Symmetry-resolved CO desorption and oxidation dynamics on O/Ru(0001) probed at the C K-edge by ultrafast x-ray spectroscopy.
We report on carbon monoxide desorption and oxidation induced by 400 nm femtosecond laser excitation on the O/Ru(0001) surface probed by time-resolved x-ray absorption spectroscopy (TR-XAS) at the carbon K-edge. The experiments were performed under constant background pressures of CO (6 × 10-8 Torr) and O2 (3 × 10-8 Torr). Under these conditions, we detect two transient CO species with narrow 2π* peaks, suggesting little 2π* interaction with the surface. Based on polarization measurements, we find that these two species have opposing orientations: (1) CO favoring a more perpendicular orientation and (2) CO favoring a more parallel orientation with respect to the surface. We also directly detect gas-phase CO2 using a mass spectrometer and observe weak signatures of bent adsorbed CO2 at slightly higher x-ray energies than the 2π* region. These results are compared to previously reported TR-XAS results at the O K-edge, where the CO background pressure was three times lower (2 × 10-8 Torr) while maintaining the same O2 pressure. At the lower CO pressure, in the CO 2π* region, we observed adsorbed CO and a distribution of OC-O bond lengths close to the CO oxidation transition state, with little indication of gas-like CO. The shift toward "gas-like" CO species may be explained by the higher CO exposure, which blocks O adsorption, decreasing O coverage and increasing CO coverage. These effects decrease the CO desorption barrier through dipole-dipole interaction while simultaneously increasing the CO oxidation barrier.


Event-related potential evidence that automatic recollection can be voluntarily avoided.
Voluntary control processes can be recruited to facilitate recollection in situations where a retrieval cue fails to automatically bring to mind a desired episodic memory. We investigated whether voluntary control processes can also stop recollection of unwanted memories that would otherwise have been automatically recollected. Participants were trained on cue-associate word-pairs, then repeatedly presented with the cue and asked to either recollect or avoid recollecting the associate, while having the event-related potential (ERP) correlate of conscious recollection measured. Halfway through the phase, some cues switched instructions so that participants had to start avoiding recall of associates they had previously repeatedly recalled, and vice versa. ERPs during recollection avoidance showed a significantly reduced positivity in the correlate of conscious recollection, and switching instructions reversed the ERP effect even for items that had been previously repeatedly recalled, suggesting that voluntary control processes can override highly practiced, automatic recollection. Avoiding recollection of particularly prepotent memories was associated with an additional, earlier ERP negativity that was separable from the later voluntary modulation of conscious recollection. The findings have implications for theories of memory retrieval by highlighting the involvement of voluntary attentional processes in controlling conscious recollection.


Hsc/Hsp70 interacting protein (hip) associates with CXCR2 and regulates the receptor signaling and trafficking.
The ligand-induced trafficking of chemokine receptors plays a significant role in the regulation of inflammatory processes and human immunodeficiency infection. Although many chemokine receptors have been demonstrated to internalize through clathrin-coated vesicles, a process that involves the binding of arrestins to the receptors, accumulating evidence has suggested the possible existence of other regulators. In a yeast two-hybrid screening using the C-terminal domain of CXCR2 as a bait, the Hsc70-interacting protein (Hip) was identified to interact with CXCR2. Hip binds CXCR2 through its C-terminal domain binding to the C-terminal leucine-rich domain (KILAIHGLI) of CXCR2. Hip associates with CXCR2 or CXCR4 in intact cells, and agonist stimulation increases the association. Mutation of the Ile-Leu motif in the C-terminal domain of CXCR2 blocks the agonist-dependent association of the mutant receptor with Hip. Overexpression of a tetratricopeptide repeat (TPR) deletion mutant form of Hip (Delta TPR), which is unable to bind Hsc70 (Prapapanich, V., Chen, S., Nair, S. C., Rimerman, R. A., and Smith, D. F. (1996) Mol. Endocrinol. 10, 420-431), but retains the ability to bind CXCR2, does not affect CXCR2-mediated mitogen-activated protein kinase activation. However, overexpression of Delta TPR significantly attenuates the agonist-induced internalization of CXCR2 and CXCR4 and attenuates CXCR2-mediated chemotaxis. These findings open the possibility for regulation of chemokine receptor signaling and trafficking by protein chaperone molecules.


Renal tubular arginase-2 participates in the formation of the corticomedullary urea gradient and attenuates kidney damage in ischemia-reperfusion injury in mice.
Arginase 2 (ARG2) is a mitochondrial enzyme that catalyses hydrolysis of l-arginine into urea and l-ornithine. In the kidney, ARG2 is localized to the S3 segment of the proximal tubule. It has been shown that expression and activity of this enzyme are upregulated in a variety of renal pathologies, including ischemia-reperfusion (IR) injury. However, the (patho)physiological role of ARG2 in the renal tubule remains largely unknown. We addressed this question in mice with conditional knockout of Arg2 in renal tubular cells (Arg2lox/lox /Pax8-rtTA/LC1 or, cKO mice). We demonstrate that cKO mice exhibit impaired urea concentration and osmolality gradients along the corticomedullary axis. In a model of unilateral ischemia-reperfusion injury (UIRI) with an intact contralateral kidney, ischemia followed by 24 hours of reperfusion resulted in significantly more pronounced histological damage in ischemic kidneys from cKO mice compared to control and sham-operated mice. In parallel, UIRI-subjected cKO mice exhibited a broad range of renal functional abnormalities, including albuminuria and aminoaciduria. Fourteen days after UIRI, the cKO mice exhibited complex phenotype characterized by significantly lower body weight, increased plasma levels of early predictive markers of kidney disease progression (asymmetric dimethylarginine and symmetric dimethylarginine), impaired mitochondrial function in the ischemic kidney but no difference in kidney fibrosis as compared to control mice. Collectively, these results establish the role of ARG2 in the formation of corticomedullary urea and osmolality gradients and suggest that this enzyme attenuates kidney damage in ischemia-reperfusion injury.


[Nursing ethics and the access to nursing care].
The increasing number of ethical issues highlighted in everyday nursing care demonstrates the connectedness between nursing ethics and nursing practice. However, what is the role of ethical theories in this context? This question will be examined in this article by analysing the contribution made by the ethics of care, in particular in understandings of gender roles, asymmetries of power, professional knowledge and experience. The adoption and criticism of an emergent nursing ethics is discussed and stated from different viewpoints. The actuality of the caring approach is affirmed by a new reading of the given situation. This article first describes the traditional perception of nurses as marginalised actors in the health sector. By making reference to the current and growing global scarcity of nursing care, it contends that nursing will no longer be marginalised, but instead at the centre of public health attention and reputation. Nevertheless, marginalisation will persist by increasingly affecting the care receivers, especially those groups that are pushed to the fringes by the consequences of the healthcare market, such as persons of extreme old age, suffering from multiple morbidities, or with poor health literacy. Whereas the "classical" understanding of the ethics of care focuses on the nurse-patient relationship and on individual care and understanding of ethics, the new understanding confirms the classical, but adds an understanding of social ethics: caring for the access to care is seen as a main ethical goal of social justice within a nursing ethic.


Embodying an outgroup: the role of racial bias and the effect of multisensory processing in somatosensory remapping.
We come to understand other people's physical and mental states by re-mapping their bodily states onto our sensorimotor system. This process, also called somatosensory resonance, is an essential ability for social cognition and is stronger when observing ingroup than outgroup members. Here we investigated, first, whether implicit racial bias constrains somatosensory resonance, and second, whether increasing the ingroup/outgroup perceived physical similarity results in an increase in the somatosensory resonance for outgroup members. We used the Visual Remapping of Touch effect as an index of individuals' ability in resonating with the others, and the Implicit Association Test to measure racial bias. In Experiment 1, participants were asked to detect near-threshold tactile stimuli delivered to their own face while viewing either an ingroup or an outgroup face receiving a similar stimulation. Our results showed that individuals' tactile accuracy when viewing an outgroup face being touched was negatively correlated to their implicit racial bias. In Experiment 2, participants received the interpersonal multisensory stimulation (IMS) while observing an outgroup member. IMS has been found to increase the perceived physical similarity between the observer's and the observed body. We tested whether such increase in ingroup/outgroup perceived physical similarity increased the remapping ability for outgroup members. We found that after sharing IMS experience with an outgroup member, tactile accuracy when viewing touch on outgroup faces increased. Interestingly, participants with stronger implicit bias against the outgroup showed larger positive change in the remapping. We conclude that shared multisensory experiences might represent one key way to improve our ability to resonate with others by overcoming the boundaries between ingroup and outgroup categories.


A systematic literature review of the clinical and health economic burden of schizophrenia in privately insured patients in the United States.
The aim of this study was to conduct a systematic literature review on the burden of schizophrenia in privately insured US patients. A systematic literature review of English language peer-reviewed journal articles of observational studies published from 2006 to 2016 was conducted using EMBASE/MEDLINE databases. Abstracts covering substantial numbers of patients with schizophrenia or schizoaffective disorder (i.e., N ≥ 100) were included for full-text review. Articles that did not clearly specify private insurance types were excluded. A total of 25 studies were reviewed; 10 included only privately insured patients; and 15 included a mix of different types of insurance. The review of the clinical burden of schizophrenia revealed the following: compared to patients with no mental disorders, those with schizophrenia had significantly increased odds of systemic disorders and both alcohol and substance abuse. Antipsychotic (AP) adherence was low, ranging from 31.5% to 68.7%. The medication possession ratio for AP adherence ranged from 0.22 to 0.73. The review of the health economic burden of schizophrenia revealed the following: patients with a recent (vs. chronic) diagnosis of schizophrenia had significantly higher frequencies of emergency department visits and hospitalizations and greater length of stay (LOS) and total annual per-capita costs. Mean all-cause hospitalizations and LOS decreased significantly after (vs. before) initiating long-acting injectable APs (LAIs). Patients also had significantly decreased mean all-cause, and schizophrenia-related, hospitalization costs after initiating LAIs. Total direct per-capita costs of care (but not pharmacy costs) for patients who were nonadherent to their oral APs within the first 90 days of their index event were significantly higher (vs. early adherent patients). Despite these potential benefits, only 0.25%-13.1% of patients were treated with LAIs across all studies. Privately insured US patients with schizophrenia experience a substantial clinical and health economic burden related to comorbidities, acute care needs, nonadherence, and polypharmacy and have relatively low use of LAIs. Further study is warranted to understand prescribing patterns and clinical policies related to this patient population.


