Ratiometric quantitation of redox status with a molecular Fe2 magnetic resonance probe.
We demonstrate the ability of a molecular Fe2 complex to enable magnetic resonance (MR)-based ratiometric quantitation of redox status, namely through redox-dependent paramagnetic chemical exchange saturation transfer (PARACEST). Metalation of a tetra(carboxamide) ligand with FeII and/or FeIII in the presence of etidronate ion affords analogous FeII2, FeIIFeIII, and FeIII2 complexes. Both FeII2 and FeIIFeIII complexes give highly-shifted, sharp, and non-overlapping NMR spectra, with multiple resonances for each complex corresponding to exchangeable carboxamide protons. These protons can be selectively irradiated to give CEST peaks at 74 and 83 ppm vs. H2O for the FeIIFeIII complex and at 29, 40 and 68 ppm for the FeII2 complex. The CEST spectra obtained from a series of samples containing mixtures of FeII2 and FeIIFeIII are correlated with independently-determined open-circuit potentials to construct a Nernstian calibration curve of potential vs. CEST peak intensity ratio. In addition, averaged intensities of phantom images collected on a 9.4 T MRI scanner show analogous Nernstian behavior. Finally, both the FeII2 and FeIIFeIII forms of the complex are stable to millimolar concentrations of H2PO4-/HPO42-, CO32-, SO42-, CH3COO-, and Ca2+ ions, and the FeIII2 form is air-stable in aqueous buffer and shows >80% viability in melanoma cells at millimolar concentration. The stability suggests the possible application of this or related complexes for in vivo studies. To our knowledge, this concentration-independent method based on a single Fe2 probe provides the first example of MR-based ratiometric quantitation of redox environment.


Evaluation of the Effect of Topical Application of Nigella sativa on Acute Radiation-Induced Nasal Mucositis.
The goal of this study was to demonstrate the effect of radiotherapy (RT) on nasal mucosa in rats and to evaluate the radioprotective effects of the topical application of black seed oil (Nigella sativa [NS]) to treat acute radiation-induced nasal mucositis.A total of 18 rats were randomized into 3 groups, with 6 animals per group. The rats in group 1 were topically administered saline in the nasal cavity after sham irradiation. Group 2 received saline at the same dose after irradiation. Group 3 was given NS after irradiation. The rats in groups 2 and 3 were irradiated with a single dose of 40 Gy to the nasal and paranasal area. Only one drop of saline (0.05 mL) was applied to each nostril in the first, second, and third days after RT in groups 1 and 2. One drop of cold press NS (0.05 mL) was applied to each nostril in group 3. Fourteen days after irradiation, the nasal mucosal tissues were excised for histopathological evaluation. Vascular dilatation, inflammatory cell infiltration, superficial erosion, and formation of exudates were classified according to the severity.No evidence of mucositis was observed in group 1. Of all the parameters the only statistically significant difference between groups 2 and 3 were observed for "superficial erosion' (P < 0.05). Overall microscopic observations in the NS-treated group were better than in group 2.The preliminary results of our study have shown that local application of NS to the nasal mucosa may be an effective treatment of acute nasal mucositis due to RT.


Transcription of subtelomerically located var gene variant in Plasmodium falciparum appears to require the truncation of an adjacent var gene.
The Plasmodium falciparum R29 clone preferentially transcribes the R29var gene variant on rosette selection, unlike other isogenic clones from the same parasite lineage. Characterisation of the R29var gene locus revealed that this gene lies internal to, and is in a tail-to-tail orientation with, a second var gene variant (A4var) at one end of chromosome 13. In the R29 clone, a spontaneous deletion event between these two var variants deletes all of the A4var gene and the subtelomeric repetitive sequence arrays. We have previously shown that a simple disruption of the A4var gene is not sufficient to preferentially activate the R29var gene in rosette-selected parasites. We therefore hypothesised that the truncation of the chromosome end may be a key factor in predisposing the R29var variant to transcription under rosette selection conditions. Here, we have generated a panel of isogenic parasite clones with both intact and truncated A4var-R29var loci, and show that R29var transcription is only detected in rosette-selected clones with a truncated locus. Furthermore, we present provisional data describing the relative frequency with which this spontaneous deletion event occurs. These data have implications in our understanding of how spontaneous deletion events within subtelomeric var loci may affect transcription of these var gene variants.


Improved understanding of factors contributing to quantification of anhydrate/hydrate powder mixtures.
Different spectroscopic approaches have proved to be excellent analytical tools for monitoring process-induced transformations of active pharmaceutical ingredients during pharmaceutical unit operations. In order to use these tools effectively, it is necessary to build calibration models that describe the relationship between the amount of each solid-state form of interest and the spectroscopic signal. In this study, near-infrared (NIR) and Raman spectroscopic methods have been evaluated for the quantification of hydrate and anhydrate forms in pharmaceutical powders. Process type spectrometers were used to collect the data and the role of the sampling procedure was examined. Multivariate regression models were compared with traditional univariate calibrations and special emphasis was placed on data treatment prior to multivariate modeling by partial least squares (PLS). It was found that the measured sample volume greatly affected the performance of the model whereby the calibrations were significantly improved by utilizing a larger sampling area. In addition, multivariate regression did not always improve the predictability of the data compared to univariate analysis. The data treatment prior to multivariate modeling had a significant influence on the quality of predictions with standard normal variate transformation generally proving to be the best preprocessing method. When the appropriate sampling techniques and data analysis methods were utilized, both NIR and Raman spectroscopy were found to be suitable methods for the quantification of anhydrate/hydrate in powder systems, and thus the method of choice will depend on the conditions in the process under investigation.


Targeted maximum likelihood estimation for dynamic treatment regimes in sequentially randomized controlled trials.
Sequential Randomized Controlled Trials (SRCTs) are rapidly becoming essential tools in the search for optimized treatment regimes in ongoing treatment settings. Analyzing data for multiple time-point treatments with a view toward optimal treatment regimes is of interest in many types of afflictions: HIV infection, Attention Deficit Hyperactivity Disorder in children, leukemia, prostate cancer, renal failure, and many others. Methods for analyzing data from SRCTs exist but they are either inefficient or suffer from the drawbacks of estimating equation methodology. We describe an estimation procedure, targeted maximum likelihood estimation (TMLE), which has been fully developed and implemented in point treatment settings, including time to event outcomes, binary outcomes and continuous outcomes. Here we develop and implement TMLE in the SRCT setting. As in the former settings, the TMLE procedure is targeted toward a pre-specified parameter of the distribution of the observed data, and thereby achieves important bias reduction in estimation of that parameter. As with the so-called Augmented Inverse Probability of Censoring Weight (A-IPCW) estimator, TMLE is double-robust and locally efficient. We report simulation results corresponding to two data-generating distributions from a longitudinal data structure.


El Niño-like teleconnection increases California precipitation in response to warming.
Future California (CA) precipitation projections, including those from the most recent Climate Model Intercomparison Project (CMIP5), remain uncertain. This uncertainty is related to several factors, including relatively large internal climate variability, model shortcomings, and because CA lies within a transition zone, where mid-latitude regions are expected to become wetter and subtropical regions drier. Here, we use a multitude of models to show CA may receive more precipitation in the future under a business-as-usual scenario. The boreal winter season-when most of the CA precipitation increase occurs-is associated with robust changes in the mean circulation reminiscent of an El Niño teleconnection. Using idealized simulations with two different models, we further show that warming of tropical Pacific sea surface temperatures accounts for these changes. Models that better simulate the observed El Niño-CA precipitation teleconnection yield larger, and more consistent increases in CA precipitation through the twenty-first century.


Engineered Amp C β-lactamase as a fluorescent screening tool for class C β-lactamase inhibitors.
Class C β-lactamases mediate antibiotic resistance in bacteria by efficiently hydrolyzing a broad range of β-lactam antibiotics. With their clinical significance and the lack of commercially available effective inhibitors, development of class C β-lactamase inhibitors has become one of the recent hot issues in the pharmaceutical industry. In this paper, we report the protein engineering of a fluorescent Amp C β-lactamase mutant designated as V211Cf for the in vitro screening of class C β-lactamase inhibitors. When a fluorescein (f) was incorporated at the entrance of the enzyme's active site (position 211), Amp C β-lactamase from Enterobacter cloacae P99 was tailor-made into a novel fluorescent biosensing protein that could display a fluorescence enhancement upon binding with its β-lactam substrates/inhibitors. With its catalytic activity close to the wild-type level, V211Cf can act as a "natural" fluorescent drug target for screening small binding molecules. In addition, V211Cf can allow specific detection for its active-site binding molecules and discriminate them from nondruglike molecules in the screen. Furthermore, V211Cf is amenable to a high throughput format. Taken together, V211Cf demonstrates the potential as an efficient tool for screening class C β-lactamase inhibitors and facilitates the discovery of therapeutics that can combat the clinically important class C β-lactamases.


SOCS1 Is a Key Molecule That Prevents Regulatory T Cell Plasticity under Inflammatory Conditions.
We previously showed that regulatory T cells (Tregs) from T cell-specific Socs1-deficient mice (Socs1fl/flLck-Cre+ mice) easily convert into Th1- or Th17-like cells (ex-Tregs), which lose Foxp3 expression and suppressive functions in vivo. Because Tregs in Socs1fl/flLck-Cre+ mice are constantly exposed to a large amount of inflammatory cytokines produced by non-Tregs in vivo, in this study we analyzed Treg-specific Socs1-deficient mice (Socs1fl/flFoxp3YFP-Cre mice). These mice developed dermatitis, splenomegaly, and lymphadenopathy that were much milder than those in Socs1fl/flLck-Cre+ mice. A fate mapping study revealed that Socs1 deficiency accelerated the conversion of Tregs to Foxp3-IFN-γ+ ex-Tregs in the tumor microenvironment and suppressed tumor growth. When transferred into Rag2-/- mice, Tregs from Socs1fl/flLck-Cre+ mice easily lost Foxp3 expression, whereas those from Socs1fl/flFoxp3YFP-Cre mice maintained Foxp3 expression. Although Tregs from Socs1fl/flLck-Cre+ mice produced IFN-γ after a 3-d culture in response to anti-CD3/CD28 Ab stimulation in vitro, Tregs from Socs1fl/flFoxp3YFP-Cre mice did not. This finding suggested that the inflammatory conditions in Socs1fl/flLck-Cre+ mice modified the born nature of Socs1-deficient Tregs. To investigate this mechanism, Tregs from Socs1fl/flFoxp3YFP-Cre mice were cultured with APCs from Socs1fl/flLck-Cre+ mice. These APCs facilitated STAT4 phosphorylation, IFN-γ production, and loss of Foxp3 expression in Tregs from Socs1fl/flFoxp3YFP-Cre mice in an IL-12-dependent manner. The results indicate that Socs1-deficient Tregs tend to convert into ex-Tregs under the inflammatory conditions in which APCs are highly activated, and that SOCS1 could be a useful target for enhancement of anti-tumor immunity.


