Global Lysine Acetylation in Escherichia coli Results from Growth Conditions That Favor Acetate Fermentation.
Lysine acetylation is thought to provide a mechanism for regulating metabolism in diverse bacteria. Indeed, many studies have shown that the majority of enzymes involved in central metabolism are acetylated and that acetylation can alter enzyme activity. However, the details regarding this regulatory mechanism are still unclear, specifically with regard to the signals that induce lysine acetylation. To better understand this global regulatory mechanism, we profiled changes in lysine acetylation during growth of Escherichia coli on the hexose glucose or the pentose xylose at both high and low sugar concentrations using label-free mass spectrometry. The goal was to see whether lysine acetylation differed during growth on these two different sugars. No significant differences, however, were observed. Rather, the initial sugar concentration was the principal factor governing changes in lysine acetylation, with higher sugar concentrations causing more acetylation. These results suggest that acetylation does not target specific metabolic pathways but rather simply targets accessible lysines, which may or may not alter enzyme activity. They further suggest that lysine acetylation principally results from conditions that favor accumulation of acetyl phosphate, the principal acetate donor in E. coliIMPORTANCE Bacteria alter their metabolism in response to nutrient availability, growth conditions, and environmental stresses using a number of different mechanisms. One is lysine acetylation, a posttranslational modification known to target many metabolic enzymes. However, little is known about this regulatory mode. We investigated the factors inducing changes in lysine acetylation by comparing growth on glucose and xylose. We found that the specific sugar used for growth did not alter the pattern of acetylation; rather, the amount of sugar did, with more sugar causing more acetylation. These results imply that lysine acetylation is a global regulatory mechanism that is responsive not to the specific carbon source per se but rather to the accumulation of downstream metabolites.


The CDK4/6-EZH2 pathway is a potential therapeutic target for psoriasis.
Psoriasis is a frequent, inflammatory skin disease characterized by keratinocyte hyperproliferation and a disease-related infiltration of immune cells. Here, we identified a novel proinflammatory signaling pathway driven by cyclin-dependent kinase 4 (CDK4) and CDK6 and the methyltransferase EZH2 as a valid target for psoriasis therapy. Delineation of the pathway revealed that CDK4/6 phosphorylated EZH2 in keratinocytes, thereby triggering a methylation-induced activation of STAT3. Subsequently, active STAT3 resulted in the induction of IκBζ, which is a key proinflammatory transcription factor required for cytokine synthesis in psoriasis. Pharmacological or genetic inhibition of CDK4/6 or EZH2 abrogated psoriasis-related proinflammatory gene expression by suppressing IκBζ induction in keratinocytes. Importantly, topical application of CDK4/6 or EZH2 inhibitors on the skin was sufficient to fully prevent the development of psoriasis in various mouse models by suppressing STAT3-mediated IκBζ expression. Moreover, we found a hyperactivation of the CDK4/6-EZH2 pathway in human and mouse psoriatic skin lesions. Thus, this study not only identifies a novel psoriasis-relevant proinflammatory pathway, but also proposes the repurposing of CDK4/6 or EZH2 inhibitors as a new therapeutic option for patients with psoriasis.


Men's behavior surrounding use of contraceptives in Guinea.
To analyze the sociocultural determinants that influence the attitude and practices of men toward contraceptive use in Guinea. A sequential, mixed methods, qualitative and quantitative study was carried out in two regions of Guinea with a low rate of contraceptive prevalence, and in the capital city of Conakry. A total of 1170 people (men and women) were interviewed. Findings showed a positive perception of family planning overall, but reluctance to use modern contraception. The reasons for non-use of contraceptive methods were primarily the hope of having many children and religious prohibition associated with customs. Making decisions on contraceptive use within a couple represents a major cause of misunderstanding between spouses. Communication within a couple on the use of contraception is quickly declined by men. The findings demonstrate the need to develop communication strategies within a couple to improve the use of contraceptives.


TU-E-211-01: Establishing Multidisciplinary Collaboration as a Medical Physicist.
Many medical physicists are scientists at heart and their career fulfillment includes a balance of clinical service and research development. Multidisciplinary collaboration is a great way for the medical physicists to advance science and technology of our fields and the fields of our collaborators. Cross-pollination among scientists of different fields has been the key for some of the most significant breakthroughs in science and medicine and produced some of the most rewarding experiences for the individuals involved. However, medical physicists face unique challenges in establishing multidisciplinary collaboration because our time and resources for research are often quite limited compared to basic scientists. Yet we medical physicists are uniquely positioned and have a tremendous opportunity to create/contribute to multidisciplinary research: our fields are already multidisciplinary in nature and hospital environment is problem rich. How do we establish and carry out research collaboration with scientists of other fields? How to balance research with your higher priority clinical service? How do you find the right multidisciplinary collaboration in your own environment? We will discuss the challenges, provide real exemplary solutions to the above questions, and offer advise to medical physicists who are interested in starting or improving their multidisciplinary collaboration. There are different kinds of multidisciplinary collaborations a medical physicist can create and participate at different involvement levels. Multidisciplinary collaboration is not for every medical physicist but for those who seek and devote time to it, the experience can be truly rewarding and the impact can be enormous. 1. Learn the types of multidisciplinary collaboration medical physicists can created/participated 2. Learn the approaches and strategies to develop collaborations with scientists and professional of other fields3. Understand the challenges and different approaches to balance clinical service and multidisciplinary research collaboration.


Entangling the spatial properties of laser beams.
Position and momentum were the first pair of conjugate observables explicitly used to illustrate the intricacy of quantum mechanics. We have extended position and momentum entanglement to bright optical beams. Applications in optical metrology and interferometry require the continuous measurement of laser beams, with the accuracy fundamentally limited by the uncertainty principle. Techniques based on spatial entanglement of the beams could overcome this limit, and high-quality entanglement is required. We report a value of 0.51 for inseparability and 0.62 for the Einstein-Podolsky-Rosen criterion, both normalized to a classical limit of 1. These results are a conclusive optical demonstration of macroscopic position and momentum quantum entanglement and also confirm that the resources for spatial multimode protocols are available.


Effect of low-dose selenium on thyroid autoimmunity and thyroid function in UK pregnant women with mild-to-moderate iodine deficiency.
Selenium is an essential trace mineral and a component of selenoproteins that are involved in the production of thyroid hormones and in regulating the immune response. We aimed to explore the effect of low-dose selenium supplementation on thyroid peroxidase antibody (TPO-Ab) concentration and thyroid function in pregnant women from a mild-to-moderate iodine-deficient population. Samples and data were from a secondary analysis of Selenium in PRegnancy INTervention (SPRINT), a double-blind, randomized, placebo-controlled study that recruited 230 women with singleton pregnancies from a UK antenatal clinic at 12 weeks of gestation. Women were randomized to receive 60 µg/day selenium or placebo until delivery. Serum thyroid peroxidase antibodies (TPO-Ab), thyrotropin (TSH) and free thyroxine (FT4) were measured at 12, 20 and 35 weeks and thyroglobulin antibodies (Tg-Ab) at 12 weeks. 93.5% of participants completed the study. Se supplementation had no more effect than placebo in decreasing TPO-Ab concentration or the prevalence of TPO-Ab positivity during the course of pregnancy. In women who were either TPO-Ab or Tg-Ab negative at baseline (Thy-Ab(-ve)), TSH increased and FT4 decreased significantly throughout gestation (P < 0.001), with no difference between treatment groups. In women who were Thy-Ab(+ve) at baseline, TSH tended to decrease and was lower than placebo at 35 weeks (P = 0.050). FT4 fell more on Se than placebo supplementation and was significantly lower at 35 weeks (P = 0.029). Low-dose selenium supplementation in pregnant women with mild-to-moderate deficiency had no effect on TPO-Ab concentration, but tended to change thyroid function in Thy-Ab(+ve) women.


The guanylate binding protein-1 GTPase controls the invasive and angiogenic capability of endothelial cells through inhibition of MMP-1 expression.
Expression of the large GTPase guanylate binding protein-1 (GBP-1) is induced by inflammatory cytokines (ICs) in endothelial cells (ECs), and the helical domain of the molecule mediates the repression of EC proliferation by ICs. Here we show that the expression of GBP-1 and of the matrix metalloproteinase-1 (MMP-1) are inversely related in vitro and in vivo, and that GBP-1 selectively inhibits the expression of MMP-1 in ECs, but not the expression of other proteases. The GTPase activity of GBP-1 was necessary for this effect, which inhibited invasiveness and tube-forming capability of ECs in three-dimensional collagen-I matrices. A GTPase-deficient mutant (D184N-GBP-1) operated as a transdominant inhibitor of wild-type GBP-1 and rescued MMP-1 expression in the presence of ICs. Expression of D184N-GBP-1, as well as paracrine supplementation of MMP-1, restored the tube-forming capability of ECs in the presence of wild-type GBP-1. The latter finding indicated that the inhibition of capillary formation is specifically due to the repression of MMP-1 expression by GBP-1, and is not affected by the anti-proliferative activity of the helical domain of GBP-1. These findings substantiate the role of GBP-1 as a major regulator of the anti-angiogenic response of ECs to ICs.


A High Fat Diet Increases Bone Marrow Adipose Tissue (MAT) But Does Not Alter Trabecular or Cortical Bone Mass in C57BL/6J Mice.
Obesity has been associated with high bone mineral density (BMD) but a greater propensity to fracture. Some obese individuals have increased marrow adipose tissue (MAT), but the impact of MAT on bone turnover remains controversial, as do changes in BMD associated with a high fat diet (HFD). In this study we hypothesized that MAT volume would increase in response to HFD but would be independent of changes in BMD. Hence, we fed C57BL/6J (B6) male mice at 3 weeks of age either a high fat diet (60 kcal %) or regular diet (10 kcal %) for 12 weeks (n = 10/group). We measured MAT volume by osmium staining and micro-CT (µCT) as well as bone parameters by µCT, histomorphometry, and dual-energy X-ray absorptiometry. We also performed a short-term pilot study using 13-week-old B6 males and females fed a HFD (58 kcal %) for 2 weeks (n = 3/sex). Both long- and short-term HFD feedings were associated with high MAT volume, however, femoral trabecular bone volume fraction (BV/TV), bone formation rate and cortical bone mass were not altered in the long-term study. In the short-term pilot study, areal BMD was unchanged after 2 weeks of HFD. We conclude that, for B6 mice fed a HFD starting at wean or 13 weeks of age, MAT increases whereas bone mass is not altered. More studies are needed to define the mechanism responsible for the rapid storage of energy in the marrow and its distinction from other adipose depots.