Coordinated zinc homeostasis is essential for the wild-type virulence of Brucella abortus.
Metal homeostasis in bacterial cells is a highly regulated process requiring intricately coordinated import and export, as well as precise sensing of intracellular metal concentrations. The uptake of zinc (Zn) has been linked to the virulence of Brucella abortus; however, the capacity of Brucella strains to sense Zn levels and subsequently coordinate Zn homeostasis has not been described. Here, we show that expression of the genes encoding the zinc uptake system ZnuABC is negatively regulated by the Zn-sensing Fur family transcriptional regulator, Zur, by direct interactions between Zur and the promoter region of znuABC. Moreover, the MerR-type regulator, ZntR, controls the expression of the gene encoding the Zn exporter ZntA by binding directly to its promoter. Deletion of zur or zntR alone did not result in increased zinc toxicity in the corresponding mutants; however, deletion of zntA led to increased sensitivity to Zn but not to other metals, such as Cu and Ni, suggesting that ZntA is a Zn-specific exporter. Strikingly, deletion of zntR resulted in significant attenuation of B. abortus in a mouse model of chronic infection, and subsequent experiments revealed that overexpression of zntA in the zntR mutant is the molecular basis for its decreased virulence. The importance of zinc uptake for Brucella pathogenesis has been demonstrated previously, but to date, there has been no description of how overall zinc homeostasis is maintained and genetically controlled in the brucellae. The present work defines the predominant zinc export system, as well as the key genetic regulators of both zinc uptake and export in Brucella abortus. Moreover, the data show the importance of precise coordination of the zinc homeostasis systems as disregulation of some elements of these systems leads to the attenuation of Brucella virulence in a mouse model. Overall, this study advances our understanding of the essential role of zinc in the pathogenesis of intracellular bacteria.


Stroke in estrogen receptor-alpha-deficient mice.
Recent evidence suggests that endogenous estrogens or hormone replacement therapy can ameliorate brain damage from experimental stroke. Protective mechanisms involve enhanced cerebral vasodilation during ischemic stress as well as direct preservation of neuronal viability. We hypothesized that if the intracellular estrogen receptor subtype-alpha (ERalpha) is important to estrogen's signaling in the ischemic brain, then ERalpha-deficient (knockout) (ERalphaKO) female mice would sustain exaggerated cerebral infarction damage after middle cerebral artery occlusion. The histopathology of cresyl violet-stained tissues was evaluated after reversible middle cerebral artery occlusion (2 hours, followed by 22 hours of reperfusion) in ERalphaKO transgenic and wild-type (WT) mice (C57BL/6J background strain). End-ischemic cerebral blood flow mapping was obtained from additional female murine cohorts by using [(14)C]iodoantipyrine autoradiography. Total hemispheric tissue damage was not altered by ERalpha deficiency in female mice: 51.9+/-10.6 mm(3) in ERalphaKO versus 60.5+/-5.0 mm(3) in WT. Striatal infarction was equivalent, 12.2+/-1.7 mm(3) in ERalphaKO and 13.4+/-1.0 mm(3) in WT mice, but cortical infarction was paradoxically smaller relative to that of the WT (20.7+/-4.5 mm(3) in ERalphaKO versus 30.6+/-4.1 mm(3) in WT). Intraocclusion blood flow to the parietal cortex was higher in ERalphaKO than in WT mice, likely accounting for the reduced infarction in this anatomic area. There were no differences in stroke outcomes by region or genotype in male animals. Loss of ERalpha does not enhance tissue damage in the female animal, suggesting that estrogen inhibits brain injury by mechanisms that do not depend on activation of this receptor subtype.


The Ethics of Supernumerary Robotic Limbs. An Enactivist Approach.
Supernumerary robotic limbs are innovative devices in the field of wearable robotics which can provide humans with unprecedented sensorimotor abilities. However, scholars have raised awareness of the ethical issues that would arise from the large adoption of technologies for human augmentation in society. Most negative attitudes towards such technologies seem to rely on an allegedly clear distinction between therapy and enhancement in the use of technological devices. Based on such distinction, people tend to accept technologies when used for therapeutic purposes (e.g., prostheses), but tend to raise issues when similar devices are used for upgrading a physical or cognitive ability (e.g., supernumerary robotics limbs). However, as many scholars have pointed out, the distinction between therapy and enhancement might be theoretically flawed. In this paper, we present an alternative approach to the ethics of supernumerary limbs which is based on two related claims. First, we propose to conceive supernumerary limbs as tools that necessarily modify our psychological and bodily identity. At the same time, we stress that such a modification is not ethically bad in itself; on the contrary, it drives human interaction with the environment. Second, by comparing our view with the extended mind thesis, we claim that the mediation through tools is crucial for the formation of novel meanings and skills that constitute human interaction with the world. We will relate the latter claim to enactivism as a helpful theoretical perspective to frame issues related to artificial limbs and, more in general, to technologies for augmentation. Based on this approach, we finally sketch some suggestions for future directions in the ethics of supernumerary limbs.


Origins of the current outbreak of multidrug-resistant malaria in southeast Asia: a retrospective genetic study.
Antimalarial resistance is rapidly spreading across parts of southeast Asia where dihydroartemisinin-piperaquine is used as first-line treatment for Plasmodium falciparum malaria. The first published reports about resistance to antimalarial drugs came from western Cambodia in 2013. Here, we analyse genetic changes in the P falciparum population of western Cambodia in the 6 years before those reports. We analysed genome sequence data on 1492 P falciparum samples from 11 locations across southeast Asia, including 464 samples collected in western Cambodia between 2007 and 2013. Different epidemiological origins of resistance were identified by haplotypic analysis of the kelch13 artemisinin resistance locus and the plasmepsin 2-3 piperaquine resistance locus. We identified more than 30 independent origins of artemisinin resistance, of which the KEL1 lineage accounted for 140 (91%) of 154 parasites resistant to dihydroartemisinin-piperaquine. In 2008, KEL1 combined with PLA1, the major lineage associated with piperaquine resistance. By 2013, the KEL1/PLA1 co-lineage had reached a frequency of 63% (24/38) in western Cambodia and had spread to northern Cambodia. The KEL1/PLA1 co-lineage emerged in the same year that dihydroartemisinin-piperaquine became the first-line antimalarial drug in western Cambodia and spread rapidly thereafter, displacing other artemisinin-resistant parasite lineages. These findings have important implications for management of the global health risk associated with the current outbreak of multidrug-resistant malaria in southeast Asia. Wellcome Trust, Bill & Melinda Gates Foundation, Medical Research Council, UK Department for International Development, and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases.


Delivery of replication-competent retrovirus expressing Escherichia coli purine nucleoside phosphorylase increases the metabolism of the prodrug, fludarabine phosphate and suppresses the growth of bladder tumor xenografts.
We have developed unique replication-competent retroviral (RCR) vectors based on murine leukemia virus that provide improved efficiency of viral delivery, allow for long-term transgene expression and demonstrate an intrinsic selectivity for transduction of rapidly dividing tumor cells. The purpose of this study was to evaluate the in vivo transduction efficiency and the therapeutic efficacy of the RCR vector mediated delivery of Escherichia coli purine nucleoside phosphorylase (PNP) in combination with fludarabine phosphate for bladder cancer. We constructed vectors containing green fluorescent protein (GFP) gene (ACE)-GFP) or PNP gene (ACE-PNP). KU-19-19 bladder tumors exhibited 28.3+/-16.1, 46.6+/-5.8 and 93.7+/-7.8% of GFP expression on 14, 18 and 26 days after intratumoral injection of ACE-GFP, respectively. GFP expression could not be observed in normal tissues surrounding the injected tumors. No detectable polymerase chain reaction products of GFP gene could be observed in any distant organs. Intratumoral injection of ACE-PNP, followed by systemically administered fludarabine phosphate, significantly inhibited the growth of pre-established KU-19-19 tumors. Our results indicate that RCR vectors are a potentially efficient gene delivery method and that the RCR vector mediated PNP gene transfer and fludarabine phosphate treatment might be a novel and potentially therapeutic modality for bladder cancer.


Graph theoretical analysis of functional brain networks: test-retest evaluation on short- and long-term resting-state functional MRI data.
Graph-based computational network analysis has proven a powerful tool to quantitatively characterize functional architectures of the brain. However, the test-retest (TRT) reliability of graph metrics of functional networks has not been systematically examined. Here, we investigated TRT reliability of topological metrics of functional brain networks derived from resting-state functional magnetic resonance imaging data. Specifically, we evaluated both short-term (<1 hour apart) and long-term (>5 months apart) TRT reliability for 12 global and 6 local nodal network metrics. We found that reliability of global network metrics was overall low, threshold-sensitive and dependent on several factors of scanning time interval (TI, long-term>short-term), network membership (NM, networks excluding negative correlations>networks including negative correlations) and network type (NT, binarized networks>weighted networks). The dependence was modulated by another factor of node definition (ND) strategy. The local nodal reliability exhibited large variability across nodal metrics and a spatially heterogeneous distribution. Nodal degree was the most reliable metric and varied the least across the factors above. Hub regions in association and limbic/paralimbic cortices showed moderate TRT reliability. Importantly, nodal reliability was robust to above-mentioned four factors. Simulation analysis revealed that global network metrics were extremely sensitive (but varying degrees) to noise in functional connectivity and weighted networks generated numerically more reliable results in compared with binarized networks. For nodal network metrics, they showed high resistance to noise in functional connectivity and no NT related differences were found in the resistance. These findings provide important implications on how to choose reliable analytical schemes and network metrics of interest.


