Human autoantibody-reactive epitopes of SS-B/La are highly conserved in comparison with epitopes recognized by murine monoclonal antibodies.
SS-B/La, an ubiquitous nuclear protein of 46-48 kD, is a target antigen of autoantibodies in SLE and Sjogren's syndrome and is involved in the maturation of RNA polymerase III transcripts such as 5S RNA and tRNAs. We have previously shown (14, 15) that SS-B consists of two protease-resistant domains of 23 and 28 kD, with the latter containing the RNA binding site. The epitopes of SS-B/La reactive with human autoantibodies are conserved among several mammalian species examined. BALB/c mice immunized with affinity-purified calf thymus SS-B produce IgG anti-SS-B/La antibodies, which reacted with bovine, human, and rabbit SS-B but not with mouse SS-B/La. The spleen of a mouse with the highest antibody titer was selected for fusion with P3 myeloma. Five IgG1k mAbs (A1-5) were selected by ELISA and immunoblotting. All except A3 reacted with the 28-kD domain. A1, A2, and A3 were capable of immuno-precipitating the 48-kD SS-B protein and its associated RNAs. A1, A2, and A3 also gave fine nuclear speckled staining on human, monkey, bovine, and rabbit cells that was similar in appearance to that with human autoantibodies, but in contrast to staining with human autoantibodies, they did not stain cells from rat, mouse, or rat kangaroo. It appears that human autoantibodies target highly conserved epitopes that can be distinguished from epitopes recognized by immunization-induced murine mAbs. Taken together with other data, it appears that human autoantibodies may be recognizing epitopes that are active or catalytic sites of molecules subserving important cellular functions.


The autonomic nervous system in congestive heart failure.
Congestive heart failure is a complex clinical syndrome characterized by striking abnormalities of the autonomic nervous system. The mechanisms and biological importance of these disturbances are not clearly defined. Nonetheless, it is possible that autonomic disturbances play an important role in the pathophysiology and prognosis of heart failure, and therefore drugs that alter autonomic function may provide additional therapeutic options in the management of this syndrome.


Blueberry Malvidin-3-galactoside Suppresses Hepatocellular Carcinoma by Regulating Apoptosis, Proliferation, and Metastasis Pathways In Vivo and In Vitro.
Anthocyanin, a natural antioxidant, is reported to have cytotoxicity against cancer cells; however, the mechanism remains unclear. The aim of the present study was to investigate the mechanism by which malvidin-3-galactoside (M3G), the prominent anthocyanin in blueberry, suppresses the development of hepatocellular carcinoma. In vitro, M3G suppressed the proliferation, polarization, migration, and invasion activities of HepG2 cells by regulating the protein expression of cyclin D1, cyclin B, cyclin E, caspase-3, cleaved caspase-3, Bax, p-JNK, and p-p38, activating phosphatase and tensin homologue deleted on chromosome 10 (PTEN), accompanied by a decrease in the p-AKT level, and lowering the protein expression levels of MMP-2 and MMP-9. In vivo, M3G promoted the apoptosis of liver tumor cells, as determined by immunohistochemistry (cleaved caspase-3, Ki-67, PTEN, and p-AKT), a terminal deoxynucleotidyl transferase dUTP nick end labeling assay, and hematoxylin-eosin staining. Overall, these results suggest that M3G, as an adjuvant ingredient or nutritional supplement, may be beneficial for liver cancer prevention and the modulatory mechanism seems to be associated with inhibition of proliferation, apoptosis, migration, and invasion-related pathways.


Fermentation with Aspergillus awamori enhanced contents of amino nitrogen and total phenolics as well as the low-density lipoprotein oxidation inhibitory activity of black soybeans.
A solid fermentation was performed on black soybeans with Aspergillus awamori. The effects of fermentation on the contents of total phenolics and amino nitrogen and on the inhibitory effect on low-density lipoprotein (LDL) oxidation of black soybeans were examined. Results revealed that fermentation significantly enhanced the LDL oxidation inhibitory activity and total phenolics and amino nitrogen contents of black soybeans. The increased content of amino nitrogen was closely related to the enhanced LDL oxidation inhibitory activity of fermented black soybeans and its water extract. Fermentation temperature and length affected the LDL oxidation inhibitory effect exerted by the prepared fermented black soybeans. The A. awamori-fermented black soybean prepared at 30 °C for 3 days exhibited the highest inhibitory effect on LDL oxidation. The bioactive principles related to the inhibitory effect on LDL oxidation in black soybeans, regardless of fermentation, could be most efficiently extracted with water rather than 80% methanol or 80% ethanol.


NT3-chitosan enables de novo regeneration and functional recovery in monkeys after spinal cord injury.
Spinal cord injury (SCI) often leads to permanent loss of motor, sensory, and autonomic functions. We have previously shown that neurotrophin3 (NT3)-loaded chitosan biodegradable material allowed for prolonged slow release of NT3 for 14 weeks under physiological conditions. Here we report that NT3-loaded chitosan, when inserted into a 1-cm gap of hemisectioned and excised adult rhesus monkey thoracic spinal cord, elicited robust axonal regeneration. Labeling of cortical motor neurons indicated motor axons in the corticospinal tract not only entered the injury site within the biomaterial but also grew across the 1-cm-long lesion area and into the distal spinal cord. Through a combination of magnetic resonance diffusion tensor imaging, functional MRI, electrophysiology, and kinematics-based quantitative walking behavioral analyses, we demonstrated that NT3-chitosan enabled robust neural regeneration accompanied by motor and sensory functional recovery. Given that monkeys and humans share similar genetics and physiology, our method is likely translatable to human SCI repair.


Berberine suppresses androgen receptor signaling in prostate cancer.
The androgen receptor (AR) is critical in the normal development and function of the prostate, as well as in prostate carcinogenesis. Androgen deprivation therapy is the mainstay in the treatment of advanced prostate cancer; however, after an initial response, the disease inevitably progresses to castration-resistant prostate cancer (CRPC). Recent evidence suggests that continued AR activation, sometimes in a ligand-independent manner, is commonly associated with the development of CRPC. Thus, novel agents targeting the AR are urgently needed as a strategic step in developing new therapies for this disease state. In this study, we investigated the effect of berberine on AR signaling in prostate cancer. We report that berberine decreased the transcriptional activity of AR. Berberine did not affect AR mRNA expression, but induced AR protein degradation. Several ligand-binding, domain-truncated AR splice variants have been identified, and these variants are believed to promote the development of CRPC in patients. Interestingly, we found that these variants were more susceptible to berberine-induced degradation than the full-length AR. Furthermore, although the growth of LNCaP xenografts in nude mice was inhibited by berberine, and AR expression was reduced in the tumors, the morphology and AR expression in normal prostates were not affected. This study is the first to show that berberine suppresses AR signaling and suggests that berberine, or its derivatives, presents a promising agent for the prevention and/or treatment of prostate cancer.


Cocaine self-administration differentially activates microglia in the mouse brain.
The evidence showing the involvement of microglial activation in the development of drug addiction remain scarce as microglia have not been systematically investigated in self-administered mice, a gold standard rodent model for drug addiction. Here we established the stable cocaine self-administration mice to examine microglial activation levels in various brain regions related to reward circuitry. Immunostaining for Iba1 showed a significant upregulation of intensity in the striatum but not in the medial prefrontal cortex (mPFc), hippocampus or thalamus. Further validation experiments showed that cocaine self-administered mice had significantly increased mRNA expression of ccl2 and IL1β in the striatum but not the mPFc compared to saline controls. Consistently, we found elevated protein levels of Iba1, CCL2, TLR4 and mature IL1β in the striatum, not in the mPFc of cocaine-receiving mice. In addition, cocaine-stimulated microglia had modified morphology including a reduced number of intersections, a shortened length and number of processes in the NAc. In summary, our results demonstrated that cocaine mediated microglial activation in a region-specific manner in vivo. These findings indicate that microglia could be activated in the early stage of cocaine addiction directly supporting the rationale that dysregulation on neuroimmune signaling is inherently involved in the development of drug addiction.


Life beyond cancer: women's experiences 5 years after treatment for gynaecological cancer.
The number of long-term survivors after cancer is increasing, mainly as a consequence of more efficient treatment. This creates a need for knowledge about experiences of life after cancer. The aim of this study is to gain a deeper understanding of lived experience of long-term cancer survivors and how they experienced cancer care. A qualitative study was performed, based on 32 in-depth interviews with 16 women declared as long-term survivors, aged 39-66. The first interview was made 5 years after treatment and the second a year later. The study has a phenomenological-hermeneutical approach in which the women's own experiences are the basis for understanding their life-world. The long-term surviving women experienced profound changes in their lives and had to adapt to new ways of living. Three core themes were identified: living with tension between personal growth and fear of recurrence: the women spoke of a deep gratitude for being alive and of basic values that had become revitalized. They also lived with a preparedness for recurrence of cancer. Living in a changed female body: the removal of reproductive organs raised questions about sexual life and difficulties related to menopause. Feeling left alone - not receiving enough information and guidance after treatment: the process of sorting things out, handling anxiety, bodily changes and menopause were described as a lonesome journey, existentially and psycho-socially. The findings are discussed in relation to Heidegger's perspective of anxiety towards death, existential loneliness and humans as self-interpreting beings. Surviving cancer entails living with profound life-changes, demanding as well as enriching. Existing follow-up regimes need to sharpen focus on psycho-social aspects, information and guidance. Additional follow-up programmes, focusing solely on the individual woman and her specific needs, are necessary.


Methylmercury exposure, PON1 gene variants and serum paraoxonase activity in Eastern James Bay Cree adults.
There is growing evidence that cardiovascular health can be affected by exposure to methylmercury (MeHg), by a mechanism involving oxidative stress. Paraoxonase 1 (PON1) is a high-density lipoprotein-bound enzyme that hydrolyzes toxic oxidized lipids and protects against cardiovascular diseases. Evidence from in vitro studies indicates that MeHg can inhibit PON1 activity but little is known regarding this effect in humans. We investigated whether increased blood mercury levels are associated with decreased serum PON1 activity in Cree people who are exposed to MeHg by fish consumption. We conducted a multi-community study of 881 Cree adults living in Eastern James Bay communities (Canada). Multivariate analyses considered sociodemographic, anthropometric, clinical, dietary and lifestyle variables and six PON1 gene variants (rs705379 (-108C/T), rs662 (Q192R), rs854560 (L55M), rs854572 (-909C/G), rs854571 (-832C/T) and rs705381 (-162C/T)). In a multiple regression model adjusted for all potential confounding factors and the rs854560 PON1 variant, a statistically significant MeHg*rs705379 interaction was observed. Blood mercury levels were inversely associated with serum PON1 activities in individual homozygous for the -108T allele (P=0.009). Our results suggest a gene-environment interaction between the rs705379 polymorphism and MeHg exposure on PON1 activity levels in this aboriginal population. This finding will need to be replicated in other population studies.