Effect of surface polarity on the structure and dynamics of water in nanoscale confinement.
We present a molecular dynamics simulation study of the structure and dynamics of water confined between silica surfaces using beta-cristobalite as a model template. We scale the surface Coulombic charges by means of a dimensionless number, k, ranging from 0 to 1, and thereby we can model systems ranging from hydrophobic apolar to hydrophilic, respectively. Both rotational and translational dynamics exhibit a nonmonotonic dependence on k characterized by a maximum in the in-plane diffusion coefficient, D||, at values between 0.6 and 0.8, and a minimum in the rotational relaxation time, tauR, at k=0.6. The slow dynamics observed in the proximity of the hydrophobic apolar surface are a consequence of beta-cristobalite templating an ice-like water layer. The fully hydrophilic surfaces (k=1.0), on the other hand, result in slow interfacial dynamics due to the presence of dense but disordered water that forms strong hydrogen bonds with surface silanol groups. Confinement also induces decoupling between translational and rotational dynamics, as evidenced by the fact that tauR attains values similar to that of the bulk, while D|| is always lower than in the bulk. The decoupling is characterized by a more drastic reduction in the translational dynamics of water compared to rotational relaxation.


Possible positive selection for an arsenic-protective haplotype in humans.
Arsenic in drinking water causes severe health effects. Indigenous people in the South American Andes have likely lived with arsenic-contaminated drinking water for thousands of years. Inhabitants of San Antonio de los Cobres (SAC) in the Argentinean highlands generally carry an AS3MT (the major arsenic-metabolizing gene) haplotype associated with reduced health risks due to rapid arsenic excretion and lower urinary fraction of the monomethylated metabolite. We hypothesized an adaptation to high-arsenic living conditions via a possible positive selection for protective AS3MT variants and compared AS3MT haplotype frequencies among different indigenous groups. Indigenous groups we evaluated were a) inhabitants of SAC and villages near Salta in northern Argentina (n = 346), b) three Native American populations from the Human Genome Diversity Project (HGDP; n = 25), and c) five Peruvian populations (n = 97). The last two groups have presumably lower historical exposure to arsenic. We found a significantly higher frequency of the protective AS3MT haplotype in the SAC population (68.7%) compared with the HGDP (14.3%, p < 0.001, Fisher exact test) and Peruvian (50.5%, p < 0.001) populations. Genome-wide microsatellite (n = 671) analysis showed no detectable level of population structure between SAC and Peruvian populations (measure of population differentiation FST = 0.006) and low levels of structure between SAC and HGDP populations (FST < 0.055 for all pairs of populations compared). Because population stratification seems unlikely to explain the differences in AS3MT haplotype frequencies, our data raise the possibility that, during a few thousand years, natural selection for tolerance to the environmental stressor arsenic may have increased the frequency of protective variants of AS3MT. Further studies are needed to investigate this hypothesis.


Family Background, Private Tutoring, and Children's Educational Performance in Contemporary China.
The prevalence of private tutoring is often noted in the literature on education in East Asia. Empirical evidence concerning the causes and consequences of private tutoring, however, is sparse, especially for China. In this article, we draw upon data from the 2010 China Family Panel Studies to explore whether children's tutoring experiences are influenced by family background and whether private tutoring benefits children's educational performance. Our empirical analyses show that higher parental education, higher family income, and fewer siblings are all associated with a higher likelihood of private tutoring and higher levels of spending on it. Furthermore, private tutoring and spending on tutoring are predictive of higher verbal and math performances, although the difference in math performance between children who received private tutoring and those who did not is statistically insignificant after controlling for family background.


Readmission rates of patients discharged against medical advice: a matched cohort study.
We compared the readmission rates and the pattern of readmission among patients discharged against medical advice (AMA) to control patients discharged with approval over a one-year follow-up period. A retrospective matched-cohort study of 656 patients(328 were discharged AMA) who were followed for one year after their initial hospitalization at an urban university-affiliated teaching hospital in Vancouver, Canada that serves a population with high prevalence of addiction and psychiatric disorders. Multivariate conditional logistic regression was used to examine the independent association of discharge AMA on 14-day related diagnosis hospital readmission. We fit a multivariate conditional negative binomial regression model to examine the readmission frequency ratio between the AMA and non-AMA group. AMA patients were more likely to be homeless (32.3% vs. 11%) and have co-morbid conditions such as psychiatric illnesses, injection drug use, HIV, hepatitis C and previous gastrointestinal bleeding. Patients discharged AMA were more likely to be readmitted: 25.6% vs. 3.4%, p<0.001 by day 14. The AMA group were more likely to be readmitted within 14 days with a related diagnosis than the non-AMA group (Adjusted Odds Ratio 12.0; 95% Confidence Interval [CI]: 3.7-38.9). Patients who left AMA were more likely to be readmitted multiple times at one year compared to the non-AMA group (adjusted frequency ratio 1.6; 95% CI: 1.3-2.0). There was also higher all-cause in-hospital mortality during the 12-month follow-up in the AMA group compared to non-AMA group (6.7% vs. 2.4%, p = 0.01). Patients discharged AMA were more likely to be homeless and have multiple co-morbid conditions. At one year follow-up, the AMA group had higher readmission rates, were predisposed to multiple readmissions and had a higher in-hospital mortality. Interventions to reduce discharges AMA in high-risk groups need to be developed and tested.


The next generation of scenarios for climate change research and assessment.
Advances in the science and observation of climate change are providing a clearer understanding of the inherent variability of Earth's climate system and its likely response to human and natural influences. The implications of climate change for the environment and society will depend not only on the response of the Earth system to changes in radiative forcings, but also on how humankind responds through changes in technology, economies, lifestyle and policy. Extensive uncertainties exist in future forcings of and responses to climate change, necessitating the use of scenarios of the future to explore the potential consequences of different response options. To date, such scenarios have not adequately examined crucial possibilities, such as climate change mitigation and adaptation, and have relied on research processes that slowed the exchange of information among physical, biological and social scientists. Here we describe a new process for creating plausible scenarios to investigate some of the most challenging and important questions about climate change confronting the global community.


The Emperor's New Clothes: a Critical Appraisal of Evidence-based Medicine.
Evidence-Based Medicine (EBM) is the way we are expected to deliver our healthcare in the 21st century. It has been described as the integration of information from best available evidence with the doctor's experience and the patient's point of view. Unfortunately, the original meaning of EBM has been lost and the worldwide medical community has shifted the paradigm to Guidelines-Based Medicine, that has displaced the figures of the doctor and the patient from the decision-making process and relegated them to mere executor and final target of decisions taken by someone else. Problems related to the reliability of evidence and to the way guidelines are constructed, implemented and followed are discussed in detail. It is mandatory that the whole medical community takes responsibility and tries to reverse this apparently inexorable process so to re-establish a proper evidence-based care, where patients and their healing relation with practitioners are at the centre and where doctors are able to critically evaluate the available evidence and use it in light of their personal experience and knowledge.


Intrarenal insulin-like growth factor-1 axis after unilateral nephrectomy in rat.
It has been suggested that insulin-like growth factor-1 (IGF-1) may play a role in early compensatory renal growth. Since IGF-1 action is influenced by IGF binding proteins (IGFBP), this study was conducted to characterize the changes in gene expression not only of IGF-1 and its receptor, but also of IGFBP in the hypertrophying kidney of adult and weanling rats 1 wk after removal of the other kidney. At this time, there were distinct age-dependent changes in the renal IGF-1 axis. In the mature kidney, IGF-1 mRNA levels fell without a change in kidney IGF-1 peptide content. Likewise, although IGFBP-2, -3, and -5 mRNA levels fell, membrane-associated IGFBP did not change. IGF-1 receptor mRNA levels and IGF-1 receptor number both fell. In the weanling kidneys, IGF-1 mRNA and peptide levels and IGF-1 receptor binding were unaltered. However, IGFBP-3, -4, and -5 mRNA levels were increased, as were plasma membrane-associated IGFBP. Although these changes in the intrarenal IGF-1 axis were distinct, it is difficult to conceive how in either the mature or immature rat they could contribute to the ongoing compensatory renal growth that occurs 1 wk after loss of kidney mass unless IGF-1 were acting in a synergistic manner with other growth promoters.


Delineation of subsurface hydrocarbon contamination at a former hydrogenation plant using spectral induced polarization imaging.
Broadband spectral induced polarization (SIP) measurements were conducted at a former hydrogenation plant in Zeitz (NE Germany) to investigate the potential of SIP imaging to delineate areas with different BTEX (benzene, toluene, ethylbenzene, and xylene) concentrations. Conductivity images reveal a poor correlation with the distribution of contaminants; whereas phase images exhibit two main anomalies: low phase shift values (<5 mrad) for locations with high BTEX concentrations, including the occurrence of free-phase product (BTEX concentrations >1.7 g/l), and higher phase values for lower BTEX concentrations. Moreover, the spectral response of the areas with high BTEX concentration and free-phase products reveals a flattened spectrum in the low frequencies (<40 Hz), while areas with lower BTEX concentrations exhibit a response characterized by a frequency peak. The SIP response was modelled using a Debye decomposition to compute images of the median relaxation-time. Consistent with laboratory studies, we observed an increase in the relaxation-time associated with an increase in BTEX concentrations. Measurements were also collected in the time domain (TDIP), revealing imaging results consistent with those obtained for frequency domain (SIP) measurements. Results presented here demonstrate the potential of the SIP imaging method to discriminate source and plume of dissolved contaminants at BTEX contaminated sites.