The receptor TGR5 protects the liver from bile acid overload during liver regeneration in mice.
Many regulatory pathways are involved in liver regeneration after partial hepatectomy (PH) to initiate growth, protect liver cells, and sustain functions of the remnant liver. Bile acids (BAs), whose levels rise in the blood early after PH, stimulate both hepatocyte proliferation and protection, in part through their binding to the nuclear farnesoid X receptor (FXR). However, the effect of the BA receptor, TGR5 (G-protein-coupled BA receptor 1) after PH remains to be studied. Liver histology, hepatocyte proliferation, BA concentrations (plasma, bile, liver, urine, and feces), bile flow and composition, and cytokine production were studied in wild-type (WT) and TGR5 KO (knockout) mice before and after PH. BA composition (plasma, bile, liver, urine, and feces) was more hydrophobic in TGR5 KO than in WT mice. After PH, severe hepatocyte necrosis, prolonged cholestasis, exacerbated inflammatory response, and delayed regeneration were observed in TGR5 KO mice. Although hepatocyte adaptive response to post-PH BA overload was similar in WT and TGR5 KO mice, kidney and biliary adaptive responses were strongly impaired in TGR5 KO mice. Cholestyramine treatment, as well as Kupffer cell depletion, significantly improved the post-PH TGR5 KO mice phenotype. After bile duct ligation or upon a cholic acid-enriched diet, TGR5 KO mice exhibited more severe liver injury than WT as well as impaired BA elimination in urine. TGR5 is crucial for liver protection against BA overload after PH, primarily through the control of bile hydrophobicity and cytokine secretion. In the absence of TGR5, intrahepatic stasis of abnormally hydrophobic bile and excessive inflammation, in association with impaired bile flow adaptation and deficient urinary BA efflux, lead to BA overload-induced liver injury and delayed regeneration.


Genotypes Associated with Listeria monocytogenes Isolates Displaying Impaired or Enhanced Tolerances to Cold, Salt, Acid, or Desiccation Stress.
The human pathogen Listeria monocytogenes is a large concern in the food industry where its continuous detection in food products has caused a string of recalls in North America and Europe. Most recognized for its ability to grow in foods during refrigerated storage, L. monocytogenes can also tolerate several other food-related stresses with some strains possessing higher levels of tolerances than others. The objective of this study was to use a combination of phenotypic analyses and whole genome sequencing to elucidate potential relationships between L. monocytogenes genotypes and food-related stress tolerance phenotypes. To accomplish this, 166 L. monocytogenes isolates were sequenced and evaluated for their ability to grow in cold (4°C), salt (6% NaCl, 25°C), and acid (pH 5, 25°C) stress conditions as well as survive desiccation (33% RH, 20°C). The results revealed that the stress tolerance of L. monocytogenes is associated with serotype, clonal complex (CC), full length inlA profiles, and the presence of a plasmid which was identified in 55% of isolates. Isolates with full length inlA exhibited significantly (p < 0.001) enhanced cold tolerance relative to those harboring a premature stop codon (PMSC) in this gene. Similarly, isolates possessing a plasmid demonstrated significantly (p = 0.013) enhanced acid tolerance. We also identified nine new L. monocytogenes sequence types, a new inlA PMSC, and several connections between CCs and the presence/absence or variations of specific genetic elements. A whole genome single-nucleotide-variants phylogeny revealed sporadic distribution of tolerant isolates and closely related sensitive and tolerant isolates, highlighting that minor genetic differences can influence the stress tolerance of L. monocytogenes. Specifically, a number of cold and desiccation sensitive isolates contained PMSCs in σB regulator genes (rsbS, rsbU, rsbV). Collectively, the results suggest that knowing the sequence type of an isolate in addition to screening for the presence of full-length inlA and a plasmid, could help food processors and food agency investigators determine why certain isolates might be persisting in a food processing environment. Additionally, increased sequencing of L. monocytogenes isolates in combination with stress tolerance profiling, will enhance the ability to identify genetic elements associated with higher risk strains.


Striatal-enriched protein tyrosine phosphatase expression and activity in Huntington's disease: a STEP in the resistance to excitotoxicity.
Striatal-enriched protein tyrosine phosphatase (STEP) is highly expressed in striatal projection neurons, the neuronal population most affected in Huntington's disease. Here, we examined STEP expression and phosphorylation, which regulates its activity, in N-terminal exon-1 and full-length mutant huntingtin mouse models. R6/1 mice displayed reduced STEP protein levels in the striatum and cortex, whereas its phosphorylation was increased in the striatum, cortex, and hippocampus. The early increase in striatal STEP phosphorylation levels correlated with a deregulation of the protein kinase A pathway, and decreased calcineurin activity at later stages further contributes to an enhancement of STEP phosphorylation and inactivation. Accordingly, we detected an accumulation of phosphorylated ERK2 and p38, two targets of STEP, in R6/1 mice striatum at advanced stages of the disease. Activation of STEP participates in excitotoxic-induced cell death. Because Huntington's disease mouse models develop resistance to excitotoxicity, we analyzed whether decreased STEP activity was involved in this process. After intrastriatal quinolinic acid (QUIN) injection, we detected higher phosphorylated STEP levels in R6/1 than in wild-type mice, suggesting that STEP inactivation could mediate neuroprotection in R6/1 striatum. In agreement, intrastriatal injection of TAT-STEP increased QUIN-induced cell death. R6/2, Tet/HD94, and Hdh(Q7/Q111) mice striatum also displayed decreased STEP protein and increased phosphorylation levels. In Tet/HD94 mice striatum, mutant huntingtin transgene shutdown reestablished STEP expression. In conclusion, the STEP pathway is severely downregulated in the presence of mutant huntingtin and may participate in compensatory mechanisms activated by striatal neurons that lead to resistance to excitotoxicity.


Olive oil polyphenols enhance the expression of cholesterol efflux related genes in vivo in humans. A randomized controlled trial.
Both oleic acid and polyphenols have been shown to increase high-density lipoprotein (HDL) cholesterol and to protect HDL from oxidation, a phenomenon associated with a low cholesterol efflux from cells. Our goal was to determine whether polyphenols from olive oil could exert an in vivo nutrigenomic effect on genes related to cholesterol efflux in humans. In a randomized, controlled, cross-over trial, 13 pre/hypertensive patients were assigned 30 ml of two similar olive oils with high (961 mg/kg) and moderate (289 mg/kg) polyphenol content. We found an increase in ATP binding cassette transporter-A1, scavenger receptor class B type 1, peroxisome proliferator-activated receptor (PPAR)BP, PPARα, PPARγ, PPARδ and CD36 gene expression in white blood cells at postprandial after high polyphenol olive oil when compared with moderate polyphenol olive oil intervention (P<.017), with COX-1 reaching borderline significance (P=.024). Linear regression analyses showed that changes in gene expression were related to a decrease in oxidized low-density lipoproteins and with an increase in oxygen radical absorbance capacity and olive oil polyphenols (P<.05). Our results indicate a significant role of olive oil polyphenols in the up-regulation of genes involved in the cholesterol efflux from cells to HDL in vivo in humans. These results are in agreement with previous ones concerning the fact that benefits associated with polyphenol-rich olive oil consumption on cardiovascular risk could be mediated through an in vivo nutrigenomic effect in humans.


Autobiographical memory, autonoetic consciousness, and identity in Asperger syndrome.
Previous results from research on individuals with Asperger syndrome (AS) suggest a diminished ability for recalling episodic autobiographical memory (AM). The primary aim of this study was to explore autobiographical memory in individuals with Asperger syndrome and specifically to investigate whether memories in those with AS are characterized by fewer episodic 'remembered' events (due to a deficit in autonoetic consciousness). A further aim was to examine whether such changes in AM might also be related to changes in identity, due to the close relationship between memory and the self and to the established differences in self-referential processes in AS. Eleven adults with AS and fifteen matched comparison participants were asked to recall autobiographical memories from three lifetime periods and for each memory to give either a remember response (autonoetic consciousness) or a know response (noetic consciousness). The pattern of results shows that AS participants recalled fewer memories and that these memories were more often rated as known, compared to the comparison group. AS participants also showed differences in reported identity, generating fewer social identity statements and more abstract, trait-linked identities. The data support the view that differences in both memory and reported personal identities in AS are characterized by a lack of specificity.


Genomic Analysis Revealed New Oncogenic Signatures in TP53-Mutant Hepatocellular Carcinoma.
The TP53 gene is the most commonly mutated gene in human cancers and mutations in TP53 have been shown to have either gain-of-function or loss-of-function effects. Using the data generated by The Cancer Genome Atlas, we sought to define the spectrum of TP53 mutations in hepatocellular carcinomas (HCCs) and their association with clinicopathologic features, and to determine the oncogenic and mutational signatures in TP53-mutant HCCs. Compared to other cancer types, HCCs harbored distinctive mutation hotspots at V157 and R249, whereas common mutation hotspots in other cancer types, R175 and R273, were extremely rare in HCCs. In terms of clinicopathologic features, in addition to the associations with chronic viral infection and high Edmondson grade, we found that TP53 somatic mutations were less frequent in HCCs with cholestasis or tumor infiltrating lymphocytes, but were more frequent in HCCs displaying necrotic areas. An analysis of the oncogenic signatures based on the genetic alterations found in genes recurrently altered in HCCs identified four distinct TP53-mutant subsets, three of which were defined by CTNNB1 mutations, 1q amplifications or 8q24 amplifications, respectively, that co-occurred with TP53 mutations. We also found that mutational signature 12, a liver cancer-specific signature characterized by T>C substitutions, was prevalent in HCCs with wild-type TP53 or with missense TP53 mutations, but not in HCCs with deleterious TP53 mutations. Finally, whereas patients with HCCs harboring deleterious TP53 mutations had worse overall and disease-free survival than patients with TP53-wild-type HCCs, patients with HCCs harboring missense TP53 mutations did not have worse prognosis. In conclusion, our results highlight the importance to consider the genetic heterogeneity among TP53-mutant HCCs in studies of biomarkers and molecular characterization of HCCs.