A health priorities model: application to mammography screening.
This study describes and empirically tests a health priorities model. This model predicts underuse of regular mammography screening among adult women within the larger health context in which such decisions are made. The model incorporates women's comparative illness threats, comparative importance of health behaviors, and demographic variables. A telephone survey was conducted with a sample of women (N = 887) older than 50, in 40 rural communities in the state of Washington. Logistic regression analyses showed that women who perceived themselves at low risk for getting breast cancer and/or who perceived another disease (i.e. heart attack) as an equal or greater threat than breast cancer were less likely to be regular screeners of mammography. In addition, women who perceived other health behaviors as more important than regular mammography screening were less likely to be regular screeners than those women who perceived regular mammography screening as more important. Current or anticipated health problems were not related to screening behavior. The results are discussed in light of the practical, theoretical, and empirical implications.


Modulation of Proteome Profile in AβPP/PS1 Mice Hippocampus, Medial Prefrontal Cortex, and Striatum by Palm Oil Derived Tocotrienol-Rich Fraction.
Tocotrienol-rich fraction (TRF) is a mixture of vitamin E analogs derived from palm oil. We previously demonstrated that supplementation with TRF improved cognitive function and modulated amyloid pathology in AβPP/PS1 mice brains. The current study was designed to examine proteomic profiles underlying the therapeutic effect of TRF in the brain. Proteomic analyses were performed on samples of hippocampus, medial prefrontal cortex (mPFC), and striatum using liquid chromatography coupled to Q Exactive HF Orbitrap mass spectrometry. From these analyses, we profiled a total of 5,847 proteins of which 155 proteins were differentially expressed between AβPP/PS1 and wild-type mice. TRF supplementation of these mice altered the expression of 255 proteins in the hippocampus, mPFC, and striatum. TRF also negatively modulated the expression of amyloid beta A4 protein and receptor-type tyrosine-protein phosphatase alpha protein in the hippocampus. The expression of proteins in metabolic pathways, oxidative phosphorylation, and those involved in Alzheimer's disease were altered in the brains of AβPP/PS1 mice that received TRF supplementation.


Modelling an industrial anaerobic granular reactor using a multi-scale approach.
The objective of this paper is to show the results of an industrial project dealing with modelling of anaerobic digesters. A multi-scale mathematical approach is developed to describe reactor hydrodynamics, granule growth/distribution and microbial competition/inhibition for substrate/space within the biofilm. The main biochemical and physico-chemical processes in the model are based on the Anaerobic Digestion Model No 1 (ADM1) extended with the fate of phosphorus (P), sulfur (S) and ethanol (Et-OH). Wastewater dynamic conditions are reproduced and data frequency increased using the Benchmark Simulation Model No 2 (BSM2) influent generator. All models are tested using two plant data sets corresponding to different operational periods (#D1, #D2). Simulation results reveal that the proposed approach can satisfactorily describe the transformation of organics, nutrients and minerals, the production of methane, carbon dioxide and sulfide and the potential formation of precipitates within the bulk (average deviation between computer simulations and measurements for both #D1, #D2 is around 10%). Model predictions suggest a stratified structure within the granule which is the result of: 1) applied loading rates, 2) mass transfer limitations and 3) specific (bacterial) affinity for substrate. Hence, inerts (XI) and methanogens (Xac) are situated in the inner zone, and this fraction lowers as the radius increases favouring the presence of acidogens (Xsu,Xaa, Xfa) and acetogens (Xc4,Xpro). Additional simulations show the effects on the overall process performance when operational (pH) and loading (S:COD) conditions are modified. Lastly, the effect of intra-granular precipitation on the overall organic/inorganic distribution is assessed at: 1) different times; and, 2) reactor heights. Finally, the possibilities and opportunities offered by the proposed approach for conducting engineering optimization projects are discussed.


Moving in time: Simulating how neural circuits enable rhythmic enactment of planned sequences.
Many complex actions are mentally pre-composed as plans that specify orderings of simpler actions. To be executed accurately, planned orderings must become active in working memory, and then enacted one-by-one until the sequence is complete. Examples include writing, typing, and speaking. In cases where the planned complex action is musical in nature (e.g. a choreographed dance or a piano melody), it appears to be possible to deploy two learned sequences at the same time, one composed from actions and a second composed from the time intervals between actions. Despite this added complexity, humans readily learn and perform rhythm-based action sequences. Notably, people can learn action sequences and rhythmic sequences separately, and then combine them with little trouble (Ullén & Bengtsson 2003). Related functional MRI data suggest that there are distinct neural regions responsible for the two different sequence types (Bengtsson et al. 2004). Although research on musical rhythm is extensive, few computational models exist to extend and inform our understanding of its neural bases. To that end, this article introduces the TAMSIN (Timing And Motor System Integration Network) model, a systems-level neural network model capable of performing arbitrary item sequences in accord with any rhythmic pattern that can be represented as a sequence of integer multiples of a base interval. In TAMSIN, two Competitive Queuing (CQ) modules operate in parallel. One represents and controls item order (the ORD module) and the second represents and controls the sequence of inter-onset-intervals (IOIs) that define a rhythmic pattern (RHY module). Further circuitry helps these modules coordinate their signal processing to enable performative output consistent with a desired beat and tempo.


Detection of Acoustic Plasmons in Hole-Doped Lanthanum and Bismuth Cuprate Superconductors Using Resonant Inelastic X-Ray Scattering.
High T_{c} superconductors show a rich variety of phases associated with their charge degrees of freedom. Valence charges can give rise to charge ordering or acoustic plasmons in these layered cuprate superconductors. While charge ordering has been observed for both hole- and electron-doped cuprates, acoustic plasmons have only been found in electron-doped materials. Here, we use resonant inelastic x-ray scattering to observe the presence of acoustic plasmons in two families of hole-doped cuprate superconductors (La_{1.84}Sr_{0.16}CuO_{4} and Bi_{2}Sr_{1.6}La_{0.4}CuO_{6+δ}), crucially completing the picture. Interestingly, in contrast to the quasistatic charge ordering which manifests at both Cu and O sites, the observed acoustic plasmons are predominantly associated with the O sites, revealing a unique dichotomy in the behavior of valence charges in hole-doped cuprates.


Analysis of structural changes during hypotonic swelling in Ehrlich ascites tumor cells.
Studies were undertaken to quantify structural changes associated with swelling of Ehrlich ascites tumor cells in hypotonic medium. Cells transferred from isotonic (294 mosmol/kg H2O) to hypotonic (98 mosmol/kg H2O) medium swelled rapidly. Subsequently, approximately 40% of the water initially gained was lost, a phenomenon referred to as volume-regulatory decrease (VRD). During the initial rapid cell swelling, blister-like protrusions or blebs were formed on the cell surface. These blebs were examined by routine light microscopy, differential interference-contrast (DIC) microscopy, and scanning and transmission electron microscopy. Microscopic observations and the distribution of ATPase antibodies indicated that the blebs were formed from plasma membrane. During VRD, the blebs coalesced to form a smooth but expanded membrane surface that appeared to be separated from the original cytoplasm by a layer of less dense ground substance. Computer-assisted morphometry from digitized DIC images of the initial swelling phase indicated that all of the volume gained was sequestered in the blebs. We suggest that bleb formation may allow increases in cell volume without disruption of cytoplasmic organization and may be a protective response to a variety of stressful stimuli. The subsequent VRD is accompanied by reduction of this expanded compartment.


Adjuvant action of capsular polysaccharide of Klebsiella pneumoniae on antibody response. VIII. Its effect on the size and the number of cells of regional lymph node and other lymphoid organs.
Changes in the number of cells and the weight of various lymphoid organs of mice, such as the regional lymph node (right inguinal node), spleen, thymus, bone marrow, and peripheral blood, were followed after the subcutaneous injection of the capsular polysaccharide of Klebsiella pneumoniae (CPS-K). For comparison, the changes after injection of various polyclonal lymphocyte activators (PLA) including various preparations of bacterial lipopolysaccharide (LPS) were concurrently studied. The number of cells of all of the lymphoid organs tested and that of nucleated cells in the peripheral blood decreased significantly within a few days after injection of CPS-K, and increased later. Above all, the increase in the number of cells and in the weight of the regional lymph node was most prominent (about 10 times larger than that of the normal control). Such a marked increase in the number of cells of the regional lymph node was not induced by the injection of any preparation of LPS or any other PLA tested. The initial decrease in the number of cells after CPS-K injection was most marked and long lasting in the thymus. Although LPS prepared by Westphal's method from Escherichia coli 055 or Salmonella enteritidis exhibited a stronger decreasing effect on the number of cells of the thymus, the effect of LPS prepared by Westphal's method from E. coli O111 or that by Boivin's method from E. coli O55 was similar to that of CPS-K. It is concluded therefore that CPS-K has the ability to decrease the number of cells of various lymphoid organs, especially that of the thymus, initially after injection, which is a property in common with LPS, and CPS-K has a unique ability to increase markedly the cells of various lymphoid organs, especially those of the regional lymph node, at later stages after injection. Considering that CPS-K exhibits a much stronger adjuvant effect on the antibody response than does LPS or other polyclonal lymphocyte activators, it is suggested that this extraordinarily potent activity of CPS-K in increasing the number of cells of the regional lymph node is closely related to its strong adjuvant action.


Detection of RB1 deletions by fluorescence in situ hybridization in malignant hematologic disorders.
We evaluated the usefulness of fluorescence in situ hybridization (FISH) using different-colored commercial RB1 and 13qter DNA probes to identify RB1 deletions in interphase nuclei of bone marrow from 24 patients with agnogenic myeloid metaplasia (AMM), 20 patients with multiple myeloma (MM), 21 patients with other hematologic malignancies, and 25 normal bone marrow transplant (BMT) donors. Based on the 25 normal BMT donors, the upper boundary for the normal percentage of nuclei with one RB1 signal was 6.5%. Based on eight specimens known to have a deletion of 13q14 by cytogenetic studies, the lower limit of abnormal for the percentage of nuclei with one RB1 signal was 12.5%. More than 12.5% of nuclei had a single RB1 signal in 7/24 (29%) patients with AMM and 3/20 (15%) patients with MM. None of the 21 patients with hematologic malignancies other than AMM or MM had more than 12.5% nuclei with loss of RB1. The results of this study suggest that FISH with RB1 probes is useful to detect loss of RB1 in interphase nuclei from patients with hematologic disorders who have chromosome abnormalities involving 13q14. Thus, FISH with probes for RB1 is efficacious to investigate the pathogenesis of RB1 in malignant neoplasms and is a useful adjunct to conventional cytogenetic studies in clinical practice when abnormalities of 13q14 are involved.