Embodying Others in Immersive Virtual Reality: Electro-Cortical Signatures of Monitoring the Errors in the Actions of an Avatar Seen from a First-Person Perspective.
Brain monitoring of errors in one's own and other's actions is crucial for a variety of processes, ranging from the fine-tuning of motor skill learning to important social functions, such as reading out and anticipating the intentions of others. Here, we combined immersive virtual reality and EEG recording to explore whether embodying the errors of an avatar by seeing it from a first-person perspective may activate the error monitoring system in the brain of an onlooker. We asked healthy participants to observe, from a first- or third-person perspective, an avatar performing a correct or an incorrect reach-to-grasp movement toward one of two virtual mugs placed on a table. At the end of each trial, participants reported verbally how much they embodied the avatar's arm. Ratings were maximal in first-person perspective, indicating that immersive virtual reality can be a powerful tool to induce embodiment of an artificial agent, even through mere visual perception and in the absence of any cross-modal boosting. Observation of erroneous grasping from a first-person perspective enhanced error-related negativity and medial-frontal theta power in the trials where human onlookers embodied the virtual character, hinting at the tight link between early, automatic coding of error detection and sense of embodiment. Error positivity was similar in 1PP and 3PP, suggesting that conscious coding of errors is similar for self and other. Thus, embodiment plays an important role in activating specific components of the action monitoring system when others' errors are coded as if they are one's own errors. Detecting errors in other's actions is crucial for social functions, such as reading out and anticipating the intentions of others. Using immersive virtual reality and EEG recording, we explored how the brain of an onlooker reacted to the errors of an avatar seen from a first-person perspective. We found that mere observation of erroneous actions enhances electrocortical markers of error detection in the trials where human onlookers embodied the virtual character. Thus, the cerebral system for action monitoring is maximally activated when others' errors are coded as if they are one's own errors. The results have important implications for understanding how the brain can control the external world and thus creating new brain-computer interfaces.


The Acyl Desaturase CER17 Is Involved in Producing Wax Unsaturated Primary Alcohols and Cutin Monomers.
We report n-6 monounsaturated primary alcohols (C26:1, C28:1, and C30:1 homologs) in the cuticular waxes of Arabidopsis (Arabidopsis thaliana) inflorescence stem, a class of wax not previously reported in Arabidopsis. The Arabidopsis cer17 mutant was completely deficient in these monounsaturated alcohols, and CER17 was found to encode a predicted ACYL-COENZYME A DESATURASE LIKE4 (ADS4). Studies of the Arabidopsis cer4 mutant and yeast variously expressing CER4 (a predicted fatty acyl-CoA reductase) with CER17/ADS4, demonstrated CER4's principal role in synthesis of these monounsaturated alcohols. Besides unsaturated alcohol deficiency, cer17 mutants exhibited a thickened and irregular cuticle ultrastructure and increased amounts of cutin monomers. Although unsaturated alcohols were absent throughout the cer17 stem, the mutation's effects on cutin monomers and cuticle ultrastructure were much more severe in distal than basal stems, consistent with observations that the CER17/ADS4 transcript was much more abundant in distal than basal stems. Furthermore, distal but not basal stems of a double mutant deficient for both CER17/ADS4 and LONG-CHAIN ACYL-COA SYNTHETASE1 produced even more cutin monomers and a thicker and more disorganized cuticle ultrastructure and higher cuticle permeability than observed for wild type or either mutant parent, indicating a dramatic genetic interaction on conversion of very long chain acyl-CoA precursors. These results provide evidence that CER17/ADS4 performs n-6 desaturation of very long chain acyl-CoAs in both distal and basal stems and has a major function associated with governing cutin monomer amounts primarily in the distal segments of the inflorescence stem.


Monitoring Energy Balance in Breast Cancer Survivors Using a Mobile App: Reliability Study.
The majority of breast cancer survivors do not meet recommendations in terms of diet and physical activity. To address this problem, we developed a mobile health (mHealth) app for assessing and monitoring healthy lifestyles in breast cancer survivors, called the Energy Balance on Cancer (BENECA) mHealth system. The BENECA mHealth system is a novel and interactive mHealth app, which allows breast cancer survivors to engage themselves in their energy balance monitoring. BENECA was designed to facilitate adherence to healthy lifestyles in an easy and intuitive way. The objective of the study was to assess the concurrent validity and test-retest reliability between the BENECA mHealth system and the gold standard assessment methods for diet and physical activity. A reliability study was conducted with 20 breast cancer survivors. In the study, tri-axial accelerometers (ActiGraphGT3X+) were used as gold standard for 8 consecutive days, in addition to 2, 24-hour dietary recalls, 4 dietary records, and sociodemographic questionnaires. Two-way random effect intraclass correlation coefficients, a linear regression-analysis, and a Passing-Bablok regression were calculated. The reliability estimates were very high for all variables (alpha≥.90). The lowest reliability was found in fruit and vegetable intakes (alpha=.94). The reliability between the accelerometer and the dietary assessment instruments against the BENECA system was very high (intraclass correlation coefficient=.90). We found a mean match rate of 93.51% between instruments and a mean phantom rate of 3.35%. The Passing-Bablok regression analysis did not show considerable bias in fat percentage, portions of fruits and vegetables, or minutes of moderate to vigorous physical activity. The BENECA mHealth app could be a new tool to measure energy balance in breast cancer survivors in a reliable and simple way. Our results support the use of this technology to not only to encourage changes in breast cancer survivors' lifestyles, but also to remotely monitor energy balance. ClinicalTrials.gov NCT02817724; https://clinicaltrials.gov/ct2/show/NCT02817724 (Archived by WebCite at http://www.webcitation.org/6xVY1buCc).


Penicillin resistance in the intestinal spirochaete Brachyspira pilosicoli associated with OXA-136 and OXA-137, two new variants of the class D beta-lactamase OXA-63.
Penicillin resistance mediated by beta-lactamase activity has been reported previously in the anaerobic intestinal spirochaete Brachyspira pilosicoli, and a novel class D beta-lactamase (OXA-63) hydrolysing oxacillin was described recently in a resistant human strain from France. In the current study, 18 B. pilosicoli strains from Australia and Papua New Guinea were tested for ampicillin and oxacillin susceptibility, and investigated for the presence of the class D beta-lactamase gene blaOXA-63 using PCR. PCR products were amplified from seven human and four porcine strains that were penicillin resistant, but not from seven penicillin-sensitive strains. Sequence analysis of the whole gene amplified from seven of the resistant strains from humans and pigs revealed only minor nucleotide differences among them, but there were significant differences compared with blaOXA-63. The predicted amino acid sequence of the enzyme from all seven strains had the same key structural motifs as the previously reported OXA-63, but two variants with 94-95% identity with OXA-63 were identified. OXA-136 had an additional amino acid and 12 other consistent amino acid substitutions compared with OXA-63. OXA-137 had the same differences compared with OXA-63 as OXA-136, but had an additional amino acid substitution at position 16. No structures consistent with integrons or transposons were found in the nucleotide sequences in the vicinity of blaOXA-136 in partially sequenced B. pilosicoli strain 95/1000, and the GC content (25.2 mol%) of the gene was similar to that of the whole genome. The gene encoding OXA-136 from B. pilosicoli strain Cof-10 conferred penicillin resistance on Escherichia coli. This study shows that penicillin resistance in human and porcine B. pilosicoli strains from Australia is associated with the production of two variants of OXA-63, and that susceptible strains lack the genes encoding OXA-63 or the variants.


SU-E-T-159: Sensitivity of in Line Real Time Scintillating Fiber Detectors for External Beam Treatment Verification and Patient Safety.
We studied the sensitivity of a novel transmission fiber scintillator array designed and built for in line treatment verification. The purpose of this project is to assess the capability of the fiber detector array technology to detect treatment errors in real time without false positives to enhance patient safety. We developed a linear scintillator array detector using radiation hard scintillating fibers and high speed parallel signal conditioning and data acquisition to monitor external beam treatment fluence in real time. The detector captures and resolves the time and amplitude of each linac pulse at each MLC segment. The detector has 60 fibers aligned to each MLC leaf and two output channels per fiber. The data is captured by a high speed parallel digitizer to determine the IMRT beam output delivered to a patient in real time. We evaluated the detector peak pulse linearity according to dose rate, MLC positioning, and beam energy. We analyzed the detector sensitivity, signal to noise ratio, and pulse distribution statistics to determine beam output and fluence in real time. We analyzed the response of the detector to 6 MV and 10 MV photon beams. The statistical analysis of the detected linac pulses indicates that a minimum of 20 pulses are required to evaluate MLC positioning and fluence with 3 mm and 3% resolution, respectively. During testing, no false positives were detected. Linearity with respect to output rate, MLC or jaw opening, and fluence is within 2%. Measured sensitivity and signal to noise ratio of a real time linear fiber array detector show that delivered beam fluence can be monitored every 55 msec, with no observed false positives during treatment to provide in vivo real time patient safety and beam monitoring.


Time-domain representation of ventricular-arterial coupling as a windkessel and wave system.
The differences in shape between central aortic pressure (P(Ao)) and flow waveforms have never been explained satisfactorily in that the assumed explanation (substantial reflected waves during diastole) remains controversial. As an alternative to the widely accepted frequency-domain model of arterial hemodynamics, we propose a functional, time-domain, arterial model that combines a blood conducting system and a reservoir (i.e., Frank's hydraulic integrator, the windkessel). In 15 anesthetized dogs, we measured P(Ao), flows, and dimensions and calculated windkessel pressure (P(Wk)) and volume (V(Wk)). We found that P(Wk) is proportional to thoracic aortic volume and that the volume of the thoracic aorta comprises 45.1 +/- 2.0% (mean +/- SE) of the total V(Wk). When we subtracted P(Wk) from P(Ao), we found that the difference (excess pressure) was proportional to aortic flow, thus resolving the differences between P(Ao) and flow waveforms and implying that reflected waves were minimal. We suggest that P(Ao) is the instantaneous summation of a time-varying reservoir pressure (i.e., P(Wk)) and the effects of (primarily) forward-traveling waves in this animal model.


Highlights of the ecancer/SAC First International Prostate Cancer Symposium, 11-12 March 2016, Buenos Aires, Argentina.
The ecancer/SAC First International Prostate Cancer Symposium, held in Buenos Aires, included national, regional, and international experts in the field of prostate cancer. More than 200 professionals from a variety of areas (clinical urologists, pathologists, oncologists, biologists, imaging specialists, radiation therapists, and generalist doctors, among others) attended, and they proposed multidisciplinary management of prostate pathology from the start in concordance with the ideas set forth by the organising committee. A radiotherapy workshop was also held during the symposium, in which new techniques and their possible uses were specifically discussed. In addition to the local doctors, Dr Lilian Faroni (COI Group, Rio de Janeiro, Brazil), Dr Leonardo Carmona (Chilean Head and Neck Institute, Chile), and Dr Anthony Addesa (Jupiter Medical Centre, Florida, USA) also participated in this symposium.