Opposite effects of bone marrow-derived cells transplantation in MPTP-rat model of Parkinson's disease: a comparison study of mononuclear and mesenchymal stem cells.
The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model is a useful tool to study Parkinson's disease (PD) and was used in the present study to investigate the potential beneficial as well as deleterious effects of systemic bone-marrow mononuclear cell (BMMC) or mesenchymal stem cell (BM-MSC) transplantation. MPTP administration resulted in a breakdown of the blood-brain barrier and motor impairment in the open field test 24 h after surgery. Three and 7 days after receiving the lesion, the injured animals showed remaining motor impairment compared to the sham groups along with a significant loss of tyrosine hydroxylase-immunoreactive (TH-ir) cells in the substantia nigra pars compacta (SNpc). The MPTP-lesioned rats treated with BMMCs immediately after lesioning exhibited motor impairment similar to the MPTP-saline group, though they presented a significantly higher loss of TH-ir cells in the SNpc compared to the MPTP-saline group. This increased loss of TH-ir cells in the SNpc was not observed when BMMC transplantation was performed 24 h after MPTP administration. In contrast, in the MPTP animals treated early with systemic BM-MSCs, no loss of TH-ir cells was observed. BMMCs and BM-MSCs previously labeled with CM-DiI cell tracker were found in brain sections of all transplanted animals. In addition, cells expressing CD45, an inflammatory white blood cell marker, were found in all brain sections analyzed and were more abundant in the MPTP-BMMC animals. In these animals, Iba1+ microglial cells showed also marked morphological changes indicating increased microglial activation. These results show that systemic BMMC transplantation did not ameliorate or prevent the lesion induced by MPTP. Instead, BMMC transplantation in MPTP-lesioned rats accelerated dopaminergic neuronal damage and induced motor impairment and immobility behavior. These findings suggest that caution should be taken when considering cell therapy using BMMCs to treat PD. However, systemic BM-MSC transplantation that reaches the injury site and prevents neuronal damage after an MPTP infusion could be considered as a potential treatment for PD during the early stage of disease development.


Studies on the anti-inflammatory action of 6-mercaptopurine.
The mechanism of action of 6-mercaptopurine (6-MP) on an egg albumin-induced inflammatory lesion in the skin has been studied in rabbits treated with 6-MP in a daily dosage of 18 mg/kg. Relative to control animals, significant decreases in the numbers of large lymphocytes and monocytes in the blood were observed in the 6-MP-treated animals by the 9th day of treatment, without significant decrease in the numbers of polymorphonuclear leukocytes and small and medium lymphocytes. Concurrently, a significant decrease was also seen in the percentage of tissue mononuclear cells in the inflammatory skin lesion. There was a highly significant correlation between the numbers of monocytes in the blood and the per cent of mononuclear cells in the lesion. A mean of 52% of the mononuclear cells in the tissue lesion phagocytosed carbon offering further evidence that the major cell involved was the blood monocyte. In vitro incorporation of (3)H-Tdr by blood mononuclear cells was significantly reduced in the 6-MP-treated animals as determined by scintillation counting and radioautography. The large lymphocyte was the predominant cell type which was labeled in vitro. Small lymphocytes and monocytes were rarely labeled. The data obtained suggest that the anti-inflammatory effect of 6-MP, reflected in these experiments by a decrease in mononuclear cells in a tissue lesion, results from suppression of a bone marrow response to local inflammation, affecting principally proliferating precursors of blood monocytes and large lymphocytes. The possible importance of this action of 6-MP in the treatment of inflammatory and immunologically mediated disease is discussed.


Predicting onset of drinking in a community sample of adolescents: the role of expectancy and temperament.
We report results of a prospective examination of the influence of outcome expectancy variables and inherited temperaments on the onset of drinking over a 12-month period in a sample of 1,164 high school students. While univariate prospective analysis indicated that drinkers and nondrinkers were different both on measures of outcome expectancy and temperament, multivariate analysis supported, most strongly, a social learning account of the processes influencing the onset and maintenance of drinking behavior in this sample. The multivariate analysis revealed that only expectancies for enhanced social behavior were consistently associated with the onset of drinking from baseline to 12-month follow-up (p < .001). Among all nondrinkers at baseline, those entertaining higher expectancies about the positive effects of alcohol on social interaction were more likely to begin drinking between baseline and follow-up. At present, few, if any, alcohol abuse prevention studies with adolescents have explicitly attempted to alter alcohol expectancies or to establish a link between expectancy and behavior change. Our results suggest that it may be useful to do so.


Neighborhood matters: divergent patterns of stress-induced plasticity across the brain.
The fact that exposure to severe stress leads to the development of psychiatric disorders serves as the basic rationale for animal models of stress disorders. Clinical and neuroimaging studies have shown that three brain areas involved in learning and memory--the hippocampus, amygdala and prefrontal cortex--undergo distinct structural and functional changes in individuals with stress disorders. These findings from patient studies pose several challenges for animal models of stress disorders. For instance, why does stress impair cognitive function, yet enhance fear and anxiety? Can the same stressful experience elicit contrasting patterns of plasticity in the hippocampus, amygdala and prefrontal cortex? How does even a brief exposure to traumatic stress lead to long-lasting behavioral abnormalities? Thus, animal models of stress disorders must not only capture the unique spatio-temporal features of structural and functional alterations in these brain areas, but must also provide insights into the underlying neuronal plasticity mechanisms. This Review will address some of these key questions by describing findings from animal models on how stress-induced plasticity varies across different brain regions and thereby gives rise to the debilitating emotional and cognitive symptoms of stress-related psychiatric disorders.


Expression of the forkhead box transcription factor FOXP1 is associated with oestrogen receptor alpha, oestrogen receptor beta and improved survival in familial breast cancers.
The role of FOXP1 in sporadic breast cancers has been widely studied but its role in familial breast cancers is yet unexplored. To investigate FOXP1 expression in different molecular subtypes of familial breast cancers and to correlate its expression with clinicopathological parameters, oestrogen receptors (ER) and survival. Immunohistochemical staining for FOXP1 was performed in 126 familial breast carcinomas comprising 35 BRCA1, 34 BRCA2 and 57 BRCAX. Nuclear FOXP1 expression ranged from focal weak to widespread strong expression. Expression of FOXP1 was higher in familial breast cancers (54%) compared with sporadic cancers (46%) (p<0.001). There was a significant correlation between FOXP1 with ERalpha (p = 0.038) and ERbeta (p = 0.007) in familial breast cancers. FOXP1 was more highly expressed in familial breast cancers compared with sporadic cancers for luminal (p = 0.021) and basal (p<0.001), but not HER2 and null phenotypes (both p>0.05). The absence of FOXP1 expression was associated with a shorter relapse-free (p = 0.025) and overall survival (p = 0.009) in familial breast cancer. Negativity for FOXP1 was associated with a significantly worse overall survival in BRCA2 cancers (p = 0.021) and there was a non-significant separation of the survival curves for BRCA1 cancers (p = 0.183). No differences in survival were seen for BRCAX cancers (p = 0.762). Results suggest that FOXP1 demonstrates different expression patterns in familial breast cancers than sporadic tumours, even in tumours showing similar phenotypes. They also suggest a different role of FOXP1 as a tumour suppressor in familial tumours, which is unrelated to ER expression and may impact on therapeutic options.


Prevention of type 2 diabetes in subjects with prediabetes and metabolic syndrome treated with phentermine and topiramate extended release.
OBJECTIVE To evaluate over 108 weeks the effect of phentermine and topiramate extended release (PHEN/TPM ER) treatment on progression to type 2 diabetes and/or cardiometabolic disease in subjects with prediabetes and/or metabolic syndrome (MetS) at baseline. RESEARCH DESIGN AND METHODS Subanalysis of a phase 3, randomized, placebo-controlled, double-blind study of overweight/obese subjects (BMI ≥27 to ≤45 kg/m(2)) with two or more comorbidities. Subjects were randomized to placebo, PHEN 7.5 mg/TPM ER 46 mg (7.5/46), or PHEN 15 mg/TPM ER 92 mg (15/92) plus lifestyle modifications for 108 weeks. Percent weight loss in the intent-to-treat population using multiple imputation (ITT-MI), annualized incidence rate of progression to type 2 diabetes, and changes in glycemia, lipid parameters, blood pressure, and waist circumference were evaluated. RESULTS At baseline, 475 subjects met the criteria for prediabetes and/or MetS. After 108 weeks, subjects with prediabetes and/or MetS in the placebo, 7.5/46, and 15/92 groups experienced mean percent weight loss of 2.5, 10.9, and 12.1%, respectively (ITT-MI; P < 0.0001 vs. placebo), associated with reductions of 70.5 and 78.7% in the annualized incidence rate of type 2 diabetes for those receiving 7.5/46 and 15/92, respectively (ITT, P < 0.05), versus placebo. The ability of PHEN/TPM ER to prevent diabetes was related to degree of weight lost and was accompanied by significant improvements in cardiometabolic parameters. PHEN/TPM ER was well tolerated by this subgroup over 2 years. CONCLUSIONS PHEN/TPM ER plus lifestyle modification produced significant weight loss and markedly reduced progression to type 2 diabetes in overweight/obese patients with prediabetes and/or MetS, accompanied by improvements in multiple cardiometabolic disease risk factors.


Electronically controlled optical beam-steering by an active phased array of metallic nanoantennas.
An optical phased array of nanoantenna fabricated in a CMOS compatible silicon photonics process is presented. The optical phased array is fed by low loss silicon waveguides with integrated ohmic thermo-optic phase shifters capable of 2π phase shift with ∼ 15 mW of applied electrical power. By controlling the electrical power to the individual integrated phase shifters fixed wavelength steering of the beam emitted normal to the surface of the wafer of 8° is demonstrated for 1 × 8 phased arrays with periods of both 6 and 9 μm.


Therapeutic Advances and New Directions for Triple-Negative Breast Cancer.
Triple-negative breast cancer (TNBC) is a molecularly diverse grouping with poor prognosis for which chemotherapy remains the foundation of treatment. The molecular heterogeneity of the disease rationalizes its diverse biological behavior and differential response to treatment. Estimates of up to 20% of patients diagnosed have germline mutations in DNA-damage repair-pathway genes, namely BRCA1 and 2, and this can be used to select patients likely to respond to platinums and/or inhibitors of poly(ADP-ribose) polymerase (PARP). Similar strategies can be utilized in other subtypes of TNBC that have 'BRCA-like' tumor biology due to the presence of mutations in alternate DNA-damage repair genes. The diverse biological behavior of TNBC and its variable response to chemotherapy were largely decoded following genotyping studies that enabled the identification of distinct molecular subtypes, such that the biological and genetic heterogeneity of the disease could be understood. This subsequently enabled the identification of therapeutic 'vulnerabilities' for each subtype that encompass biological processes including proliferation, DNA repair, apoptosis, angiogenesis, immune modulation, and invasion and metastasis. To expedite the development of therapies for high-risk, early-stage breast cancer, we have adopted novel trial designs and re-defined endpoints as surrogates of clinical outcomes. The purpose of this review is to highlight the current standard and experimental treatment options for TNBC.