Splicing abnormalities in congenital myasthenic syndromes.
A total of 173 mutations has been reported to date in eight genes in congenital myasthenic syndromes. Sixteen intronic and five exonic mutations in three genes affect pre-mRNA splicing. Eight of these are of particular interest, and are reviewed in this article. An A-to-G mutation at intron position +3 results in exon skipping only when there are mismatched nucleotides to U1 snRNA at positions +4 to +6. Similarly, a mutation at the last nucleotide of an exon causes exon skipping when a nucleotide at position +6 is not complementary to U1 snRNA. We observe the similar compensation mechanisms for mismatches to U1 snRNA at 179,917 native human splice donor sites. A 7-bp deletion in CHRNE exon 7 causes skipping of the preceding 101-bp exon 6. We found in general that the nonsense-mediated altered splicing of a remote exon (NASRE) is mediated by inherent weak splicing signals flanking the skipped exon and degradation of a normally spliced transcript by the nonsense-mediated mRNA decay (NMD). A 16-bp duplication spanning the CHRNE intron 10/exon 11 boundary generates two copies of 3' splice sites, and the downstream copy is exclusively silenced. Analysis of a series of artificial mutants conforms to the scanning model of recognition of the 3' splice site that predicts that the first 'ag' more than 13 nucleotides downstream of the branch point is selected for splicing. Splicing mutations may be more frequent than suspected, and one must always be aware of possible splicing abnormalities when analyzing human mutations.


A differential PCR assay for the detection of c-erbB 2 amplification used in a prospective study of breast cancer.
To establish a robust differential polymerase chain reaction (PCR) assay for the detection of c-erbB 2 amplification in breast cancer that can be used in a routine pathology laboratory. Once established, the assay was used in a prospective study of breast tumours to investigate the relation between c-erbB 2 amplification and both recognised prognostic features and short term clinical outcome. The differential PCR was used for the co-amplification of c-erbB 2 and a reference gene from 48 tumour DNA samples and control DNA samples. The ratio of the two genes was determined by image analysis of the PCR products electrophoresed on a highly resolving agarose gel. The differential PCR assay was shown to be accurate and reproducible using the conditions outlined. Twenty six per cent of the breast cancer patients were shown to have c-erbB 2 amplification in their tumour biopsies. Twenty eight per cent of the patients died of their disease or had disease recurrence during the follow up period and 73% of these patients had amplification of c-erbB 2. A significant association was found between c-erbB 2 amplification and early disease recurrence. This assay could be used to provide a marker for poor prognosis in breast cancer.


A ribosomal protein AgRPS3aE from halophilic Aspergillus glaucus confers salt tolerance in heterologous organisms.
High salt in soils is one of the abiotic stresses that significantly reduces crop yield, although saline lands are considered potential resources arable for agriculture. Currently, genetic engineering for enhancing salt tolerance is being tested as an efficient and viable strategy for crop improvement. We previously characterized a large subunit of the ribosomal protein RPL44, which is involved in osmotic stress in the extremely halophilic fungus Aspergillus glaucus. Here, we screened another ribosomal protein (AgRPS3aE) that also produced high-salt tolerance in yeast. Bioinformatics analysis indicated that AgRPS3aE encodes a 29.2 kDa small subunit of a ribosomal protein belonging to the RPS3Ae family in eukaryotes. To further confirm its protective function against salinity, we expressed AgRPS3aE in three heterologous systems, the filamentous fungus Magnaporthe oryzae and two model plants Arabidopsis and tobacco. Overexpression of AgRPS3aE in all tested transformants significantly alleviated stress symptoms compared with controls, suggesting that AgRPS3aE functions not only in fungi but also in plants. Considering that ribosomal proteins are housekeeping components in organisms from prokaryotes to eukaryotes, we propose that AgRPS3aE is one of the optimal genes for improving high-salt tolerance in crops.


Temperature tolerance of different larval stages of the spider crab Hyas araneus exposed to elevated seawater PCO2.
Exposure to elevated seawater PCO2 limits the thermal tolerance of crustaceans but the underlying mechanisms have not been comprehensively explored. Larval stages of crustaceans are even more sensitive to environmental hypercapnia and possess narrower thermal windows than adults. In a mechanistic approach, we analysed the impact of high seawater CO2 on parameters at different levels of biological organization, from the molecular to the whole animal level. At the whole animal level we measured oxygen consumption, heart rate and activity during acute warming in zoea and megalopa larvae of the spider crab Hyas araneus exposed to different levels of seawater PCO2. Furthermore, the expression of genes responsible for acid-base regulation and mitochondrial energy metabolism, and cellular responses to thermal stress (e.g. the heat shock response) was analysed before and after larvae were heat shocked by rapidly raising the seawater temperature from 10°C rearing temperature to 20°C. Zoea larvae showed a high heat tolerance, which decreased at elevated seawater PCO2, while the already low heat tolerance of megalopa larvae was not limited further by hypercapnic exposure. There was a combined effect of elevated seawater CO2 and heat shock in zoea larvae causing elevated transcript levels of heat shock proteins. In all three larval stages, hypercapnic exposure elicited an up-regulation of genes involved in oxidative phosphorylation, which was, however, not accompanied by increased energetic demands. The combined effect of seawater CO2 and heat shock on the gene expression of heat shock proteins reflects the downward shift in thermal limits seen on the whole animal level and indicates an associated capacity to elicit passive thermal tolerance. The up-regulation of genes involved in oxidative phosphorylation might compensate for enzyme activities being lowered through bicarbonate inhibition and maintain larval standard metabolic rates at high seawater CO2 levels. The present study underlines the necessity to align transcriptomic data with physiological responses when addressing mechanisms affected by an interaction of elevated seawater PCO2 and temperature extremes.


Experience with monovalent and bivalent influenza vaccines in Canada 1976. Clinical evaluation of vaccines from four sources.
Clinical trials in adults of monovalent (200 CCA Units per dose) and bivalent (400 CCA Units per dose) inactivated influenza whole virus A/Swine and A/Victoria vaccines from different sources resulted in variations in clinical reactivity which may not be significant because of lack of controls and observer bias. In adults with no pre-vaccine antibody (HI less than 1/10) the A/Swine Monovalent vaccine from one source evoked significantly lower response than did the A/Swine component of the Bivalent vaccine from another source. Serologic response to A/Victoria antigen was comparable for vaccines prepared with material from two sources. In medically high risk children two doses of Bivalent A/Swine A/Victoria influenza vaccine, with the dosage adjusted according to age, stimulated acceptable serologic response without an unacceptable frequency of local and general reactions. The response was higher in the youngest and older age groups included in the clinical trial than in the seven to twelve year old group implying a dose to age relationship.


Attenuation of pain and inflammation in adjuvant-induced arthritis by the proteasome inhibitor MG132.
In rheumatoid arthritis (RA), pain and joint destruction are initiated and propagated by the production of proinflammatory mediators. Synthesis of these mediators is regulated by the transcription factor NF-kappaB, which is controlled by the ubiquitin proteasome system (UPS). The present study explored the effects of the proteasome inhibitor MG132 on inflammation, pain, joint destruction, and expression of sensory neuropeptides as markers of neuronal response in a rat model of arthritis. Arthritis was induced in rats by injection of heat-killed Mycobacterium butyricum. Arthritis severity was scored, and nociception was evaluated by mechanical pressure applied to the hind paw. Joint destruction was assessed by radiologic and histologic analyses. NF-kappaB DNA-binding activity was analyzed by electromobility shift assay, and changes in the expression of the p50 NF-kappaB subunit and the proinflammatory neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) were detected by immunohistochemistry. Arthritic rats treated with MG132 demonstrated a marked reduction in inflammation, pain, and joint destruction. The elevated DNA-binding activity of the NF-kappaB/p50 homodimer and p50, as well as the neuronal expression of SP and CGRP, observed in the ankle joints of arthritic rats were normalized after treatment with MG132. In arthritic rats, inhibition of proteasome reduced the severity of arthritis and reversed the pain behavior associated with joint inflammation. These effects may be mediated through the inhibition of NF-kappaB activation and may possibly involve the peripheral nervous system. New generations of nontoxic proteasome inhibitors may represent a novel pharmacotherapy for RA.


Motivators and barriers to HIV testing among street-based female sex workers in St. Petersburg, Russia.
Female sex workers are particularly susceptible to HIV-infection in Russia. However, a dearth of information exists on their utilisation of HIV services. A mixed-methods, cross-sectional study was conducted to examine motivators and barriers to HIV testing among street-based sex workers in St. Petersburg, Russia. The health belief model was the theoretical framework for the study. Twenty-nine sex workers participated in in-depth interviews, and 139 sex workers completed interviewer-administered surveys between February and September 2009. Barriers to getting an HIV test were fear of learning the results, worrying that other people would think they were sick, and the distance needed to travel to obtain services. Motivators for getting tested were protecting others from infection, wanting to know one's status and getting treatment if diagnosed. Logistic regression analysis demonstrated that knowing people living with HIV [aOR = 6.75, 95% CI (1.11, 41.10)] and length of time since start of injection drug use [aOR = 0.30, 95% CI (0.09, 0.97)] were significantly associated with recently getting tested. These results are important to consider when developing public health interventions to help female sex workers in Russia learn their HIV status and get linked to care and treatment services if needed.


Definition of Personalized Medicine and Targeted Therapies: Does Medical Familiarity Matter?
Personalized medicine (PM) is increasingly becoming a topic of discussion in public health policies and media. However, there is no consensus among definitions of PM in the scientific literature and the terms used to designate it, with some definitions emphasizing patient-centered aspects and others emphasizing biomedical aspects. Furthermore, terms used to refer to PM (e.g., "pharmacogenomics" or, more often, "targeted therapies") are diverse and differently used. To our knowledge, no study has apprehended the differences of definition and attitudes toward personalized medicine and targeted therapies according to level of familiarity with the medical field. Our cohort included 349 French students from three different academic fields, which modulated their familiarity level with the medical field. They were asked to associate words either to "personalized medicine" or "target therapies". Then, they were asked to give an emotional valence to their associations. Results showed that nonfamiliar students perceived PM as more positive than targeted therapies (TT), whereas familiar students showed no difference. Only familiar students defined PM and TT with technical aspects such as genetics or immunology. Further studies are needed in the field in order to determine which other factors could influence the definitions of PM and TT and determine how these definitions could have an impact in a clinical setting.