Cerebellar involvement in an evidence-accumulation decision-making task.
To make successful evidence-based decisions, the brain must rapidly and accurately transform sensory inputs into specific goal-directed behaviors. Most experimental work on this subject has focused on forebrain mechanisms. Using a novel evidence-accumulation task for mice, we performed recording and perturbation studies of crus I of the lateral posterior cerebellum, which communicates bidirectionally with numerous forebrain regions. Cerebellar inactivation led to a reduction in the fraction of correct trials. Using two-photon fluorescence imaging of calcium, we found that Purkinje cell somatic activity contained choice/evidence-related information. Decision errors were represented by dendritic calcium spikes, which in other contexts are known to drive cerebellar plasticity. We propose that cerebellar circuitry may contribute to computations that support accurate performance in this perceptual decision-making task.


Perceived need for mental health care in Canada: Results from the 2012 Canadian Community Health Survey-Mental Health.
Past research and national survey data on Canadians' perceived need for mental health care (MHC) have focused on unmet needs overall, and have not considered specific types of MHC needs or the extent to which needs are met. Using data from the 2012 Canadian Community Health Survey-Mental Health, this article describes the prevalence of perceived MHC needs for information, medication, counselling and other services. The degree to which each type of need was met is explored. Associations between risk factors for having MHC needs and the extent to which needs were met are investigated. In 2012, an estimated 17% of the population aged 15 or older reported having had an MHC need in the past 12 months. Two-thirds (67%) reported that their need was met; for another 21%, the need was partially met; and for 12%, the need was unmet. The most commonly reported need was for counselling, which was also the least likely to be met. Distress was identified as a predictor of perceived MHC need status. Many Canadians are estimated to have MHC needs, particularly for counselling. People with elevated levels of distress are significantly more likely to have unmet and partially met MHC needs than to have fully met MHC needs, regardless of the presence of mental or substance disorders.


A doublet-separated sensitivity-enhanced HSQC for the determination of scalar and dipolar one-bond J-couplings.
A simple, sensitivity-enhanced HSQC experiment is described which separates the upfield and downfield components in the indirect dimension into different subspectra. The sequence is similar to the generalized TROSY scheme; however, decoupling of the X-nucleus is used during detection. A detailed analysis of relaxation effects, precision and sensitivity of the method is presented. The approach is demonstrated in a two-dimensional water flip-back 1H-15N HSQC which measures 1JHN splittings in isotropic and oriented samples of ubiquitin and the hepatitis C protease. The results are in excellent agreement with splittings obtained from a conventional 1H-coupled HSQC.


Mechanisms and evolution of oxidative sulfur metabolism in green sulfur bacteria.
Green sulfur bacteria (GSB) constitute a closely related group of photoautotrophic and thiotrophic bacteria with limited phenotypic variation. They typically oxidize sulfide and thiosulfate to sulfate with sulfur globules as an intermediate. Based on genome sequence information from 15 strains, the distribution and phylogeny of enzymes involved in their oxidative sulfur metabolism was investigated. At least one homolog of sulfide:quinone oxidoreductase (SQR) is present in all strains. In all sulfur-oxidizing GSB strains except the earliest diverging Chloroherpeton thalassium, the sulfide oxidation product is further oxidized to sulfite by the dissimilatory sulfite reductase (DSR) system. This system consists of components horizontally acquired partly from sulfide-oxidizing and partly from sulfate-reducing bacteria. Depending on the strain, the sulfite is probably oxidized to sulfate by one of two different mechanisms that have different evolutionary origins: adenosine-5'-phosphosulfate reductase or polysulfide reductase-like complex 3. Thiosulfate utilization by the SOX system in GSB has apparently been acquired horizontally from Proteobacteria. SoxCD does not occur in GSB, and its function in sulfate formation in other bacteria has been replaced by the DSR system in GSB. Sequence analyses suggested that the conserved soxJXYZAKBW gene cluster was horizontally acquired by Chlorobium phaeovibrioides DSM 265 from the Chlorobaculum lineage and that this acquisition was mediated by a mobile genetic element. Thus, the last common ancestor of currently known GSB was probably photoautotrophic, hydrogenotrophic, and contained SQR but not DSR or SOX. In addition, the predominance of the Chlorobium-Chlorobaculum-Prosthecochloris lineage among cultured GSB could be due to the horizontally acquired DSR and SOX systems. Finally, based upon structural, biochemical, and phylogenetic analyses, a uniform nomenclature is suggested for sqr genes in prokaryotes.


How does childhood maltreatment influence ensuing cognitive functioning among people with the exposure of childhood maltreatment? A systematic review of prospective cohort studies.
Childhood maltreatment is closely related to normal cognitive development and ensuing adverse mental health outcomes and cognitive dysfunction. Our current comprehensive systematic review examines the relationship between childhood maltreatment and cognitive functioning focusing only on prospective studies, which allow us to draw inferences about the temporal relationships among the constructs and make causal inferences. The databases, EMBASE, HealthStar, PsychoInfo, Medline, and Cochrane Library, were searched using a systematic methodology to identify prospective studies published up to December, 2017 to explore the relationship between childhood maltreatment and cognitive functioning. Quality assessment of each study was rated using Newcastle-Ottawa-Scale (NOS). 10 articles with 11 studies were included evaluating cognitive development, memory, academic achievement, literacy/verbal comprehension, intelligence, executive function, processing speed, perceptional reasoning, and non-verbal reasoning among children exposed to abuse, neglect or domestic violence either individually or combined. Intelligence and executive function were the most frequently reported cognitive impairments. The findings of this review collectively indicated that nine domains of the cognitive functioning impairments were significantly related to multiple forms of maltreatment and that significance remained in multivariable analyses after controlling for potential confounders. A high degree of heterogeneity of various domains of cognitive functioning and different measurements among selected studies precluded the use of meta-analysis. Childhood maltreatment is considered as one of the most consistent factors related to later life cognitive dysfunction. The study outcomes provide direction for future research on children who have experienced child abuse and have implications for the delivery of health and mental health services to develop clinical practice and intervention for maltreated children.


Probiotics and immunity.
Probiotics are defined as live microorganisms that, when administered in adequate amounts, confer a health benefit on the host, including the gastrointestinal tract. While this beneficial effect was originally thought to stem from improvements in the intestinal microbial balance, there is now substantial evidence that probiotics can also provide benefits by modulating immune functions. In animal models, probiotic supplementation is able to provide protection from spontaneous and chemically induced colitis by downregulating inflammatory cytokines or inducing regulatory mechanisms in a strain-specific manner. In animal models of allergen sensitization and murine models of asthma and allergic rhinitis, orally administered probiotics can strain-dependently decrease allergen-specific IgE production, in part by modulating systemic cytokine production. Certain probiotics have been shown to decrease airway hyperresponsiveness and inflammation by inducing regulatory mechanisms. Promising results have been obtained with probiotics in the treatment of human inflammatory diseases of the intestine and in the prevention and treatment of atopic eczema in neonates and infants. However, the findings are too variable to allow firm conclusions as to the effectiveness of specific probiotics in these conditions.


Fabrication and characterization of deep ridge InGaAsP/InP light emitting transistors.
Deep Ridge InGaAsP/InP Light Emitting Transistors (LET) with ~1.5 μm light emissions have been fabricated and characterized. In the deep ridge LETs, all the light emissions are from the intrinsic base area, which makes them more suitable for high speed direct modulation. A collector emitter voltage (V CE) dependent output power, which has been predicted numerically, is observed experimentally for the first time and may facilitate the use of LETs in optoelectronic integrations. A novel trend of self-heating related saturation of light power with base current is also observed, which is explained by the three port operation of the device. Further, an abnormal common-emitter current-voltage (I-V) characteristic of the deep ridge LETs is shown and is attributed to the non-radiative recombination centers at the ridge side walls. With the good quality of the quantum wells, laser operation at near room temperature is achieved in the deep ridge LET with 800 μm cavity length. With proper surface passivation techniques and device optimizations, performance of the deep ridge transistor based optoelectronic devices can be further enhanced greatly and ultra low power consumption which is highly desirable can be expected.


Does Ramadan fasting increase acute upper gastrointestinal haemorrhage?
The epidemiological characteristics and clinical results of patients who presented with acute upper gastrointestinal haemorrhage (AUGIH) during the month of Ramadan (October 2007) were compared with those who presented with AUGIH during another, non-Ramadan, month (December 2007). The following were evaluated: age, gender, symptoms, gastrointestinal disease history, risk factors, co-existing diseases, results of rectal, nasogastric and endoscopic examinations, treatment modalities and clinical outcomes. Significantly more patients were diagnosed with AUGIH during Ramadan compared with the non-Ramadan month (43 versus 28, respectively). Significantly more patients diagnosed during Ramadan had a history of previous haemorrhage compared with the non-Ramadan month (72.1% versus 42.9%, respectively). Peptic ulcer was the most common event in both groups and overall endoscopy findings differed between the groups. No other significant differences were found. In conclusion, the number of patients presenting with AUGIH during Ramadan was significantly higher than that of an ordinary month, which suggests that fasting during Ramadan reactivates and aggravates pre-existing gastrointestinal diseases.


