosterone without altering maternal condition or egg quality per se. Hormonal elevation resulted in the following: female-biased hatching sex ratios (caused by elevated male embryonic mortality), lighter male offspring at hatching (which subsequently grew more slowly during postnatal development), and lower cell-mediated immune (phytohemagglutinin) responses in males compared with control-born males; female offspring were unaffected by the manipulation in both years of the study. Elevated maternal corticosterone therefore resulted in a sex-biased adjustment of offspring quality favorable to female offspring via both a sex ratio bias and a modulation of male phenotype at hatching. In birds, deposition of yolk corticosterone may benefit mothers by acting as a bet-hedging strategy in stochastic environments where the correlation between environmental cues at laying (and therefore potentially maternal condition) and conditions during chick-rearing might be low and unpredictable. Together with recent studies in other vertebrate taxa, these results suggest that maternal stress hormones provide a mechanistic link between maternal quality and sex-biased maternal investment in offspring.


In situ demonstration of improvement of liver mitochondria function by melatonin after cold ischemia.
In a previous investigation, reperfusion with a melatonin-containing medium was demonstrated to enhance bile production and tissue ATP levels in rat livers, cold-preserved with University of Wisconsin (UW) or Celsior solutions, with respect to melatonin-free reperfusion; lipid peroxidation products in the perfusate were not influenced by the indole. This was ascribed to an increased efficiency of the hepatocyte mitochondria induced by melatonin. Reactive oxygen species (ROS) normally leak from the electron transfer chain in mitochondria and excessive ROS production is presumed to mediate ischemia-reperfusion (I/R) damage. A histochemical reaction was used to demonstrate ROS on the same model. Compared to the lobular zonation of ROS in control livers, the stained area of cold-preserved livers reperfused without melatonin was restricted to a narrow portal region, in keeping with the much lower ATP content. When reperfusion was performed with melatonin, the liver morphology was improved and the ROS reaction in hepatocytes more intense, though not reaching the control liver pattern. Sinusoidal cells were poorly-stained in both cases. In conclusion, with this different approach, melatonin was confirmed to improve mitochondrial performance and to discriminate parenchymal from sinusoidal cell behavior. Our observations confirm that melatonin mitigates I/R injury and support its potential in liver transplantation.


[Hyperlipidemia and glucose intolerance in patients with HIV infection receiving antiretroviral therapy].
To determine the prevalence of secondary effects on lipid metabolism as a result of highly active antiretroviral therapy (HAART), as well as the impact of different types of antiretroviral regimens on lipids and glucose in a group of patients in Yucatan, Mexico. A cross-sectional study was conducted. A questionnaire created for this study was administered to each patient and total cholesterol, triglycerides and fasting glucose values were determined. The presence of hyperlipidemia and alterations in glucose were determined as well as their relation to the epidemiological variables obtained from the questionnaire. A total of 211 subjects were studied [36 (17%) of which were women and 175 (83%) men]. Ninety-two patients (44%) were found to have hyperlipidemia. Of these, 43 (20%) had hypercholesterolemia (HC) and 82 (39%) hypertriglyceridaemia (HT). The presence of combined HC and HT was observed in 30 (14%) patients. Nineteen (9%) patients had alterations in glucose, six (3%) diabetes mellitus and 13 (6%) impaired glucose tolerance. The variables associated with the presence of hyperlipidemia were: levels of lymphocytes CD4 >350 cells/microl (OR = 2.79 1.08-7.27, p = 0.03), male gender (OR = 3.6 1.4-9.12, p = 0.006) and the use of nucleoside-reverse transcriptase inhibitors (NRTI) (OR = 3.1 1.2-8.1, p = 0.01). Patients with HIV infection who receive HAART have an increased risk of presenting hyperlipidemia. In this group of patients the presence of hyperlipidemia and impaired glucose tolerance was significant. Unlike what has been indicated in most published reports, the alterations of lipids were associated more frequently with INTR use, for which it is concluded that the pathogeny of these alterations is not unique, that it is probable that concurrent effects exist between different antiretroviral drug families and that other host factors are involved in the pathogenic mechanism of these alterations.


The symptom phenotype of oncology outpatients remains relatively stable from prior to through 1 week following chemotherapy.
Some oncology outpatients experience a higher number of and more severe symptoms during chemotherapy (CTX). However, little is known about whether this high risk phenotype persists over time. Latent transition analysis (LTA) was used to examine the probability that patients remained in the same symptom class when assessed prior to the administration of and following their next dose of CTX. For the patients whose class membership remained consistent, differences in demographic and clinical characteristics, and quality of life (QOL) were evaluated. The Memorial Symptom Assessment Scale (MSAS) was used to evaluate symptom burden. LTA was used to identify subgroups of patients with distinct symptom experiences based on the occurrence of the MSAS symptoms. Of the 906 patients evaluated, 83.9% were classified in the same symptom occurrence class at both assessments. Of these 760 patients, 25.0% were classified as Low-Low, 44.1% as Moderate-Moderate and 30.9% as High-High. Compared to the Low-Low class, the other two classes were younger, more likely to be women and to report child care responsibilities, and had a lower functional status and a higher comorbidity scores. The two higher classes reported lower QOL scores. The use of LTA could assist clinicians to identify higher risk patients and initiate more aggressive interventions.


Occupational Exposure to Respirable Dust, Respirable Crystalline Silica and Diesel Engine Exhaust Emissions in the London Tunnelling Environment.
Personal 8-h shift exposure to respirable dust, diesel engine exhaust emissions (DEEE) (as respirable elemental carbon), and respirable crystalline silica of workers involved in constructing an underground metro railway tunnel was assessed. Black carbon (BC) concentrations were also assessed using a MicroAeth AE51. During sprayed concrete lining (SCL) activities in the tunnel, the geometric mean (GM) respirable dust exposure level was 0.91mg m(-3), with the highest exposure measured on a back-up sprayer (3.20mg m(-3)). The GM respirable crystalline silica concentration for SCL workers was 0.03mg m(-3), with the highest measurement also for the back-up sprayer (0.24mg m(-3)). During tunnel boring machine (TBM) activities, the GM respirable dust concentration was 0.54mg m(-3). The GM respirable elemental carbon concentration for all the TBM operators was 18 µg m(-3); with the highest concentration measured on a segment lifter. The BC concentrations were higher in the SCL environment in comparison to the TBM environment (daily GM 18-54 µg m(-3) versus 3-6 µg m(-3)). This small-scale monitoring campaign provides additional personal data on exposures experienced by underground tunnel construction workers.


Microbiota Quality and Mitochondrial Activity Link with Occurrence of Muscle Cramps in Hemodialysis Patients using Citrate Dialysate: A Pilot Study.
Hemodialysis-associated muscle cramp (HAMC) is a common complication under citrate dialysate (CD) occurring in 30% of cases. Our objectives were to assess the gut microbiota quality, mitochondrial activity, and to investigate their possible relationship with HAMC. Ten end-stage renal disease patients (78.9 ± 2.1 years) treated by hemodialysis (HD) with CD were enrolled and then classified according to the frequency of HAMCs: "frequent HAMCs group" (n = 5) and "absence of HAMCs group" (n = 5). Gut microbiota quality, mitochondrial activity, and some markers of oxidative stress (OS) were investigated. In patients with cramps, gut microbiota diversity seemed lower and some genera including Helicobacter, Lachnospira, Roseburia, and Haemophilus seemed over-expressed, a significant increase of citratemia and significant lowering mitochondrial function were observed. No difference was observed on the OS markers. This first clinical study revealed a possible dysbiosis of microbiota and a mitochondrial dysfunction into HD patients with cramps under CD compared to patients without cramp.


Isolation and Characterization of Monodisperse Core-Shell Nanoparticle Fractions.
Monodispersity is a key property to control the self-assembly of colloidal particles, and is typically reached after fine-tuning of the synthesis conditions. Monodisperse particle fractions can also be separated from polydisperse suspensions via ultracentrifugation. This paper demonstrates the capability of isolating and characterizing suspensions of core-shell iron oxide-polymer nanoparticles with extremely low polydispersity (p < 0.01) and, thus, of complementing nanoparticle synthetic approaches in the pursuit of highly monodisperse materials.