Hand function and activity performance of children with longitudinal radial deficiency.
The effects of treatment of children with longitudinal radial deficiency are generally evaluated by measuring grip and pinch strength and joint mobility. Insight into limitations of activities of children with radial deficiency is scarce. In this study, we used standardized instruments to assess impairments in hand function and activity limitations and explored the relationship between the two. We evaluated the hand function of twenty children with radial deficiency who were between four and twelve years of age. Impairments in hand function were assessed by measuring grip and pinch strength and the active range of motion of the wrist and of the metacarpophalangeal and proximal interphalangeal joints of the second digit. Functional activities were assessed with use of the Assisting Hand Assessment (AHA), to measure the effectiveness of the affected hand, and the Prosthetic Upper Extremity Functional Index (PUFI), to evaluate the ease of activity performance. The relationship between hand function and activity performance and the relationship of those measures with the type of radial deficiency were determined. The average grip and pinch strengths were 36% and 30% of reference values. We found reductions in the active range of motion, particularly of the metacarpophalangeal and proximal interphalangeal joints. The mean AHA score was 85.5 points and the mean PUFI score was 81.8 points, with both measured on a 0 to 100-point scale. Grip and pinch strength, the active range of joint motion, and the sum scores on the two functional tests were related to the type of radial deficiency. Significant relationships were found between impairments in hand function and activity performance. There was a large variation in the activity performance of the children with poor strength, whereas a more linear relationship was found between the active ranges of motion of the wrist and finger joints and activity performance. Despite marked impairments in hand function, children with radial deficiency performed functional activities fairly well. Relationships between impairments in hand function and limitation of activities were not linear. We recommend that evaluations of the results of treatment include assessment of both aspects of hand function.


Effects of auricular acupressure on menstrual symptoms and nitric oxide for women with primary dysmenorrhea.
The aim of this study was to evaluate the effects of auricular acupressure on relieving menstrual symptoms and decreasing nitric oxide (NO) for women with primary dysmenorrhea. This was a randomized clinical trial comparing the effects of auricular acupressure by seed-pressure method and placebo adhesive patch. Settings included colleges in northern and central Taiwan. Serum CA-125 testing was used as a screening test for primary dysmenorrhea (<35 mg/dL). The study included 36 college females randomized to acupressure group, 35 to control group. The acupressure group received auricular acupressure by seed-pressure method on liver (CO12), kidney (CO10), and endocrine (CO18) acupoints. The control group had a plain adhesive patch placed on the same acupoints with no seed attached. Acupressure protocol included massaging 15 times on each acupoint, 3 times a day, for a total of 20 days. Primary: Short-form Menstrual Distress Questionnaire (MDQs). Secondary: blood sample of NO. Assessments of MDQs and NO were performed at baseline and within the first 2 days of their next menses (after completion of 20 days of acupressure). In the acupressure group, the overall menstrual symptoms (95% confidence interval [CI] = -49.8 to -6.5, effect size [ES] = 0.43, p = 0.01) and two subscales, menstrual pain (95% CI = -16.4 -to -2.2, ES = 0.45, p = 0.01) and negative affects (95% CI = -11.9-2.0, ES = 0.38, p = 0.04), revealed that menstrual symptoms decreased significantly after auricular acupressure by the seed-pressure method. The ES for the MDQs were in favor of the auricular acupressure by seed-pressure method. NO level increased in the acupressure group, although this difference did not achieve statistical significance (p > 0.05). This study supports the effects of auricular acupressure by seed-pressure method in improving menstrual symptoms, and offers a noninvasive complementary therapy for women with primary dysmenorrhea.


Porous aromatic framework with mesopores as a platform for a super-efficient heterogeneous Pd-based organometallic catalysis.
A strategy using a mesoporous amine-tagged porous aromatic framework (PAF70-NH2 ) to immobilize a palladium (Pd)-based molecular catalyst has been developed. The resulting immobilized catalyst PAF70-Pd, in which the framework is entirely constructed by phenyl rings linked with stable carbon-carbon bonds, has high structural rigidity and stability. Compared with the known porous organic material immobilized Pd-based catalysts, PAF70-Pd has the highest Pd content so far. Moreover, PAF70-Pd has extremely high catalytic activity with good size selectivity and very easy recyclability in catalyzing the Suzuki-Miyaura coupling reaction. In the current system, the catalyst loading could be as low as 0.001 mol% and the TOF value could go up to 28 800 h-1 which is far higher than those of the known porous organic material immobilized Pd-based catalysts. In order to elucidate the particularly high catalytic efficiency of PAF70-Pd, we prepared PAF1-Pd from PAF1-NH2 for comparison. PAF1-Pd has a higher Pd content than PAF70-Pd. However, due to the absence of large enough mesopores in PAF1-NH2 , PAF1-Pd has almost no catalytic activity under the same conditions, which definitely demonstrated that the intrinsic mesoporosity of PAF70-NH2 plays a crucial role in the superb catalytic efficiency of PAF70-Pd. This strategy to immobilize Pd-based molecular catalysts has very good expansibility to be applied in the immobilization of different organometallic catalysts into the pores of PAFs, which also has very high potential in the chemical and pharmaceutical industry.


Therapeutic targeting of MLL.
Treatment of hematologic malignancies is evolving from a uniform approach to targeted therapies directed at the underlying molecular abnormalities of disease. The mixed lineage leukemia (MLL) proto-oncogene is a recurrent site of genetic rearrangements in acute leukemias; and since its discovery in 1992, many advances have been made in understanding its role in leukemogenesis. A variety of MLL translocation partners have been described, and detailed structure/function studies have identified functional domains that are required for transformation. Proteins associated with the MLL core complex or its fusion partners have been isolated and characterized for their critical roles in leukemia pathogenesis. Downstream mediators of MLL transcriptional regulation and multiple collaborating signaling pathways have been described and characterized. These advances in our understanding of MLL-related leukemogenesis provide a foundation for ongoing and future efforts to develop novel therapeutic strategies that will hopefully result in better treatment outcomes.


Clinicopathologic significance of HIF-1α, CXCR4, and VEGF expression in colon cancer.
We investigated the clinicopathologic significance of HIF-1, CXCR4, and VEGF expression using immumohistochemistry in human colon cancer. HIF-1, CXCR4, and VEGF high expression levels were correlated positively with TNM stage, lymph node involvement, and distant metastasis Furthermore, we found that combined high expression of any two of the three molecules (P = .028 for HIF-1/CXCR4, P = .007 for HIF-1/VEGF, and P = .004 for CXCR4/VEGF) had stronger correlation with lymph node metastasis than did each alone. However, a relationship with distant metastasis is seen only with the combinations CXCR4/VEGF (P = .069 for HIF-1/CXCR4, P = .062 for HIF-1/VEGF, and P = .035 for CXCR4/VEGF) as compared with those of single molecule high expression alone. Combined expression of all three molecules strongly correlates with lymph node metastasis and distant metastasis. The mRNA expression of HIF-1, CXCR4, and VEGF were quantified by real-time PCR in different colon cancer tissue samples, the experiment results shown that fresh colon tissue samples significantly overexpressed CXCR4 and VEGF mRNA compared with negative control. Therefore, the disease-free survival of all patients after curative resection can be considered in association with all three markers expression.


Early mortality after cardiac transplantation: should we do better?
According to International Society for Heart and Lung Transplantation (ISHLT) data, the 30-day survival after heart transplantation has continually improved from 84% (1979-85) to 91% (1996-2001). This has probably been achieved by better donor/recipient selection, along with improved surgical technique and immunosuppressive therapy. On the other hand, the data concerning the early causes of death after cardiac transplantation is incomplete, because in 25% of cases, an unknown cause is listed. This study investigated the incidence and causes of 30-day mortality (determined by postmortem studies) after cardiac transplantation and assessed the possibility of improvements. A retrospective study of all patients who underwent heart transplantation at Papworth Hospital from 1979 to June 2001 (n = 879) and who died within 30 days of surgery was carried out. Postmortem examination data were available for all patients. The mean (standard deviation) recipient and donor ages were 46 (12) and 31 (12) years, respectively. Overall, the 30-day mortality was 8.5% (n = 75), 12.1% for the 1979 to 1985 period and 6.9% for the 1996 to 2001 period. The primary causes of death were graft failure (30.7%), acute rejection (22.7%) (1.3% for the 1996-2001 era), sepsis (18.7%) gastrointestinal problems (bowel infarction and pancreatitis; (9.3%), postoperative bleeding (6.7%), and other (12%). Our 30-day mortality compares favorably with the data from the ISHLT registry, with great improvement in the early mortality. Acute rejection is no longer a major cause of early mortality. Further reduction may be achieved by a better protection of the donor heart against the effects of brainstem death and ischemic injuries. However, the quest to improve early outcome should not be at the expense of needy patients by being overselective.


Structure and function of LCI1: a plasma membrane CO2 channel in the Chlamydomonas CO2 concentrating mechanism.
Microalgae and cyanobacteria contribute roughly half of the global photosynthetic carbon assimilation. Faced with limited access to CO2 in aquatic environments, which can vary daily or hourly, these microorganisms have evolved use of an efficient CO2 concentrating mechanism (CCM) to accumulate high internal concentrations of inorganic carbon (Ci ) to maintain photosynthetic performance. For eukaryotic algae, a combination of molecular, genetic and physiological studies using the model organism Chlamydomonas reinhardtii, have revealed the function and molecular characteristics of many CCM components, including active Ci uptake systems. Fundamental to eukaryotic Ci uptake systems are Ci transporters/channels located in membranes of various cell compartments, which together facilitate the movement of Ci from the environment into the chloroplast, where primary CO2 assimilation occurs. Two putative plasma membrane Ci transporters, HLA3 and LCI1, are reportedly involved in active Ci uptake. Based on previous studies, HLA3 clearly plays a meaningful role in HCO3- transport, but the function of LCI1 has not yet been thoroughly investigated so remains somewhat obscure. Here we report a crystal structure of the full-length LCI1 membrane protein to reveal LCI1 structural characteristics, as well as in vivo physiological studies in an LCI1 loss-of-function mutant to reveal the Ci species preference for LCI1. Together, these new studies demonstrate LCI1 plays an important role in active CO2 uptake and that LCI1 likely functions as a plasma membrane CO2 channel, possibly a gated channel.