Trigeminal neuralgia related to megadolichobasilar artery compression: a prospective series of twenty-nine patients treated with gamma knife surgery, with more than one year of follow-up.
Trigeminal neuralgia (TN) secondary to megadolichobasilar artery (MBA) compression is considerably difficult to manage surgically. This study aims to evaluate the safety/efficacy of Gamma Knife surgery (GKS) in this special group of patients. Between July 1992 and November 2010, 29 patients with >1 year of follow-up presenting with MBA compression were treated with GKS at Timone University Hospital. Radiosurgery was performed using a Gamma Knife (model B, C or Perfexion). A single 4-mm isocenter was positioned in the cisternal portion of the trigeminal nerve at a median distance of 9.1 mm (range: 6-18.2 mm) from the emergence. The median follow-up period was 46.1 months (range: 12.9-157.9 months). Initially, all patients (100%) were pain free; the average time to complete pain relief was 13.5 days (range: 0-240 days). Their actuarial probability of remaining pain free without medication at 0.5, 1 and 2 years was 93.1, 79.3 and 75.7%, respectively, and remained stable until 13 years after treatment. The actuarial probability of hypoesthesia onset at 6 months was 4.3%; at 1 year it reached 13% and remained stable until 13 years after treatment. GKS proved to be reasonably safe and effective on a long-term basis as a first- and/or second-line surgical treatment for TN due to MBA compression.


Characterizing causality in cancer.
Philosophers have explored the concept of causality for centuries. Here we argue that ideas about causality from philosophy can help scientists to better understand how cancerous tumors grow and spread in the body. After outlining six characteristics of causality that are relevant to cancer, we emphasize the importance of feedback loops and interactions between tumor-cell-intrinsic and tumor-cell-extrinsic factors for explaining the formation and dissemination of tumors.


Altered expression of zonula occludens-2 precedes increased blood-brain barrier permeability in a murine model of fulminant hepatic failure.
Brain edema secondary to increased blood-brain barrier (BBB) permeability is a lethal complication in fulminant hepatic failure (FHF). Intact tight junctions (TJ) between brain capillary endothelial cells are critical for normal BBB function. However, the role of TJ in FHF has not been explored. We hypothesized that alterations in the composition of TJ proteins would result in increased BBB permeability in FHF. In this study, FHF was induced in C57BL/6J mice by using azoxymethane. BBB permeability was assessed with sodium fluorescein. Expression of TJ proteins was determined by Western blot, and their cellular distribution was examined using immunofluorescent microscopy. Comatose FHF mice had significant cerebral sodium fluorescein extravasation compared with control and precoma FHF mice, indicating increased BBB permeability. Western blot analysis showed a significant decrease in zonula occludens (ZO)-2 expression starting in the precoma stage. Immunofluorescent microscopy showed a significantly altered distribution pattern of ZO-2 in isolated microvessels from precoma FHF mice. These changes were more prominent in comatose FHF animals. Significant alterations in ZO-2 expression and distribution in the tight junctions preceded the increased BBB permeability in FHF mice. These results suggest that ZO-2 may play an important role in the pathogenesis of brain edema in FHF.


Thrombotic antiphospholipid syndrome shows strong haplotypic association with SH2B3-ATXN2 locus.
Thrombotic antiphospholipid syndrome is defined as a complex form of thrombophilia that is developed by a fraction of antiphospholipid antibody (aPLA) carriers. Little is known about the genetic risk factors involved in thrombosis development among aPLA carriers. To identify new loci conferring susceptibility to thrombotic antiphospholipid syndrome, a two-stage genotyping strategy was performed. In stage one, 19,000 CNV loci were genotyped in 14 thrombotic aPLA+ patients and 14 healthy controls by array-CGH. In stage two, significant CNV loci were fine-mapped in a larger cohort (85 thrombotic aPLA+, 100 non-thrombotic aPLA+ and 569 healthy controls). Array-CGH and fine-mapping analysis led to the identification of 12q24.12 locus as a new susceptibility locus for thrombotic APS. Within this region, a TAC risk haplotype comprising one SNP in SH2B3 gene (rs3184504) and two SNPs in ATXN2 gene (rs10774625 and rs653178) exhibited the strongest association with thrombotic antiphospholipid syndrome (p-value = 5,9 × 10(-4) OR 95% CI 1.84 (1.32-2.55)). The presence of a TAC risk haplotype in ATXN2-SH2B3 locus may contribute to increased thrombotic risk in aPLA carriers.


Evaluation of primary care patients with chronic stable angina: guidelines from the American College of Physicians.
In 1999, the American College of Physicians (ACP), then the American College of Physicians-American Society of Internal Medicine, and the American College of Cardiology/American Heart Association (ACC/AHA) developed joint guidelines on the management of patients with chronic stable angina. The ACC/AHA then published an updated guideline in 2002, which the ACP recognized as a scientifically valid review of the evidence and background paper. This ACP guideline summarizes the recommendations of the 2002 ACC/AHA updated guideline and underscores the recommendations most likely to be important to physicians seeing patients in the primary care setting. This guideline is the first of 2 that will provide guidance on the management of patients with chronic stable angina. This document will cover diagnosis and risk stratification for symptomatic patients who have not had an acute myocardial infarction or revascularization procedure in the previous 6 months. Sections addressing asymptomatic patients are also included. Asymptomatic refers to patients with known or suspected coronary disease based on history or on electrocardiographic evidence of previous myocardial infarction, coronary angiography, or abnormal results on noninvasive tests. A future guideline will cover pharmacologic therapy and follow-up.


Current concepts about chromium supplementation in type 2 diabetes and insulin resistance.
Chromium has been established to be an essential trace element in mammals in regard to maintenance of normal carbohydrate metabolism. Studies that provided chromium to human subjects in documented deficiency states noted improved glucose levels. However, controversy exists as to whether dietary supplementation with chromium should be routinely recommended in subjects without documented deficiencies. Over the recent past, several well-designed clinical trials have provided evidence in favor of and against a beneficial effect of chromium. It appears that across all subject phenotypes (eg, lean and obese, insulin sensitive and insulin resistant), a consistent significant and beneficial effect of chromium may not be observed. Specifically, recent data fail to demonstrate significant improvement in carbohydrate metabolism in individuals with metabolic syndrome, impaired glucose tolerance, or consistently in individuals with type 2 diabetes. However, patient selection may be an important factor in determining clinical response, as it was concluded that a clinical response to chromium (ie, decreased glucose and improved insulin sensitivity) may be more likely in insulin-resistant individuals with type 2 diabetes who have more elevated fasting glucose and hemoglobin A(1c) levels.


Acquired protein S deficiency leads to obliterative portal venopathy and to compensatory nodular regenerative hyperplasia in HIV-infected patients.
To identify the mechanism of nodular regenerative hyperplasia in HIV-infected patients. Case-control study. The hepatology and the infectious disease units of two tertiary care centers in France. We compared 13 consecutive HIV-positive patients with unexplained nodular regenerative hyperplasia to 16 consecutive HIV-positive patients without nodular regenerative hyperplasia, to eight HIV-negative patients with nodular regenerative hyperplasia from an identified cause and to 10 anonymous healthy blood donors. Patients and controls were screened for diminished protein S activity and antiprotein S immunoglobulin G (IgG) antibodies. The antiprotein S activity of purified IgG from patients and controls was assessed in a functional test of activation of protein C in which protein S serves as a cofactor. A full liver CT portography was realized on the liver explant of a case patient. The CT portography disclosed diffuse obliterative portal venopathy. Levels of protein S activity were lower among patients with HIV-associated nodular regenerative hyperplasia when compared with HIV-positive patients without nodular regenerative hyperplasia and when compared with HIV-negative patients with nodular regenerative hyperplasia (P < 0.005 for all comparisons). HIV-positive patients with nodular regenerative hyperplasia had significantly higher levels of antiprotein S IgG than HIV-positive patients without nodular regenerative hyperplasia and healthy controls. Purified IgG from patients with HIV-associated nodular regenerative hyperplasia specifically inhibited the protein S-dependent protein C activation. Acquired autoimmune protein S paucity and secondary thrombophilia appear to be causes of obliterative portal venopathy and compensatory nodular regenerative hyperplasia in HIV-positive patients.


Association Between Systemic Hypertension and Macular Thickness Measured by Optical Coherence Tomography.
This study aimed to evaluate an association between hypertension and macular thickness. A total of 827 Korean adults composed of 163 pairs of twins and their family members were included in this population-based cross-sectional study. Macular thickness was measured with optical coherence tomography at nine macular subfields defined by the Early Treatment of Diabetic Retinopathy Study. Cardiometabolic risk factors, including body mass index (BMI), hypertension, diabetes, lipid profiles, and smoking status, were assessed. Linear mixed regression analysis was conducted with consideration of familial correlations and adjustment for covariates. Age-, sex-, and axial length-adjusted analysis showed that systemic hypertension was associated with a significant change in macular thickness in most subfields except for the fovea. Compared with normotensive subjects, macular thickness was lower in subjects with systemic hypertension (P ≤ 0.05), with the highest difference (2.52%) in the outer temporal region and the lowest difference (1.44%) in the inner temporal region. This association persisted even after adjusting for other cardiometabolic risk factors. Other cardiometabolic risk factors were not independently associated with macular thickness in any subfields. Stratified analysis showed that the inverse association between macular thickness and hypertension was stronger in the group with elevated fasting glucose compared with the group with normal fasting glucose (P for interaction ≤ 0.05). Systemic hypertension was inversely associated with macular thickness in most macular subfields, particularly in subjects with an elevated fasting glucose level. This finding suggests that it may be necessary to consider the presence of hypertension when macular thickness and pericentral macular area volume are evaluated.