A role for histone H4K16 hypoacetylation in Saccharomyces cerevisiae kinetochore function.
Hypoacetylated H4 is present at regional centromeres; however, its role in kinetochore function is poorly understood. We characterized H4 acetylation at point centromeres in Saccharomyces cerevisiae and determined the consequences of altered H4 acetylation on chromosome segregation. We observed low levels of tetra-acetylated and K16 acetylated histone H4 (H4K16Ac) at centromeres. Low levels of H4K16Ac were also observed at noncentromeric regions associated with Cse4p. Inhibition of histone deacetylases (HDAC) using nicotinamide (NAM) caused lethality in cse4 and hhf1-20 kinetochore mutants and increased centromeric H4K16Ac. Overexpression of Sas2-mediated H4K16 acetylation activity in wild-type cells led to increased rates of chromosome loss and synthetic dosage lethality in kinetochore mutants. Consistent with increased H4K16 acetylation as a cause of the phenotypes, deletion of the H4K16 deacetylase SIR2 or a sir2-H364Y catalytic mutant resulted in higher rates of chromosome loss compared to wild-type cells. Moreover, H4K16Q acetylmimic mutants displayed increased rates of chromosome loss compared to H4K16R nonacetylatable mutants and wild-type cells. Our work shows that hypoacetylated centromeric H4 is conserved across eukaryotic centromeres and hypoacetylation of H4K16 at centromeres plays an important role in accurate chromosome segregation.


Current Status of Healthy Aging and Dementia Research: A Symposium Summary.
The purpose of the 'First Regional Healthy Aging and Dementia Research Symposium' was to discuss the latest research in healthy aging and dementia research, public health trends related to neurodegenerative diseases of aging, and community-based programs and research studying health, nutrition, and cognition. This symposium was organized by the Garrison Institute on Aging (GIA) of the Texas Tech University Health Sciences Center (TTUHSC), and was held in Lubbock, Texas, October 24-25, 2018. The Symposium joined experts from educational and research institutions across the United States. The two-day Symposium included all GIA staff and researchers. Students, postdoctoral fellows, and faculty members involved in dementia research presented at the Symposium. Healthcare professionals, from geriatricians to social workers working with patients with neurodegenerative diseases, also presented. In addition, experts traveled from across the United States to participate. This event was comprised of multiple sessions, each with several oral presentations, followed by questions and answers, and discussion.


Prevention by specific perceptual remediation for vulnerable first-graders. Controlled study and follow-up of lasting effects.
In a pretest-posttest design with two matched control groups, 86 first-graders screened as vulnerable to academic failure and behavioral decompensation were each assigned to one of three groups: (1) channel-specific perceptual stimulation, (2) regular academic tutoring (contact controls), or (3) no contact. On most measures, including perceptual and achievement tests and behavior ratings by teachers, group 1 showed more improvement than either of the control groups. Several of these differences were significant (P less than .05, two-tailed). In general, the two control groups came closer to each other than to group 1. With no further intervention, follow-up one year later showed more dramatic significance. On every measure, group 1's improvement surpassed that of the control groups, and diverged from them even more than at posttest; this divergence was significant on most measures. Group 1 improved significantly (P less than .05 to P less than .01) in reading, IQ, and three behavior scales, while both control groups showed only deterioration on these measures. Group 1 gained five IQ points on the Wechsler Intelligence Scale for Children, while the controls lost five. On the Davids Scale, group 1 improved significantly (P less than .01) to "probably not hyperkinetic," while both control groups deteriorated to "probably hyperkinetic." The hypothesized mechanism of group 1's behavioral superiority at follow-up was its significant (P less than 0.1) reading improvement, with secondary emotional benefits.


Photoreceptor protection by cardiotrophin-1 in transgenic rats with the rhodopsin mutation s334ter.
This work examines the effects of cardiotrophin (CT)-1 on photoreceptor survival in transgenic rats that carry the rhodopsin mutation S334ter. Recombinant CT-1 was injected intravitreally into eyes of heterozygous animals. Photoreceptor survival was analyzed by histology. Phosphorylation of signal transducer and activator of transcription1 (STAT1), STAT3, extracellular signal-regulated kinase (ERK), or Akt was assessed by immunoblot analysis. Localization of phosphorylated STAT3 was determined by immunocytochemistry. Heterozygous S334ter rats experience rapid photoreceptor degeneration. By postnatal day (PD)20, the outer nuclear layer (ONL) retained only 1 to 2 rows of nuclei compared with 10 to 12 rows in wild-type animals. Repeated administration of CT-1 resulted in significant survival of photoreceptors. At PD20, a CT-1-treated eye (2 micro g/2 micro L every 3 days, starting at PD9) had six to seven rows of nuclei, and the vehicle-treated eyes had only one to two rows. At PD30, eyes treated every 3 days still had five to six rows of nuclei, in contrast to no rows to one row in vehicle-treated eyes. Eyes treated every 4 days retained three to four rows, whereas eyes treated every 5 days had two to three rows. There was a significant increase in phosphorylated STAT1 and -3 in the retina after CT-1 injection. The increase in phosphorylated STAT3 was colocalized with glutamine synthetase, a Müller cell marker, by immunocytochemistry. These results indicate that CT-1 promotes photoreceptor survival and that Müller cells probably mediate this effect. They also suggest that sustained delivery of the protein is essential for long-term rescue of photoreceptors.


Alzheimer's disease biomarker discovery using in silico literature mining and clinical validation.
Alzheimer's Disease (AD) is the most widespread form of dementia in the elderly but despite progress made in recent years towards a mechanistic understanding, there is still an urgent need for disease modification therapy and for early diagnostic tests. Substantial international efforts are being made to discover and validate biomarkers for AD using candidate analytes and various data-driven 'omics' approaches. Cerebrospinal fluid is in many ways the tissue of choice for biomarkers of brain disease but is limited by patient and clinician acceptability, and increasing attention is being paid to the search for blood-based biomarkers. The aim of this study was to use a novel in silico approach to discover a set of candidate biomarkers for AD. We used an in silico literature mining approach to identify potential biomarkers by creating a summarized set of assertional metadata derived from relevant legacy information. We then assessed the validity of this approach using direct assays of the identified biomarkers in plasma by immunodetection methods. Using this in silico approach, we identified 25 biomarker candidates, at least three of which have subsequently been reported to be altered in blood or CSF from AD patients. Two further candidate biomarkers, indicated from the in silico approach, were choline acetyltransferase and urokinase-type plasminogen activator receptor. Using immunodetection, we showed that, in a large sample set, these markers are either altered in disease or correlate with MRI markers of atrophy. These data support as a proof of concept the use of data mining and in silico analyses to derive valid biomarker candidates for AD and, by extension, for other disorders.


Interrater agreement in the assessment of motor manifestations of Huntington's disease.
With prospects improving for experimental therapeutics aimed at postponing the onset of illness in preclinical carriers of the Huntington's disease (HD) gene, we assessed agreement among experienced clinicians with respect to the motor manifestations of HD, a relevant outcome measure for preventive trials in this population. Seventy-five clinicians experienced in the evaluation of patients with early HD and six non-clinicians were shown a videotape compiled from the film archives of the United States-Venezuela Collaborative HD Research Project. Observers were asked to rate a 2-3-minute segment of the motor examination for each of 17 at-risk subjects. The rating scale ranged from 0 (normal) to 4 (unequivocal extrapyramidal movement disorder characteristic of HD). As measured by a weighted kappa statistic, there was substantial agreement among the 75 clinicians in the judgment of unequivocal motor abnormalities comparing scale ratings of 4 with ratings that were not 4 (weighted kappa = 0.67; standard error (SE) = 0.09). Agreement among the non-clinicians was only fair (weighted kappa = 0.28; SE = 0.10). Even under the artificial conditions of a videotape study, experienced clinicians show substantial agreement about the signs that constitute the motor manifestations of illness in subjects at risk for HD. We expect these findings to translate to a similar level of interobserver agreement in the clinical trial setting involving experienced investigators examining live patients.


Lipid disorders in diabetes.
Hyperlipidemia is common in diabetic patients. While our understanding of lipid and lipoprotein metabolism in diabetes is incomplete, a pathophysiologic approach to this problem is presented. It is based on the recognition that diabetes is metabolically heterogeneous. Thus the roles of insulin deficiency, insulin resistance, obesity, and genetic factors are discussed in relation to their effects on lipoprotein production and catabolism. The most important defect in insulin-deficient subjects appears to be a deficiency of lipoprotein lipase, which is responsible for the removal of the triglyceride-rich lipoproteins. In non-insulin-dependent subjects there is evidence for a removal defect as well as, in some patients, for overproduction of VLDL-triglyceride. Cholesterol levels may be elevated and it is important to distinguish between VLDL, LDL, and HDL as the causes for these increases. HDL-cholesterol levels may be increased in insulin-dependent subjects, whereas they may be decreased in obese non-insulin-dependent patients. Mild elevations of LDL-cholesterol may occur in inadequately controlled type I and II diabetic patients, while elevated VLDL may raise the serum cholesterol in addition to the triglyceride levels. The rationale for therapy is based on the complications of severe hypertriglyceridemia and the risk of occlusive atherosclerosis. Management is directed at improving glycemic control, altering dietary composition, and reducing calories in obese patients. Improved glycemic control is effective in reducing triglyceride and cholesterol levels in insulin-deficient subjects. The response of the non-insulin-dependent diabetic patient to improved control may be complicated by associated obesity or familial hyperlipidemia. The advantages and disadvantages of fat versus carbohydrate restriction in the diet are discussed. Finally, resistant hyperlipidemia may require drug therapy. Diabetic hyperlipidemia should be viewed as resulting from an interaction between the diabetic syndrome, the genetic background of the patient, and the environment.