Quasi-monodimensional polyaniline nanostructures for enhanced molecularly imprinted polymer-based sensing.
Recent advances in nanotechnology have allowed significant progress in utilising cutting-edge techniques associated with nanomaterials and nano-fabrication to expand the scope and capability of biosensors to a new level of novelty and functionality. The aim of this work was the development and characterisation of conductive polyaniline (PANI) nanostructures for applications in electrochemical biosensing. We explore a simple, inexpensive and fast route to grow PANI nanotubes, arranged in an ordered structure directly on an electrode surface, by electrochemical polymerisation using alumina nanoporous membranes as a 'nano-mould'. The deposited nanostructures have been characterised electrochemically and morphologically prior to grafting with a molecularly imprinted polymer (MIP) receptor in order to create a model sensor for catechol detection. In this way, PANI nanostructures resulted in a conductive nanowire system which allowed direct electrical connection between the electrode and the synthetic receptor (MIP). To our knowledge, this is the first example of integration between molecularly imprinted polymers and PANI nanostructured electrodes. The advantages of using nanostructures in this particular biosensing application have been evaluated by comparing the analytical performance of the sensor with an analogous non-nanostructured MIP-sensor for catechol detection that was previously developed. A significantly lower limit of detection for catechol has been obtained (29 nM, one order of magnitude), thus demonstrating that the nanostructures are capable of improving the analytical performance of the sensor.


Testing for drugs of abuse in children and adolescents. American Academy of Pediatrics Committee on Substance Abuse.
The American Academy of Pediatrics (AAP) recognizes the abuse of psychoactive drugs as one of the greatest problems facing children and adolescents and condemns all such use. Diagnostic testing for drugs of abuse is frequently an integral part of the pediatrician's evaluation and management of those suspected of such use. "Voluntary screening" is the term applied to many mass non-suspicion-based screening programs, yet such programs may not be truly voluntary as there are often negative consequences for those who choose not to take part. Participation in such programs should not be a prerequisite to participation in school activities. Involuntary testing is not appropriate in adolescents with decisional capacity-even with parental consent-and should be performed only if there are strong medical or legal reasons to do so. The AAP reaffirms its position that the appropriate response to the suspicion of drug abuse in a young person is the referral to a qualified health care professional for comprehensive evaluation.


Noise properties in a two-arm microscope imaging system with classical thermal light.
We present an analysis of the noise properties in a two-arm microscope imaging system. The aperture of the reference lens affects the imaging quality significantly. Using large apertures will enhance the resolution but also increase the noise. The effects from the distance the object is moved away from the original plane are also discussed, and we can obtain both good resolution and small noise by changing the distance.


Effects of the cold pressor test on muscle sympathetic nerve activity in humans.
The purpose of this study was to determine the effects of the cold pressor test on sympathetic outflow with direct measurements of nerve traffic in conscious humans and to test the strength of correlation between sympathetic nerve discharge and the changes in arterial pressure, heart rate, and plasma norepinephrine. In 25 healthy subjects, arterial pressure, heart rate, and muscle sympathetic nerve activity were measured with microelectrodes inserted percutaneously into a peroneal muscle nerve fascicle in the leg during immersion of the hand in ice water for 2 minutes. Arterial pressure rose steadily during the first and second minutes of the cold pressor test. Muscle sympathetic activity (burst frequency X amplitude) did not increase in the first 30 seconds of the test but increased from 230 +/- 27 to 386 +/- 52 units (mean +/- SE, p less than 0.05) by the end of the first minute of the test and to 574 +/- 73 (p less than 0.01) during the second minute. In contrast, heart rate increased maximally during the first 30 seconds of the cold pressor test and returned to control during the second minute. The increases in heart rate were abolished by beta-adrenergic blockade. The increases in muscle sympathetic activity during the cold pressor test were correlated with the increases in both mean arterial pressure (r = 0.86, p less than 0.01) and peripheral venous norepinephrine (r = 0.72, p less than 0.05); however, large changes in nerve traffic were associated with small changes in plasma norepinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)


Trophoblast Glycoprotein (TPGB/5T4) in Human Placenta: Expression, Regulation, and Presence in Extracellular Microvesicles and Exosomes.
Many parallels exist between growth and development of the placenta and that of cancer. One parallel is shared expression of antigens that may have functional importance and may be recognized by the immune system. Here, we characterize expression and regulation of one such antigen, Trophoblast glycoprotein (TPGB; also called 5T4), in the placenta across gestation, in placentas of preeclamptic (PE) pregnancies, and in purified microvesicles and exosomes. Trophoblast glycoprotein expression was analyzed by real-time reverse transcription-polymerase chain reaction (RT-PCR), Western blot, and immunohistochemistry. Regulation of 5T4 in cytotrophoblast cells was examined under either differentiating conditions of epidermal growth factor or under varying oxygen conditions. Microvesicles and exosomes were purified from supernatant of cultured and perfused placentas. Trophoblast glycoprotein expression was prominent at the microvillus surface of syncytiotrophoblast and on the extravillous trophoblast cells, with minimal expression in undifferentiated cytotrophoblasts and normal tissues. Trophoblast glycoprotein expression was elevated in malignant tumors. In cytotrophoblasts, 5T4 was induced by in vitro differentiation, and its messenger RNA (mRNA) was increased under conditions of low oxygen. PE placentas expressed higher 5T4 mRNA than matched control placentas. Trophoblast glycoprotein was prominent within shed placental microvesicles and exosomes. Given the potential functional and known immunological importance of 5T4 in cancer, these studies reveal a class of proteins that may influence placental development and/or sensitize the maternal immune system. In extravillous trophoblasts, 5T4 may function in epithelial-to-mesenchymal transition during placentation. The role of syncytiotrophoblast 5T4 is unknown, but its abundance in shed syncytial vesicles may signify route of sensitization of the maternal immune system.


Incorporating new data on colorectal cancer into nursing practice.
Treatment for colorectal cancer (CRC) has seen major advances, resulting in longer survival times for many patients. New data about improvements can appear daily in the form of updated journal articles, news reports, and study results reported at national and international oncology meetings. Practicing oncology nurses have a responsibility to keep current on treatments and symptom-management strategies for patients with cancer. Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) are approved in metastatic CRC, and new data are helping to define appropriate patients. Additionally, symptom-management strategies for commonly administered agents in CRC have been refined for EGFR inhibitor-associated rash and neurotoxicity; new information on hypersensitivity and cetuximab also has been reported. This article will discuss the role of the oncology nurse in the management of patients with CRC.


Identification of Grb10 as a direct substrate for members of the Src tyrosine kinase family.
Treatment of cells with insulin and protein tyrosine phosphatase inhibitors such as vanadate and pervanadate resulted in the tyrosine phosphorylation of Grb10, a Src homology 2 (SH2) and pleckstrin homology domain-containing adaptor protein which binds to a number of receptor tyrosine kinases including the insulin receptor (IR). Although Grb10 binds directly to the kinase domain of the IR, our data show that Grb10 is not a direct substrate for the IR tyrosine kinase. Consistent with this finding, Grb10 tyrosine phosphorylation in cells was inhibited by herbimycin A, a relatively specific inhibitor for members of the Src tyrosine kinase family, and by the expression of dominant negative Src or Fyn. In addition, Grb10 tyrosine phosphorylation was stimulated by expression of constitutively active Src or Fyn in cells and by incubation with purified Src or Fyn in vitro. The insulin stimulated or Src/Fyn-mediated tyrosine phosphorylation in vivo was significantly reduced when Grb10 tyrosine 67 was changed to glycine. This mutant form of Grb10 bound with higher affinity to the IR in cells than that of the wild-type protein, suggesting that tyrosine phosphorylation of Grb10 may normally negatively regulate its binding to the IR. Our data show that Grb10 is a new substrate for members of the Src tyrosine kinase family and that the tyrosine phosphorylation of the protein may play a potential role in cell signaling processes mediated by these kinases. Oncogene (2000).


Ectopic and Visceral Fat Deposition in Lean and Obese Patients With Type 2 Diabetes.
Type 2 diabetes (T2D) and obesity are associated with nonalcoholic fatty liver disease, cardiomyopathy, and cardiovascular mortality. Both show stronger links between ectopic and visceral fat deposition, and an increased cardiometabolic risk compared with subcutaneous fat. This study investigated whether lean patients (Ln) with T2D exhibit increased ectopic and visceral fat deposition and whether these are linked to cardiac and hepatic changes. Twenty-seven obese patients (Ob) with T2D, 15 Ln-T2D, and 12 normal-weight control subjects were studied. Subjects underwent cardiac computed tomography, cardiac magnetic resonance imaging (MRI), proton and phosphorus MR spectroscopy, and multiparametric liver MR, including hepatic proton MRS, T1- and T2*-mapping yielding "iron-corrected T1" [cT1]. Diabetes, with or without obesity, was associated with increased myocardial triglyceride content (p = 0.01), increased hepatic triglyceride content (p = 0.04), and impaired myocardial energetics (p = 0.04). Although cardiac structural changes, steatosis, and energetics were similar between the T2D groups, epicardial fat (p = 0.04), hepatic triglyceride (p = 0.01), and insulin resistance (p = 0.03) were higher in Ob-T2D. Epicardial fat, hepatic triglyceride, and insulin resistance correlated negatively with systolic strain and diastolic strain rates, which were only significantly impaired in Ob-T2D (p < 0.001 and p = 0.006, respectively). Fibroinflammatory liver disease (elevated cT1) was only evident in Ob-T2D patients. cT1 correlated with hepatic and epicardial fat (p < 0.001 and p = 0.01, respectively). Irrespective of body mass index, diabetes is related to significant abnormalities in cardiac structure, energetics, and cardiac and hepatic steatosis. Obese patients with T2D show a greater propensity for ectopic and visceral fat deposition.


Mechanism of action of St John's wort in depression : what is known?
Extracts of Hypericum perforatum L. (St John's wort) are now successfully competing for status as a standard antidepressant therapy. Because of this, great effort has been devoted to identifying the active antidepressant compounds in the extract. From a phytochemical point of view, St John's wort is one of the best-investigated medicinal plants. A series of bioactive compounds has been detected in the crude material, namely flavonol derivatives, biflavones, proanthocyanidines, xanthones, phloroglucinols and naphthodianthrones. Although St John's wort has been subjected to extensive scientific studies in the last decade, there are still many open questions about its pharmacology and mechanism of action. Initial biochemical studies reported that St John's wort is only a weak inhibitor of monoamine oxidase-A and -B activity but that it inhibits the synaptosomal uptake of serotonin, dopamine and noradrenaline (norepinephrine) with approximately equal affinity. However, other in vitro binding assays carried out using St John's wort extract demonstrated significant affinity for adenosine, GABA(A), GABA(B) and glutamate receptors. In vivo St John's wort extract leads to a downregulation of beta-adrenergic receptors and an upregulation of serotonin 5-HT(2) receptors in the rat frontal cortex and causes changes in neurotransmitter concentrations in brain areas that are implicated in depression. In studies using the rat forced swimming test, an animal model of depression, St John's wort extracts induced a significant reduction of immobility. In other experimental models of depression, including acute and chronic forms of escape deficit induced by stressors, St John's wort extract was shown to protect rats from the consequences of unavoidable stress. Recent neuroendocrine studies suggest that St John's wort is involved in the regulation of genes that control hypothalamic-pituitary-adrenal axis function. With regard to the antidepressant effects of St John's wort extract, many of the pharmacological activities appear to be attributable to the naphthodianthrone hypericin, the phloroglucinol derivative hyperforin and several flavonoids. This review integrates new findings of possible mechanisms that may underlie the antidepressant action of St John's wort and its active constituents with a large body of existing literature.