Population genomics of pearl millet (Pennisetum glaucum (L.) R. Br.): Comparative analysis of global accessions and Senegalese landraces.
Pearl millet is a staple food for people in arid and semi-arid regions of Africa and South Asia due to its high drought tolerance and nutritional qualities. A better understanding of the genomic diversity and population structure of pearl millet germplasm is needed to support germplasm conservation and genetic improvement of this crop. Here we characterized two pearl millet diversity panels, (i) a set of global accessions from Africa, Asia, and the America, and (ii) a collection of landraces from multiple agro-ecological zones in Senegal. We identified 83,875 single nucleotide polymorphisms (SNPs) in 500 pearl millet accessions, comprised of 252 global accessions and 248 Senegalese landraces, using genotyping by sequencing (GBS) of PstI-MspI reduced representation libraries. We used these SNPs to characterize genomic diversity and population structure among the accessions. The Senegalese landraces had the highest levels of genetic diversity (π), while accessions from southern Africa and Asia showed lower diversity levels. Principal component analyses and ancestry estimation indicated clear population structure between the Senegalese landraces and the global accessions, and among countries in the global accessions. In contrast, little population structure was observed across in the Senegalese landraces collections. We ordered SNPs on the pearl millet genetic map and observed much faster linkage disequilibrium (LD) decay in Senegalese landraces compared to global accessions. A comparison of pearl millet GBS linkage map with the foxtail millet (Setaria italica) and sorghum (Sorghum bicolor) genomes indicated extensive regions of synteny, as well as some large-scale rearrangements in the pearl millet lineage. We identified 83,875 SNPs as a genomic resource for pearl millet improvement. The high genetic diversity in Senegal relative to other regions of Africa and Asia supports a West African origin of this crop, followed by wide diffusion. The rapid LD decay and lack of confounding population structure along agro-ecological zones in Senegalese pearl millet will facilitate future association mapping studies. Comparative population genomics will provide insights into panicoid crop evolution and support improvement of these climate-resilient crops.


Laser-speckle-based detection of fluid pulsation in the presence of motion artifacts: in vitro and in vivo study.
We have performed an in vitro and in vivo study, based on laser speckle contrast analysis, to detect fluid pulsation in the presence of artifacts caused by the relative motion between the sample and the illumination source. We observe that the pulsation signal is clearly detectable for a range of motion amplitudes and oscillation frequencies; however, for higher amplitudes and oscillation frequencies of motion, the signal, due to pulsation, becomes increasingly difficult to detect.


The history of natural progesterone, the never-ending story.
The term progesterone should only be used for the natural hormone produced by the ovaries or included in a registered drug. The modern history of progesterone begins with the first book-length description of the female reproductive system including the corpus luteum and later with the Nobel Prize winner, Adolf Butenandt who took a crucial step when he succeeded in converting pregnanediol into a chemically pure form of progesterone, the corpus luteum hormone. The deficient production of progesterone was shown first to be the cause of the luteal-phase deficiency responsible for infertility and early pregnancy loss due to inadequate secretory transformation of the endometrium. Later, progesterone was confirmed to be the best and safest method of providing luteal-phase support in assisted reproductive technology. Progesterone provides adequate endometrial protection and is suggested to be the optimal progestagen in menopausal hormone therapy in terms of cardiovascular effects, venous thromboembolism, probably stroke and even breast cancer risk. Neuroprotective effects of progesterone have also been demonstrated in several of experimental models including cerebral ischemic stroke and Alzheimer's disease. Vaginal progesterone was shown to decrease the risk of preterm birth in women with a mid-trimester sonographic short cervix and to improve perinatal outcomes in singleton and twin gestations.


Serotonin syndrome in a postoperative patient.
Depression is common in patients with ischemic heart disease. According to mental health surveys, approximately one-fifth of the patients with angiographic evidence of coronary artery disease have major depression.[1] It is well-recognized that stigma associated with mental disorders leads to individuals avoiding treatment or concealing treatment for them. We report a case of serotonin syndrome that occurred during postoperative period in a patient who underwent coronary artery bypass grafting. The patient was receiving 60 mg/day fluoxetine for the last 4 years, which she and her attendants concealed during the preoperative evaluation. To our knowledge this is the first case of serotonin syndrome, reported in biomedical literature, in a postoperative patient. We suggest that history taking should also focus on antidepressant drug intake by patients. If serotonin syndrome occurs in such patients aggressive and timely management can help avert mortality.


Molecular conductance: chemical trends of anchoring groups.
Combining density functional theory calculations for molecular electronic structure with a Green function method for electron transport, we calculate from first principles the molecular conductance of benzene connected to two Au leads through different anchoring atoms-S, Se, and Te. The relaxed atomic structure of the contact, different lead orientations, and different adsorption sites are fully considered. We find that the molecule-lead coupling, electron transfer, and conductance all depend strongly on the adsorption site, lead orientation, and local contact atomic configuration. For flat contacts the conductance decreases as the atomic number of the anchoring atom increases, regardless of the adsorption site, lead orientation, or bias. For small bias this chemical trend is, however, dependent on the contact atomic configuration: an additional Au atom at the contact with the (111) lead changes the best anchoring atom from S to Se, although for large bias the original chemical trend is recovered.


Retrospective correction of nonuniform illumination on bi-level images.
We propose a novel method for correcting the effect of nonuniform illumination on a bi-level image. The proposed method is based on a penalized nonlinear least squares objective function that measures the binariness of an image and the roughness of illumination. Compared with conventional methods, it has the advantages of 1) not suffering from a trivial minimizer, 2) not requiring tuning of design parameters, and 3) effective optimization. In addition, it yields a unique solution since the minimization of the objective function is well-posed. In simulations and experiments, the method showed better accuracy and speed than the conventional entropy-based method.


Matrix metalloproteinase-9 degrades amyloid-beta fibrils in vitro and compact plaques in situ.
The pathological hallmark of Alzheimer disease is the senile plaque principally composed of tightly aggregated amyloid-beta fibrils (fAbeta), which are thought to be resistant to degradation and clearance. In this study, we explored whether proteases capable of degrading soluble Abeta (sAbeta) could degrade fAbeta as well. We demonstrate that matrix metalloproteinase-9 (MMP-9) can degrade fAbeta and that this ability is not shared by other sAbeta-degrading enzymes examined, including endothelin-converting enzyme, insulin-degrading enzyme, and neprilysin. fAbeta was decreased in samples incubated with MMP-9 compared with other proteases, assessed using thioflavin-T. Furthermore, fAbeta breakdown with MMP-9 but not with other proteases was demonstrated by transmission electron microscopy. Proteolytic digests of purified fAbeta were analyzed with matrix-assisted laser desorption ionization time-of-flight mass spectrometry to identify sites of Abeta that are cleaved during its degradation. Only MMP-9 digests contained fragments (Abeta(1-20) and Abeta(1-30)) from fAbeta(1-42) substrate; the corresponding cleavage sites are thought to be important for beta-pleated sheet formation. To determine whether MMP-9 can degrade plaques formed in vivo, fresh brain slices from aged APP/PS1 mice were incubated with proteases. MMP-9 digestion resulted in a decrease in thioflavin-S (ThS) staining. Consistent with a role for endogenous MMP-9 in this process in vivo, MMP-9 immunoreactivity was detected in astrocytes surrounding amyloid plaques in the brains of aged APP/PS1 and APPsw mice, and increased MMP activity was selectively observed in compact ThS-positive plaques. These findings suggest that MMP-9 can degrade fAbeta and may contribute to ongoing clearance of plaques from amyloid-laden brains.


Improvement of drug dose calculations by classroom teaching or e-learning: a randomised controlled trial in nurses.
Insufficient skills in drug dose calculations increase the risk for medication errors. Even experienced nurses may struggle with such calculations. Learning flexibility and cost considerations make e-learning interesting as an alternative to classroom teaching. This study compared the learning outcome and risk of error after a course in drug dose calculations for nurses with the two methods. In a randomised controlled open study, nurses from hospitals and primary healthcare were randomised to either e-learning or classroom teaching. Before and after a 2-day course, the nurses underwent a multiple choice test in drug dose calculations: 14 tasks with four alternative answers (score 0-14), and a statement regarding the certainty of each answer (score 0-3). High risk of error was being certain that incorrect answer was correct. The results are given as the mean (SD). 16 men and 167 women participated in the study, aged 42.0 (9.5) years with a working experience of 12.3 (9.5) years. The number of correct answers after e-learning was 11.6 (2.0) and after classroom teaching 11.9 (2.0) (p=0.18, NS); improvement were 0.5 (1.6) and 0.9 (2.2), respectively (p=0.07, NS). Classroom learning was significantly superior to e-learning among participants with a pretest score below 9. In support of e-learning was evaluation of specific value for the working situation. There was no difference in risk of error between groups after the course (p=0.77). The study showed no differences in learning outcome or risk of error between e-learning and classroom teaching in drug dose calculations. The overall learning outcome was small. Weak precourse knowledge was associated with better outcome after classroom teaching.


Occupational therapy students' perspectives on occupation as an agent that promotes healthful lifestyles.
This study was conducted to determine occupational therapy students' perspectives on occupation as an agent that promotes healthful lifestyles, what factors influence these perspectives, and the extent to which formal classroom instruction in occupation as a health-promoting agent influenced their perspective transformation. Through a precourse and postcourse survey, weekly log sheets, and audiotaped class discussions, data regarding attitudes and beliefs about health promotion were collected from 23 occupational therapy master's students enrolled in the course Wellness Through Occupation. The data were analyzed with a priori concept coding to determine whether perspective transformation occurred as a result of formal classroom instruction. Participants indicated that family values, previous formal and informal instruction, and personal experience were the major factors that influenced their perspectives on occupation as an agent that promotes a healthful lifestyle. The results demonstrated that participants had a perspective transformation, which is the first step in the behavioral change process. Formal classroom instruction can be a factor in promoting healthful lifestyles through occupation. Such instruction can be an important step in empowering people to take responsibility for their own health.