Application of a model for delivering occupational safety and health to smaller businesses: Case studies from the US.
Smaller firms are the majority in every industry in the US, and they endure a greater burden of occupational injuries, illnesses, and fatalities than larger firms. Smaller firms often lack the necessary resources for effective occupational safety and health activities, and many require external assistance with safety and health programming. Based on previous work by researchers in Europe and New Zealand, NIOSH researchers developed for occupational safety and health intervention in small businesses. This model was evaluated with several intermediary organizations. Four case studies which describe efforts to reach small businesses with occupational safety and health assistance include the following: trenching safety training for construction, basic compliance and hazard recognition for general industry, expanded safety and health training for restaurants, and fall prevention and respirator training for boat repair contractors. Successful efforts included participation by the initiator among the intermediaries' planning activities, alignment of small business needs with intermediary offerings, continued monitoring of intermediary activities by the initiator, and strong leadership for occupational safety and health among intermediaries. Common challenges were a lack of resources among intermediaries, lack of opportunities for in-person meetings between intermediaries and the initiator, and balancing the exchanges in the initiator-intermediary-small business relationships. The model offers some encouragement that initiator organizations can contribute to sustainable OSH assistance for small firms, but they must depend on intermediaries who have compatible interests in smaller businesses and they must work to understand the small business social system.


A clash of old and new scientific concepts in toxicity, with important implications for public health.
A core assumption of current toxicologic procedures used to establish health standards for chemical exposures is that testing the safety of chemicals at high doses can be used to predict the effects of low-dose exposures, such as those common in the general population. This assumption is based on the precept that "the dose makes the poison": higher doses will cause greater effects. We challenge the validity of assuming that high-dose testing can be used to predict low-dose effects for contaminants that behave like hormones. We review data from endocrinology and toxicology that falsify this assumption and summarize current mechanistic understanding of how low doses can lead to effects unpredictable from high-dose experiments. Falsification of this assumption raises profound issues for regulatory toxicology. Many exposure standards are based on this assumption. Rejecting the assumption will require that these standards be reevaluated and that procedures employed to set health standards be changed. The consequences of these changes may be significant for public health because of the range of health conditions now plausibly linked to exposure to endocrine-disrupting contaminants. We recommend that procedures to establish acceptable exposure levels for endocrine-disrupting compounds incorporate the inability for high-dose tests to predict low-dose results. Setting acceptable levels of exposure must include testing for health consequences at prevalent levels of human exposure, not extrapolations from the effects observed in high-dose experiments. Scientists trained in endocrinology must be engaged systematically in standard setting for endocrine-disrupting compounds.


Hepatotoxic effects of cyproconazole and prochloraz in wild-type and hCAR/hPXR mice.
The agricultural fungicides cyproconazole and prochloraz exhibit hepatotoxicity in rodent studies and are tumorigenic following chronic exposure. Both substances are suspected to act via a CAR (constitutive androstane receptor)/PXR (pregnane-X-receptor)-dependent mechanism. Human relevance of these findings is under debate. A 28-day toxicity study was conducted in mice with humanized CAR and PXR (hCAR/hPXR) with two dose levels (50 or 500 ppm) of both substances, using the model CAR activator phenobarbital as a reference. Results were compared to wild-type mice. A treatment-related increase in liver weights was observed for all three substances at least at the high-dose level. Changes in the expression of classic CAR/PXR target genes such as Cyp2b10 were induced by cyproconazole and phenobarbital in both genotypes, while prochloraz treatment resulted in gene expression changes indicative of additional aryl hydrocarbon receptor activation, e.g. by up-regulation of Cyp1a1 expression. Cyproconazole-induced effects on CAR-dependent gene expression, liver weight, and hepatic lipid accumulation were more prominent in wild-type mice, where significant genotype differences were observed at the high-dose level. Moreover, high-dose cyproconazole-treated mice from the wild-type group responded with a marked increase in hepatocellular proliferation, while hCAR/hPXR mice did not. In conclusion, our data demonstrate that cyproconazole and PB induce CAR/PXR downstream effects in hepatocytes in vivo via both, the murine and human receptors. At high doses of cyproconazole, however, the responses were clearly more pronounced in wild-type mice, indicating increased sensitivity of rodents to CAR agonist-induced effects in hepatocytes.


Worksite medical home: health services use and claim costs.
To examine the relationship among use of an on-site employer-provided primary care medical home, and health services use and health plan costs for inpatient and outpatient services and pharmaceuticals. The study was a retrospective observational analysis of health plan claims, human resources data, and Health Care Center (HCC) encounters. Three years of data for employees and dependents designating the HCC as their primary care provider (HCC major users) were compared with data from 2 comparison groups: "casual" HCC users and HCC nonusers. The outcomes of interest were: 1) health services utilization, and 2) monetized use of the health plan. Secondary data from an employer-provided Health Care Center (HCC). After adjusting for several potential confounders, HCC major users had less use of external healthcare services than the comparison groups (employees had 2.7 fewer external encounters than HCC casual users [P < .001] and 1.2 fewer external encounters than nonusers [P < .001]; dependents had 3.5 fewer external encounters than HCC casual users [P < .001] and 1.9 fewer external encounters than non-users [P < .001]). Annual monetized use of the health plan for employees and dependents was highest for HCC casual users relative to HCC major users (employees: $482 greater, P < .01; dependents: $598 greater, P < .001). Employees and their dependents who were "casual users" of the HCC had the highest claims costs and use of outside healthcare services. Additional research is needed to assess the extent to which employees' utilization of services at on-site primary care medical homes affects employee health outcomes, resulting in potential effects on company healthcare plan expenditures, worker productivity, and return on investment.


The assessment of vascular risk in men with erectile dysfunction: the role of the cardiologist and general physician.
Erectile dysfunction (ED) and cardiovascular disease (CVD) share risk factors and frequently coexist, with endothelial dysfunction believed to be the pathophysiologic link. ED is common, affecting more than 70% of men with known CVD. In addition, clinical studies have demonstrated that ED in men with no known CVD often precedes a CVD event by 2-5 years. ED severity has been correlated with increasing plaque burden in patients with coronary artery disease. ED is an independent marker of increased CVD risk including all-cause and especially CVD mortality, particularly in men aged 30-60 years. Thus, ED identifies a window of opportunity for CVD risk mitigation. We recommend that a thorough history, physical exam (including visceral adiposity), assessment of ED severity and duration and evaluation including fasting plasma glucose, lipids, resting electrocardiogram, family history, lifestyle factors, serum creatinine (estimated glomerular filtration rate) and albumin:creatinine ratio, and determination of the presence or absence of the metabolic syndrome be performed to characterise cardiovascular risk in all men with ED. Assessment of testosterone levels should also be considered and biomarkers may help to further quantify risk, even though their roles in development of CVD have not been firmly established. Finally, we recommend that a question about ED be included in assessment of CVD risk in all men and be added to CVD risk assessment guidelines.