The WWP1 ubiquitin E3 ligase increases TRAIL resistance in breast cancer.
WW domain containing E3 ubiquitin protein ligase 1 (WWP1) is an HECT domain-containing E3 ligase regulating apoptosis. The WWP1 gene is frequently amplified and overexpressed in estrogen receptor α (ERα)-positive breast cancer. Inhibition of WWP1 by siRNA induced apoptosis in MCF7 and HCC1500. In our study, we demonstrate that WWP1 depletion by siRNA activated the extrinsic apoptotic pathway. WWP1 depletion-induced apoptosis was rescued by the overexpression of the wild-type WWP1 but not the E3 ligase inactive WWP1-C890A mutant in MCF7 cells. In contrast, WWP1-C890A enhanced apoptosis, suggesting that the E3 ligase activity is required for WWP1 to promote cell survival. The expression levels of WWP1 in four breast cancer cell lines were specifically correlated with the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) resistance, but not TNFα and doxorubicin resistance. Both WWP1 depletion and dominant negative WWP1 overexpression increased the TRAIL-induced caspase-8 recruitment and apoptosis although WWP1 did not regulate FLIP and death receptor levels. Depletion of the initial caspase-8 blocked WWP1 inhibition-induced apoptosis in MCF7. These findings suggest that inhibition of WWP1 may be combined with TRAIL to suppress ERα-positive breast cancer cell survival.


Quantifying the Resistive Losses of the Catalytic Layers in Anion-Exchange Membrane Fuel Cells.
The existing gap in the ability to quantify the impacts of resistive losses on the performance of anion-exchange membrane fuel cells (AEMFCs) during the lifetime of their operation is a serious concern for the technology. In this paper, we analyzed the ohmic region of an operating AEMFC fed with pure oxygen followed by CO2 -free air at various operating currents, using a combination of electrochemical impedance spectroscopy (EIS) and a novel technique called impedance spectroscopy genetic programming (ISGP). Presented here for the first time in this work, we isolated and quantified the individual effective resistance (Reff ) values occurring in the AEMFC and their influence on performance as operating conditions change. We believe that this first work is vital to help distinguish the influence of the individual catalytic and mass-transfer processes in this technology thereby providing valuable data to the AEMFC community, with potentially wider applicability to other electrochemical devices where individual physical processes occur simultaneously and need to be sequestered for deeper understanding.


Comorbid Conditions, Mental Health and Cognitive Functions in Adults with Fibromyalgia.
This study examined age group differences across adulthood in comorbid conditions, mental health, and cognitive function in people with fibromyalgia. Participants completed an online survey about how fibromyalgia affects their everyday life. Chi square analyses were conducted to examine associations between age groups and (a) comorbid conditions and (b) severity of anxiety and depression. ANOVA analyses examined age group differences on aspects of self-report cognitive function. The greatest prevalence of comorbid conditions was found in middle adulthood. Early adulthood was associated with more cases of severe anxiety with the lowest number of cases being in the oldest age group. Middle adulthood was associated with worse self-report pain compared to the youngest age group. Older adults showed better self-report cognitive function compared to younger adults. Distinct age profiles based on comorbid conditions, mental health, and symptom severity across adulthood in fibromyalgia have been demonstrated.


Receptor binding sites for atrial natriuretic factor are expressed by brown adipose tissue.
To explore the possibility that atrial natriuretic factor (ANF) is involved in thermoregulation we used quantitative receptor autoradiography and homogenate receptor binding assays to identify ANF bindings sites in neonatal rat and sheep brown adipose tissue, respectively. Using quantitative receptor autoradiography were were able to localize high levels of specific binding sites for 125I-rat ANF in neonatal rat brown adipose tissue. Homogenate binding assays on sheep brown fat demonstrated that the radioligand was binding to the membrane fraction and that the specific binding was not due to a lipophilic interaction between 125I-rat ANF and brown fat. Specific binding of 125I-rat ANF to the membranes of brown fat cells was inhibited by unlabeled rat ANF with a Ki of 8.0 x 10(-9) M, but not by unrelated peptides. These studies demonstrate that brown fat cells express high levels of ANF receptor binding sites in neonatal rat and sheep and suggest that ANF may play a role in thermoregulation.


One-step-immunoassay of procalcitonin enables rapid and accurate diagnosis of bacterial infection.
Procalcitonin (PCT) (i.e. a precursor of calcitonin) attracts much attention as a reliable biomarker of bacterial infections because its concentration increases rapidly in the blood when bacterial infections occur in the body. Sepsis may occur due to indiscriminate and vigorous proliferation of infectious bacteria, and accordingly early diagnosis and treatment of bacterial infection are of crucial importance. However, current diagnostic methods for sepsis suffer from long assay time, multiple and complex assay steps, inaccuracy, and requirement of analytical equipments. The goal of this study is to develop an advanced one-step-immunoassay that enables quick and accurate diagnosis of sepsis through measuring the PCT concentration in patient sera, which is based on self-enhancement of optical detection signals from large gold particles (i.e. clusters of gold nanoparticles) that are formed on the agglomerates of PCT-bound 3-dimensional (3D) probes. The 3D probe is constructed through attaching polyclonal anti-PCT antibodies (IgGs) to the surface of a modified hepatitis B virus (HBV) capsid, where both tandem repeats of the B domain of Staphylococcal protein A (SPAB) and the hexa-histidine tag are inserted into each HBV core protein (i.e. subunit of HBV capsid). That is, anti-PCT IgGs are attached via strong interaction between the Fc region and surface-exposed SPAB. Furthermore, hook effect-free and PCT concentration-dependent optical signals were consistently generated by adding both bovine serum albumin (BSA) and nickel ions to patient sera and also by optimally adjusting the 3D probe concentration. Compared to conventional chemiluminescent microparticle immunoassay (CMIA) showing poor linearity of detection signals, this novel immunoassay accurately detected PCT with good linearity between PCT concentrations and optical signals in a wide range of PCT concentrations (0.05-200 ng mL-1) and also showed a sufficiently low limit of detection, resulting in 100% sensitivity and 100% specificity when tested with 30 sepsis patients and 30 healthy individuals.


Dose-related antihypertensive effects of irbesartan in patients with mild-to-moderate hypertension.
Two multicenter, double-blind, placebo-controlled, parallel group studies were conducted to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of the angiotensin II receptor (AT1 subtype) antagonist irbesartan. The effect of irbesartan withdrawal and the effect of adding hydrochlorothiazide (HCTZ) to irbesartan were also assessed. After a placebo lead-in phase, all patients were randomized to 8 weeks of double-blind therapy with either placebo (n = 158) or irbesartan at doses of 1, 5, 10, 25, 50, 100, 200, or 300 mg (n = 731 total) orally once daily. Irbesartan reduced blood pressure in a dose-related manner. Reductions from baseline in trough seated diastolic blood pressure ranged from 7.5 mm Hg for 50 mg irbesartan to 11.6 mm Hg for 300 mg irbesartan. At week 8, statistically significant reductions over placebo were observed in trough seated blood pressure with all irbesartan doses > or = 50 mg. These reductions reached statistical significance versus placebo within 2 weeks with 100, 200, and 300 mg irbesartan. Plasma irbesartan concentrations correlated with dose. Angiotensin II and aldosterone levels generally showed dose-related changes, consistent with AT1 receptor blockade. In patients not controlled at 8 weeks, the addition of 12.5 mg HCTZ resulted in further dose-related reductions in blood pressure. Irbesartan demonstrated a placebo-like safety profile and no dose-related toxicity. Irbesartan, administered alone or in combination with HCTZ, was well tolerated. Withdrawal of irbesartan did not result in rebound hypertension or adverse events. Thus, once-daily irbesartan is both an effective and safe antihypertensive agent for the treatment of mild-to-moderate hypertension.


Condensed phase QM/MM simulations utilizing the exchange core functions to describe exchange repulsions at the QM boundary region.
In a recent work, we developed a method [H. Takahashi et al., J. Chem. Phys. 143, 084104 (2015)] referred to as exchange-core function (ECF) approach, to compute exchange repulsion Eex between solute and solvent in the framework of the quantum mechanical (QM)/molecular mechanical (MM) method. The ECF, represented with a Slater function, plays an essential role in determining Eex on the basis of the overlap model. In the work of Takahashi et al. [J. Chem. Phys. 143, 084104 (2015)], it was demonstrated that our approach is successful in computing the hydrogen bond energies of minimal QM/MM systems including a cationic QM solute. We provide in this paper the extension of the ECF approach to the free energy calculation in condensed phase QM/MM systems by combining the ECF and the QM/MM-ER approach [H. Takahashi et al., J. Chem. Phys. 121, 3989 (2004)]. By virtue of the theory of solutions in energy representation, the free energy contribution δμex from the exchange repulsion was naturally formulated. We found that the ECF approach in combination with QM/MM-ER gives a substantial improvement on the calculation of the hydration free energy of a hydronium ion. This can be attributed to the fact that the ECF reasonably realizes the contraction of the electron density of the cation due to the deficit of an electron.


Vitamin D receptor gene polymorphisms and susceptibility M. tuberculosis in native Paraguayans.
Tuberculosis (TB) is a significant health problem for most of the world's populations, and prevalence among indigenous groups is typically higher than among their nonindigenous neighbors. Native South Americans experience high rates of TB, but while research in several other world populations indicates that susceptibility is multifactorial, polygenic, and population-specific, little work has been undertaken to investigate factors involved in Native American susceptibility. We conducted a family-based association study to examine immunologically relevant polymorphisms of a candidate gene, the vitamin D receptor, in conjunction with three measures of TB status in two Native Paraguayan populations, the Aché and the Avá. This is the first large-scale genetic analysis of Native South Americans to examine susceptibility to both infection and disease following exposure to M. tuberculosis. These two types of susceptibility reflect differences in innate and acquired immunity that have proven difficult to elucidate in other populations. Our results indicate that among the Aché, the FokI F allele protects individuals from infection, while the TaqI t allele protects against active disease but not infection. In particular, FF homozygotes are 17 times more likely to test positive for exposure to TB, but no more likely to have ever been diagnosed with active TB. TT individuals are 42 times less likely to mount a delayed-type hypersensitivity response, and the T allele was significantly more likely to have been transmitted to offspring who have been diagnosed with active TB. This ongoing research is of vital importance to indigenous groups of the Americas, because if there is a population-specific component to TB susceptibility, it will likely prove most effective to incorporate this into future treatment and prevention strategies.