Circadian sensitivity to the chemotherapeutic agent cyclophosphamide depends on the functional status of the CLOCK/BMAL1 transactivation complex.
The circadian clock controls many aspects of mammalian physiology, including responses to cancer therapy. We find that wild-type and circadian mutant mice demonstrate striking differences in their response to the anticancer drug cyclophosphamide (CY). While the sensitivity of wild-type mice varies greatly, depending on the time of drug administration, Clock mutant and Bmal1 knockout mice are highly sensitive to treatment at all times tested. On the contrary, mice with loss-of-function mutations in Cryptochrome (Cry1-/-Cry2-/- double knockouts) were more resistant to CY compared with their wild-type littermates. Thus, both time-of-day and allelic-dependent variations in response to chemotherapy correlate with the functional status of the circadian CLOCK/BMAL1 transactivation complex. Pharmacokinetic analysis of plasma concentration of different CY metabolites shows that, in contrast to the traditional view, circadian variations in drug sensitivity cannot be attributed to the changes in the rates of CY metabolic activation and/or detoxification. At the same time, mice of different circadian genotypes demonstrate significant differences in B cell responses to toxic CY metabolites: B cell survival/recovery rate was directly correlated with the in vivo drug sensitivity. Based on these results, we propose that the CLOCK/BMAL1 transcriptional complex affects the lethality of chemotherapeutic agents by modulating the survival of the target cells necessary for the viability of the organism.


Magnetic resonance imaging of the canine shoulder: an anatomic study.
To describe the normal anatomy of the soft tissue stabilizing components of the canine shoulder identified by magnetic resonance imaging (MRI) and to evaluate specific acquisition sequences and planes for observing structures of diagnostic interest. Descriptive study. Canine cadavers (n=3). T1-weighted, proton density fat saturation (PD), and T2(*)-weighted gradient echo (GE) MRI sequences were obtained in the sagittal, transverse, and dorsal planes of the left shoulder of 3 canine cadavers. After imaging, each shoulder was embedded and thin sectioned. The corresponding right shoulder was frozen and thick sectioned. The anatomic structures on the histologic and frozen thick sections were visually correlated with the MR images. The sagittal plane provided a longitudinal view of the bicep, infraspinatus, and supraspinatus tendons. The biceps, supraspinatus, infraspinatus, and subscapularis tendons, and the medial and lateral glenohumeral ligaments were identified in the transverse and dorsal planes. The dorsal plane allowed for the bicep tendon to be evaluated transversely as it passed over the humeral head. The GE sequence was more useful in identifying tendons and ligaments. The PD sequence was more helpful in identifying fluid accumulations in the joint and around tendons. The tendinous and ligamentous structures that stabilize the canine shoulder joint can be readily identified with MRI. MRI has the potential to be a useful tool in the diagnosis of canine soft tissue shoulder injuries.


Reconstructing the origins of human hepatitis viruses.
Infections with hepatitis B and C viruses (HBV, HCV) are widespread in human populations throughout the world, and are major causes of chronic liver disease and liver cancer. HBV, HCV and the related hepatitis G virus or GB virus C (referred to here as HGV/GBV-C) are capable of establishing persistent, frequently lifelong infections characterized by high levels of continuous replication. All three viruses show substantial genetic heterogeneity, which has allowed each to be classified into a number of distinct genotypes that have different geographical distributions and associations with different risk groups for infection. Information on their past transmission and epidemiology might be obtained by estimation of the time of divergence of the different genotypes of HCV, HBV and HGV/GBV-C using knowledge of their rates of sequence change. While information on the latter is limited to short observation periods and is therefore subject to considerable error and uncertainty, the relatively recent times of origin for genotype of each virus predicted by this method (HCV, 500-2000 years; HBV, 3000 years; HGV/GBV-C, 200 years) are quite incompatible with their epidemiological distributions in human populations. They also cannot easily be reconciled with the recent evidence for species-associated variants of HBV and HGV/GBV-C in a range of non-human primates. The apparent conservatism of viruses over long periods implied by their epidemiological distributions instead suggests that nucleotide sequence change may be subject to constraints peculiar to viruses with single-stranded genomes, or with overlapping reading frames that defy attempts to reconstruct evolution according to the principles of the 'molecular clock'. Large population sizes and intense selection pressures that optimize fitness may be additional factors that set virus evolution apart from that of their hosts.


Optical set-up for dynamic superposition of three laser beams for structuring and polishing applications.
Structuring by remelting is an innovative approach for structuring metallic surfaces with laser radiation, where no material is removed but reallocated while molten. Based on this remelting principle an innovative structuring technique is investigated, where laser beams are superposed. A melt pool is generated by a cw laser beam with constant feed rate. A pulsed laser is superposed onto the cw laser and evaporates a small amount of molten material and, therefore, generates vapour pressure, which shapes the melt pool surface. The solidification follows this newly shaped surface. For this process a new optical system was designed and built up, which allows the combination of cw and pulsed laser beams.


Intratissue surgery with 80 MHz nanojoule femtosecond laser pulses in the near infrared.
The use of 1 nanojoule near infrared 80 MHz femtosecond laser pulses for highly precise intratissue processing, in particular for intraocular refractive surgery, was evaluated. Destructive optical breakdown at TW/cm2 light intensities in a subfemtoliter intrastromal volume was obtained by diffraction-limited focussing with an 40x objective (N.A. 1.3) and beam scanning 50 to 140 microm below the epithelial surface. Using the same system at GW/cm2 intensities two-photon excited autofluorescence imaging was used to determine the target of interest and to visualize intraocular laser effects. Histological examination of laser-exposed porcine eyes reveal a minimum cut size below 1 microm without destructive effects to surrounding tissues.


Characterization of a Mannose-6-Phosphate Isomerase from Bacillus amyloliquefaciens and Its Application in Fructose-6-Phosphate Production.
The BaM6PI gene encoding a mannose-6-phosphate isomerase (M6PI, EC 126.96.36.199) was cloned from Bacillus amyloliquefaciens DSM7 and overexpressed in Escherichia coli. The enzyme activity of BaM6PI was optimal at pH and temperature of 7.5 and 70°C, respectively, with a kcat/Km of 13,900 s-1 mM-1 for mannose-6-phosphate (M6P). The purified BaM6PI demonstrated the highest catalytic efficiency of all characterized M6PIs. Although M6PIs have been characterized from several other sources, BaM6PI is distinguished from other M6PIs by its wide pH range and high catalytic efficiency for M6P. The binding orientation of the substrate M6P in the active site of BaM6PI shed light on the molecular basis of its unusually high activity. BaM6PI showed 97% substrate conversion from M6P to fructose-6-phosphate demonstrating the potential for using BaM6PI in industrial applications.


Assessment of a mussel as a metal bioindicator of coastal contamination: relationships between metal bioaccumulation and multiple biomarker responses.
This is the first study to use a multiple biomarker approach on the green-lipped mussel, Perna canaliculus to test its feasibility as a bioindicator of coastal metal contamination in New Zealand (NZ). Mussels were collected from six low intertidal sites varying in terms of anthropogenic impacts, within two regions (West Coast and Nelson) of the South Island of NZ. Trace elements, including arsenic (As), cadmium (Cd), copper (Cu), lead (Pb), nickel (Ni), and zinc (Zn), were measured in the gills, digestive gland, foot and mantle, and in the surface sediments from where mussels were collected. Metal levels in the sediment were relatively low and there was only one site (Mapua, Nelson) where a metal (Ni) exceeded the Australian and New Zealand Interim Sediment Quality Guideline values. Metal levels in the digestive gland were generally higher than those from the other tissues. A variety of biomarkers were assessed to ascertain mussel health. Clearance rate, a physiological endpoint, correlated with metal level in the tissues, and along with scope for growth, was reduced in the most contaminated site. Metallothionein-like protein content and catalase activity in the digestive gland, and catalase activity and lipid peroxidation in the gill, were also correlated to metal accumulation. Although there were few regional differences, the sampling sites were clearly distinguishable based on the metal contamination profiles and biomarker responses. P. canaliculus appears to be a useful bioindicator species for coastal habitats subject to metal contamination. In this study tissue and whole organism responses provided insight into the biological stress responses of mussels to metal contaminants, indicating that such measurements could be a useful addition to biomonitoring programmes in NZ.


Convergent Epigenetic Mechanisms Avoid Constitutive Expression of Immune Receptor Gene Subsets.
The gene pool encoding PRR and NLR immune receptors determines the ability of a plant to resist microbial infections. Basal expression of these genes is prevented by diverse mechanisms since their hyperactivity can be harmful. To approach the study of epigenetic control of PRR/NLR genes we here analyzed their expression in mutants carrying abnormal repressive 5-methyl cytosine (5-mC) and histone 3 lysine 9 dimethylation (H3K9me2) marks, due to lack of MET1, CMT3, MOM1, SUVH4/5/6, or DDM1. At optimal growth conditions, none of the mutants showed basal expression of the defense gene marker PR1, but all of them had greater resistance to Pseudomonas syringae pv. tomato than wild type plants, suggesting they are primed to stimulate immune cascades. Consistently, analysis of available transcriptomes indicated that all mutants showed activation of particular PRR/NLR genes under some growth conditions. Under low defense activation, 37 PRR/NLR genes were expressed in these plants, but 29 of them were exclusively activated in specific mutants, indicating that MET1, CMT3, MOM1, SUVH4/5/6, and DDM1 mediate basal repression of different subsets of genes. Some epigenetic marks present at promoters, but not gene bodies, could explain the activation of these genes in the mutants. As expected, suvh4/5/6 and ddm1 activated genes carrying 5-mC and H3K9me2 marks in wild type plants. Surprisingly, all mutants expressed genes harboring promoter H2A.Z/H3K27me3 marks likely affected by the chromatin remodeler PIE1 and the histone demethylase REF6, respectively. Therefore, MET1, CMT3, MOM1, SUVH4/5/6, and DDM1, together with REF6, seemingly contribute to the establishment of chromatin states that prevent constitutive PRR/NLR gene activation, but facilitate their priming by modulating epigenetic marks at their promoters.


Impact of Population Recruitment on the HIV Epidemics and the Effectiveness of HIV Prevention Interventions.
Mechanistic mathematical models are increasingly used to evaluate the effectiveness of different interventions for HIV prevention and to inform public health decisions. By focusing exclusively on the impact of the interventions, the importance of the demographic processes in these studies is often underestimated. In this paper, we use simple deterministic models to assess the effectiveness of pre-exposure prophylaxis in reducing the HIV transmission and to explore the influence of the recruitment mechanisms on the epidemic and effectiveness projections. We employ three commonly used formulas that correspond to constant, proportional and logistic recruitment and compare the dynamical properties of the resulting models. Our analysis exposes substantial differences in the transient and asymptotic behavior of the models which result in 47 % variation in population size and more than 6 percentage points variation in HIV prevalence over 40 years between models using different recruitment mechanisms. We outline the strong influence of recruitment assumptions on the impact of HIV prevention interventions and conclude that detailed demographic data should be used to inform the integration of recruitment processes in the models before HIV prevention is considered.