Watch Where You Point That: Pneumomediastinum From Pneumatic Nail Gun Injury to the Hand.
Pneumatic nail guns are hand-held tools used in industrial and construction settings. Nail guns cause the most trauma with hospitalization among construction workers. To our knowledge, we report for the first time a case of pneumomediastinum from a nail gun injury to the hand. Our patient was a 40-year-old male construction worker who shot a nail gun into his hand. He became acutely dyspneic and was found to have a pneumomediastinum due to air insufflation. He later underwent tube thoracostomy and intubation. To our knowledge, this is the first report of pneumomediastinum from a nail gun injury to the hand.


Quantitatively measuring in situ flows using a self-contained underwater velocimetry apparatus (SCUVA).
The ability to directly measure velocity fields in a fluid environment is necessary to provide empirical data for studies in fields as diverse as oceanography, ecology, biology, and fluid mechanics. Field measurements introduce practical challenges such as environmental conditions, animal availability, and the need for field-compatible measurement techniques. To avoid these challenges, scientists typically use controlled laboratory environments to study animal-fluid interactions. However, it is reasonable to question whether one can extrapolate natural behavior (i.e., that which occurs in the field) from laboratory measurements. Therefore, in situ quantitative flow measurements are needed to accurately describe animal swimming in their natural environment. We designed a self-contained, portable device that operates independent of any connection to the surface, and can provide quantitative measurements of the flow field surrounding an animal. This apparatus, a self-contained underwater velocimetry apparatus (SCUVA), can be operated by a single scuba diver in depths up to 40 m. Due to the added complexity inherent of field conditions, additional considerations and preparation are required when compared to laboratory measurements. These considerations include, but are not limited to, operator motion, predicting position of swimming targets, available natural suspended particulate, and orientation of SCUVA relative to the flow of interest. The following protocol is intended to address these common field challenges and to maximize measurement success.


The Role of Cognitive Development and Strategic Task Tendencies in the Bilingual Advantage Controversy.
Recent meta-analyses have indicated that the bilingual advantage in cognitive control is not clear-cut. So far, the literature has mainly focussed on behavioral differences and potential differences in strategic task tendencies between monolinguals and bilinguals have been left unexplored. In the present study, two groups of younger and older bilingual Dutch-French children were compared to monolingual controls on a Simon and flanker task. Beside the classical between-group comparison, we also investigated potential differences in strategy choices as indexed by the speed-accuracy trade-off. Whereas we did not find any evidence for an advantage for bilingual over monolingual children, only the bilinguals showed a significant speed-accuracy trade-off across tasks and age groups. Furthermore, in the younger bilingual group, the trade-off effect was only found in the Simon and not the flanker task. These findings suggest that differences in strategy choices can mask variations in performance between bilinguals and monolinguals, and therefore also provide inconsistent findings on the bilingual cognitive control advantage.


Prevalence and covariates of problematic gambling among a US military cohort.
The availability of and participation in gambling has increased substantially the past several decades, however studies of military members' gambling behaviors are limited. The present study aimed to investigate potential problematic gambling and its association with demographics and behavioral characteristics in a US military cohort. We analyzed cohort data from a telephone survey during 2015-2016 of 1553 Ohio Army National Guard members. We assessed potential problematic gambling by using the 3-item National Opinion Research Center Diagnostic Screen-Loss of Control, Lying, and Preoccupation Screen (NODS-CLiP). Potential correlates examined were demographics, depression, suicidal ideation, smoking status, alcohol use, legal and financial problems, perceived general health status, pain, and impulsivity. Results indicated past-year frequent gambling (at least once per week) and lifetime potential problematic gambling was reported by 13% and 8% of respondents, respectively. Problematic gambling and past-year gambling behaviors were associated in a dose-response relationship from 18% among soldiers gambling once per week to 44% among those gambling 4 or more times per week. Correlates of screening positive for potential problematic gambling included the following: being male, currently unmarried, having left the Guard or retired, minor depression, alcohol dependence, legal problems, and increased pain. Given the higher prevalence of frequent gambling in this military cohort (8%), nearly twice the US prevalence (5%), and the association with negative psychological and behavioral outcomes, routine screening of gambling frequency and problem gambling may be needed to ensure military and veteran populations live the healthiest lives possible.


Integrating liquid biopsies into the management of cancer.
During cancer progression and treatment, multiple subclonal populations of tumour cells compete with one another, with selective pressures leading to the emergence of predominant subclones that replicate and spread most proficiently, and are least susceptible to treatment. At present, the molecular landscapes of solid tumours are established using surgical or biopsy tissue samples. Tissue-based tumour profiles are, however, subject to sampling bias, provide only a snapshot of tumour heterogeneity, and cannot be obtained repeatedly. Genomic profiles of circulating cell-free tumour DNA (ctDNA) have been shown to closely match those of the corresponding tumours, with important implications for both molecular pathology and clinical oncology. Analyses of circulating nucleic acids, commonly referred to as 'liquid biopsies', can be used to monitor response to treatment, assess the emergence of drug resistance, and quantify minimal residual disease. In addition to blood, several other body fluids, such as urine, saliva, pleural effusions, and cerebrospinal fluid, can contain tumour-derived genetic information. The molecular profiles gathered from ctDNA can be further complemented with those obtained through analysis of circulating tumour cells (CTCs), as well as RNA, proteins, and lipids contained within vesicles, such as exosomes. In this Review, we examine how different forms of liquid biopsies can be exploited to guide patient care and should ultimately be integrated into clinical practice, focusing on liquid biopsy of ctDNA - arguably the most clinically advanced approach.


Three-dimensional spherical gelatin bubble-based scaffold improves the myotube formation of H9c2 myoblasts.
Microenvironmental factors including physical and chemical cues can regulate stem cells as well as terminally differentiated cells to modulate their biological function and differentiation. However, one of the physical cues, the substrate's dimensionality, has not been studied extensively. In this study, the flow-focusing method with a microfluidic device was used to generate gelatin bubbles to fabricate highly ordered three-dimensional (3D) scaffolds. Rat H9c2 myoblasts were seeded into the 3D gelatin bubble-based scaffolds and compared to those grown on 2D gelatin-coating substrates to demonstrate the influences of spatial cues on cell behaviors. Relative to cells on the 2D substrates, the H9c2 myoblasts were featured by a good survival and normal mitochondrial activity but slower cell proliferation within the 3D scaffolds. The cortical actin filaments of H9c2 cells were localized close to the cell membrane when cultured on the 2D substrates, while the F-actins distributed uniformly and occupied most of the cell cytoplasm within the 3D scaffolds. H9c2 myoblasts fused as multinuclear myotubes within the 3D scaffolds without any induction but cells cultured on the 2D substrates had a relatively lower fusion index even differentiation medium was provided. Although there was no difference in actin α 1 and myosin heavy chain 1, H9c2 cells had a higher myogenin messenger RNA level in the 3D scaffolds than those of on the 2D substrates. This study reveals that the dimensionality influences differentiation and fusion of myoblasts.


Structure of the human type II 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD) gene: adrenal and gonadal specificity.
While classical 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase deficiency (3 beta-HSD) is a known cause of adrenal hyperplasia resulting in ambiguous genitalia and adrenal insufficiency at birth, nonclassical or late-onset 3 beta-HSD deficiency is found in an important proportion of women with androgen excess. We have previously isolated and sequenced the cDNA and gene for the human type I 3 beta-HSD, which represents the main species expressed in the placenta and skin. Recently, we isolated, sequenced, and expressed the functional cDNA encoding type II 3 beta-HSD, which is the predominant 3 beta-HSD expressed in human adrenals and gonads. The present study describes the isolation and complete sequence of the corresponding type II 3 beta-HSD gene, which is the form most likely responsible for human 3 beta-HSD deficiency. The structural gene contains four exons of 57, 231, 165, and 1,214 bp, respectively, separated by introns of 128, 3,383, and 2,162 bp. DNA sequence analysis of the 5'-flanking region reveals the existence of two putative TATA boxes situated 28 and 140 nucleotides upstream from the transcription start site whereas two putative CAAT boxes are located 57 and 38 nucleotides upstream from the TATA boxes, respectively. A restriction fragment length pattern specific for each gene has been characterized. The present findings should provide the tools required for detailed analysis of the molecular basis of 3 beta-HSD deficiency as well as of normal sex steroid biosynthesis.


Microbiological study of dacryocystitis in northwest of Iran.
The prevalence of bacterial pathogens isolated from patients with acute and chronic dacryocystitis and the pattern of antibiotic susceptibility tests are varied in each region. Moreover, the management of dacryocystitis is only based on clinical observations without microbiological evaluation. The present study aimed to identify epidemiologic and etiologic factors of dacryocystitis in our geographical area. This cross-sectional and analytical study was carried out in the ophthalmology department of Hamadan University of Medical Sciences (northwest of Iran) during 2016-2017. Nasolacrimal duct discharges were inoculated to culture media including blood agar, eosin methylene blue, chocolate agar, and Sabouraud agar for the determination of microbial agents. Disc diffusion method with MAST antibiogram discs was used for antibiotic susceptibility tests, according to the Clinical and Laboratory Standards Institute, 2017. Of the total 129 patients enrolled in the study, 34.1% had acute dacryocystitis and 65.9% showed chronic type. The result of culture was positive in 75.2% of patients. Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Pseudomonas spp., and Candida albicans were the most prevalent microorganisms. The most sensitive antibiotics used against prevalent bacteria were ciprofloxacin (75.9%), ceftriaxone (73.6%), vancomycin (67.8%), and chloramphenicol (60.9%), respectively. The present study is useful for determining the appropriate antibiotic for systemic treatment of dacryocystitis in our region. Ciprofloxacin and vancomycin are the most sensitive antibiotics against the most common isolated microorganisms in both age groups (under and above 10 years) that can be used for empirical therapy of dacryocystitis in both acute and chronic type.


A novel "patient-like" treatment model of human pancreatic cancer constructed using orthotopic transplantation of histologically intact human tumor tissue in nude mice.
Pancreatic cancer is a disease with essentially no effective treatment. To increase the potential for discovering effective treatment, we have developed a new treatment model whereby a human pancreatic cancer line, PANC-4, was orthotopically transplanted to the pancreas of nude mice as histologically intact tumor tissue. The tumor grew with subsequent invasive local tumor growth and liver and peritoneal metastases. The antitumor activity of 5-fluorouracil (5-FU) and mitomycin C (MMC) against PANC-4 was initially determined in the in vitro collagen-sponge-gel supported histoculture drug-response assay with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide end point. Inhibition rates were 5.6% for 5-FU and 39.4% for MMC indicating higher efficacy of MMC than 5-FU against PANC-4. When the antitumor activities of 5-FU and MMC against PANC-4 were determined in vivo using the nude mouse orthotopic transplant treatment model, slight local tumor growth inhibition with equivalent incidence of metastases to the liver and the peritoneum as the control were observed in the mice treated with 5-FU, while those treated with MMC had considerably reduced local tumor growth without liver and peritoneal metastases. Thus the histoculture drug-response assay in combination with the orthotopic transplant metastatic models provides for the first time a paradigm for evaluation of agents which may be effective against not only locally growing human pancreatic cancer but resulting metastases as well.