Sticklebacks adapted to divergent osmotic environments show differences in plasticity for kidney morphology and candidate gene expression.
Novel physiological challenges in different environments can promote the evolution of divergent phenotypes, either through plastic or genetic changes. Environmental salinity serves as a key barrier to the distribution of nearly all aquatic organisms, and species diversification is likely to be enabled by adaptation to alternative osmotic environments. The threespine stickleback (Gasterosteus aculeatus) is a euryhaline species with populations found both in marine and freshwater environments. It has evolved both highly plastic and locally adapted phenotypes due to salinity-derived selection, but the physiological and genetic basis of adaptation to salinity is not fully understood. We integrated comparative cellular morphology of the kidney, a key organ for osmoregulation, and candidate gene expression to explore the underpinnings of evolved variation in osmotic plasticity within two populations of sticklebacks from distinct salinity zones in the Baltic Sea: the high salinity Kattegat, representative of the ancestral marine habitat; and the low salinity Bay of Bothnia. A common-garden experiment revealed that kidney morphology in the ancestral high-salinity population had a highly plastic response to salinity conditions whereas this plastic response was reduced in the low-salinity population. Candidate gene expression in kidney tissue revealed a similar pattern of population-specific differences, with a higher degree of plasticity in the native high-salinity population. Together these results suggest that renal cellular morphology has become canalized to low salinity, and that these structural differences may have functional implications for osmoregulation.


Effects of combined exposure to polystyrene microplastics and 17α-Methyltestosterone on the reproductive system of zebrafish.
Polystyrene microplastics (PS-MPs) are important carriers of pollutants in water. 17α-Methyltestosterone (MT) is a synthetic environmental endocrine disrupting chemical (EDC) with androgenic effects. To study the effects of PS-MPs and MT on zebrafish reproductive systems, zebrafish were exposed to 0 or 50 ng L-1 MT, 0.5 mg∙L-1 PS-MPs, or 50 ng∙L-1 MT + 0.5 mg∙L-1 PS-MPs for 21 d. The results showed that the different exposure reagents caused varying degrees of damage to the reproductive systems in zebrafish, with the extent of damage increasing as the exposure duration increased. Histological analysis of the gonads revealed that the ratio of mature oocytes and mature spermatozoa in the gonad decreased gradually with increased exposure time, with the ratio being Control > PS-MPs > MT > MT + PS-MPs in decreasing order. The results of quantitative real-time PCR (qRT‒PCR) showed that in female fish treated for 7 d, the expression of cyp11a mRNA was significantly reduced in all three treatment groups(MT, PS-MPs, and MT + PS-MPs), while in the group treated for 14 d with MT + PS-MPs, the expression of cyp19a1a and StAR mRNA was significantly increased. In male fish exposed for 21 d, the expression of cyp11a, cyp17a1, cyp19a1a, StAR, 3β-HSD, and 17β-HSD3 mRNA was significantly decreased in MT + PS-MPs. ELISA results showed that after 14 d of exposure, the levels of E2, LH, and FSH in the ovaries of female fish were significantly reduced in all three treatment groups. Similarly, the levels of T, E2, LH, and FSH in the testis of male fish were significantly reduced after 14 d of exposure to PS-MPs and MT + PS-MPs. Offspring of zebrafish exposed to MT and MT + PS-MPs exhibited delayed incubation time and slow development. The cross-generational toxicity of PS-MPs themselves may be negligible, but it can exacerbate the toxicity of MT, making the cross-generational effects more pronounced in the offspring, causing offspring mortality and malformations. Offspring of zebrafish exposed to MT and MT + PS-MPs exhibited delayed incubation time and slow development. In addition, MT caused malformations such as pericardial edema, yolk cysts, and spinal deformities in zebrafish during the incubation period.


Genetic variation in 1253 immune and inflammation genes and risk of non-Hodgkin lymphoma.
Smaller-scale evaluations suggest that common genetic variation in candidate genes related to immune function may predispose to the development of non-Hodgkin lymphoma (NHL). We report an analysis of variants within genes associated with immunity and inflammation and risk of NHL using a panel of 9412 single-nucleotide polymorphisms (SNPs) from 1253 genes in a study of 458 patients with NHL and 484 frequency-matched controls. We modeled haplotypes and risk of NHL, as well as the main effects for all independent SNPs from a gene in multivariate logistic regression models; we separately report results for nonsynonymous (ns) SNPs. In gene-level analyses, the strongest findings (P < or = .001) were for CREB1, FGG, MAP3K5, RIPK3, LSP1, TRAF1, DUSP2, and ITGB3. In nsSNP analyses, the strongest findings (P < or = .01) were for ITGB3 L59P (odds ratio [OR] = 0.66; 95% confidence interval [CI] 0.52-0.85), TLR6 V427A (OR = 5.20; CI 1.77-15.3), SELPLG M264V (OR = 3.20; CI 1.48-6.91), UNC84B G671S (OR = 1.50; CI 1.12-2.00), B3GNT3 H328R (OR = 0.74; CI 0.59-0.93), and BAT2 V1883L (OR = 0.64; CI 0.45-0.90). Our results suggest that genetic variation in genes associated with immune response (TRAF1, RIPK3, BAT2, and TLR6), mitogen-activated protein kinase (MAPK) signaling (MAP3K5, DUSP2, and CREB1), lymphocyte trafficking and migration (B3GNT3, SELPLG, and LSP1), and coagulation pathways (FGG and ITGB3) may be important in the etiology of NHL, and should be prioritized in replication studies.


Binding of aldosterone metabolites in isolated tubular segments.
High-performance liquid chromatography (HPLC) analysis was performed on tissue extracts from whole kidney cortex (after in vivo injection or in vitro incubation with [3H]-aldosterone ([3H]A], from products bound to aldosterone receptors in cytoplasmic and nuclear fractions, and from the convoluted (PCT) and straight (PR) portion of the proximal tubule and cortical collecting tubule (CCT) isolated by micro-dissection after in vitro incubation with [3H]A (10 and 80 nM). After in vitro incubation of whole tissue, about 10% of the radioactivity corresponded to three groups of metabolites, two polar ones, which eluted earlier than aldosterone, and one less polar, which eluted later than aldosterone. When HPLC analysis was performed on bound products, after removal of free [3H]A, only one group of polar metabolites was detected (about 8% of the radioactivity) in addition to native [3H]A in the cytoplasmic and nuclear fractions. The binding of polar metabolites was nonspecific (nondisplaceable) and did not vary with incubation time and aldosterone concentration. In isolated tubules, in addition to [3H]A, an early peak of polar metabolites, corresponding to that observed in bound fractions, was present in PCT (10%) and in PR and CCT (20-25%). Other metabolites were not found in isolated tubules. We conclude the following: 1) The kidney is able to form at least three groups of aldosterone metabolites in small amounts. 2) Only one of them (more polar) was detected, as a nonspecifically bound product, in cellular fractions containing hormone-receptor complexes after removal of free [3H]A. Other metabolites were removed with free [3H]A. 3) These polar metabolites were found in both mineralocorticoid target segments such as CCT and in classically nontarget segments such as the proximal tubule. 4) The nonspecificity of the binding of polar metabolites and the absence of selective localization along the nephron suggest that they have no major mineralocorticoid action.


Effects of a Flavonoid-Rich Extract from Citrus sinensis Juice on a Diet-Induced Obese Zebrafish.
Obesity is a pathological condition that has reached epidemic proportions; hence, it is necessary to find novel strategies aimed at fighting this disease. The present study was designed to evaluate the effect of a flavonoid-rich extract of orange (Citrus sinensis) juice (OJe) in diet-induced obese zebrafish. Adult zebrafish were divided into four diet groups: (i) normally fed (NF); (ii) overfed (OF); (iii) NF supplemented with OJe (5 mL/L in fish water; NF + OJe); and (iv) OF supplemented with OJe (OF + OJe). Each week, body weight (BW) and body mass index (BMI) were measured, and, at the end of the fifth week, euthanized zebrafish were processed for both microscopic evaluations and qPCR analyses. In OF zebrafish, OJe significantly decreased both BW and BMI values and lowered the visceral adipose tissue, while it had little effect in the NF group. Moreover, it significantly reduced adipocyte cell size in both NF and OF groups in both visceral and subcutaneous adipose tissues, as well as their number in OF fish. Finally, OJe modulated some obesity-related genes, such as leptin A, ghrelin, orexin, pro-opiomelanocortin (POMC), and neuropeptide Y (NPY), in both gut and brain. This study adds new insights into the anti-obesity properties of orange juice and its flavonoids, suggesting their role as weight management agents through a lipolytic action linked to a restoration of metabolism-regulating gene expression.


Neurophysiological evidence of increased cortical reactivity in migraine.
Cortical reactivity in migraine can be studied with evoked potentials. The majority of the evidence shows increased reactivity in migraine, which may be due to abnormal inhibition. At present, the techniques are not useful for diagnosis. Discrepancies between reports may be due to fluctuations in reactivity over time. Documenting this changing reactivity requires refinement of analysis techniques.


Giemsa stain as a marker in the pitcher-plant mosquito, Wyeomyia smithii.
Third and fourth instars of Wyeomyia smithii were reared in Giemsa stain at 4 concentrations between 4 x 10(-7) and 10(-5) g/liter. The mosquitoes retained the blue mark as adults and remained marked throughout their laboratory life. Concentration of Giemsa significantly affected eclosion success but had no significant effect on mean days to pupation or days as a pupa, male or female adult longevity, per-capita female fecundity or fertility. Larval exposure to low concentrations (4 x 10(-7) or 10(-6) g/liter) of Giemsa stain provides an effective lifetime tag for otherwise indistinguishable laboratory populations.