Fish Oil, but Not Olive Oil, Ameliorates Depressive-Like Behavior and Gut Microbiota Dysbiosis in Rats under Chronic Mild Stress.
This study investigated the effects of fish oil and olive oil in improving dysbiosis and depressive-like symptoms. Male rats were fed normal, fish oil-rich or olive oil-rich diets for 14 weeks. Chronic mild stress (CMS) was administered from week 2. The sucrose preference test (SPT) and forced swimming test (FST) were used to determine depressive-like behavior. The SPT results revealed that the CMS, CMS with imipramine (CMS+P) treatment, and CMS with olive oil diet (CMS+O) groups exhibited significantly reduced sucrose intake from week 8, whereas the fish oil diet (CMS+F) group exhibited significantly reduced sucrose intake from week 10. The FST results showed that the immobile time of the CMS+F group was significantly less than that of the CMS-only group. Next generation sequencing (NGS) results showed CMS significantly reduced the abundance of Lactobacillus and increased that of Marvinbryantia and Ruminiclostridium_6. However, the CMS+F group showed an increase in the abundance of Eisenbergiella, Ruminococcaceae_UCG_009, and Holdemania, whereas the CMS+O group showed an increase in the abundance of Akkermansia. CMS stimuli altered the gut microbiome in depressed rats. Fish oil and olive oil exerted part of a prebiotic-like effect to ameliorate dysbiosis induced by CMS. However, only fish oil ameliorated depressive-like symptoms.


Racial differences in response to antiretroviral therapy for HIV infection: an AIDS clinical trials group (ACTG) study analysis.
In the United States, black individuals infected with human immunodeficiency virus (HIV) have higher rates of virologic failure on antiretroviral therapy (ART) and of death compared to white individuals. The cause for these disparities is uncertain. We sought to examine differences in virologic outcomes among antiretroviral-naive clinical trial participants starting randomized ART and to investigate factors to explain the differences. Individual-level data from participants initiating ART in 5 AIDS Clinical Trials Group studies were analyzed. Included studies were those conducted during 1998-2006 with a primary outcome of virologic failure. The primary outcome measure was time to virologic failure, regardless of ART changes. A total of 2495 individuals (1151 black; 1344 white) were included with a median follow-up of 129 weeks. Compared to whites, blacks had an increased hazard of virologic failure (hazard ratio [HR]; 1.7; 95% confidence interval [CI], 1.4-1.9; P < .001), with no evidence of heterogeneity across regimens (P = .97); the association remained after adjustment for measured confounders (HR, 1.4; 95% CI, 1.2-1.6; P < .001). Increased hazard of virologic failure was associated with younger age, higher pretreatment HIV type 1 RNA level, lower pretreatment CD4 cell count, hepatitis C antibody, less education, and recent nonadherence to treatment. Sensitivity analyses with different endpoint definitions demonstrated similar results. In this analysis, blacks had a 40% higher virologic failure risk than whites that was not explained by measured confounders. The observation was consistent over a range of regimens, suggesting that the difference may be driven by social factors; however, biological factors cannot be ruled out. Further research should identify the sources of racial disparities and develop strategies to reduce them.


The effects of sexual partnership and relationship characteristics on three sexual risk variables in young men who have sex with men.
Young men who have sex with men (YMSM) in the United States are experiencing an alarming increase in HIV incidence. Recent evidence suggests that the majority of new HIV infections in YMSM occur in the context of serious relationships, which underscores the importance of examining predictors of sexual risk behavior in the context of sexual partnerships, including relationship type, sexual partner characteristics, and relationship dynamics. The current study aimed to evaluate relationship and sexual partnership influences on sexual risk behavior in YMSM, including differentiating between multiple sexual risk variables (i.e., any unprotected anal or vaginal intercourse, unprotected insertive anal or vaginal intercourse, and unprotected receptive anal intercourse). More serious/familiar partnerships were associated with more sexual risk across all three risk variables, while wanting a relationship to last was protective against risk across all three risk variables. Some variables were differentially linked to unprotected insertive sex (partner gender) or unprotected receptive sex (partner age, partner race, believing a partner was having sex with others, and partners repeated across waves). Sexual risk behavior in YMSM is inconsistent across sexual partnerships and appears to be determined in no small part by sexual partner characteristics, relationship dynamics, and sexual role (i.e., insertive or receptive partner). These influences are critical in understanding sexual risk in YMSM and provide important targets for intervention.


Medical education and primary health care in Nigeria: the Sokoto University experience.
Despite the acknowledgement and adoption of the Alma-Ata declaration by majority of the countries of the world as a strategy for achieving Health For All, medical educational systems often remain as ivory towers from the health service system. This traditional system of medical education does not adequately prepare doctors in developing countries for their expected leadership role in meeting the health needs for their communities through primary health care. In Nigeria, primary health care forms the basis for an official health policy aimed at meeting the health care needs of the entire population particularly those in the rural areas. This article, while highlighting the need for integration of medical education and the primary health care services, also examines the structural relationships between the two components at the Sokoto University in Nigeria, a West African country with one of the oldest medical educational system in the area.


4-O-(1-carboxyethyl)-L-rhamnose, a second unique acidic sugar found in an extracellular polysaccharide from Butyrivibrio fibrisolvens strain 49.
Butyrivibrio fibrisolvens strain 49 excretes a polysaccharide that contains D-glucose, D-galactose, 4-O-(1-carboxyethyl)-D-galactose, and an acidic component of previously unknown structure. We report here the identity of the unknown as 4-O-(1-carboxyethyl)-L-rhamnose. The structure of this previously unknown compound was deduced from (1) comprehensive electron-impact and chemical-ionization mass-spectroscopic studies of differentially labelled derivatives prepared from the unknown, (2) 13C-n.m.r. and 1H-n.m.r. studies of purified neutral sugars derived from the unknown and (3) chemical degradation experiments.


Predicting the expression of recombinant monoclonal antibodies in Chinese hamster ovary cells based on sequence features of the CDR3 domain.
Despite the development of high-titer bioprocesses capable of producing >10 g L(-1) of recombinant monoclonal antibody (MAb), some so called "difficult-to-express" (DTE) MAbs only reach much lower process titers. For widely utilized "platform" processes the only discrete variable is the protein coding sequence of the recombinant product. However, there has been little systematic study to identify the sequence parameters that affect expression. This information is vital, as it would allow us to rationally design genetic sequence and engineering strategies for optimal bioprocessing. We have therefore developed a new computational tool that enables prediction of MAb titer in Chinese hamster ovary (CHO) cells based on the recombinant coding sequence of the expressed MAb. Model construction utilized a panel of MAbs, which following a 10-day fed-batch transient production process varied in titer 5.6-fold, allowing analysis of the sequence features that impact expression over a range of high and low MAb productivity. The model identified 18 light chain (LC)-specific sequence features within complementarity determining region 3 (CDR3) capable of predicting MAb titer with a root mean square error of 0.585 relative expression units. Furthermore, we identify that CDR3 variation influences the rate of LC-HC dimerization during MAb synthesis, which could be exploited to improve the production of DTE MAb variants via increasing the transfected LC:HC gene ratio. Taken together these data suggest that engineering intervention strategies to improve the expression of DTE recombinant products can be rationally implemented based on an identification of the sequence motifs that render a recombinant product DTE.


The role of physical activity in type 2 diabetes prevention: physiological and practical perspectives.
Lifestyle changes that include a nutritionally balanced diet and increased physical activity (PA) are effective intervention options for persons with prediabetes who want to prevent progression to type 2 diabetes mellitus. Although nutritional counseling is standard practice for patients in a clinical setting, an individualized PA prescription, including recommendations on the type, frequency, duration, and intensity, is much less likely to occur. This is surprising because lifestyle modifications including a PA program are at least as effective in diabetes prevention as any single pharmacological agent. The success of regular PA in improving glycemic control in persons with either prediabetes or type 2 diabetes likely results from adaptations that occur in several organs and tissues, including adipose, skeletal muscle, liver, and pancreas. Increased insulin sensitivity is an important link between increased PA, body composition, and metabolic health, and it is at this link where increases in PA and energy expenditure exert much of their effect on preventing metabolic disorders and improving symptoms of existing disease. In addition to improving insulin sensitivity, regular PA has several cardioprotective effects, especially for persons with metabolic dysfunction, and has been shown to elicit minimal adverse events in these populations. Effective PA prescription is contingent on an understanding of the underlying physiological adaptations and the differing responses to diverse modes and intensities of PA. This article highlights recent findings on the beneficial role of regular PA for improving and/or maintaining insulin sensitivity in persons with prediabetes. We also provide an evidence-informed prescription for the type, intensity, and duration of both resistance and aerobic PA in persons with prediabetes.


Social contagion of mental health: evidence from college roommates.
From a policy standpoint, the spread of health conditions in social networks is important to quantify, because it implies externalities and possible market failures in the consumption of health interventions. Recent studies conclude that happiness and depression may be highly contagious across social ties. The results may be biased, however, because of selection and common shocks. We provide unbiased estimates by using exogenous variation from college roommate assignments. Our findings are consistent with no significant overall contagion of mental health and no more than small contagion effects for specific mental health measures, with no evidence for happiness contagion and modest evidence for anxiety and depression contagion. The weakness of the contagion effects cannot be explained by avoidance of roommates with poor mental health or by generally low social contact among roommates. We also find that similarity of baseline mental health predicts the closeness of roommate relationships, which highlights the potential for selection biases in studies of peer effects that do not have a clearly exogenous source of variation. Overall, our results suggest that mental health contagion is lower, or at least more context specific, than implied by the recent studies in the medical literature.