Relationship between dopamine system genes and extraversion and novelty seeking.
Dopamine transmission is known to play an important role in the reinforcement system of the brain. Studies have identified dopamine system genes whose polymorphic variants have been linked with the intensity of psychological traits reflecting the tendency to form behaviors characterized by impulsivity and the need for additional stimulation. The aim of the present work was to seek associations between polymorphisms in the catechol-O-methyltransferase (COMT) and D4 dopamine receptor (DRD4) genes and personality traits in the Russian population. Studies of 130 subjects showed that carriers of the Met/Met genotype of the COMT gene had a greater intensity of the novelty-seeking trait than carriers of the Val/Val and Val/Met genotypes, though this association was seen only in women. In addition, the presence of the C allele of the DRD4 gene in carriers of the Met/Met genotype showed high levels of extraversion and hypomania. These results are consistent with current theoretical concepts of the regulation of dopamine transmission in the brain.


Broadening the concept of patient safety culture through value-based healthcare.
Decision-makers are looking for innovative approaches to improve patient experience and outcomes with the finite resources available in healthcare. The concept of value-based healthcare has been proposed as one such approach. Since unsafe care hinders patient experience and contributes to waste, the purpose of this paper is to investigate how the value-based approach can help broaden the existing concept of patient safety culture and thus, improve patient safety and healthcare value. In the arguments, the authors use the triple value model which consists of personal, technical and allocative value. These three aspects together promote healthcare in which the experience of care is improved through the involvement of patients, while also considering the optimal utilisation and allocation of finite healthcare resources. While the idea that patient involvement should be integrated into patient safety culture has already been suggested, there is a lack of emphasis that economic considerations can play an important role as well. Patient safety should be perceived as an investment, thus, relevant questions need to be addressed such as how much resources should be invested into patient safety, how the finite resources should be allocated to maximise health benefits at a population level and how resources should be utilised to get the best cost-benefit ratio. Thus far, both the importance of patient safety culture and value-based healthcare have been advocated; this paper emphasizes the need to consider these two approaches together.


Identification of health risk behaviours among adolescent refugees resettling in Western Australia.
Adolescent refugees encounter traumatic stressors and are at risk of developing psychosocial health problems; limited research data exist internationally. This study aims to identify health risk behaviours among adolescent refugees resettling in Western Australia and assess the feasibility of using a standardised adolescent health questionnaire for this purpose. Refugees aged 12 years and above attending a tertiary Refugee Health Service (RHS) were recruited over 12 months. Sociodemographic data were collected. Psychosocial assessments based on the 'Home, Education/Eating, Activities, Drugs, Sexuality, Suicide/mental health' (HEADSS) framework were undertaken utilising interpreters where required. Health concerns identified were managed through the RHS. A total of 122 adolescents (20 ethnicities) participated; 65% required interpreters. Median age (range) was 14 (12-17) years. Most (80%) had nuclear family separation. Almost half (49%) had a deceased/missing family member. A third (37%) had lived in refugee camps and 20% had experienced closed detention. The median time (range) since arrival in Australia was 11 (2-86) months. Every adolescent had at least one health concern identified during the psychosocial assessment. Frequency of health concerns identified in each domain were 87% for home, 66% for education, 23% for eating, 93% for activities, 5% for drugs, 88% for sexuality and 61% for suicide/mental health. Most adolescents (75%) required intervention, consisting of counselling for health risk behaviours and/or referral to health or community services. It is feasible to use a standardised adolescent health questionnaire to identify health risk behaviours among a cohort of ethnically diverse adolescent refugees. Use of the questionnaire identified a large burden of psychosocial health issues requiring multidisciplinary intervention.


Estimates, trends, and drivers of the global burden of type 2 diabetes attributable to PM2·5 air pollution, 1990-2019: an analysis of data from the Global Burden of Disease Study 2019.
Experimental and epidemiological studies indicate an association between exposure to particulate matter (PM) air pollution and increased risk of type 2 diabetes. In view of the high and increasing prevalence of diabetes, we aimed to quantify the burden of type 2 diabetes attributable to PM2·5 originating from ambient and household air pollution. We systematically compiled all relevant cohort and case-control studies assessing the effect of exposure to household and ambient fine particulate matter (PM2·5) air pollution on type 2 diabetes incidence and mortality. We derived an exposure-response curve from the extracted relative risk estimates using the MR-BRT (meta-regression-Bayesian, regularised, trimmed) tool. The estimated curve was linked to ambient and household PM2·5 exposures from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019, and estimates of the attributable burden (population attributable fractions and rates per 100 000 population of deaths and disability-adjusted life-years) for 204 countries from 1990 to 2019 were calculated. We also assessed the role of changes in exposure, population size, age, and type 2 diabetes incidence in the observed trend in PM2·5-attributable type 2 diabetes burden. All estimates are presented with 95% uncertainty intervals. In 2019, approximately a fifth of the global burden of type 2 diabetes was attributable to PM2·5 exposure, with an estimated 3·78 (95% uncertainty interval 2·68-4·83) deaths per 100 000 population and 167 (117-223) disability-adjusted life-years (DALYs) per 100 000 population. Approximately 13·4% (9·49-17·5) of deaths and 13·6% (9·73-17·9) of DALYs due to type 2 diabetes were contributed by ambient PM2·5, and 6·50% (4·22-9·53) of deaths and 5·92% (3·81-8·64) of DALYs by household air pollution. High burdens, in terms of numbers as well as rates, were estimated in Asia, sub-Saharan Africa, and South America. Since 1990, the attributable burden has increased by 50%, driven largely by population growth and ageing. Globally, the impact of reductions in household air pollution was largely offset by increased ambient PM2·5. Air pollution is a major risk factor for diabetes. We estimated that about a fifth of the global burden of type 2 diabetes is attributable PM2·5 pollution. Air pollution mitigation therefore might have an essential role in reducing the global disease burden resulting from type 2 diabetes. Bill & Melinda Gates Foundation.


Field evaluation of the performance and testing costs of a rapid point-of-care test for syphilis in a red-light district of Manaus, Brazil.
To assess the performance, usefulness and cost of a rapid treponemal antibody assay (VisiTect Syphilis) to detect syphilis in high risk populations. People who attended STI clinics in Manaus, Brazil, were screened for syphilis using the fluorescent treponemal antibody absorption (FTA-Abs) test and a non-treponemal test (Venereal Diseases Research Laboratory (VDRL)), and for HIV. Finger prick blood samples were tested with VisiTect Syphilis. The rapid test was evaluated against the reference FTA-Abs and for its usefulness in detecting active syphilis (FTA-Abs and VDRL positive). Operational performance was assessed through providers' and patients' interviews. An economic evaluation was conducted from the provider's perspective. 510 patients (60% men) were enrolled, of whom 13 (2.5%) were HIV-1 seropositive. Syphilis prevalence (FTA-Abs) was 18% and active syphilis prevalence was 7.5%. 11% (57/506) of samples were positive by VisiTect. The sensitivity, specificity, positive and negative predictive values of VisiTect Syphilis were 57% (95% CI 45.8 to 66.7), 99% (95% CI 97.0 to 99.6), 91% (95% CI 80.0 to 96.7) and 91% (95% CI 88.0 to 93.5), respectively. VisiTect Syphilis identified 79% (30/38) of active syphilis cases. The cost per case of syphilis was $16.8 for VDRL, $33.2 for low cost and $56.3 for high cost VisiTect Syphilis; the cost per case of active syphilis was $21.3, $57.5 and $97.6, respectively. Patients identified finger prick pain and preference for venous blood collection as minor barriers to test use. VisiTect Syphilis had low sensitivity in field use and was less cost effective than conventional VDRL. However, rapid and correct identification of a high proportion of active syphilis cases combined with operational characteristics suggest a role in high risk populations.


L-arginine reduces exercise-induced increase in plasma lactate and ammonia.
To investigate the effect of L-arginine supplementation (L-ARG) on physiological and metabolic changes during exercise, we determined in a double-blind study the cardiorespiratory (heart rate, oxygen consumption (VO(2)) and carbon dioxide production (VCO(2)) and the metabolic (lactate and ammonia) responses to maximal exercise after either an intravenous L-ARG hydrochloride salt or placebo load in 8 healthy subjects. Exercise-induced increases in heart rate, VO(2) and VCO(2) were not significantly different after L-ARG or placebo. By contrast, peak plasma ammonia and lactate were significantly decreased after L-ARG load (60.6 +/- 8.2 vs. 73.1 +/- 9.1 micro mol x l(-1), p < 0.01 and 7.1 +/- 0.7 vs. 8.2 +/- 1.1 mmol x l(-1), p < 0.01, for ammonia and lactate, respectively). Plasma L-citrulline increased significantly during exercise only after L-ARG load, despite a concomitant decrease in plasma L-ARG. Furthermore, a significant inverse relationship was observed between changes in lactate and L-citrulline concentrations after L-ARG load (r = -0.84, p = 0.009). These results demonstrate that intravenous L-ARG reduces significantly exercise-induced increase in plasma lactate and ammonia. Taken together, the specific L-citrulline increase and the inverse relationship observed between L-citrulline and plasma lactate after L-ARG might support that L-ARG supplementation enhances the L-arginine-nitric oxide (NO) pathway during exercise.


Venous resection during pancreatectomy for pancreatic cancer: a systematic review.
Pancreatic cancer is one of the most aggressive and lethal malignancies with a dismal prognosis and survival. The curative effects of venous resection (VR) in pancreatic cancer remain controversial. A systematic literature search was performed in PubMed, Embase and the Cochrane Library. The overall postoperative complications, perioperative mortality, histopathology, and long-term survival were compared between patients undergoing pancreatectomy combined with (VR+ group) or without (VR- group) VR. Forty-one studies were included in the systematic review. Pancreatectomy combined with VR required longer operation time and led to increased perioperative blood loss, whereas postoperative complications were similar. Patients in the VR+ group showed larger tumors and reduced R0 rates. Regarding long-term survival, patients with VR+ seemed to have impaired 1-, 3-, and 5-year survival. Based on our results, VR in pancreatic cancer is a safe and feasible procedure. Given the fact that patients have miserable outcomes and survival in the palliative setting alone, extended resection including VR is required for the purpose of achieving radical resection.