Dupuytren's disease. A model for the mechanism of fibrosis and its modulation by steroids.
Dupuytren's disease is a chronic inflammatory process which produces contractures of the fingers. The nodules present in Dupuytren's tissue contain inflammatory cells, mainly lymphocytes and macrophages. These express a common integrin known as VLA4. The corresponding binding ligands to VLA4 are vascular cell adhesion molecule-1 (VCAM-1) present on the endothelial cells and the CS1 sequence of the fibronectin present in the extracellular matrix. Transforming growth factor-beta (TGF-beta) is a peptide hormone which has a crucial role in the process of fibrosis. We studied tissue from 20 patients with Dupuytren's disease, four samples of normal palmar fascia from patients undergoing carpal tunnel decompression and tissue from ten patients who had received perinodular injections of depomedrone into the palm five days before operation. The distribution of VLA4, VCAM-1, CS1 fibronectin and TGF-beta was shown by immunohistochemistry using an alkaline phosphorylase method for light microscopy. In untreated Dupuytren's tissue CS1 fibronectin stained positively around the endothelial cells of blood vessels and also around the surrounding myofibroblasts, principally at the periphery of many of the active areas of the Dupuytren's nodule. VCAM-1 stained very positively for the endothelial cells of blood vessels surrounding and penetrating the areas of high nodular activity. VCAM-1 was more rarely expressed outside the blood vessels. VLA4 was expressed by inflammatory cells principally in and around the blood vessels expressing VCAM-1 and CS1 but also on some cells spreading into the nodule. TGF-beta stained positively around the inflammatory cells principally at the perivascular periphery of nodules. These cells often showed VLA4 expression and co-localised with areas of strong production of CS1 fibronectin. Normal palmar fascia contained only scanty amounts of CS1 fibronectin, almost no VCAM-1 and only an occasional cell staining positively for VLA4 or TGF-beta. In the steroid-treated group, VCAM-1 expression was downregulated in the endothelium of perinodular blood vessels and only occasional inflammatory cell expression remained. Expression of CS1 fibronectin was also much reduced but still occurred in the blood vessels and around the myofibroblast stroma. VLA4-expressing cells were also reduced in numbers. A similar but reduced distribution of production of TGF-beta was also noted. Our findings show that adherence of inflammatory cells to the endothelial wall and the extravasation into the periphery of the nodule may be affected by steroids, which reduce expression of VCAM-1 in vivo. This indicates that therapeutic intervention to prevent the recommencement of the chronic inflammatory process and subsequent fibrosis necessitating further surgery may be possible.


Toxic effects of lead on plants: integrating multi-omics with bioinformatics to develop Pb-tolerant crops.
Lead disrupts plant metabolic homeostasis and key structural elements. Utilizing modern biotechnology tools, it's feasible to develop Pb-tolerant varieties by discovering biological players regulating plant metabolic pathways under stress. Lead (Pb) has been used for a variety of purposes since antiquity despite its toxic nature. After arsenic, lead is the most hazardous heavy metal without any known beneficial role in the biological system. It is a crucial inorganic pollutant that affects plant biochemical and morpho-physiological attributes. Lead toxicity harms plants throughout their life cycle and the extent of damage depends on the concentration and duration of exposure. Higher levels of lead exposure disrupt numerous key metabolic activities of plants including oxygen-evolving complex, organelles integrity, photosystem II connectivity, and electron transport chain. This review summarizes the detrimental effects of lead toxicity on seed germination, crop growth, and yield, oxidative and ultra-structural alterations, as well as nutrient absorption, transport, and assimilation. Further, it discusses the Pb-induced toxic modulation of stomatal conductance, photosynthesis, respiration, metabolic-enzymatic activity, osmolytes accumulation, and antioxidant activity. It is a comprehensive review that reports on omics-based studies along with morpho-physiological and biochemical modifications caused by lead stress. With advances in DNA sequencing technologies, genomics and transcriptomics are gradually becoming popular for studying Pb stress effects in plants. Proteomics and metabolomics are still underrated and there is a scarcity of published data, and this review highlights both their technical and research gaps. Besides, there is also a discussion on how the integration of omics with bioinformatics and the use of the latest biotechnological tools can aid in developing Pb-tolerant crops. The review concludes with core challenges and research directions that need to be addressed soon.


Shape-memory effects in molecular crystals.
Molecular crystals can be bent elastically by expansion or plastically by delamination into slabs that glide along slip planes. Here we report that upon bending, terephthalic acid crystals can undergo a mechanically induced phase transition without delamination and their overall crystal integrity is retained. Such plastically bent crystals act as bimorphs and their phase uniformity can be recovered thermally by taking the crystal over the phase transition temperature. This recovers the original straight shape and the crystal can be bent by a reverse thermal treatment, resulting in shape memory effects akin of those observed with some metal alloys and polymers. We anticipate that similar memory and restorative effects are common for other molecular crystals having metastable polymorphs. The results demonstrate the advantage of using intermolecular interactions to accomplish mechanically adaptive properties with organic solids that bridge the gap between mesophasic and inorganic materials in the materials property space.


Suicide prevention curriculum development for health and social care students: Protocol for a scoping review.
Suicide has become a serious public health concern and international research has shown that the majority of individuals who die by suicide had receive healthcare in the year prior to their death. This presents an opportunity for suicide prevention by strategically training healthcare students in suicide prevention knowledge and skills. The objective of this scoping review is to identify literature that describes the design, development, implementation and/or evaluation of suicide prevention training for healthcare and/or social care students in higher education settings. Studies will only be considered eligible for inclusion if they describe the design, development, implementation and/or evaluation of suicide prevention curricula being delivered to healthcare or social care degree students in higher education. Quantitative, qualitative, and mixed method studies published between 2011 and 2023 (inclusive) and in the English language will be considered eligible. This scoping review will be conducted according to the PRISMA guidelines for scoping reviews (PRISMA-ScR). The developed search strategy will be implemented across six databases: PubMed, ERIC (Education Resources Information Center), PsycINFO, Embase, CINAHL and Web of Science. Several grey literature sources will also be consulted. Further potential results will be located by hand-searching the reference lists of included articles. The search strategy will include variations of the terms: 'student', 'suicide prevention' and 'education'. The search will be limited to titles, abstracts, and keywords in databases that allow it. Two reviewers will complete the screening using the predefined inclusion criteria. A third reviewer will resolve any conflicts during the screening and eligibility appraisal processes. Results will be presented in the form of tabulated results and an accompanying narrative summary, describing key findings and context related to learning outcomes, methodologies employed and implementation of the identified programmes.


Comparison of self-collected vaginal, vulvar and urine samples with physician-collected cervical samples for human papillomavirus testing to detect high-grade squamous intraepithelial lesions.
Certain types of human papillomavirus (HPV) in cervical samples are strongly associated with squamous intraepithelial lesions (SIL) and invasive cervical carcinoma. We determined and compared the test characteristics of testing for HPV with samples obtained by patients and with samples obtained by their physicians. In a consecutive series of women referred to a colposcopy clinic at a teaching hospital because of abnormalities on cervical cytologic screening, 200 agreed to collect vulvar, vaginal and urine samples for HPV testing. The physician then collected cervical samples for HPV testing, and colposcopy, with biopsy as indicated, was performed. Presence of HPV was evaluated using the hybrid capture II assay (Digene Corp., Silver Spring, Md.) with a probe cocktail for 13 carcinogenic types. Cervical specimens were also tested for HPV by polymerase chain reaction and hybridization with type-specific probes. Cervical smears for cytologic examination were obtained from all women. High-grade lesions (high-grade squamous intraepithelial lesions [HSIL], equivalent to cervical intraepithelial neoplasia [CIN] grade 2 or 3, and adenocarcinoma) were found in 58 (29.0%) of the 200 women. Carcinogenic types of HPV were detected in the self-collected vaginal samples of 50 (86.2%) of these 58 women, in the self-collected vulvar samples of 36 (62.1%) and in the self-collected urine samples of 26 (44.8%). Carcinogenic types of HPV were detected in the cervical samples collected by physicians for 57 (98.3%) of these 58 women. The remaining 142 women (71.0%) had normal findings or low-grade squamous intraepithelial lesions (LSIL, CIN grade 1). Test results were negative or noncarcinogenic types of HPV were detected in the self-collected vaginal samples of 76 (53.5%) of these 142 women, in the self-collected vulvar samples of 89 (62.7%) and in the self-collected urine samples of 99 (69.7%). The sensitivity for self-collected samples ranged from 44.8% to 86.2%, and the specificity from 53.5% to 69.7%. For the samples collected by physicians, the sensitivity was 98.3% and the specificity 52.1%. The self-sampling methods were generally acceptable to the women: 98.4% of respondents (126/128) deemed urine sampling acceptable, 92.9% (118/127) found vulvar sampling acceptable, and 88.2% (112/127) found vaginal sampling acceptable. Self-collection of samples for HPV testing was acceptable to women attending a colposcopy clinic for investigation of suspected cervical lesions and shows sufficient sensitivity to warrant further evaluation as a screening test for cervical cancer prevention programs.


Phaseless computational ghost imaging at microwave frequencies using a dynamic metasurface aperture.
We demonstrate a dynamic metasurface aperture as a unique tool for computational ghost imaging at microwave frequencies. The aperture consists of a microstrip waveguide loaded with an array of metamaterial elements, each of which couples energy from the waveguide mode to the radiation field. With a tuning mechanism introduced into each independently addressable metamaterial element, the aperture can produce diverse radiation patterns that vary as a function of tuning state. Here, we show that fields from such an aperture approximately obey speckle statistics in the radiative near field. Inspired by the analogy with optical correlation imaging, we use the dynamic aperture as a means of illuminating a scene with structured microwave radiation, receiving the backscattered intensity with a simple waveguide probe. By correlating the magnitude of the received signal with the structured intensity patterns, we demonstrate high-fidelity, phaseless imaging of sparse targets. The dynamic metasurface aperture as a novel ghost imaging structure can find application in security screening, through-wall imaging, as well as biomedical diagnostics.


The triallelic serotonin transporter gene polymorphism is associated with depressive symptoms in adults with chronic pain.
The serotonin (5-HT) transporter-linked polymorphic region (5-HTTLPR) moderates the relationship between stressful life events and depression. Given the high prevalence of depression in chronic pain, the primary aim of this preliminary study was to investigate the associations between the 5-HTTLPR and the severity of depressive symptoms in a cohort of adults with chronic pain. Adults with chronic pain who were consecutively admitted to an outpatient pain rehabilitation program and met inclusion criteria were recruited for study participation (n=277). Individuals were genotyped for the 5-HTTLPR (including rs25531) and categorized as high, intermediate, or low expressors of the 5-HT transporter. The severity of depressive symptoms at admission was measured by using the Center for Epidemiologic Depression scale (CES-D). The distribution of the high-, intermediate-, and low-expressing genotypes was 61 (22%), 149 (54%), and 67 (24%), respectively. The Hardy-Weinberg P-value was 0.204, which indicated no departure from equilibrium. A main effect of 5-HTTLPR was observed for depressive symptoms (P=0.040) where Center for Epidemiologic Depression scale (CES-D) scores were significantly greater in the low-expressing group compared to the high- (P=0.019) and intermediate (P=0.029)-expressing groups. In multivariate multinomial logistic regression analysis adjusted for age, sex, pain severity, pain catastrophizing, and pain anxiety, greater CES-D scores were significantly associated with the 5-HTTLPR low-expressing group compared to the high-expressing group (P=0.023), but not for the low-expressing group compared to the intermediate-expressing group (P=0.056). These preliminary findings suggest that the triallelic 5-HTTLPR could influence the severity of depressive symptoms in adults with chronic pain. Individuals with chronic pain may be particularly vulnerable to the moderating effects of 5-HTTLPR due to high levels of pain-related stress that are inherently present in this population.