Effects of selected bronchodilators on antigen- and A23187-induced contraction of guinea-pig trachea.
Antigen and the calcium ionophore A23187 contract isolated tracheal spirals from sensitized guinea pigs and A23187 also contracts normal airways. The contractions appear to be the result of released bronchoconstrictor mediators, likely products of the lipoxygenase pathway of arachidonic acid metabolism. Pretreatment (10-30 min) with a series of bronchodilators resulted in inhibition of ovalbumin-induced airways contractions. The order of potency on the trachea was isoprenaline greater than forskolin greater than prostaglandin E2 much greater than aminophylline greater than dibutyryl cyclic AMP congruent to prostacyclin. The IC50 values and order of potency were similar to their capacity to relax tracheal smooth muscle. Only isoprenaline (10(-6) M), forskolin (10(-6) M) and aminophylline (10(-3) M) inhibited A23187-induced contraction of trachea. These agents lost their inhibitory capacity 20 to 30 min after A23187 challenge. This was not observed with ovalbumin challenge because the membrane stimulation with ovalbumin occurs immediately whereas A23187 induction of Ca++ influx is continual. The recovery from inhibition is probably not receptor desensitization as recovery also occurs in the presence of forskolin, a direct activator of adenylate cyclase. Sensitized trachea responded to A23187 in the presence of bronchodilators differently than normal tissue. Low concentrations of isoprenaline (10(-8) to 10(-7) M), forskolin (10(-8) to 10(-7) M), prostaglandin E2 (10(-7) to 10(-5) M), aminophylline (10(-4) M) and dibutyryl cyclic AMP (10(-3) M) all enhanced A23187-induced contraction. Pools of cyclic AMP are known to be involved both in secretion and in modulation of mediator release involved in airways smooth muscle contraction and sensitization may affect the differential availability of these pools. That this enhancement occurred only in sensitized trachea emphasized an intrinsic difference between sensitized and normal tissues.


The Population Education Transition Curve: Education Gradients Across Population Exposure to New Health Risks.
The salutary effect of formal education on health-risk behaviors and mortality is extensively documented: ceteris paribus, greater educational attainment leads to healthier lives and longevity. Even though the epidemiological evidence has strongly indicated formal education as a leading "social vaccine," there is intermittent reporting of counter-education gradients for health-risk behavior and associated outcomes for certain populations during specific periods. How can education have both beneficial and harmful effects on health, and under which contexts do particular effects emerge? It is useful to conceptualize the influence of education as a process sensitive to the nature, timing of entry, and uniqueness of a new pleasurable and desirable lifestyle and/or product (such as smoking) with initially unclear health risks for populations. Developed herein is a hypothesis that the education gradient comprises multiple potent pathways (material, psychological, cognitive) by which health-risk behaviors are influenced, and that there can be circumstances under which pathways act in opposite directions or are differentially suppressed and enhanced. We propose the population education transition (PET) curve as a unifying functional form to predict shifting education gradients across the onset and course of a population's exposure to new health risks and their associated consequences. Then, we estimate PET curves for cases with prior epidemiological evidence of heterogeneous education gradients with health-risk behaviors related to mass-produced cigarettes in China and the United States; saturated fats, sugar, and processed food diets in Latin America; and HIV infection in sub-Saharan Africa. Each offers speculation on interactions between environmental factors during population exposure and education pathways to health-risk behaviors that could be responsible for the temporal dynamics of PET curves. Past epidemiological studies reporting either negative or positive education gradients may not represent contradictory findings as much as come from analyses unintentionally limited to just one part of the PET process. Last, the PET curve formulation offers richer nuances about educational pathways, macro-historical population dynamics, and the fundamental cause of disease paradigm.


Nonoperative management of dens fracture nonunion in elderly patients without myelopathy.
A retrospective review of elderly patients treated without surgery for chronic mobile nonunions of the odontoid process. Patients were observed on an annual basis with clinical examinations and flexion/extensions plain film radiographs. To evaluate the clinical and radiographic results of elderly patients without myelopathy treated without surgery for dens fracture nonunion. Because of the risk of progressive myelopathy or sudden neurologic injury, many surgeons recommend operative stabilization for patients with mobile dens nonunions who are able to withstand an operation. There is, however, a lack of information about the radiographic and neurologic progression of dens nonunions. Although a less aggressive surgical approach has been recommended by some authors for elderly or medically compromised patients with acute fractures, long-term follow-up evaluation of patients with resulting nonunions has not been reported. A series of elderly patients with chronic, unstable, dens nonunions without myelopathy were treated with a nonoperative treatment protocol. Patients were informed of the nature of their lesion, including the risk of acute or chronic spinal cord injury and the options for operative treatment. Patients were evaluated yearly for clinical and radiographic progression. No intervention to slow progression of atlantoaxial instability was undertaken. None of the patients developed myelopathic symptoms during the follow-up period, and no patient experienced more than a 1 mm radiographic increase in atlantoaxial excursion. None of the reported patients had less than 14 mm available for the spinal cord in either flexion or extension at the start of clinical monitoring. Although further follow-up evaluation is needed, the authors believe on the basis of this review that this treatment protocol may be considered for patients who are poor candidates for surgical fusion.


Adolescent women can perform a point-of-care test for trichomoniasis as accurately as clinicians.
To compare the accuracy (ie, correlation, sensitivity, specificity) of self-performed point-of-care (POC) tests with clinician-performed tests for trichomoniasis in adolescent women. Sexually experienced women aged 14-22 years (n=209) collected a vaginal swab and performed a POC test for trichomoniasis. Using a speculum, the clinician obtained vaginal swabs that were tested for trichomoniasis using the POC test, wet mount, culture and transcription-mediated amplification (TMA) using standard and alternative primers. Self and clinician results were compared with true positives, defined as either culture-positive or TMA-positive with both sets of primers. Participants' mean age was 17.8 years; 87% were African-American; 74% reported vaginal itching or discharge and 51 (24%) had trichomoniasis. Over 99% correctly performed and interpreted her self-test. Self and clinician POC tests were highly correlated (95.7% agreement, κ 0.87). Compared with true positives, the sensitivity of the self-POC test was 78% (CI 65% to 89%), similar to that of the clinician-POC test (84%, CI 71% to 93%) and culture (82%, CI 69% to 92%), and significantly better than wet mount (39%, CI 26% to 54%). The specificity of the self-POC test was 99% (CI 96% to 100%), similar to that of the clinician-POC test (100%, CI 98% to 100%). The sensitivity of the self-POC test was not affected by vaginal symptoms or other variables. Young women performing a self-POC test detected as many trichomoniasis infections as clinician-POC tests or culture, twice as many as wet mount and slightly fewer than an amplified test. Incorporating self-obtained or self-performed POC tests into routine practice could effectively increase the identification and treatment of trichomoniasis in this vulnerable population.


Vascular hyperpolarization to β-adrenoceptor agonists evokes spreading dilatation in rat isolated mesenteric arteries.
β-Adrenoceptor stimulation causes pronounced vasodilatation associated with smooth muscle hyperpolarization. Although the hyperpolarization is known to reflect K(ATP) channel activation, it is not known to what extent it contributes to vasodilatation. Smooth muscle membrane potential and tension were measured simultaneously in small mesenteric arteries in a wire myograph. The spread of vasodilatation over distance was assessed in pressurized arteries following localized intraluminal perfusion of either isoprenaline, adrenaline or noradrenaline. Isoprenaline stimulated rapid smooth muscle relaxation associated at higher concentrations with robust hyperpolarization. Noradrenaline or adrenaline evoked a similar hyperpolarization to isoprenaline if the α(1)-adrenoceptor antagonist prazosin was present. With each agonist, glibenclamide blocked hyperpolarization without reducing relaxation. Focal, intraluminal application of isoprenaline, noradrenaline or adrenaline during block of α(1)-adrenoceptors evoked a dilatation that spread along the entire length of the isolated artery. This response was endothelium-dependent and inhibited by glibenclamide. Hyperpolarization is not essential for β-adrenoceptor-mediated vasodilatation. However, following focal β-adrenoceptor stimulation, this hyperpolarization underlies the ability of vasodilatation to spread along the artery wall. The consequent spread of vasodilatation is dependent upon the endothelium and likely to be of physiological relevance in the coordination of tissue blood flow.


Features in visual search combine linearly.
Single features such as line orientation and length are known to guide visual search, but relatively little is known about how multiple features combine in search. To address this question, we investigated how search for targets differing in multiple features (intensity, length, orientation) from the distracters is related to searches for targets differing in each of the individual features. We tested race models (based on reaction times) and co-activation models (based on reciprocal of reaction times) for their ability to predict multiple feature searches. Multiple feature searches were best accounted for by a co-activation model in which feature information combined linearly (r = 0.95). This result agrees with the classic finding that these features are separable i.e., subjective dissimilarity ratings sum linearly. We then replicated the classical finding that the length and width of a rectangle are integral features-in other words, they combine nonlinearly in visual search. However, to our surprise, upon including aspect ratio as an additional feature, length and width combined linearly and this model outperformed all other models. Thus, length and width of a rectangle became separable when considered together with aspect ratio. This finding predicts that searches involving shapes with identical aspect ratio should be more difficult than searches where shapes differ in aspect ratio. We confirmed this prediction on a variety of shapes. We conclude that features in visual search co-activate linearly and demonstrate for the first time that aspect ratio is a novel feature that guides visual search.