Translating the Intention to Seek Treatment into Action: Does Symptom Monitoring Make a Difference? Results from a Randomized Controlled Trial.
Most people with common mental health problems do not seek evidence-based psychological interventions. The aim of this study was to investigate whether monitoring symptoms of depression and anxiety using an app increased treatment-seeking. Three hundred and six people with significant levels of anxiety and depression, none of whom were currently receiving treatment, were randomly allocated to receive either (a) information about local psychological services only, (b) information plus regular symptom monitoring (every 6 days), or (c) information plus open symptom monitoring (monitoring when they felt like it). An app was used to provide information and monitor mood. The proportion of participants who reported receiving treatment after starting the study was 7.2% (10/138) in the information only group, 8.1% (9/111) in the information plus regular monitoring group and 15.8% (9/57) in the information plus open monitoring group. There was a trend for participants who were able to monitor whenever they wished to be more likely to report receiving treatment than people who were only given information about their local treatment services. The impact of the intervention was greatest among participants who intended to seek treatment before taking part. Limitations were that only a small minority of those who downloaded the app completed the study and that the study relied on self-reported measures of treatment-seeking. Symptom monitoring can increase actual treatment-seeking in those with an intention to seek treatment.


Antibiotics ameliorate lupus-like symptoms in mice.
Gut microbiota and the immune system interact to maintain tissue homeostasis, but whether this interaction is involved in the pathogenesis of systemic lupus erythematosus (SLE) is unclear. Here we report that oral antibiotics given during active disease removed harmful bacteria from the gut microbiota and attenuated SLE-like disease in lupus-prone mice. Using MRL/lpr mice, we showed that antibiotics given after disease onset ameliorated systemic autoimmunity and kidney histopathology. They decreased IL-17-producing cells and increased the level of circulating IL-10. In addition, antibiotics removed Lachnospiraceae and increased the relative abundance of Lactobacillus spp., two groups of bacteria previously shown to be associated with deteriorated or improved symptoms in MRL/lpr mice, respectively. Moreover, we showed that the attenuated disease phenotype could be recapitulated with a single antibiotic vancomycin, which reshaped the gut microbiota and changed microbial functional pathways in a time-dependent manner. Furthermore, vancomycin treatment increased the barrier function of the intestinal epithelium, thus preventing the translocation of lipopolysaccharide, a cell wall component of Gram-negative Proteobacteria and known inducer of lupus in mice, into the circulation. These results suggest that mixed antibiotics or a single antibiotic vancomycin ameliorate SLE-like disease in MRL/lpr mice by changing the composition of gut microbiota.


Extracellular suppression allows mating by pheromone-deficient sterile mutants of Saccharomyces cerevisiae.
MAT alpha haploids with mutations in the STE13 or KEX2 gene, and MATa haploids with mutations in the STE6 or STE14 gene, do not mate with wild-type cells of the opposite mating type. We found that such mutants were able to mate with partners that carry mutations (sst1 and sst2) that cause cells to be supersensitive to yeast mating pheromone action. Mating ability of MAT alpha ste13 and MAT alpha kex2 mutants could also be restored by adding normal MAT alpha cells to mating mixtures or by adding just the appropriate purified pheromone (alpha-factor). Therefore, the mating deficiencies caused by the ste13 and kex2 lesions, and by inference, the ste6 and ste14 mutations, appear to result only from secretion of an insufficient amount of pheromone or a nonfunctional pheromone.


Yield and Seed Quality of Soybean Cultivars Infected with Sclerotinia sclerotiorum.
Sclerotinia stem rot (SSR) is one of the most important diseases of soybean in the United States. Five maturity group III cultivars, Asgrow A3304 STS (A3304), Pioneer Brand 9342 (P9342), Pioneer Brand 9381 (P9381), Probst, and Yale, grown in fields in east-central Illinois, were used to determine the relationship of SSR incidence to yield, 100-seed weight, seed protein and oil content, visual seed quality, and seed germination. In addition, the number of sclerotia in seed samples and the seedborne incidence of Sclerotinia sclerotiorum were determined. For each cultivar, at least 23 two-row plots, 3 m long, that represented a range of SSR incidence from low to high, were used to count the number of plants with and without SSR stem symptoms and were used to estimate yields and evaluate seed quality. Disease incidence ranged from 2 to 45% for Probst, 0 to 65% for P9381, 0 to 68% for P9342, 1 to 93% for Yale, and 0 to 95% for A3304. Regression of yields on SSR incidences for each cultivar was significant (P < 0.05); for every 10% increase in SSR incidence, yields were reduced by 147, 194, 203, 254, and 263 kg/ha for Probst, A3304, P9342, Yale, and P9381, respectively. Disease incidence was negatively correlated (P < 0.05) with seed germination for all cultivars but Probst, and to oil content and seed weight for P9381 and Yale. Disease incidence was positively correlated (P < 0.05) with seed quality for all cultivars and to the number of sclerotia in harvested seeds for P9342, P9381, and Probst. The seedborne incidence of S. sclerotiorum was 0.3, 0.3, 0.3, 0.4 and 0.7% in A3304, P9381, Yale, Probst, and P9342, respectively, and represents a significant potential for further spread of this pathogen and disease.


Occupational health risks associated with the use of germicides in health care.
Environmental surfaces have been clearly linked to transmission of key pathogens in health care facilities, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, Clostridium difficile, norovirus, and multidrug-resistant gram-negative bacilli. For this reason, routine disinfection of environmental surfaces in patient rooms is recommended. In addition, decontamination of shared medical devices between use by different patients is also recommended. Environmental surfaces and noncritical shared medical devices are decontaminated by low-level disinfectants, most commonly phenolics, quaternary ammonium compounds, improved hydrogen peroxides, and hypochlorites. Concern has been raised that the use of germicides by health care personnel may increase the risk of these persons for developing respiratory illnesses (principally asthma) and contact dermatitis. Our data demonstrate that dermatitis and respiratory symptoms (eg, asthma) as a result of chemical exposures, including low-level disinfectants, are exceedingly rare. Unprotected exposures to high-level disinfectants may cause dermatitis and respiratory symptoms. Engineering controls (eg, closed containers, adequate ventilation) and the use of personal protective equipment (eg, gloves) should be used to minimize exposure to high-level disinfectants. The scientific evidence does not support that the use of low-level disinfectants by health care personnel is an important risk for the development of asthma or contact dermatitis.


Brief structured observation of medical student hospital visits.
Students' clinical, communication, and professionalism skills are best assessed when faculty directly observe clinical encounters with patients. Prior to 2009, third-year medical students at our institution had one observed clinical encounter by clinic-based faculty during a required internal medicine clerkship. These observations averaged 45 minutes, feedback was not standardized, and student and faculty satisfaction was low. Two hospital-based faculty members redesigned a shorter, standardized exercise during which a faculty member observed the student making rounds on a hospitalized patient that they were actively following. On a checklist, faculty recorded observations about communication (8 items), physical examination (5 items), and professionalism (4 items). Faculty provided immediate feedback. Faculty's direct observation of medical students prerounding on hospitalized internal medicine patients averaged 27 minutes including the feedback to students. In one year, 67/71 (94%) students completed the exercise; records were available for 66 (99%) of these encounters. Time of observation averaged 13.5 minutes (range 3-26 minutes). Feedback averaged 13.4 minutes (range 8-25 minutes). Faculty provided feedback in the following areas (proportion of students): Communication (66/66, 100%); examination skills (63/66, 95%); and professionalism (65/66, 98%). Forty-three students (64%) completed an anonymous satisfaction survey. Thirty-nine of these (91%) found the exercise useful or very useful (average 5-point Likert score = 4.30) and 38 (88%) found it easy or very easy to schedule (average 5-point Likert score = 4.30). Students found this exercise useful and easy to schedule. Faculty consistently provided feedback to students in areas of communication, physical examination, and professionalism.


Monoclonal Antibodies Against Human Papillomavirus E6 and E7 Oncoproteins Inhibit Tumor Growth in Experimental Cervical Cancer.
Nearly all cases of cervical cancer are initiated by persistent infection with high-risk strains of human papillomavirus (hr-HPV). When hr-HPV integrates into the host genome, the constitutive expression of oncogenic HPV proteins E6 and E7 function to disrupt p53 and retinoblastoma regulation of cell cycle, respectively, to favor malignant transformation. HPV E6 and E7 are oncogenes found in over 99% of cervical cancer, they are also expressed in pre-neoplastic stages making these viral oncoproteins attractive therapeutic targets. Monoclonal antibodies (mAbs) represent a novel potential approach against the actions of hr-HPV E6 and E7 oncoproteins. In this report, we describe the utilization of anti-HPV E6 and HPV E7 mAbs in an experimental murine model of human cervical cancer tumors. We used differential dosing strategies of mAbs C1P5 (anti-HPV 16 E6) and TVG701Y (anti-HPV E7) administered via intraperitoneal or intratumoral injections. We compared mAbs to the action of chemotherapeutic agent Cisplatin and demonstrated the capacity of mAbs to significantly inhibit tumor growth. Furthermore, we investigated the contribution of the immune system and found increased complement deposition in both C1P5 and TVG701Y treated tumors compared to irrelevant mAb therapy. Taken together, the results suggest that anti-HPV E6 and E7 mAbs exert inhibition of tumor growth in a viral-specific manner and stimulate an immune response that could be exploited for an additional treatment options for patients.