Adenine decreases hypertrophic effects through interleukin-18 receptor.
Cardiac hypertrophy is the main cause of heart failure. Levels of circulating interleukin-18 (IL-18) have been reported to increase in congestive heart disease and cardiac hypertrophy. Relationships among IL-18 levels, IL-18 receptor (IL-18R) expression, and cardiac hypertrophy remain unclear. IL-18 can induce cardiac hypertrophy in cardiomyoblasts. We also studied IL-18R messenger RNA (mRNA) and protein expression through quantitative-polymerase chain reaction and Western blotting. Furthermore, we treated cardiomyoblasts with adenine, gold nanoparticles (AuNPs), and inhibitors to analyze the morphology and identify signaling pathways involved in cardiac hypertrophy. Moreover, we studied the effects of IL-18R small interfering RNA (siRNA) on signaling pathways through Western blotting. The mRNA expression of IL-18R in H9c2 cardiomyoblasts, which was induced by IL-18, increased significantly after 8 h, and the protein level increased significantly after 15 h. Morphological examination of H9c2 cardiomyoblasts showed that cell volume and cell diameter decreased after adenine pretreatment. Both p38 MAPK and PI3 kinase are biomarkers in the pathway correlated with cardiac hypertrophy. After treatment with inhibitors SB203580 and LY294002, the levels of p38 MAPK and PI3 kinase, respectively, decreased along with cell size and IL-18R expression. Treatment with adenine, but not AuNPs, reduced the levels of phosphorylated p38 and PI3 kinase expression more effectively than did treatment with the respective inhibitors alone. IL-18R siRNA significantly reduced cell size but not PI3 kinase expression and phosphorylation of p38 MAPK. However, adenine treatment reduced PI3 kinase expression after treatment with IL-18R siRNA. In this study, IL-18 induced cardiomyoblast hypertrophy through IL-18R upregulation, which was found to be related to p38 MAPK and PI3 kinase signaling. Adenine, but not AuNPs, showed antihypertrophic effects possibly because of decreased levels of signaling.


A Pharmacodynamic Analysis of Choroidal Neovascularization in a Porcine Model Using Three Targeted Drugs.
To compare the efficacy of microneedle-delivered suprachoroidal (SC) pazopanib to intravitreal (Ivit) delivery of pazopanib, bevacizumab, or a fusion protein hI-con1 versus vehicle controls on choroidal neovascularization (CNV) growth in a pig model. Forty-one pigs were injected on the day of CNV induction (hI-con1 on postinduction day 14) with either 2.5 mg Ivit bevacizumab (n = 9), 1 mg Ivit pazopanib (n = 9), 300 Ivit μg hI-con1 (n = 4), or 1 mg SC pazopanib (n = 9), vs. 10 vehicle controls (3 SC + 7 Ivit = 10). Pigs were euthanized at week 2 (11), 3 (8), 4 (11), and 8 (11), and eyes were fixed for histology. The size of the CNV was determined from histology, and CNV height was the primary outcome measure. Immunostaining for cytotoxic T-cells was performed in the hI-con1 study. In 39 of 41 (95%) eyes, type 2 CNV lesions were identified. One CNV lesion was lost during dissection. One animal was euthanized due to surgical complications. For mean CNV size comparisons, Ivit pazopanib had smaller mean height measurements (90 ± 20 μm) versus controls (180 ± 20 μm; P = 0.009), and Ivit pazopanib had smaller maximum CNV height (173 ± 43 μm) compared to SC pazopanib (478 ± 105 μm; P = 0.018). The mean lesion size in hI-con1-treated animals trended smaller than in controls (P = 0.11). Immunostaining did not detect cytotoxic T-cells. Intravitreal pazopanib and to a lesser extent hI-con1 reduced the size of CNV lesions. The pig model has nearly a 100% rate of type 2 CNV induction and is a reliable preclinical model with pharmacodynamics similar to humans.


Logical and arithmetic circuits in Belousov-Zhabotinsky encapsulated disks.
Excitation waves on a subexcitable Belousov-Zhabotinsky (BZ) substrate can be manipulated by chemical variations in the substrate and by interactions with other waves. Symbolic assignment and interpretation of wave dynamics can be used to perform logical and arithmetic computations. We present chemical analogs of elementary logic and arithmetic circuits created entirely from interconnected arrangements of individual BZ encapsulated cell-like disk. Interdisk wave migration is confined in carefully positioned connecting pores. This connection limits wave expansion and unifies the input-output characteristic of the disks. Circuit designs derived from numeric simulations are optically encoded onto a homogeneous photosensitive BZ substrate.


Gut-resident CX3CR1hi macrophages induce tertiary lymphoid structures and IgA response in situ.
Intestinal mononuclear phagocytes (MPs) are composed of heterogeneous dendritic cell (DC) and macrophage subsets necessary for the initiation of immune response and control of inflammation. Although MPs in the normal intestine have been extensively studied, the heterogeneity and function of inflammatory MPs remain poorly defined. We performed phenotypical, transcriptional, and functional analyses of inflammatory MPs in infectious Salmonella colitis and identified CX3CR1+ MPs as the most prevalent inflammatory cell type. CX3CR1+ MPs were further divided into three distinct populations, namely, Nos2 +CX3CR1lo, Ccr7 +CX3CR1int (lymph migratory), and Cxcl13 +CX3CR1hi (mucosa resident), all of which were transcriptionally aligned with macrophages and derived from monocytes. In follow-up experiments in vivo, intestinal CX3CR1+ macrophages were superior to conventional DC1 (cDC1) and cDC2 in inducing Salmonella-specific mucosal IgA. We next examined spatial organization of the immune response induced by CX3CR1+ macrophage subsets and identified mucosa-resident Cxcl13 +CX3CR1hi macrophages as the antigen-presenting cells responsible for recruitment and activation of CD4+ T and B cells to the sites of Salmonella invasion, followed by tertiary lymphoid structure formation and the local pathogen-specific IgA response. Using mice we developed with a floxed Ccr7 allele, we showed that this local IgA response developed independently of migration of the Ccr7 +CX3CR1int population to the mesenteric lymph nodes and contributed to the total mucosal IgA response to infection. The differential activity of intestinal macrophage subsets in promoting mucosal IgA responses should be considered in the development of vaccines to prevent Salmonella infection and in the design of anti-inflammatory therapies aimed at modulating macrophage function in inflammatory bowel disease.


Adrenal cortical neoplasms: a study of clinicopathological features related to epidermal growth factor receptor gene status.
Adrenocortical carcinoma (ACC) is a rare but highly malignant neoplasm with limited treatment options. In this study, the clinicopathological features of 22 ACCs and 22 adrenocortical adenomas (ACA) were analyzed, and the EGFR protein expression, EGFR gene mutation status and EGFR gene copy number alteration of all tumors were examined using immunohistochemistry, fluorescence in situ hybridization (FISH), and the Scorpion Amplification Refractory Mutation System (ARMS), respectively. EGFR protein expression was detected in 63.6% of the ACC samples, and EGFR FISH was positive in 50% of the ACC samples (all were high polysomy on chromosome 7). In contrast, 27.3% of the ACA samples demonstrated EGFR expression, and none of the ACA samples tested positive by FISH. There were significant differences between the ACC and ACA in terms of protein expression (P = 0.035) and gene copy number alterations (P < 0.001). EGFR protein expression and high polysomy on chromosome 7 are frequent abnormalities in ACC than in ACA. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2068470757103500.


Dynamic stability of gait cycles as a function of speed and system constraints.
The purpose of this study was to examine the dynamic stability of two groups of children with different dynamic resources in changing contexts. The stability of the lower extremity segments of preadolescent children (8-10 years old) with and without Down syndrome (DS) was evaluated as children walked on a motorized treadmill at varying speeds. Tools from nonlinear dynamics, maximum Lyapunov exponent, and approximate entropy were used to assess the behavioral stability of segmental angular displacements of the thigh, shank, and foot. Our results suggest that children with DS show decreased dynamic stability during walking in all segments and that this might be a consequence of inherently different subsystem constraints between these groups. Differences between groups also varied, though not uniformly, with speed, suggesting that inherent differences could further constrain the behavioral response to changing task demands.


The Hydrogenation Impact on Electronic Properties of p-Diamond/n-Si Heterojunctions.
The undoped polycrystalline diamond films (PDFs) have been deposited on n-type silicon (Si) by Hot Filament Chemical Vapor Deposition (HF CVD) technique. The reaction gases are a mixture of methane and hydrogen. The obtained PDFs were characterized by scanning electron microscopy (SEM) and Raman spectroscopy which, in addition to the diamond phase, also confirms the presence of sp2 hybridized carbon bonds. As-grown CVD diamond layers are hydrogen terminated and show p-type conductivity. The effect of the level of hydrogenation on the electrical properties of p-diamond/n-Si heterojunctions has been investigated by temperature dependent current-voltage (J-V/T) characteristics. The obtained results suggest that the energy distribution of interface states at the grain boundary (GB) subjected to hydrogenation becomes shallower, and the hole capture cross-section can be reduced. Hydrogenation can lead to a significant reduction of the GB potential barrier. These results can be interesting from the point of view of hydrogen passivation of GBs in microelectronics.


Nanostructured nickel oxide films prepared by chemical vapor deposition and their electrochromic properties.
The influence of the deposition conditions on the structural features and electrochromic properties of nickel oxide (NiO) films prepared by chemical vapor deposition has been investigated. NiO films have been prepared on fluorine doped tin oxide (FTO) coated glass substrates from nickel-acetylacetonate precursor and their electrochromic properties have been studied by cyclic voltammetry in a 0.1 M KOH solution at room temperature. Films exhibiting only the NiO phase were obtained at deposition temperatures higher than 450 degrees C in a wide range of reactor pressures (0.13 to 66.6 kPa). Particularly, NiO films prepared at 500-550 degrees C from 0.13 to 53.3 kPa are transparent in nature and exhibit a crystallite size varying from 10 to 60 nm. An appreciable anodic electrochromic change from transparent to black coloured resulted from a very porous surface morphology and film thickness of about 3.5 microm. The electrochromic change was maintained over 3000 switching cycles. Nanostructured 3.5 microm-thick NiO films showed a maximum difference in optical transmittance of about 40% in the near-infrared region. These results make the nanostructured NiO films comparables with those prepared by other deposition techniques.