Exploring the boundaries of direct detection and characterization of labile isomers - a case study of copper(ii)-dipeptide systems.
The investigation of the linkage isomers of biologically essential and kinetically labile metal complexes in aqueous solutions poses a challenge, as these microspecies cannot be separately studied. Therefore, derivatives are commonly used to initially determine the stability or spectral characteristics of at least one of the isomers. Here we directly detect the isomers, describe the metal ion coordination sphere, speciation and thermodynamic parameters by a synergistic application of temperature dependent EPR and CD spectroscopic measurements in copper(ii)-dipeptide systems including His-Gly and His-Ala ligands. The ΔH = (-23 ± 4) kJ mol-1 value of the standard enthalpy change corresponding to the peptide-type to histamine-type isomerisation equilibrium of the [CuL]+ complex was corroborated by several techniques. The preferential coordination of the side-chains was observed at lower temperatures, whereas, metal-binding of the backbone atoms became favourable upon increasing temperature. This study exemplifies the necessity of using temperature dependent multiple methodologies for a reliable description of similar systems for upstream applications.


Investigation of common and rare genetic variation in the BAMBI genomic region in light of human obesity.
The aim of this study was to confirm the previously identified link between BAMBI and human obesity by means of a genetic and functional analysis. We performed both a mutation analysis, using high-resolution melting curve analysis, and a genetic association study, including 8 common tagSNPs in the BAMBI gene region. Three of the identified genetic variants (R151W, H201R, and C229R) were evaluated for their Wnt signaling enhancing capacity in a Wnt luciferase reporter assay. Mutation screening of the BAMBI coding region and exon-intron boundaries on our population of 677 obese children and adolescents and 529 lean control subjects resulted in the identification of 18 variants, 10 of which were not previously reported and 12 of which were exclusively found in obese individuals. The difference in variant frequency, not taking into account common polymorphisms, between obese (3.1 %) and lean (0.9 %) subjects was statistically significant (p = 0.004). Our Wnt luciferase assay, using WT and mutant BAMBI constructs, showed a significantly reduced activity for all of the investigated variants. Logistic and linear regression analysis on our Caucasian population of 1022 obese individuals and 606 lean controls, did not identify associations with obesity parameters (p values >0.05). We found several rare genetic variations, which represent the first naturally occurring missense variants of BAMBI in obese patients. Three variants (R151W, H201R, and C229R) were shown to reduce Wnt signaling enhancing capacity of BAMBI and we believe this result should encourage further study of this gene in other obese populations. In addition, we did not find evidence for the involvement of BAMBI common variation in human obesity in our population.


Improved Dwarf Mongoose Optimization for Constrained Engineering Design Problems.
This paper proposes a modified version of the Dwarf Mongoose Optimization Algorithm (IDMO) for constrained engineering design problems. This optimization technique modifies the base algorithm (DMO) in three simple but effective ways. First, the alpha selection in IDMO differs from the DMO, where evaluating the probability value of each fitness is just a computational overhead and contributes nothing to the quality of the alpha or other group members. The fittest dwarf mongoose is selected as the alpha, and a new operator ω is introduced, which controls the alpha movement, thereby enhancing the exploration ability and exploitability of the IDMO. Second, the scout group movements are modified by randomization to introduce diversity in the search process and explore unvisited areas. Finally, the babysitter's exchange criterium is modified such that once the criterium is met, the babysitters that are exchanged interact with the dwarf mongoose exchanging them to gain information about food sources and sleeping mounds, which could result in better-fitted mongooses instead of initializing them afresh as done in DMO, then the counter is reset to zero. The proposed IDMO was used to solve the classical and CEC 2020 benchmark functions and 12 continuous/discrete engineering optimization problems. The performance of the IDMO, using different performance metrics and statistical analysis, is compared with the DMO and eight other existing algorithms. In most cases, the results show that solutions achieved by the IDMO are better than those obtained by the existing algorithms.


Overexpression of the chloroplastic 2-oxoglutarate/malate transporter disturbs carbon and nitrogen homeostasis in rice.
The chloroplastic 2-oxaloacetate (OAA)/malate transporter (OMT1 or DiT1) takes part in the malate valve that protects chloroplasts from excessive redox poise through export of malate and import of OAA. Together with the glutamate/malate transporter (DCT1 or DiT2), it connects carbon with nitrogen assimilation, by providing 2-oxoglutarate for the GS/GOGAT (glutamine synthetase/glutamate synthase) reaction and exporting glutamate to the cytoplasm. OMT1 further plays a prominent role in C4 photosynthesis: OAA resulting from phosphoenolpyruvate carboxylation is imported into the chloroplast, reduced to malate by plastidic NADP-malate dehydrogenase, and then exported for transport to bundle sheath cells. Both transport steps are catalyzed by OMT1, at the rate of net carbon assimilation. To engineer C4 photosynthesis into C3 crops, OMT1 must be expressed in high amounts on top of core C4 metabolic enzymes. We report here high-level expression of ZmOMT1 from maize in rice (Oryza sativa ssp. indica IR64). Increased activity of the transporter in transgenic rice was confirmed by reconstitution of transporter activity into proteoliposomes. Unexpectedly, overexpression of ZmOMT1 in rice negatively affected growth, CO2 assimilation rate, total free amino acid content, tricarboxylic acid cycle metabolites, as well as sucrose and starch contents. Accumulation of high amounts of aspartate and the impaired growth phenotype of OMT1 rice lines could be suppressed by simultaneous overexpression of ZmDiT2. Implications for engineering C4 rice are discussed.


[Acromegaly: recognition of a rare disease in psychiatric practice].
Acromegaly is a rare disease which is caused by a tumour in the anterior lobe of the pituitary gland. The tumour stimulates excessive production of the growth hormone. As a result, all the organs and tissues in the body are induced to grow. This growth is responsible for a wide range of symptoms, some of which can be neuro-psychiatric.
 AIM: To promote the early detection of acromegaly so that treatment can be started as soon as possible and further damage can be prevented.
 METHOD: We searched PubMed for articles relating to quality of life and cognitive, psychological and psychiatric symptoms and personality changes associated with acromegaly.
 RESULTS: We describe the pathophysiology and epidemiology of acromegaly. Then we present the characteristic, external changes, neuro-cognitive complications, psychiatric disorders, personality changes and relevant comorbid somatic symptoms. Acromegaly is a disease in which patients, long before being diagnosed, present with cognitive and affective disorders. Before patients are diagnosed, they have often visited several consultants in connection with their nonspecific symptoms.
 CONCLUSION: We believe that in everyday practice patients with acromegaly are frequently misdiagnosed. If patients present with extensive somatic co-morbidity and treatment-resistant depression and particularly if these symptoms are combined with the typical external features of acromegaly, then acromegaly can be suspected and further investigation should proceed without delay.


Impact of molecular weight on lymphatic drainage of a biopolymer-based imaging agent.
New lymphatic imaging technologies are needed to better assess immune function and cancer progression and treatment. Lymphatic uptake depends mainly on particle size (10-100 nm) and charge. The size of carriers for imaging and drug delivery can be optimized to maximize lymphatic uptake, localize chemotherapy to lymphatic metastases, and enable visualization of treatment deposition. Toward this end, female BALB/c mice were injected subcutaneously in the hind footpad or forearm with a series of six different molecular weight hyaluronan (HA) near-infrared dye (HA-IR820) conjugates (ca. 5-200 nm). Mice were imaged using whole body fluorescent imaging over two weeks. HA-IR820 fluorescence was clearly visualized in the draining lymphatic capillaries, and in the popliteal and iliac or axillary lymph nodes. The 74-kDa HA-IR820 had the largest lymph node area-under-the-curve. In contrast to prior reports, mice bearing limb tumors exhibited three-fold longer retention of 74-kDa HA-IR820 in the popliteal node compared to mice without tumors. HA conjugate kinetics and disposition can be specifically tailored by altering their molecular weight. The specific lymphatic uptake and increased nodal retention of HA conjugates indicate significant potential for development as a natural biopolymer for intralymphatic drug delivery and imaging.


Timing of Cortical Events Preceding Voluntary Movement.
We studied magnetic signals from the human brain recorded during a second before a self-paced finger movement. Sharp triangular peaks were observed in the averaged signals about 0.7 second before the finger movement. The amplitude of the peaks varied considerably from trial to trial, which indicated that the peaks were concurrent with much longer oscillatory processes. One can cluster trials into distinct groups with characteristic sequences of events. Prominent short trains of pulses in the beta frequency band were identified in the premovement period. This observation suggests that during preparation of the intended movement, cortical activity is well organized in time but differs from trial to trial. Magnetoencephalography can capture these processes with high temporal resolution and allows their study in fine detail.