The demethylating agent 5-Aza reduces the growth, invasiveness, and clonogenicity of uveal and cutaneous melanoma.
Uveal melanoma is the most common primary intraocular malignancy in adults. Although local disease can be controlled with radiation therapy or enucleation, many cases are complicated by metastases, which account for the significant mortality from this disease. To date, no chemotherapeutic regimens effectively treat local or metastatic disease. Epigenetic silencing of tumor suppressor genes has been shown to be an important factor in the growth and metastasis of many cancers. One form of epigenetic alteration is DNA methylation, which often occurs at promoter elements resulting in the silencing of target gene transcription. We used 5-aza-2'-deoxycytidine (5-Aza), a well characterized demethylating agent that is US Food and Drug Administration approved to decrease DNA methylation in multiple uveal and cutaneous melanoma cell lines. Demethylation of melanoma cell lines using 5-Aza causes significant decreases in growth, invasion, and clonogenicity. Treatment of melanoma cells with combined 5-Aza therapy and irradiation showed an even more pronounced effect on cell viability. In addition, treatment with 5-Aza decreased the number of metastases from the eye to the lung in a murine cutaneous melanoma xenograft model. We demonstrate in vitro and in vivo that demethylating agents such as 5-Aza may be promising chemotherapeutic agents for treating melanoma and decreasing progression to metastatic disease. These results provide proof of concept for an exciting potential therapy to reduce mortality from this disease. Future work will focus on identifying pathways that mediate these changes.


Immunotherapy for prostate cancer.
Whereas androgen deprivation and chemotherapy have become the cornerstone of therapy for advanced prostate cancer, novel therapies are being developed that may expand upon currently available treatments. The identification of antigens expressed by prostate tissue and/or prostate cancer that are recognized by T cells or antibodies creates opportunities to develop novel immunotherapeutic approaches including tumor vaccines. Proteins expressed in prostate cancer-including prostate-specific antigen, prostatic acid phosphatase, and prostate membrane antigen-have been used as immunologic targets for immunotherapy. Moreover, innovations in cancer genomics and proteomics also will aid in the identification of immunologic targets. Emerging trials have demonstrated that immunotherapy may generate not only immune responses in patients but also clinical responses. Future studies will be directed at capitalizing on these findings.


Understanding the Hows and Whys of Decision-Making: From Expected Utility to Divisive Normalization.
Over the course of the last century, economists and ethologists have built detailed models from first principles of how humans and animals should make decisions. Over the course of the last few decades, psychologists and behavioral economists have gathered a wealth of data at variance with the predictions of these economic models. This has led to the development of highly descriptive models that can often predict what choices people or animals will make but without offering any insight into why people make the choices that they do--especially when those choices reduce a decision-maker's well-being. Over the course of the last two decades, neurobiologists working with economists and psychologists have begun to use our growing understanding of how the nervous system works to develop new models of how the nervous system makes decisions. The result, a growing revolution at the interdisciplinary border of neuroscience, psychology, and economics, is a new field called Neuroeconomics. Emerging neuroeconomic models stand to revolutionize our understanding of human and animal choice behavior by combining fundamental properties of neurobiological representation with decision-theoretic analyses. In this overview, one class of these models, based on the widely observed neural computation known as divisive normalization, is presented in detail. The work demonstrates not only that a discrete class of computation widely observed in the nervous system is fundamentally ubiquitous, but how that computation shapes behaviors ranging from visual perception to financial decision-making. It also offers the hope of reconciling economic analysis of what choices we should make with psychological observations of the choices we actually do make.


Supercritical-Carbon Dioxide Fluid Extract from Chrysanthemum indicum Enhances Anti-Tumor Effect and Reduces Toxicity of Bleomycin in Tumor-Bearing Mice.
Bleomycin (BLM), a family of anti-tumor drugs, was reported to exhibit severe side effects limiting its usage in clinical treatment. Therefore, finding adjuvants that enhance the anti-tumor effect and reduce the detrimental effect of BLM is a prerequisite. Chrysanthemum indicum, an edible flower, possesses abundant bioactivities; the supercritical-carbon dioxide fluid extract from flowers and buds of C. indicum (CISCFE) have strong anti-inflammatory, anti-oxidant, and lung protective effects. However, the role of CISCFE combined with BLM treatment on tumor-bearing mice remains unclear. The present study aimed to investigate the potential synergistic effect and the underlying mechanism of CISCFE combined with BLM in the treatment of hepatoma 22 (H22) tumor-bearing mice. The results suggested that the oral administration of CISCFE combined with BLM could markedly prolong the life span, attenuate the BLM-induced pulmonary fibrosis, suppress the production of pro-inflammatory cytokines (interleukin-6), tumor necrosis factor-α, activities of myeloperoxidase, and malondiadehyde. Moreover, CISCFE combined with BLM promoted the ascites cell apoptosis, the activities of caspases 3 and 8, and up-regulated the protein expression of p53 and down-regulated the transforming growth factor-β1 by activating the gene expression of miR-29b. Taken together, these results indicated that CISCFE could enhance the anti-cancer activity of BLM and reduce the BLM-induced pulmonary injury in H22 tumor-bearing mice, rendering it as a potential adjuvant drug with chemotherapy after further investigation in the future.


Stroke patients ready for discharge from acute care--a multi-dimensional assessment of functions and further care.
The aim of this study was to describe actual functions, performance of activities and needs of further care in patients with stroke in acute care wards at the time the physicians decided that the patients were ready for discharge, in relation to placement after discharge and the motives for the decision. Thus 114 stroke patients in Stockholm County were assessed with the Resident Assessment Instrument, and the motives for further care were reviewed in the patients' case records. The results showed that the oldest, most severely impaired stroke patients had the shortest mean length of stay before the physician considered the patients ready for discharge to nursing homes, where resources for long-term rehabilitation and stroke care vary. It is important to secure continuing adequate care and rehabilitation for elderly severely impaired stroke patients being discharged early from acute care hospitals.


Coordination of substrate binding and ATP hydrolysis in Vps4-mediated ESCRT-III disassembly.
ESCRT-III undergoes dynamic assembly and disassembly to facilitate membrane exvagination processes including multivesicular body (MVB) formation, enveloped virus budding, and membrane abscission during cytokinesis. The AAA-ATPase Vps4 is required for ESCRT-III disassembly, however the coordination of Vps4 ATP hydrolysis with ESCRT-III binding and disassembly is not understood. Vps4 ATP hydrolysis has been proposed to execute ESCRT-III disassembly as either a stable oligomer or an unstable oligomer whose dissociation drives ESCRT-III disassembly. An in vitro ESCRT-III disassembly assay was developed to analyze Vps4 function during this process. The studies presented here support a model in which Vps4 acts as a stable oligomer during ATP hydrolysis and ESCRT-III disassembly. Moreover, Vps4 oligomer binding to ESCRT-III induces coordination of ATP hydrolysis at the level of individual Vps4 subunits. These results suggest that Vps4 functions as a stable oligomer that acts upon individual ESCRT-III subunits to facilitate ESCRT-III disassembly.


Growth environment and personality in adult migraineurs and their migraine-free siblings.
The aim of the study was to compare adult migraine discordant full siblings in terms of personality and psychosocial environment during childhood. The study, involving 30 sibling pairs and use of various personality instruments (Eysenck Personality Inventory [EPI], Color Word Test [CWT], Visual Aftereffects [VAE], Meta Contrast Technique [MCT], Cesarec-Marke Personality Schedule), showed the migraineurs scored significantly higher on neuroticism [EPI], also called emotional stress or trait anxiety; to be more sensitive (MCT); and to display signs of greater anxiety (VAE, CWT). Furthermore, migraineurs tended to report greater scarcity of friends during childhood and less verbal, as well as, nonverbal encouragement from their parents, than their migraine-free siblings. Neuroticism was found to correlate significantly with migraine, but not with headache frequency or severity in the migraine group. It is argued that, due to the high neuroticism of some migraineurs, psychotherapy should be considered as an alternative to other prophylactic treatments such as use of beta-adrenoceptor blockers, although the acute migraine onset should be pharmacologically treated.


Barriers to communication about end-of-life care in AIDS patients.
Patients and physicians do not adequately discuss patients' preferences for medical care at the end of life. Our objective was to perform a qualitative study using focus groups to identify barriers and facilitators to communication about end-of-life medical care for patients with AIDS and their physicians. Patients with AIDS and physicians with moderate or extensive HIV experience were recruited from clinics and community-based settings using network sampling. A total of 47 patients participated in six focus groups and 19 physicians participated in three groups. Patients or physicians identified 29 barriers and facilitators to communication about end-of-life care. Many patients and physicians expressed discomfort talking about death and dying, and some felt that discussing end-of-life care could cause harm or even hasten death. Several patients expressed the view that a living will obviated the need for discussion with their physician. Previous experience of discrimination from the health care system was a strong barrier to end-of-life communication for some patients with AIDS. Some patients hesitate to bring up end-of-life issues because they want to protect their physicians from uncomfortable discussions. Many patients identified the quality of communication as an important facilitator to these difficult discussions. Improving the quality of patient-physician communication about end-of-life care will require that physicians identify and overcome the barriers to this communication. To improve the quality of medical care at the end of life, we must address the quality of communication about end-of-life care.