[Takayasu's aortitis. Exploration of the aorta and its branches by digital angiography and cross-sectional echography].
In Takayasu's disease full radiological exploration of the arteries requires multiple injections of a contrast medium, and this would be difficult to achieve in the course of one single examination. In the present study, two non-invasive methods--digital angiography and cross-sectional echography--were used comparatively to evaluate arterial lesions in 13 ambulatory patients presenting with this disease. Conventional arteriography had previously been performed in 11 of them. The results obtained with digital angiography were considered satisfactory in 12 patients. All underwent aortic and pulmonary echography. Digital angiography and cross-sectional echography provide full, reliable and non-invasive exploration of the aorta and pulmonary artery. Echography shows abnormal thickness of the vascular walls, but the arterial branches can be explored only by digital angiography. The value of these two non-invasive methods is discussed.


Phase I and clinical pharmacology trial of 502U83 using a monthly single dose schedule.
502U83 is an arylmethylaminopropanediol derivative exhibiting significant antineoplastic activity in a number of murine and human tumor models. In this Phase I trial, a 1-h or 4-h infusion of the agent was administered i.v. in 250 ml of 5% dextrose in water every 28 days. Fifty-three courses at doses of 25 to 2000 mg/m2 were administered to 36 patients with refractory solid tumors. Prolongation of the PR, QRS, and QT intervals on electrocardiograms was dose limiting at 2000 mg/m2. This prolongation appeared dose related and was reversible upon discontinuation of the infusion. No hematological toxicity was observed. Other toxicities included only sporadic and mild to moderate nausea and vomiting. No tumor responses were noted. 502U83 plasma concentrations were determined by high-pressure liquid chromatography. Complete pharmacokinetic profiles were obtained for 21 of the 36 patients. After infusion, plasma concentrations declined in a biexponential or in a triexponential manner with a harmonic mean terminal t 1/2 of 8.83 h. Using a three-compartment model, the mean apparent volume of distribution at steady state and total-body clearance were 195 liters/m2 and 42.5 liters/h/m2, respectively, indicative of extensive tissue distribution. No correlation could be found between the pharmacokinetic parameters and prolongation of the cardiac conduction intervals. Because of the cardiac effects with the drug, the schedule of administration of 502U83 used in this study cannot be recommended.


Adolescent effects on mothers' bedtime cortisol: Cognitive interference as a mediating mechanism.
Prior studies have shown that parent and adolescent cortisol are associated across days and that this covariation may be adolescent-driven. This study extends this literature by (a) testing whether parents' cognitive interference (i.e., distracting and ruminative thoughts potentially due to worry) mediates the linkages between adolescent and next-day parent cortisol and (b) whether these linkages were moderated by parent gender or warmth. Daily diary data, including bedtime cortisol, were collected on two samples of employees and their adolescent-aged children (N = 318 dyads, Myouth age = 13.18 years, 74% mothers). We tested mediation with autoregressive cross-lagged models. Moderated mediation by parent gender was found in our bedtime cortisol models. Higher adolescent bedtime cortisol levels were associated with higher next-day levels of mothers' cognitive interference. In turn, higher levels of mothers' cognitive interference were linked to higher mothers' same-day bedtime cortisol levels. These linkages were not significant for fathers. Cognitive interference did not mediate the associations between child and parent area under the curve or cortisol awakening response. No moderation was evident for parental warmth. Results suggest that mothers' cognitions play a key role in the transmission of elevated bedtime cortisol levels from adolescents to their mothers.


Arteriovenous fistula geometry in hybrid recanalisation of post-thrombotic venous obstruction.
Post-thrombotic obstruction can be adequately treated by percutaneous transluminal angioplasty and stenting. When post-thrombotic trabeculations extend below the femoral confluence, proper inflow can be facilitated by endophlebectomy and creation of an arteriovenous fistula. The aim of this study was to investigate whether it is more favourable to place the arteriovenous fistula at the cranial or caudal end of the endophlebectomy to prevent stenosis or occlusion. We retrospectively analysed the clinical data of all patients who underwent a hybrid procedure in our two centres. Demographics, interventional details and post-operative imaging were collected. Data on 42 limbs with cranially and 23 limbs with caudally placed arteriovenous fistulas were collected. Post-thrombotic disease of the profunda femoral vein alone or in combination with the femoral vein was observed more often in the cranial group. The caudal group more often received a smaller sized and straight polytetrafluoroethylene fistula, while the cranial group comprised a significantly higher amount of stented segments. Logistic regression showed that only reduced femoral inflow (hazard ratio 2.934 (95%CI, 1.148-7.494)) was a significant predictor of stent stenosis and/or occlusion. Logistic regression for risk of occlusion showed a significant influence of stent-related complications (hazard ratio 4.691 (95%CI, 1.205-18.260)) and a tendency towards influence of arteriovenous fistula geometry in favour of the cranially placed fistula. Placement of the arteriovenous fistula in the cranial part of the endophlebectomy during hybrid recanalisation may result in a more favourable outcome, yet this tendency was not statistically significant. Moreover, femoral inflow is pivotal in maintaining patency and should thus be adequately assessed pre-operatively.


Organized medicine and Scandinavian professional unionism: hospital policies and exit options in Denmark and Sweden.
Strikes by junior hospital doctors over the issue of on-call remuneration in Denmark and Sweden in 1981 are analyzed to clarify the impact of public-sector cost-control policies on intra- and interprofessional solidarity within the Scandinavian professional peak associations. The junior doctors' grievances could find expression either through increased "voice" within the medical negotiating machinery, or by pursuing the exit option in having the medical associations quit the peak associations. The article explains why the "exit" option was selected in Denmark, while in Sweden the granting of additional voice helped persuade the medical association to withdraw its exit threat and to remain within the peak association. The two cases are interpreted as presaging a divergence in the paths being taken by the various Scandinavian welfare states.


A study of a pre-operative intervention in patients with diabetes undergoing cardiac surgery.
Coronary heart disease is common in Type 2 diabetes and often requires cardiac surgery. However poorer outcomes have been reported including increased rates of post-operative infection and prolonged hospital stay. The aim of the study was to determine the feasibility and acceptability of a specialist consultation model (pre-operative medical and educational intervention) for type 2 diabetes in the cardiac surgery setting. Twenty four patients were assigned usual care or to the intervention group. The intervention group were assessed by a diabetes clinical nurse consultant, dietitian, and endocrinologist during a pre-operative visit. Specific diabetes questionnaires were administered, education was delivered, and protocol-driven changes to the medical regimen were instituted. Length of stay, incidence of post-operative complications, and number of post-operative inpatient review endocrinology visits required were recorded. Twenty four patients with a pre-operative HbA(1c) greater than 6.5% (48 mmol/mol) were studied (17 males and 7 females). In the usual care group (n = 15), HbA(1c) pre-operatively was 7.2% (55.2 mmol/mol) compared to 10.1% (86.9 mmol/mol) in the intervention group (n = 9). Six weeks post-operatively HbA(1c) fell significantly in the intervention group by 1.9% (to 8.2% [66.1 mmol/mol]) compared to a reduction of 1.2% (to 7.0% [53 mmol/mol]) in the usual care group (p < 0.05). No significant differences were observed in length of stay in intensive care or in total hospital stay between the groups: length of ICU stay 54 h for intervention versus 47 h for usual care, total hospital stay (mean 8 days for both); or in rates of post-operative infection. Differences were seen between in the diabetes questionnaires: in the Problem Areas in Diabetes questionnaire and in the Diabetes Treatment Satisfaction Questionnaire (p = 0.048). This small pilot feasibility study suggests there is potential benefit in the acute optimisation of diabetes treatment before elective cardiac surgery.


The head-direction signal is critical for navigation requiring a cognitive map but not for learning a spatial habit.
Head-direction (HD) cells fire as a function of an animal's directional heading in the horizontal plane during two-dimensional navigational tasks [1]. The information from HD cells is used with place and grid cells to form a spatial representation (cognitive map) of the environment [2, 3]. Previous studies have shown that when rats are inverted (upside down), they have difficulty learning a task that requires them to find an escape hole from one of four entry points but that they can learn it when released from one or two start points [4]. Previous reports also indicate that the HD signal is disrupted when a rat is oriented upside down [5, 6]. Here we monitored HD cell activity in the two-entry-point version of the inverted task and when the rats were released from a novel start point. We found that despite the absence of direction-specific firing in HD cells when inverted, rats could successfully navigate to the escape hole when released from one of two familiar locations by using a habit-associated directional strategy. In the continued absence of normal HD cell activity, inverted rats failed to find the escape hole when started from a novel release point. The results suggest that the HD signal is critical for accurate navigation in situations that require a flexible allocentric cognitive mapping strategy, but not for situations that utilize habit-like associative spatial learning.


Global analysis of protein tyrosine phosphatase activity with ultra-sensitive fluorescent probes.
Protein tyrosine phosphatases (PTPs) consist of a large family of enzymes known to play important roles in controlling virtually all aspects of cellular processes. However, assigning functional significance of PTPs in normal physiology and in diseases remains a major challenge in cell signaling. Since the function of a PTP is directly associated with its intrinsic activity, which is subject to post-translational regulation, new tools are needed to monitor the dynamic activities of PTPs, rather than mere abundance, on a global scale within the physiologically relevant environment of cells. To meet this objective, we report the synthesis and characterization of two rhodamine-conjugated probes that covalently label the active site of the PTPs in an activity-dependent manner, thus providing a direct readout of PTP activity and superior sensitivity, robustness, and quantifiability to previously reported biotinylated probes. We present evidence that the fluorescent probes can be used to identify new PTP markers and targets for potential diagnosis and treatment of human diseases. We also show that the fluorescent probes are capable of monitoring H(2)O(2)-mediated PTP inactivation, which should facilitate the study of regulated H(2)O(2) production as a new tier of control over tyrosine phosphorylation-dependent signal transduction. The ability to profile the entire PTP family on the basis of changes in their activity is expected to yield new functional insights into pathways regulated by PTPs and contribute to the discovery of PTPs as novel therapeutic targets.