Iridovirus disease in two ornamental tropical freshwater fishes: African lampeye and dwarf gourami.
Many species of ornamental freshwater fishes are imported into Japan from all over the world. We found African lampeye Aplocheilichthys normani and dwarf gourami Colisa lalia suffering from an iridovirus infection just after being imported by tropical fish wholesalers from Singapore. African lampeye were cultured on the Indonesian Island of Sumatra and dwarf gourami were cultured in Malaysia before export. Diseased fishes displayed distinct histopathological signs of iridovirus infection: systemic appearance of inclusion body-bearing cells, and necrosis of splenocytes and hematopoietic cells. Electron microscopy revealed viral particles (African lampeye:180 to 200 nm in edge to edge diameter; dwarf gourami: 140 to 150 nm in diameter) in an inclusion body within the cytoplasm of inclusion body-bearing cells as well as in the cytoplasm of necrotized cells. Experimental infection with an iridovirus isolate from African lampeye (ALIV) revealed pathogenicity of ALIV to African lampeye and pearl gourami Trichogaster leeri. Polymerase chain reaction (PCR) products from ALIV and an iridovirus isolate from dwarf gourami (DGIV) using iridovirus-specific primers were indistinguishable. The nucleotide sequence of PCR products derived from ALIV (696 base pairs) and DGIV (701 base pairs) had 95.3% identity. These results indicate that ALIV and DGIV have a single origin.


Colocalization of vasoactive intestinal polypeptide and GABA immunoreactivities in a population of wide-field amacrine cells in the rabbit retina.
Vasoactive intestinal polypeptide (VIP) immunoreactive (IR) neurons in the rabbit retina constitute a population of wide-field amacrine cells. To better define this cell population, we examined the coexpression of VIP with other putative retinal transmitters or their biosynthetic enzymes, including gamma-aminobutryic acid (GABA), tyrosine hydroxylase (TH), and somatostatin (SRIF). Colchicine-treated retinas were immersion fixed in 4% paraformaldehyde. The retinas were cut either perpendicular or parallel to the vitreal surface and processed by double-label immunofluorescence techniques using antibodies directed to VIP, GABA, TH, and SRIF. The immunoreactive staining patterns obtained with these antibodies were the same as those described in previous studies. GABA-IR neurons were localized to the proximal inner nuclear layer (INL) and ganglion cell layer (GCL) and processes were distributed throughout the inner plexiform layer (IPL). TH- and SRIF-IR neurons were sparsely distributed to the proximal INL and GCL, respectively. TH-IR processes ramified in laminae 1, 3, and 5, and SRIF-IR processes in laminae 1 and 5 of the IPL. Colocalization experiments showed that all VIP-IR neurons contain GABA immunoreactivity. In contrast, colocalization of VIP and TH or SRIF immunoreactivities was never observed. These results demonstrate that VIP-IR wide-field amacrines of the rabbit retina make up a neurochemically and morphologically distinct subpopulation of the GABA-IR amacrine cell population. Furthermore, VIP-IR amacrine cells constitute a distinct group with respect to the TH- and SRIF-IR amacrine cells.


Multivariate analysis of micro-Raman spectra of thermoplastic polyurethane blends using principal component analysis and principal component regression.
Probing the specific hydrogen-bonding behavior of thermoplastic polyurethane (TPU) blends using vibrational spectroscopies remains the sin qua non for understanding the link between hydrogen-bonding and phase-segregation behavior. However, current literature holds to more traditional univariate approaches when studying the morphologically interesting normal molecular vibrations of TPUs. In the present study, multivariate analysis, including principal component analysis (PCA) and principal component regression (PCR), is used to scrutinize the relevant Raman bands acquired from a binary mixture of analogous TPU copolymer blends. Considering the near identical behavior of selected spectral regions, PCA was capable of isolating linear and nonlinear composition-dependent trends on PC-scores plots. From here, the PC scores, extracted from wavelengths comprising the carbonyl stretching region (1681-1764 cm(-1)), CH(2) deformations (1380-1500 cm(-1)), aromatic stretch from the hard segment (1617 cm(-1)), and amide II mixed band (1540 cm(-1)), were used to explicitly predict the mole fraction of hard segment present in each blend using PCR. Spectral preprocessing, wavelength selection, and variable scaling were major factors in PCR accurately predicting the weight fraction of each copolymer in spite of the clearly evident, blend-specific spectroscopic behavior.


Regaining health and wellbeing after traumatic spinal cord injury.
Traumatic spinal cord injury is typically a devastating event, leading to permanent physical disability. Despite the severity of the condition, many persons with traumatic spinal cord injury manage to lead both active and independent lives. The aim of this study was to investigate the experience of health and wellbeing of persons living with a traumatic spinal cord injury for at least 20 years. A qualitative design was used. Data was analysed using a phenomenological-hermeneutical method. Rich narratives were obtained from 14 persons with paraplegia due to traumatic spinal cord injury sustained at least 20 years ago. The key finding was that health and wellbeing were attained when persons were able to perceive themselves as being "normal" in everyday relationships and circumstances. The normalization process involved learning to negotiate and/or prevent potentially embarrassing situations by acting in a "parallel world", covertly "behind the scenes". The subjective experience of wellbeing and health after traumatic spinal cord injury depends upon the ability to prevent or resolve potentially embarrassing situations without this being noticed by others. Performing this work "behind the scenes", enables persons with traumatic spinal cord injury to interact smoothly with others and thereby be perceived as normal, despite substantial disability.


High degree of coordination and division of labor among subunits in a homomeric ring ATPase.
Ring NTPases of the ASCE superfamily perform a variety of cellular functions. An important question about the operation of these molecular machines is how the ring subunits coordinate their chemical and mechanical transitions. Here, we present a comprehensive mechanochemical characterization of a homomeric ring ATPase-the bacteriophage φ29 packaging motor-a homopentamer that translocates double-stranded DNA in cycles composed of alternating dwells and bursts. We use high-resolution optical tweezers to determine the effect of nucleotide analogs on the cycle. We find that ATP hydrolysis occurs sequentially during the burst and that ADP release is interlaced with ATP binding during the dwell, revealing a high degree of coordination among ring subunits. Moreover, we show that the motor displays an unexpected division of labor: although all subunits of the homopentamer bind and hydrolyze ATP during each cycle, only four participate in translocation, whereas the remaining subunit plays an ATP-dependent regulatory role.


When do short-range atomistic machine-learning models fall short?
We explore the role of long-range interactions in atomistic machine-learning models by analyzing the effects on fitting accuracy, isolated cluster properties, and bulk thermodynamic properties. Such models have become increasingly popular in molecular simulations given their ability to learn highly complex and multi-dimensional interactions within a local environment; however, many of them fundamentally lack a description of explicit long-range interactions. In order to provide a well-defined benchmark system with precisely known pairwise interactions, we chose as the reference model a flexible version of the Extended Simple Point Charge (SPC/E) water model. Our analysis shows that while local representations are sufficient for predictions of the condensed liquid phase, the short-range nature of machine-learning models falls short in representing cluster and vapor phase properties. These findings provide an improved understanding of the role of long-range interactions in machine learning models and the regimes where they are necessary.


Dropout in clinical trials of pharmacological treatment for methamphetamine dependence: the role of initial abstinence.
High rates of loss to follow-up represent a significant challenge to clinical trials of pharmacological treatments for methamphetamine (MA) use disorder. We aimed to estimate and test the relationship between achieving and maintaining abstinence in the initial weeks of study participation and subsequent retention in such trials, hypothesizing that participants able to achieve early abstinence would be less likely to drop out. Data from four randomized controlled trials (RCTs) of pharmacological treatments for MA use disorder were pooled and analyzed using a random-effects approach. All trials were conducted in the greater Los Angeles, CA, USA area. A total of 440 participants were included; trials were conducted between 2004 and 2014. Participants' ability to achieve a brief period of initial abstinence was measured as the number of MA-negative urine screens completed in the first 2 weeks of the trials. Outcomes were the likelihood of dropout, i.e. missing two consecutive weeks of scheduled urine drug screens, and the number of days participants were retained in the trials. Study participants achieved an average of three (of six possible) negative urine screens during the first 2 weeks of the trials, 51% dropped out and the average number of days retained was 60 (of 90 maximum). Each additional negative urine screen achieved during the first 2 weeks of the study reduced multiplicatively the odds of dropout by 41% [odds ratio (OR) = 0.59, 95% confidence interval (CI) = 0.53, 0.66]. Abstinence was also a significant predictor of retention time; the hazard ratio for non-completion was 0.75 per additional negative urine screen (95% CI = 0.71, 0.80). Participants in randomized controlled trials of pharmacological treatments for methamphetamine use disorder who are able to achieve a brief period of early abstinence are retained longer in the trials and are less likely to drop out overall.