New Risk Curves for NHTSA's Brain Injury Criterion (BrIC): Derivations and Assessments.
The National Highway Traffic Safety Administration (NHTSA) recently published a Request for Comments regarding a potential upgrade to the US New Car Assessment Program (US NCAP) - a star-rating program pertaining to vehicle crashworthiness. Therein, NHTSA (a) cited two metrics for assessing head risk: Head Injury Criterion (HIC15) and Brain Injury Criterion (BrIC), and (b) proposed to conduct risk assessment via its risk curves for those metrics, but did not prescribe a specific method for applying them. Recent studies, however, have indicated that the NHTSA risk curves for BrIC significantly overstate field-based head injury rates. Therefore, in the present three-part study, a new set of BrIC-based risk curves was derived, an overarching head risk equation involving risk curves for both BrIC and HIC15 was assessed, and some additional candidatepredictor- variable assessments were conducted. Part 1 pertained to the derivation. Specifically, data were pooled from various sources: Navy volunteers, amateur boxers, professional football players, simple-fall subjects, and racecar drivers. In total, there were 4,501 cases, with brain injury reported in 63. Injury outcomes were approximated on the Abbreviated Injury Scale (AIS). The statistical analysis was conducted subject to ordinal logistic regression analysis (OLR), such that the various levels of brain injury were cast as a function of BrIC. The resulting risk curves, with Goodman Kruksal Gamma=0.83, were significantly different than those from NHTSA. Part 2 pertained to the assessment relative to field data. Two perspectives were considered: "aggregate" (ΔV=0-56 km/h) and "point" (high-speed, regulatory focus). For the aggregate perspective, the new risk curves for BrIC were applied in field models pertaining to belted, mid-size, adult drivers in 11-1 o'clock, full-engagement frontal crashes in the National Automotive Sampling System (NASS, 1993-2014 calendar years). For the point perspective, BrIC data from tests were used. The assessments were conducted for minor, moderate, and serious injury levels for both Newer Vehicles (airbag-fitted) and Older Vehicles (not airbag-fitted). Curve-based injury rates and NASS-based injury rates were compared via average percent difference (AvgPctDiff). The new risk curves demonstrated significantly better fidelity than those from NHTSA. For example, for the aggregate perspective (n=12 assessments), the results were as follows: AvgPctDiff (present risk curves) = +67 versus AvgPctDiff (NHTSA risk curves) = +9378. Part 2 also contained a more comprehensive assessment. Specifically, BrIC-based risk curves were used to estimate brain-related injury probabilities, HIC15-based risk curves from NHTSA were used to estimate bone/other injury probabilities, and the maximum of the two resulting probabilities was used to represent the attendant headinjury probabilities. (Those HIC15-based risk curves yielded AvgPctDiff=+85 for that application.) Subject to the resulting 21 assessments, similar results were observed: AvgPctDiff (present risk curves) = +42 versus AvgPctDiff (NHTSA risk curves) = +5783. Therefore, based on the results from Part 2, if the existing BrIC metric is to be applied by NHTSA in vehicle assessment, we recommend that the corresponding risk curves derived in the present study be considered. Part 3 pertained to the assessment of various other candidate brain-injury metrics. Specifically, Parts 1 and 2 were revisited for HIC15, translation acceleration (TA), rotational acceleration (RA), rotational velocity (RV), and a different rotational brain injury criterion from NHTSA (BRIC). The rank-ordered results for the 21 assessments for each metric were as follows: RA, HIC15, BRIC, TA, BrIC, and RV. Therefore, of the six studied sets of OLR-based risk curves, the set for rotational acceleration demonstrated the best performance relative to NASS.


Repeated application of glucocorticoids exacerbate pruritus via inhibition of prostaglandin D2 production of mast cells in a murine model of allergic contact dermatitis.
Rebound is known to occur most typically when topical glucocorticoids are abruptly discontinued; however, its frequency and severity are poorly characterized. We previously created a novel murine model of topical glucocorticoid-induced pruritus; however, the mechanism underlying pruritus in this model has not been elucidated. Using this murine model, we aimed to determine the cause of augmentation of pruritus with a focus on the production of prostaglandin (PG) D(2). BALB/c mice with chronic allergic contact dermatitis induced by 5 weeks of repeated application of 2,4,6-trinitro-1-chlorobenzene (TNCB) were treated topically with dexamethasone for 5 weeks immediately after the elicitation of dermatitis and after ear-swelling and scratching behavior were measured. RBL-2H3 mast cells were used to investigate the effect of dexamethasone on degranulation or PGD(2) production in IgE/antigen-stimulated mast cells. The scratching behavior induced by TNCB was augmented by topical application of dexamethasone, but dexamethasone did not have any effect on scratching bouts in mice that had not been treated with TNCB. Topical dexamethasone reduced the PGD(2) level, which increase in TNCB-treated mice, to the baseline level. Moreover, dexamethasone significantly decreased the PGD(2) production in IgE/antigen-stimulated RBL-2H3 mast cells; however, the same concentration of dexamethasone did not have any effect on the degranulation of stimulated mast cells. Topical glucocorticoids may exacerbate pruritus in a mouse model of allergic contact dermatitis via inhibition of PGD(2) production in antigen-mediated activated mast cells in the skin.


Evaluation of MR thermometry with proton resonance frequency method at 7T.
Quantitative and non-invasive temperature mapping using magnetic resonance imaging (MRI) provides a unique way to measure temperature evolution inside biological tissues. The method is widely used in thermal ablation procedures with magnetic fields at or below 3T. In this paper, the sensitivity of the MRI thermometry at 7T was studied using a proton resonance frequency (PRF)-based technique. We first used an agarose gel phantom with MR-compatible thermometry to calibrate the temperature coefficient, and then this temperature coefficient was employed to measure the internal temperature in both ex vivo (beef muscle) and in vivo (rat) experiments using focused ultrasound heating. The temperature coefficient calibrated by the phantom was 0.0095 ppm/°C, and both the ex vivo and in vivo experiments exhibited clear temperature evolution. This quantitative study confirmed the sensitivity (<1 °C) of MR temperature mapping at 7T.


Bulky toroidal and vesicular self-assembled nanostructures from fullerene end-capped rod-like polymers.
In this work, we present novel fullerene (C60) end-capped rod-like polypeptide-polymers, obtained by one-pot thiol-ene chemistry. These systems are able to self-assemble in water creating precise bulky microstructures of toroidal or vesicular shapes. Independent molecular dynamics simulations supported the observed experimental results.


Altered 3,5,3'-triiodothyronine thyroxine ratio in experimentally induced kwashiorkor and obesity in rats.
The plasma triiodothyronine (T3) and thyroxine (T4) ratios have been evaluated in kwashiorkor and diet-induced obese weaned rats. The concentrations of T3 and T4 were determined in plasma by radio-immunoassay. A significant decrease in T3 level in the order kwashiorkor < obese < control was observed. However T4 concentration was more elevated (P < 0.01) in the obese than the normal controls, while more significantly depressed (P < 0.001) in the kwashiorkor than in control animals. The T3/T4 ratio decreased in the order obese < kwashiorkor < control. It was concluded from these studies that kwashiorkor and diet-induced obesity not only interfere with the absolute concentration of the thyroid hormones but also alter the T3/T4 ratio. The altered T3 and T4 ratio perhaps contributes to the maintenance of the isoenergetic state rather than to the promotion of negative or positive energy balance in kwashiorkor and obese subjects respectively.


Outcomes of paediatric liver transplant for biliary atresia.
Despite the widespread use of Kasai Portoenterostomy (KPE) for biliary atresia, more than two thirds of these patients require liver transplant. Liver transplantation is not widely available in South Africa, and Wits Donald Gordon Medical Centre is one of two centres performing paediatric liver transplantation in the country, and the only centre performing living related donor transplants. A retrospective review was performed at the centre. Demographic data were collected, and tabulated. Survival analysis was performed using the Kaplan Meier method. Complication rates were categorised into biliary, vascular and enteric, and classified as early and late. Sixty-seven first time liver transplants were performed for biliary atresia at WDGMC from 2005 to 2017. Sixty-nine percent were female patients and thirty-one percent were male patients. Forty-eight percent of patients under the age of 5 years had a z-score of -2 or worse for mid upper arm circumference (MUAC). One year overall survival of the cohort is 84.5%, and overall graft survival is 82.9%. Overall mortality was 22%, with infection being the most common cause of death. Early referral of all patients with biliary atresia to a paediatric liver transplant centre is essential for early assessment of indications, and medical and nutritional optimisation of patients. Primary liver transplant should be considered for a select group of patients with unique clinical indications.


Coastal vulnerability to climate change in China's Bohai Economic Rim.
Climate change and human activities exert a wide range of stressors on urban coastal areas. Synthetical assessment of coastal vulnerability is crucial for effective interventions and long-term planning. However, there have been few studies based on integrative analyses of ecological and physical characteristics and socioeconomic conditions in urban coastal areas. This study developed a holistic framework for assessing coastal vulnerability from three dimensions - biophysical exposure, sensitivity and adaptive capacity - and applied it to the coast of Bohai Economic Rim, an extensive and important development zone in China. A composite vulnerability index (CVI) was developed for every 1 km2 segment of the total 5627 km coastline and the areas that most prone to coastal hazards were identified by mapping the distribution patterns of the CVIs in the present and under future climate change scenarios. The CVIs show a spatial heterogeneity, with higher values concentrated along the southwestern and northeastern coasts and lower values concentrated along the southern coasts. Currently, 20% of the coastlines with approximately 350,000 people are highly vulnerable to coastal hazards. With sea-level rises under the future scenarios of the year 2100, more coastlines will be highly vulnerable, and the amount of highly-threatened population was estimated to increase by 13-24%. Among the coastal cities, Dongying was categorized as having the highest vulnerability, mainly due to poor transportation and medical services and low GDP per capita, which contribute to low adaptive capacity. Our results can benefit decision-makers by highlighting prioritized areas and identifying the most important determinants of priority, facilitating location-specific interventions for climate-change adaptation and sustainable coastal management.


The autonomic nervous system and cardiac arrhythmias: current concepts and emerging therapies.
Research into cardiac autonomic control has received great interest in the past 20 years, and we are now at a critical juncture with regard to the clinical translation of the experimental findings. A rush to develop clinical interventions and implant a range of devices aimed at cardiac neuromodulation therapy has occurred. This interest has been driven by research, superimposed on commercial opportunities and perhaps the more relaxed regulatory framework governing implantable devices and interventions compared with that for pharmacotherapy. However, many of the results of the clinical trials into these therapies have been disappointing or conflicting. This lack of positive results is partly attributable to a scramble to find simple solutions for complex problems that we do not yet fully understand. Are there reasons to be optimistic? In this Review, we highlight areas in the field of cardiac autonomic control that we feel show the most promise for clinical translation and areas in which our current range of blunt tools need to be refined to bring about long-term success in treating arrhythmias.