The HD-GYP domain, cyclic di-GMP signaling, and bacterial virulence to plants.
Cyclic di-GMP is an almost ubiquitous second messenger in bacteria that was first described as an allosteric activator of cellulose synthase but is now known to regulate a range of functions, including virulence in human and animal pathogens. Two protein domains, GGDEF and EAL, are implicated in the synthesis and degradation, respectively, of cyclic di-GMP. These domains are widely distributed in bacteria, including plant pathogens. The majority of proteins with GGDEF and EAL domains contain additional signal input domains, suggesting that their activities are responsive to environmental cues. Recent studies have demonstrated that a third domain, HD-GYP, is also active in cyclic di-GMP degradation. In the plant pathogen Xanthomonas campestris pv. campestris, a two-component signal transduction system comprising the HD-GYP domain regulatory protein RpfG and cognate sensor RpfC positively controls virulence. The signals recognized by RpfC may include the cell-cell signal DSF, which also acts to regulate virulence in X. campestris pv. campestris. Here, we review these recent advances in our understanding of cyclic di-GMP signaling with particular reference to one or more roles in the bacterial pathogenesis of plants.


Deciphering site formation processes through soil micromorphology at Contrebandiers Cave, Morocco.
Contrebandiers Cave preserves a Late Pleistocene sequence containing Middle Stone Age (MSA) so-called Maghrebian Mousterian and Aterian occupations, spanning from ∼126 to 95 ka (thousands of years ago), followed by spatially restricted Iberomaurusian industries. Micromorphological analyses, complemented by instrumental mineralogical identification and fabric orientation, allowed for the reconstruction of the main site formation processes at the site. Initial deposition is characterized by local reworking of marine shelly sands dating to Marine Isotopic Stage 5e (MIS5e). The subsequent stratification reveals sedimentary dynamics predominantly associated with gravity-driven inputs and contributions from weathering of the encasing bedrock, at the same time that anthropogenic sediments were being accumulated. The allochthonous components reflect soil degradation and vegetation changes around the cave during the last interglacial. Human occupations seems to be somewhat ephemeral in nature, with some stratigraphic units apparently lacking archaeological components, while in others the human-associated deposits (e.g., burned bones, charcoal, and ashes) can be substantial. Ephemeral breaks in sedimentation and/or erosion followed by stabilization are mainly discernible microscopically by the presence of phosphatic-rich laminae interpreted as short-lived surfaces, peaks of increased humidity and colonization by plants. More substantial erosion affects the uppermost Aterian layers, presumably due to localized reconfigurations of the cave's roof. The subsequent Iberomaurusian deposits are not in their primary position and are associated with well-sorted silts of aeolian origin. While the effects of chemical diagenesis are limited throughout the whole stratigraphic sequence, physical bioturbation (e.g., by wasps, rodents, and earthworms) is more pervasive and leads to localized movement of the original sedimentary particles.


Adaptive Randomization of Veliparib-Carboplatin Treatment in Breast Cancer.
The genetic and clinical heterogeneity of breast cancer makes the identification of effective therapies challenging. We designed I-SPY 2, a phase 2, multicenter, adaptively randomized trial to screen multiple experimental regimens in combination with standard neoadjuvant chemotherapy for breast cancer. The goal is to match experimental regimens with responding cancer subtypes. We report results for veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin. In this ongoing trial, women are eligible for participation if they have stage II or III breast cancer with a tumor 2.5 cm or larger in diameter; cancers are categorized into eight biomarker subtypes on the basis of status with regard to human epidermal growth factor receptor 2 (HER2), hormone receptors, and a 70-gene assay. Patients undergo adaptive randomization within each biomarker subtype to receive regimens that have better performance than the standard therapy. Regimens are evaluated within 10 biomarker signatures (i.e., prospectively defined combinations of biomarker subtypes). Veliparib-carboplatin plus standard therapy was considered for HER2-negative tumors and was therefore evaluated in 3 signatures. The primary end point is pathological complete response. Tumor volume changes measured by magnetic resonance imaging during treatment are used to predict whether a patient will have a pathological complete response. Regimens move on from phase 2 if and when they have a high Bayesian predictive probability of success in a subsequent phase 3 neoadjuvant trial within the biomarker signature in which they performed well. With regard to triple-negative breast cancer, veliparib-carboplatin had an 88% predicted probability of success in a phase 3 trial. A total of 72 patients were randomly assigned to receive veliparib-carboplatin, and 44 patients were concurrently assigned to receive control therapy; at the completion of chemotherapy, the estimated rates of pathological complete response in the triple-negative population were 51% (95% Bayesian probability interval [PI], 36 to 66%) in the veliparib-carboplatin group versus 26% (95% PI, 9 to 43%) in the control group. The toxicity of veliparib-carboplatin was greater than that of the control. The process used in our trial showed that veliparib-carboplatin added to standard therapy resulted in higher rates of pathological complete response than standard therapy alone specifically in triple-negative breast cancer. (Funded by the QuantumLeap Healthcare Collaborative and others; I-SPY 2 TRIAL ClinicalTrials.gov number, NCT01042379.).


The effects of lycopene on alloxan induced diabetic optic neuropathy.
To determine the effects of lycopene treatment in prevention of diabetes associated inflammatory response and oxidative stress in an experimental model. With this aim we investigated the levels of oxidative stress markers including Malondialdehyde (MDA), and total oxidative status (TOS)together with inflammatory markers including nuclear factor- kappa B (NFKB) and tumor necrosis factor α (TNF-α) and antioxidants including total glutathione (TGSH), total oxidative status (TOS) and total anti-oxidative status (TAS) levels on eye tissue. Totally 18 albino Wistar male rats (250-280 grams) assigned into three groups, with six rats in each group as follows: healthy group (HG), control group (CG), and lycopene group (LG). The diabetes was induced with alloxan administration in rats of CG and LG. Lycopene (4 mg/kg) was administered to the rats in LG once a day for 3 months. At the end of this period, the animals were sacrificed and their eyes were enucleated for histopathological evaluations. From the tissues, MDA, GSH, TOS, TAS, TNF-α and NF-κB levels were analyzed. MDA, TOS, OSI, NFKB and TNF-α levels were significantly higher, while TGSH and TAS levels were significantly lower in CG compared with HG (p < 0.001). On the other hand in LG; MDA, TOS, OSI, NFKB and TNF-α levels were significantly lower, while TGSH and TAS levels were significantly higher compared with CG (p < 0.001). Regarding histopathological findings, although there was severe damage on optic nerve of rats in CG; there was only a slight damage in lycopene administered group. For the first time in literature we determined that, lycopene was significantly effective in prevention of augmented inflammation and oxidative stress on eye tissue associated with diabetes, as well as the tissue damage on optic nerve. However, studies investigating the long-term clinical effects of lycopene on diabetic individuals are warranted.


Helicobacter pylori detection in human biopsies: a competitive PCR assay with internal control reveals false results.
A polymerase chain reaction assay (PCR) for the diagnosis of Helicobacter pylori in human gastric biopsies was developed. To prevent false-negative results while performing PCR on human tissues, an internal control is necessary. Primer set ACT1-ACT2 which specifically amplifies a 542-bp fragment of the 16S rRNA gene of H. pylori was used. dUTP and hot-start were used to prevent false-positives from carryover of previous products and avoid non-specific extension products. A competitive internal control DNA fragment was constructed to detect the presence of inhibitors. Biopsies from 101 unselected patients with gastric symptoms were tested. PCR results were compared with results from microscopy of histological sections and conventional culturing for H. pylori. Forty-two percent of the biopsies were found to contain compounds inhibiting the PCR. The addition of the internal control assures the performance of the PCR assay and is an important quality control parameter.


Bilateral retinal and brain tumors in transgenic mice expressing simian virus 40 large T antigen under control of the human interphotoreceptor retinoid-binding protein promoter.
We have previously shown that postnatal expression of the viral oncoprotein SV40 T antigen in rod photoreceptors (transgene MOT1), at a time when retinal cells have withdrawn from the mitotic cycle, leads to photoreceptor cell death (Al-Ubaidi et al., 1992. Proc. Natl. Acad. Sci. USA. 89:1194-1198). To study the effect of the specificity of the promoter, we replaced the mouse opsin promoter in MOT1 by a 1.3-kb promoter fragment of the human IRBP gene which is expressed in both rod and cone photoreceptors during embryonic development. The resulting construct, termed HIT1, was injected into mouse embryos and five transgenic mice lines were established. Mice heterozygous for HIT1 exhibited early bilateral retinal and brain tumors with varying degrees of incidence. Histopathological examination of the brain and eyes of three of the families showed typical primitive neuroectodermal tumors. In some of the bilateral retinal tumors, peculiar rosettes were observed, which were different from the Flexner-Wintersteiner rosettes typically associated with human retinoblastomas. The ocular and cerebral tumors, however, contained Homer-Wright rosettes, and showed varying degrees of immunoreactivity to antibodies against the neuronal specific antigens, synaptophysin and Leu7, but not to antibodies against photoreceptor specific proteins. Taken together, the results indicate that the specificity of the promoter used for T antigen and/or the time of onset of transgene expression determines the fate of photoreceptor cells expressing T antigen.


Prostate-specific antigen: an evolving role in diagnosis, monitoring, and treatment evaluation in prostate cancer.
Prostate specific antigen (PSA) was introduced as a prostate cancer screening tool more than 20 years ago. However, there is continuing debate regarding its utility in screening for prostate cancer. Mass screening is costly, may result in the diagnosis and treatment of prostate cancers that never become clinically significant, and the evidence of a subsequent reduction in mortality is inconclusive. In addition to its role in screening, PSA is also used to monitor the progression of the disease, both localized and metastatic. Although the evidence is contradictory, PSA is still an important tool for monitoring patient progression following treatment of definitive localized prostate cancer. However, its use in monitoring castrate-resistant prostate cancer (CRPC) is more controversial, particularly in the context of novel targeted treatments, which may have little impact on PSA levels. These issues highlight the urgent need to identify prostate cancer biomarkers that will improve early disease detection, increase accuracy of diagnosis, determine the aggressiveness of disease, and monitor treatment efficacy, particularly in late-stage disease. This review discusses the key issues associated with the use of PSA as an early screening tool for prostate cancer, as a prognostic marker to measure disease progression in both early- and late-stage prostate cancer, and as a surrogate endpoint in clinical trials with new agents.