Antibodies in scleroderma: direct pathogenicity and phenotypic associations.
Scleroderma is an autoimmune disease involving endothelial cell damage and fibroblast overproduction of extracellular matrix. Several autoantibodies present in the sera of patients with scleroderma, including anti-endothelial cell, antifibroblast, anti-matrix metalloproteinase, and antifibrillin-1 antibodies, may directly contribute to disease pathogenesis. Scleroderma also is characterized by the presence of antinuclear and antinucleolar antibodies, which correlate with particular phenotypes. These include antitopoisomerase-I, anticentromere, antihistone, anti-polymyositis/scleroderma, anti-Th/To, anti-U3-small nucleolar ribonucleoprotein particle, anti-U1-small nuclear ribonucleoprotein particle, anti-RNA polymerase, and anti-B23 antibodies. Other antibodies classically associated with other autoimmune diseases, such as antiphospholipid, antineutrophil cytoplasmic, and antimitochondrial antibodies, also have been described in patients with scleroderma. This review will summarize the various autoantibodies associated with scleroderma, their putative pathogenic roles, and their phenotypic correlations.


Consumption of bee pollen affects rat ovarian functions.
The aim of this study was to examine possible effects of bee pollen added to the feed mixture (FM) on rat ovarian functions (secretion activity and apoptosis). We evaluated the bee pollen effect on the release of insulin-like growth factor I (IGF-I) and steroid hormones (progesterone and estradiol), as well as on the expression of markers of apoptosis (Bcl-2, Bax and caspase-3) in rat ovarian fragments. Female rats (n = 15) were fed during 90 days by FM without or with rape seed bee pollen in dose either 3 kg/1000 kg FM or 5 kg/1000 kg FM. Fragments of ovaries isolated from rats of each group (totally 72 pieces) were incubated for 24 h. Hormonal secretion into the culture medium was detected by RIA. The markers of apoptosis were evaluated by Western blotting. It was observed that IGF-I release by rat ovarian fragments was significantly (p < 0.05) decreased; on the other hand, progesterone and estradiol secretion was increased after bee pollen treatment at dose 5 kg/1000 kg FM but not at 3 kg/1000 FM. Accumulation of Bcl-2 was increased by bee pollen added at 3 kg/1000 kg FM, but not at higher dose. Accumulation of Bax was increased in ovaries of rats fed by bee pollen at doses either 3 or 5 kg/1000 kg FM, whilst accumulation of caspase-3 increased after feeding with bee pollen at dose 5 kg/1000 kg FM, but not at 3 kg/1000 kg FM. Our results contribute to new insights regarding the effect of bee pollen on both secretion activity (release of growth factor IGF-I and steroid hormones progesterone and estradiol) and apoptosis (anti- and pro-apoptotic markers Bcl-2, Bax and caspase-3). Bee pollen is shown to be a potent regulator of rat ovarian functions.


Centrotemporal sharp wave EEG trait in rolandic epilepsy maps to Elongator Protein Complex 4 (ELP4).
Rolandic epilepsy (RE) is the most common human epilepsy, affecting children between 3 and 12 years of age, boys more often than girls (3:2). Focal sharp waves in the centrotemporal area define the electroencephalographic (EEG) trait for the syndrome, are a feature of several related childhood epilepsies and are frequently observed in common developmental disorders (eg, speech dyspraxia, attention deficit hyperactivity disorder and developmental coordination disorder). Here we report the first genome-wide linkage scan in RE for the EEG trait, centrotemporal sharp waves (CTS), with genome-wide linkage of CTS to 11p13 (HLOD 4.30). Pure likelihood statistical analysis refined our linkage peak by fine mapping CTS to variants in Elongator Protein Complex 4 (ELP4) in two independent data sets; the strongest evidence was with rs986527 in intron 9 of ELP4, providing a likelihood ratio of 629:1 (P=0.0002) in favor of an association. Resequencing of ELP4 coding, flanking and promoter regions revealed no significant exonic polymorphisms. This is the first report of a gene implicated in a common focal epilepsy and the first human disease association of ELP4. ELP4 is a component of the Elongator complex, involved in transcription and tRNA modification. Elongator depletion results in the brain-specific downregulation of genes implicated in cell motility and migration. We hypothesize that a non-coding mutation in ELP4 impairs brain-specific Elongator-mediated interaction of genes implicated in brain development, resulting in susceptibility to seizures and neurodevelopmental disorders.


Interobserver reproducibility in the diagnosis of invasive micropapillary carcinoma of the urinary tract among urologic pathologists.
Invasive micropapillary carcinoma (IMPC) of the urinary tract is a well-described variant of the urothelial carcinoma with aggressive clinical behavior. Recent studies have proposed that patients with IMPC on transurethral resection should be treated with radical cystectomy regardless of the pathologic stage. Despite the potentially important therapeutic implications of this diagnosis, interobserver variation in the diagnosis of IMPC has not been studied. Sixty digital images, each from hematoxylin and eosin-stained slides, representing 30 invasive urothelial carcinomas (2 images per case), were distributed to 14 genitourinary subspecialists and each pathologist was requested to classify cases as IMPC or not. These cases included "classic" IMPC (n=10) and urothelial carcinoma with retraction and variably sized nests that might potentially be regarded as IMPC (n=20). The following 13 morphologic features were recorded as positive/negative for all cases independent of the reviewers' diagnoses: columnar cells, elongate nests or processes, extensive stromal retraction, lumen formation with internal epithelial tufting, epithelial ring forms, intracytoplasmic vacuolization, multiple nests within the same lacunar space, back-to-back lacunar spaces, epithelial nest anastomosis/confluence, marked nuclear pleomorphism, peripherally oriented nuclei, randomly distributed nuclei, and tumor nest size. In addition, a mean tumor nest size was calculated for each image based on the number of nuclei spanning the width of the nests. Interobserver reproducibility was assessed and the morphologic features were correlated with the classic IMPC and nonclassic/potential IMPC groups. In addition, the relationships between morphologic features, pathologists' interpretations, and case type (classic IMPC vs. nonclassic/potential IMPC) were evaluated using unsupervised hierarchical clustering analysis. Interobserver reproducibility for a diagnosis of IMPC in the 30 study cases was moderate (kappa: 0.54). Although classification as IMPC among the 10 "classic" IMPC cases was relatively uniform (93% agreement), the classification in the subset of 20 invasive urothelial carcinomas with extensive retraction and varying sized tumor nests was more variable. Multiple nests within the same lacunar space had the highest association with a diagnosis of classic IMPC. These findings suggest that more study of IMPC is needed to identify the individual pathologic features that might potentially correlate with an aggressive outcome and response to intravesical therapy.


Clinical and molecular characteristics of MEF2D fusion-positive B-cell precursor acute lymphoblastic leukemia in childhood, including a novel translocation resulting in MEF2D-HNRNPH1 gene fusion.
Fusion genes involving MEF2D have recently been identified in precursor B-cell acute lymphoblastic leukemia, mutually exclusive of the common risk stratifying genetic abnormalities, although their true incidence and associated clinical characteristics remain unknown. We identified 16 cases of acute lymphoblastic leukemia and 1 of lymphoma harboring MEF2D fusions, including MEF2D-BCL9 (n=10), MEF2D-HNRNPUL1 (n=6), and one novel MEF2D-HNRNPH1 fusion. The incidence of MEF2D fusions overall was 2.4% among consecutive precursor B-cell acute lymphoblastic leukemia patients enrolled onto a single clinical trial. They frequently showed a cytoplasmic μ chain-positive pre-B immunophenotype, and often expressed an aberrant CD5 antigen. Besides up- and down-regulation of HDAC9 and MEF2C, elevated GATA3 expression was also a characteristic feature of MEF2D fusion-positive patients. Mutations of PHF6, recurrent in T-cell acute lymphoblastic leukemia, also showed an unexpectedly high frequency (50%) in these patients. MEF2D fusion-positive patients were older (median age 9 years) with elevated WBC counts (median: 27,300/ml) at presentation and, as a result, were mostly classified as NCI high risk. Although they responded well to steroid treatment, MEF2D fusion-positive patients showed a significantly worse outcome, with 53.3% relapse and subsequent death. Stem cell transplantation was ineffective as salvage therapy. Interestingly, relapse was frequently associated with the presence of CDKN2A/CDKN2B gene deletions. Our observations indicate that MEF2D fusions comprise a distinct subgroup of precursor B-cell acute lymphoblastic leukemia with a characteristic immunophenotype and gene expression signature, associated with distinct clinical features.