Experimental peripheral arterial disease: new insights into muscle glucose uptake, macrophage, and T-cell polarization during early and late stages.
Peripheral arterial disease (PAD) is a common disease with increasing prevalence, presenting with impaired walking ability affecting patient's quality of life. PAD epidemiology is known, however, mechanisms underlying functional muscle impairment remain unclear. Using a mouse PAD model, aim of this study was to assess muscle adaptive responses during early (1 week) and late (5 weeks) disease stages. Unilateral hindlimb ischemia was induced in ApoE(-/-) mice by iliac artery ligation. Ischemic limb perfusion and oxygenation (Laser Doppler imaging, transcutaneous oxygen pressure assessments) significantly decreased during early and late stage compared to pre-ischemia, however, values were significantly higher during late versus early phase. Number of arterioles and arteriogenesis-linked gene expression increased at later stage. Walking ability, evaluated by forced and voluntary walking tests, remained significantly decreased both at early and late phase without any significant improvement. Muscle glucose uptake ([18F]fluorodeoxyglucose positron emission tomography) significantly increased during early ischemia decreasing at later stage. Gene expression analysis showed significant shift in muscle M1/M2 macrophages and Th1/Th2 T cells balance toward pro-inflammatory phenotype during early ischemia; later, inflammatory state returned to neutrality. Muscular M1/M2 shift inhibition by a statin prevented impaired walking ability in early ischemia. High-energy phosphate metabolism remained unchanged (31-Phosphorus magnetic resonance spectroscopy). Results show that rapid transient muscular inflammation contributes to impaired walking capacity while increased glucose uptake may be a compensatory mechanisms preserving immediate limb viability during early ischemia in a mouse PAD model. With time, increased ischemic limb perfusion and oxygenation assure muscle viability although not sufficiently to improve walking impairment. Subsequent decreased muscle glucose uptake may partly contribute to chronic walking impairment. Early inflammation inhibition and/or late muscle glucose impairment prevention are promising strategies for PAD management.


Myosin-1a is critical for normal brush border structure and composition.
To develop our understanding of myosin-1a function in vivo, we have created a mouse line null for the myosin-1a gene. Myosin-1a knockout mice demonstrate no overt phenotypes at the whole animal level but exhibit significant perturbations and signs of stress at the cellular level. Among these are defects in microvillar membrane morphology, distinct changes in brush-border organization, loss of numerous cytoskeletal and membrane components from the brush border, and redistribution of intermediate filament proteins into the brush border. We also observed significant ectopic recruitment of another short-tailed class I motor, myosin-1c, into the brush border of knockout enterocytes. This latter finding, a clear demonstration of functional redundancy among vertebrate myosins-I, may account for the lack of a whole animal phenotype. Nevertheless, these results indicate that myosin-1a is a critical multifunctional component of the enterocyte, required for maintaining the normal composition and highly ordered structure of the brush border.


Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells.
ALK1 is an endothelial-specific type I receptor of the TGFbeta receptor family whose heterozygous mutations cause hereditary hemorrhagic telangiectasia type 2. Although TGFbeta1 and TGFbeta3 have been shown to bind ALK1 under specific experimental conditions, they may not represent the physiological ligands for this receptor. In the present study, we demonstrate that BMP9 induces the phosphorylation of Smad1/5/8 in microvascular endothelial cells, and this phosphorylation lasts over a period of 24 hours. BMP9 also activates the ID1 promoter-derived BMP response element (BRE) in a dose-dependent manner (EC50 = 45 +/- 27 pg/mL), and this activation is abolished by silencing ALK1 expression or addition of ALK1 extracellular domain. Overexpression of endoglin increases the BMP9 response, whereas silencing of both BMPRII and ActRIIA expressions completely abolishes it. BMP10, which is structurally close to BMP9, is also a potent ALK1 ligand. Finally, we demonstrate that BMP9 and BMP10 potently inhibit endothelial cell migration and growth, and stimulate endothelial expression of a panel of genes that was previously reported to be activated by the constitutively active form of ALK1. Taken together, our results suggest that BMP9 and BMP10 are two specific ALK1 ligands that may physiologically trigger the effects of ALK1 on angiogenesis.


Phospholipase PLA2G7, associated with aggressive prostate cancer, promotes prostate cancer cell migration and invasion and is inhibited by statins.
Prostate cancer is the second leading cause of cancer mortality in men in developed countries. Due to the heterogeneous nature of the disease, design of novel personalized treatments is required to achieve efficient therapeutic responses. We have recently identified phospholipase 2 group VII (PLA2G7) as a potential drug target especially in ERG oncogene positive prostate cancers. Here, the expression profile of PLA2G7 was studied in 1137 prostate cancer and 409 adjacent non-malignant prostate tissues using immunohistochemistry to validate its biomarker potential and putative association with disease progression. In order to reveal the molecular alterations induced by PLA2G7 impairment, lipidomic and gene expression profiling was performed in response to PLA2G7 silencing in cultured prostate cancer cells. Moreover, the antineoplastic effect of statins combined with PLA2G7 impairment was studied in prostate cancer cells to evaluate the potential of repositioning of in vivo compatible drugs developed for other indications towards anti-cancer purposes. The results indicated that PLA2G7 is a cancer-selective biomarker in 50 % of prostate cancers and associates with aggressive disease. The alterations induced by PLA2G7 silencing highlighted the potential of PLA2G7 inhibition as an anti-proliferative, pro-apoptotic and anti-migratorial therapeutic approach in prostate cancer. Moreover, the anti-proliferative effect of PLA2G7 silencing was potentiated by lipid-lowering statins in prostate cancer cells. Taken together, our results support the potential of PLA2G7 as a biomarker and a drug target in prostate cancer and present a rationale for combining PLA2G7 inhibition with the use of statins in prostate cancer management.


Effect of Hepatitis B Virus Co-Infection on CD4 Cell Count and Liver Function of HIV Infected Patients.
Human immunodeficiency virus (HIV) and Hepatitis B virus (HBV) share similar routes of transmission, making it possible for an individual to have a co-infection. HBV infection is well known to be a major cause of chronic liver diseases worldwide. The aim of this study was to determine the prevalence of HBV infection among HIV infected HAART naïve patients and investigate the effect of co-infection on CD4 count and liver function. This was a hospital based descriptive cross sectional study of one hundred consecutive therapy-naive HIV-infected individuals. The CD4 count, Hepatitis B surface antigen, Serum albumin, total Protein, and liver enzymes were determined using standard techniques. The prevalence of HIV and HBV co-infection was 37%. The mean serum ALT and ALP were significantly higher in the co- infected patients (P-values <0.05). The mean CD4 count of the mono infected patients was significantly higher (p-value of 0.014). The mean serum ALT, AST and ALP of mono and co-infected patients with CD4 count<200/µl were significantly higher than those with count ≥ 200 cells/µl. (p-value of <0.01). The mean ALT and AST of the co-infected patients and all patients with CD4 count <200 cells/µl were higher than the normal reference range. Approximately one third of HIV positive patients had hepatitis B virus co-infection. Co-infection and CD4 count <200 cells/µl are likely to result in abnormal ALT and AST. We recommend that co-infected patients and those with CD4 count <200 cells/µl should be given non-hepatotoxic antiretroviral drug.


Effect of simvastatin on plasma lipid and lipoprotein concentrations and low-density lipoprotein metabolism in the nephrotic syndrome.
1. The effect of inhibiting the rate-limiting enzyme (3-hydroxy-3-methylglutaryl-CoA reductase, EC 184.108.40.206) in cholesterol synthesis on plasma lipid and lipoprotein concentrations was investigated in 16 patients with primary glomerular disease, heavy proteinuria, well-preserved renal function and hypercholesterolaemia. 2. Detailed studies of low-density lipoprotein metabolism were performed on eight patients before and after 12 weeks of simvastatin therapy. Radioiodinated tracers were used to quantify the fractional catabolic rate of low-density lipoprotein by apolipoprotein B/E receptors and alternative pathways. 3. Simvastatin produced consistent reductions in total plasma cholesterol concentration (median 36.9%), plasma low-density lipoprotein-cholesterol concentration (43.6%) and apolipoprotein B pool size (29.9%). 4. In contrast, the changes in kinetic parameters of low-density lipoprotein metabolism showed no clear pattern. Although an increase in the receptor-mediated catabolism of low-density lipoprotein was demonstrated in five patients, no change or a slight decrease was seen in three patients. Production rates were not significantly altered, although there was a slight decrease in the median value (from 12.4 to 9.7 mg day-1 kg-1). Plasma lathosterol concentration was reduced in all eight patients (range 34-71%), indirectly confirming significant inhibition of cholesterol synthesis. 5. These results suggest that, as in patients with primary moderate hyperlipidaemia, the significant cholesterol-lowering effect of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors in the nephrotic syndrome is accompanied by variable changes in lipoprotein metabolism. The reasons for this heterogeneous response are unclear. This reflects our limited understanding of the metabolic basis of nephrotic hyperlipidaemia and the relationship between hepatic sterol synthesis and plasma lipoprotein kinetics.


Storage policies and use of the Danish Newborn Screening Biobank.
After routine newborn screening, residual dried blood spot samples (DBSS) are stored at -20 degrees C in the Danish Newborn Screening Biobank (NBS-Biobank), which contains DBSS from virtually all newborns in Denmark since 1982--about 1.8 million samples. The purpose of the storage is: (1) diagnosis and treatment of congenital disorders including documentation, repeat testing, quality assurance, statistics and improvement of screening methods; (2) diagnostic use later in infancy after informed consent; (3) legal use after court order; (4) the possibility of research projects after approval by the Scientific Ethical Committee System in Denmark, The Danish Data Protection Agency and the NBS-Biobank Steering Committee. The operation and use of the NBS-Biobank has until recently been regulated by an executive order of 1993 from the Danish Ministry of Health. The Ethical Council, the Central Scientific Ethical Committee and the National Board of Health were also involved in the regulations. These regulations have now been replaced by detailed general operational guidelines for biobanks in Denmark according to Acts on Processing of Personal Data, Patient's Rights, Health 546/2005 and the Biomedical Research Ethics Committee System. No specific Act on biobanks per se has been made in Denmark, but the new regulations and guidelines make the operations of the Danish NBS-Biobank even more clear-cut and safe. The Danish NBS-Biobank has been used in several research projects for aetiological studies of a number of disorders, recently employing new sensitive multiplex technologies and genetic analyses utilizing whole-genome amplified DNA.


Opinion modeling on social media and marketing aspects.
We introduce and discuss kinetic models of opinion formation on social networks in which the distribution function depends on both the opinion and the connectivity of the agents. The opinion formation model is subsequently coupled with a kinetic model describing the spreading of popularity of a product on the Web through a social network. Numerical experiments on the underlying kinetic models show a good qualitative agreement with some measured trends of hashtags on social media websites and illustrate how companies can take advantage of the network structure to obtain at best the advertisement of their products.