Characterization of Pieces of Paper That Form Reagent Containers for Use as Portable Analytical Devices.
Reagent-deposited pieces of paper were characterized by the use of a compact conductometer, a compact pH sensor, and a conventional spectrophotometer to assess their suitability for use as reagent containers. The pieces of paper were fabricated by wax printing to form a limited hydrophilic area to which a consistent volume of an aqueous reagent could be added. The pieces of paper without the reagent increased the conductivity of water gradually because of the release of sodium salts, whereas pH of NaOH decreased because of the acidity of the functional groups in the paper. Three reagents, sulfamic acid as an acid, Na2CO3 as a base, and BaCl2 as a metal salt, were deposited on the pieces of paper to evaluate their ability to release from the pieces of paper. Sulfamic acid and Na2CO3 were released in quantities of 58 and 73% into water after 420 s, whereas 100% of BaCl2 was released after 480 s. The conductometric titrations of NaOH, HCl, and Na2SO4, and the spectrophotometry of Fe2+ were examined using the pieces of paper that contained sulfamic acid, Na2CO3, BaCl2, and 1,10-phenanthroline. Titrations using the pieces of paper suggested that the reagents were quantitatively released into the titrant, which resulted in a linear relationship between the endpoints and the equivalent points. In 120 s of soaking time, 60-70% of the reagents were released. The spectrophotometric measurements of Fe2+ indicated that when an excess amount of the reagents was deposited onto the pieces of paper, they nonetheless sufficiently fulfilled the role of a reagent container.


Interventions to improve cortisol regulation in children: a systematic review.
Childhood adversity is associated with physiologic dysregulation across multiple biological systems; however, relatively little is known about whether these changes are reversible with intervention. The objective of this review was to examine evidence for the effectiveness of interventions to promote healthy cortisol regulation in children. We selected articles from English-language publications in PubMed and EBSCO databases through 2012. Two independent reviewers assessed articles against eligibility criteria. Eligible studies were randomized controlled or quasi-experimental studies designed to improve relationships, environments, or psychosocial functioning in children and examined cortisol as an outcome. We identified 19 articles. There was substantial heterogeneity across studies with regard to age, selection criteria, intervention design, cortisol assessment, and follow-up duration. Eighteen of the 19 articles reported at least 1 difference in baseline cortisol, diurnal cortisol, or cortisol responsivity between intervention and control participants. Importantly, however, there was remarkable inconsistency with regard to how the interventions influenced cortisol. Therefore, studies that included a low-risk comparison group (n = 8) provided critical insight, and each found some evidence that postintervention cortisol levels in the intervention group approximated the low-risk comparison group and differed from children receiving usual care. In conclusion, existing studies show that cortisol activity can be altered by psychosocial interventions. These findings are promising, not only because they indicate physiologic plasticity that can be leveraged by interventions but also because they suggest it may be possible to repair regulatory systems after childhood adversity, which could inform strategies for reducing health disparities and promoting lasting improvements in health.


Neurodegenerative diseases in the era of targeted therapeutics: how to handle a tangled issue.
Neurodegenerative diseases are age-related and relentlessly progressive with increasing prevalence and no cure or lasting symptomatic therapy. The well-recognized prodromal phase in many forms of neurodegeneration suggests a prolonged period of neuronal compensated dysfunction prior to cell loss that may be amenable to therapeutic intervention. Although most efforts to date have been focused on misfolded toxic proteins, it is now clear that widespread changes in protein homeostasis occur early in these diseases and understanding this fundamental biology is key to the design of targeted therapies. What has emerged from molecular genetics and animal studies is a previously less appreciated association of neurodegenerative diseases with defects in the molecular regulation of protein trafficking between cellular organelles, especially the intricate network of endosomes, lysosomes, autophagosomes and mitochondria. Here we summarized the broader concepts that stemmed from this Special Issue on "Protein Clearance in Neurodegenerative diseases: from mechanisms to therapies". This article is part of a Special Issue entitled 'Neuronal Protein'.


On-tissue polysulfide visualization by surface-enhanced Raman spectroscopy benefits patients with ovarian cancer to predict post-operative chemosensitivity.
Chemosensitivity to cisplatin derivatives varies among individual patients with intractable malignancies including ovarian cancer, while how to unlock the resistance remain unknown. Ovarian cancer tissues were collected the debulking surgery in discovery- (n = 135) and validation- (n = 47) cohorts, to be analyzed with high-throughput automated immunohistochemistry which identified cystathionine γ-lyase (CSE) as an independent marker distinguishing non-responders from responders to post-operative platinum-based chemotherapy. We aimed to identify CSE-derived metabolites responsible for chemoresistant mechanisms: gold-nanoparticle (AuN)-based surface-enhanced Raman spectroscopy (SERS) was used to enhance electromagnetic fields which enabled to visualize multiple sulfur-containing metabolites through detecting scattering light from Au-S vibration two-dimensionally. Clear cell carcinoma (CCC) who turned out less sensitive to cisplatin than serous adenocarcinoma was classified into two groups by the intensities of SERS intensities at 480 cm-1; patients with greater intensities displayed the shorter overall survival after the debulking surgery. The SERS signals were eliminated by topically applied monobromobimane that breaks sulfane-sulfur bonds of polysulfides to result in formation of sulfodibimane which was detected at 580 cm-1, manifesting the presence of polysulfides in cancer tissues. CCC-derived cancer cell lines in culture were resistant against cisplatin, but treatment with ambroxol, an expectorant degrading polysulfides, renders the cells CDDP-susceptible. Co-administration of ambroxol with cisplatin significantly suppressed growth of cancer xenografts in nude mice. Furthermore, polysulfides, but neither glutathione nor hypotaurine, attenuated cisplatin-induced disturbance of DNA supercoiling. Polysulfide detection by on-tissue SERS thus enables to predict prognosis of cisplatin-based chemotherapy. The current findings suggest polysulfide degradation as a stratagem unlocking cisplatin chemoresistance.


Burden of influenza-related hospitalizations among children with sickle cell disease.
Children with sickle cell disease (SCD) are considered to be at high risk for complications from influenza infection despite minimal published data that characterize the burden of influenza in this population. Our objectives were to (1) estimate the rate of influenza-related hospitalizations (IRHs) among children with SCD, (2) compare this rate with rates of children with cystic fibrosis (CF) and children with neither SCD nor CF, and (3) explore mechanisms that underlie these potentially preventable hospitalizations. We analyzed hospitalizations from 4 states (California, Florida, Maryland, and New York) across 2 influenza seasons (2003-2004 and 2004-2005) from the Healthcare Cost and Utilization Project State Inpatient Databases. We included hospitalizations with a discharge diagnosis code for influenza in a child <18 years of age. We used census data and disease prevalence estimates to calculate denominators and compare rates of IRH among children with SCD, CF, and neither disease. There were 7896 pediatric IRHs during the 2 influenza seasons. Of these, 159 (2.0%) included a co-occurring diagnosis of SCD. Annual rates of IRHs were 112 and 2.0 per 10 000 children with and without SCD, respectively, across both seasons. Children with SCD were hospitalized with influenza at 56 times (95% confidence interval: 48-65) the rate of children without SCD. Children with SCD had approximately double the risk of IRH compared with children with CF (risk ratio: 2.1 [95% confidence interval: 1.5-2.9]). IRHs among children with SCD were not longer, more costly, or more severe than IRHs among children without SCD; they were also rarely nosocomial and co-occurred with a diagnosis of asthma in 14% of cases. IRHs are substantially more common among children with SCD than among those without the disease, which supports the potential importance of vigorous influenza vaccination efforts that target children with SCD.


Analysis of pelagic species decline in the upper San Francisco Estuary using multivariate autoregressive modeling (MAR).
Four species of pelagic fish of particular management concern in the upper San Francisco Estuary, California, USA, have declined precipitously since ca. 2002: delta smelt (Hypomesus transpacificus), longfin smelt (Spirinchus thaleichthys), striped bass (Morone saxatilis), and threadfin shad (Dorosoma petenense). The estuary has been monitored since the late 1960s with extensive collection of data on the fishes, their pelagic prey, phytoplankton biomass, invasive species, and physical factors. We used multivariate autoregressive (MAR) modeling to discern the main factors responsible for the declines. An expert-elicited model was built to describe the system. Fifty-four relationships were built into the model, only one of which was of uncertain direction a priori. Twenty-eight of the proposed relationships were strongly supported by or consistent with the data, while 26 were close to zero (not supported by the data but not contrary to expectations). The position of the 2 per thousand isohaline (a measure of the physical response of the estuary to freshwater flow) and increased water clarity over the period of analyses were two factors affecting multiple declining taxa (including fishes and the fishes' main zooplankton prey): Our results were relatively robust with respect to the form of stock-recruitment model used and to inclusion of subsidiary covariates but may be enhanced by using detailed state-space models that describe more fully the life-history dynamics of the declining species.


Pharmacodynamics and pharmacokinetics of haloperidol and reduced haloperidol in schizophrenic patients.
Twelve male chronic schizophrenic inpatients, neuroleptic-free for at least 4 weeks, were given an oral test dose of 10 mg haloperidol (HAL) and reduced HAL (RHAL) in a random order, with a 2-week interval. Two weeks after the last test dose, the patients were given HAL, 5 mg orally twice daily for 7 days. Blood samples were drawn at baseline and between 0.5 and 24 hr after the test doses, and during HAL treatment as well. Plasma drug concentrations and homovanillic acid (HVA) levels were measured with high-performance liquid chromatography using electrochemical detection. HAL, but not RHAL, produced increments in plasma HVA (pHVA) levels at 24 hr after a test dose. pHVA levels remained higher than baseline during HAL treatment. Detectable interconversion between HAL and RHAL was observed in eight patients. The capacity of the reductive drug-metabolizing enzyme system, however, was greater than that of the oxidative processes. The plasma RHAL:HAL ratios on days 6 and 7 were higher than and positively correlated with those at Tmax after a single dose of HAL and were negatively correlated with the HAL:RHAL ratios at Tmax after a single dose of RHAL. Thus, both reductive and oxidative drug-metabolizing systems probably contribute to individual differences in plasma RHAL:HAL ratios in HAL-treated schizophrenic patients.