Solitary foraging in the ancestral South American ant, Pogonomyrmex vermiculatus. Is it due to constraints in the production or perception of trail pheromones?
Several North American species of Pogonomyrmex harvester ants exhibit group foraging, whereas South American species are exclusively solitary foragers. The composition of the secretions of the poison and Dufour glands in the South American species, Pogonomyrmex vermiculatus, were analyzed, and the secretions and their components were tested as trail pheromones in laboratory bioassays. The major compounds in the poison gland were the alkylpyrazines, 2,5-dimethylpyrazine, 2,3,5-trimethylpyrazine, and 3-ethyl-2,5-dimethylpyrazine. The Dufour gland contained five alkanes, from tridecane to heptadecane, with pentadecane being most abundant. In behavioral bioassays, poison gland extracts and the mixture of pyrazines produced a trail pheromone effect, whereas the Dufour gland extracts and the alkanes had no effect on ant locomotion. We conclude that group foraging in P. vermiculatus does not arise from the inability to produce or detect possible pheromones, but rather, from physiological and/or ecological factors.


[Association between vitamin D deficiency and metabolic syndrome].
Vitamin D has an essential role in calcium metabolism and bone health. Vitamin D3 or cholecalciferol is synthesized from 7-dehydrocholesterol or provitamin D3, by sunlight ultraviolet radiation to the skin. 7-dehydrocholesterol is subsequently hydroxylated in the liver and then in the kidney to produce 1,25-(OH)2D3, the active metabolite that binds to specific receptors (VDR) in target tissues, mainly bone and intestine. Other tissues, such as the immune and cardiovascular system, have also VDR. Vitamin D deficiency can induce rickets in children and osteomalacia and osteoporosis in adults. A possible inverse association between vitamin D levels and the prevalence of metabolic syndrome has been proposed. Vitamin D deficiency increases the risk of type 1 diabetes, insulin resistance, and hypertension, key components of this syndrome. However, other studies have not confirmed this association. Further clinical and experimental studies are needed to ascertain the role of vitamin D in metabolic syndrome.


Free-standing nanocomposite multilayers with various length scales, adjustable internal structures, and functionalities.
We introduce an innovative and robust method for the preparation of nanocomposite multilayers, which allows accurate control over the placement of functional groups as well as the composition and dimensions of individual layers/internal structure. By employing the photocross-linkable polystyrene (PS-N(3), M(n) = 28.0 kg/mol) with 10 wt % azide groups (-N(3)) for host polymer and/or the PS-N(3)-SH (M(n) = 6.5 kg/mol) with azide and thiol (-SH) groups for capping ligands of inorganic nanoparticles, nanocomposite multilayers were prepared by an efficient photocross-linking layer-by-layer process, without perturbing underlying layers and nanostructures. The thickness of individual layers could be controlled from a few to hundreds of nanometers producing highly ordered internal structure, and the resulting nanocomposite multilayers, consisting of polymer and inorganic nanoparticles (CdSe@ZnS, Au, and Pt), exhibit a variety of interesting physical properties. These include prolonged photoluminescent durability, facile color tuning, and the ability to prepare functional free-standing films that can have the one-dimensional photonic band gap and furthermore be patterned by photolithography. This robust and tailored method opens a new route for the design of functional film devices based on nanocomposite multilayers.


Assessment of precision and concordance of quantitative mitochondrial DNA assays: a collaborative international quality assurance study.
A number of international research groups have developed DNA quantitation assays in order to investigate the role of mitochondrial DNA depletion in anti-retroviral therapy-induced toxicities. A collaborative study was undertaken to evaluate intra-assay precision and between laboratory concordance of measurements of mitochondrial DNA quantity, as a component of a comprehensive quality assurance project. Four laboratories were asked to measure and report mitochondrial DNA and nuclear DNA genome copy number, as well as mitochondrial DNA copy number/cell, for 17 coded aliquots of DNA derived from serial dilutions of pooled DNA from a lymphoblastoid cell line. Samples included masked replicates and five standards. All samples had similar mitochondrial DNA/nuclear DNA ratios. Precision within laboratories was assessed by determining the coefficient of variation of replicates. Concordance between laboratories was assessed by determining the average coefficient of variation of the mean replicate values for each sample. The effect of standardising the assay for these three measurements was also assessed for laboratories A, B and C. Measurements of mitochondrial DNA and nuclear DNA content for replicate samples varied by an average of less than 6% (based on log(10) values, 72% non-logged values), and measurements of mitochondrial DNA/cell for replicates varied by less than 12% (based on log(10) values, 32% non-logged values), with no improvement of precision after standardisation. Standardisation did significantly improve the concordance of results for measurements of mitochondrial DNA content and mitochondrial DNA/cell. Non-standardised measurements of mitochondrial DNA content for the same sample set varied by 19% between laboratories (based on log(10) values, 96% non-logged values), and after standardisation results varied by less than 3% (based on log(10) values, 54% non-logged values). There was no significant improvement for concordance of measures of nuclear DNA content after standardisation, with results varying by 4.56% between laboratories (based on log(10) values, 45% non-logged values) before standardisation, and by 2.49% (based on log(10) values, 50% non-logged values) after standardisation. Derived values of mitochondrial DNA/cell varied between laboratories by an average of 91% (non-logged, 56% log(10) values) before and by 56% (non-logged, 13% log(10) values) after standardisation. All assays demonstrated good precision. The use of common standards is an important step in improving the comparability of data between laboratories.


Immunohistochemical analysis of EGFR and hyaluronan in tongue cancer and the development of regional recurrence in patients initially diagnosed N0.
To investigate whether the extent of expression of hyaluronan (HA) and epidermal growth factor receptor (EGFR) in squamous cell carcinoma of the mobile tongue can predict the risk of cervical metastasis and survival. Retrospective histopathologic study. Surgical specimens from 64 patients who had undergone surgery for squamous cell carcinoma of the mobile tongue were assessed using immunohistochemistry to investigate the expression of HA and EGFR in the primary tumours, and the data were then correlated to cervical metastasis and survival. There was a significant correlation between the intensity of HA staining and patient survival (p .024), and a weak correlation between the staining proportion of EGFR and the risk for regional recurrence (AUC 66). This study indicates that immunoscoring using HA could be used to provide prognostic tools for tongue cancer, and that it might be of interest to study the prognostic properties of EGFR further concerning the risk for regional recurrence after the primary treatment.


Metabolomic profiling in Selaginella lepidophylla at various hydration states provides new insights into the mechanistic basis of desiccation tolerance.
Selaginella lepidophylla is one of only a few species of spike mosses (Selaginellaceae) that have evolved desiccation tolerance (DT) or the ability to 'resurrect' from an air-dried state. In order to understand the metabolic basis of DT, S. lepidophylla was subjected to a five-stage, rehydration/dehydration cycle, then analyzed using non-biased, global metabolomics profiling technology based on GC/MS and UHLC/MS/MS(2) platforms. A total of 251 metabolites including 167 named (66.5%) and 84 (33.4%) unnamed compounds were characterized. Only 42 (16.7%) and 74 (29.5%) of compounds showed significantly increased or decreased abundance, respectively, indicating that most compounds were produced constitutively, including highly abundant trehalose, sucrose, and glucose. Several glycolysis/gluconeogenesis and tricarboxylic acid (TCA) cycle intermediates showed increased abundance at 100% relative water content (RWC) and 50% RWC. Vanillate, a potent antioxidant, was also more abundant in the hydrated state. Many different sugar alcohols and sugar acids were more abundant in the hydrated state. These polyols likely decelerate the rate of water loss during the drying process as well as slow water absorption during rehydration, stabilize proteins, and scavenge reactive oxygen species (ROS). In contrast, nitrogen-rich and γ-glutamyl amino acids, citrulline, and nucleotide catabolism products (e.g. allantoin) were more abundant in the dry states, suggesting that these compounds might play important roles in nitrogen remobilization during rehydration or in ROS scavenging. UV-protective compounds such as 3-(3-hydroxyphenyl)propionate, apigenin, and naringenin, were more abundant in the dry states. Most lipids were produced constitutively, with the exception of choline phosphate, which was more abundant in dry states and likely plays a role in membrane hydration and stabilization. In contrast, several polyunsaturated fatty acids were more abundant in the hydrated states, suggesting that these compounds likely help maintain membrane fluidity during dehydration. Lastly, S. lepidophylla contained seven unnamed compounds that displayed twofold or greater abundance in dry or rehydrating states, suggesting that these compounds might play adaptive roles in DT.