Treadmill running upregulates the expression of acetylcholine receptor in rat gastrocnemius following botulinum toxin A injection.
Treadmill running is a commonly used training method for patients with spasticity to improve functional performance. Botulinum toxin has been widely used therapeutically to reduce contraction force of spastic muscle. However, the effects of treadmill running in neuromuscular junction expression and motor unit physiology on muscle following botulinum toxin injection are not well established. To assess the effects of treadmill running on neuromuscular recovery of gastrocnemius following botulinum toxin A (BoNT-A) injection, we observed changes in gene expression. We hypothesized that the expression of acetylcholine receptor (AChR), myogenesis, and nerve plasticity could be enhanced. Twenty-four Sprague-Dawley rats received botulinum toxin injection in right gastrocnemius and were then randomly assigned into untrained control and treadmill running groups. The rats assigned to the treadmill running group were trained on a treadmill 3 times/week with a running speed of 15 m/min for 8 weeks. The duration of training was 20 min per session. Muscle strength and gene expression of AChR subunit (α, β, δ, γ, and ε), MyoD, Myf-5, MRF4, myogenin, p21, IGF-1, GAP43, were analyzed. Treadmill running had no influence on gastrocnemius mass, but improved the maximal contraction force of the gastrocnemius in the treadmill running group (p < 0.05). Upregulation of GAP-43, IGF-1, Myo-D, Myf-5, myogenin, and AChR subunits α and β were found following treadmill running. The expression of genes associated with neurite and AChR regeneration following treadmill exercise was upregulated, which may have contributed to enhanced recovery of gastrocnemius strength.


Measuring the subjective value of risky and ambiguous options using experimental economics and functional MRI methods.
Most of the choices we make have uncertain consequences. In some cases the probabilities for different possible outcomes are precisely known, a condition termed "risky". In other cases when probabilities cannot be estimated, this is a condition described as "ambiguous". While most people are averse to both risk and ambiguity(1,2), the degree of those aversions vary substantially across individuals, such that the subjective value of the same risky or ambiguous option can be very different for different individuals. We combine functional MRI (fMRI) with an experimental economics-based method(3 )to assess the neural representation of the subjective values of risky and ambiguous options(4). This technique can be now used to study these neural representations in different populations, such as different age groups and different patient populations. In our experiment, subjects make consequential choices between two alternatives while their neural activation is tracked using fMRI. On each trial subjects choose between lotteries that vary in their monetary amount and in either the probability of winning that amount or the ambiguity level associated with winning. Our parametric design allows us to use each individual's choice behavior to estimate their attitudes towards risk and ambiguity, and thus to estimate the subjective values that each option held for them. Another important feature of the design is that the outcome of the chosen lottery is not revealed during the experiment, so that no learning can take place, and thus the ambiguous options remain ambiguous and risk attitudes are stable. Instead, at the end of the scanning session one or few trials are randomly selected and played for real money. Since subjects do not know beforehand which trials will be selected, they must treat each and every trial as if it and it alone was the one trial on which they will be paid. This design ensures that we can estimate the true subjective value of each option to each subject. We then look for areas in the brain whose activation is correlated with the subjective value of risky options and for areas whose activation is correlated with the subjective value of ambiguous options.


Impaired energy homeostasis in C/EBP alpha knockout mice.
Mice homozygous for the targeted deletion of the c/ebp alpha gene, which expresses the CCAAT/enhancer-binding protein alpha (C/EBP alpha), did not store hepatic glycogen and died from hypoglycemia within 8 hours after birth. In these mutant mice, the amounts of glycogen synthase messenger RNA were 50 to 70 percent of normal and the transcriptional induction of the genes for two gluconeogenic enzymes, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, was delayed. The hepatocytes and adipocytes of the mutant mice failed to accumulate lipid and the expression of the gene for uncoupling protein, the defining marker of brown adipose tissue, was reduced. This study demonstrates that C/EBP alpha is critical for the establishment and maintenance of energy homeostasis in neonates.


Hollow mesoporous ZSM-5 zeolite/chitosan ellipsoids loaded with doxorubicin as pH-responsive drug delivery systems against osteosarcoma.
The toxic risks and adverse effects of anticancer drugs on healthy tissues limit their wide clinical application. Herein, we for the first time fabricated hollow mesoporous ZSM-5/chitosan ellipsoids loaded with doxorubicin (HM-ZSM-5/CS/DOX) as pH-responsive drug delivery systems against osteosarcoma. The HM-ZSM-5 ellipsoids including a hollow core and a mesoporous shell could efficiently load DOX drugs with a loading efficiency of 95.8%. The CS layer was uniformly distributed on the HM-ZSM-5 ellipsoids that contributed to the pH-responsive release of DOX drugs. The controlled DOX release kinetics from the HM-ZSM-5/CS/DOX ellipsoids was fitted well with the Korsmeyer-Peppas model. The HM-ZSM-5/CS/DOX ellipsoids exhibited good biocompatibility due to the low DOX release rate in the neutral media that simulated healthy tissues or blood. Moreover, the cellular uptake of the HM-ZSM-5/CS/DOX ellipsoids took place in tumor cells, and the quick release of DOX significantly promoted the apoptosis of MG63 cells. The levels of MDA, LDH and CK markers for the HM-ZSM-5/CS/DOX group were lower than those for the free DOX group, suggesting no systemic toxicity to the heart. Therefore, the HM-ZSM-5/CS/DOX ellipsoids as novel pH-responsive drug delivery systems can effectively treat osteosarcoma without systemic toxicity.


Usefulness of a program of neoplasia surveillance in liver transplantation. A preliminary report.
De novo malignancies are frequent complications after liver transplantation. Aim of the study is to evaluate whether a surveillance program for malignancy may improve patient survival. We have compared the survival after the diagnosis of malignancy (excluding cutaneous and hepatobiliary carcinomas and lymphoproliferative disease) of patients with symptomatic or incidental malignancies with patients with neoplasia diagnosed on screening. Two hundred and eighty patients with a follow-up greater than three months were followed for a median of 77.5 months (total follow-up: 1515 patient-yr). Thirty-three patients developed 41 malignancies. When compared with general population, the entire cohort of liver transplant recipients had a significantly higher risk of malignancy (relative risk: 2.34), gastrointestinal tract (relative risk: 2.52), urological tract (relative risk: 2.94) and head and neck cancer (relative risk: 4.14), and cancer-related death (relative risk: 2.35). All nine patients diagnosed with cancer with active screening are currently alive and free of malignancy after a median follow-up of 25 months. By contrast, 18/24 patients with diagnosis of cancer prompted by symptoms or incidentally diagnosed died as a consequence of the cancer (median survival: 13.5 months). The difference in survival between both groups was significant (p = 0.002). In conclusion, a close surveillance protocol for the diagnosis of malignancy could be life-saving in liver transplant recipients.


Generalized Poincaré sphere.
We present a generalized Poincaré sphere (G sphere) and generalized Stokes parameters (G parameters), as a geometric representation, which unifies the descriptors of a variety of vector fields. Unlike the standard Poincaré sphere, the radial dimension in the G sphere is not used to describe the partially polarized field. The G sphere is constructed by extending the basic Jones vector bases to the general vector bases with the continuously changeable ellipticity (spin angular momentum, SAM) and the higher dimensional orbital angular momentum (OAM). The north and south poles of different spherical shells in the G sphere represent the pair of different orthogonal vector basis with different ellipticity (SAM) and the opposite OAM. The higher-order Poincaré spheres are just the two special spherical shells of the G sphere. We present a quite flexible scheme, which can generate all the vector fields described in the G sphere.


Ability of nondepolarizing neuromuscular blocking drugs to act as partial agonists at fetal and adult mouse muscle nicotinic receptors.
We studied the ability of four nondepolarizing neuromuscular blocking agents (atracurium, gallamine, metocurine, and pancuronium) to act as competitive antagonists at mouse adult- and fetal-type muscle nictinic receptors. Receptor subunits for the fetal type (alpha, beta, gamma, and delta) and adult-type (alpha, beta, epsilon, and delta) receptors were stably expressed in quail fibroblasts. Binding for each drug was determined by the ability of the agents to reduce the initial rate of labeled alpha-bungarotoxin binding, and functional consequences were determined with the use of voltage-clamp studies of their ability to elicit currents or to block currents elicited by acetylcholine. Each agent has a different affinity for the two acetylcholine-binding sites on a single receptor; the rank order of affinities is the same for both fetal- and adult-type receptors. All agents inhibited activation of adult-type receptors by ACh, consistent with the idea that occupation of either the high or low affinity site completely blocks activation when acetylcholine binds to the other site on the receptor. The concentration dependence of the inhibition of acetylcholine-elicited current was predictable from the affinities estimated from independent measurements of the inhibition of alpha-bungarotoxin binding. Gallamine and pancuronium also acted as competitive inhibitors of fetal-type receptors, and, again, the concentration dependence of the inhibition was predictable from binding data. However, metocurine and atracurium could potentiate the responses of fetal-type receptors to low concentrations of acetylcholine. The interaction of metocurine and atracurium with acetylcholine at fetal-type receptors could be accounted for by a weak partial agonist activity. It has been suggested that some pairs of nondepolarizing neuromuscular blocking agents might be more efficacious because the high affinity site for one agent might be the low affinity site for another. This hypothesis was tested for the pair of agents metocurine and gallamine by determining the ability of a mixture of agents to inhibit the binding of alpha-bungarotoxin. The results are consistent with the idea that both metocurine and gallamine have a high affinity for the same site on the receptor. The ability of gallamine to block the partial agonist action of metocurine at fetal-type receptors was tested as well and also indicated that both agents share the same high affinity site.


Effective implementation approaches for healthy ageing interventions for older people: A rapid review.
Systematic reviews on healthy ageing interventions have primarily focused on assessing their effectiveness, not the implementation processes underpinning them, and the factors influencing program effectiveness. This has created a knowledge gap about what are effective implementation approaches, and how to scale up such interventions at the population level. Our aim in this rapid review was to synthesise the evidence on implementation of effective healthy ageing interventions, and to identify the factors that influence population-level implementation of these interventions. Following the PRISMA checklist, we searched for papers in six databases: Ovid Medline, Ovid Embase, CENTRAL, CINAHL, PsycArticles and PsycINFO. A narrative synthesis was used to summarise the results. Twenty-nine articles reporting on 21 healthy ageing interventions (studies) were included in the review. The findings show that a wide range of approaches to implementation were used including collaborative partnership, co-design, use of volunteers, person centred-care, and self-directed/professional-led approaches. The key implementation drivers were the use of behavioural change techniques, social interaction, tailoring of interventions, booster sessions, and multi-component and multi-professional team approach to intervention design and delivery. The effectiveness of healthy ageing interventions is contingent on a number of factors including the type of implementation approaches used, the context in which programs are implemented, and the specific mechanisms that may be at play at the individual older adult level.