Supramolecular Integration of Multifunctional Nanomaterial by Mannose-Decorated Azocalixarene with Ginsenoside Rb1 for Synergistic Therapy of Rheumatoid Arthritis.
The complexity and progressive nature of diseases require the exploitation of multifunctional materials. However, introducing a function inevitably increases the complexity of materials, which complicates preparation and decreases reproducibility. Herein, we report a supramolecular integration of multifunctional nanomaterials based on mannose-modified azocalix[4]arene (ManAC4A) and ginsenoside Rb1 (Rb1), which showed advances of simplicity and reproducibility. ManAC4A possesses reactive oxygen species (ROS) scavenging capacity and hypoxia-responsiveness, together with macrophage-targeting and induction functionality. Collectively, the Rb1@ManAC4A assembly simply prepared by two components is integrated with multifunction, including triple targeting (ELVIS targeting, macrophage-targeting, and hypoxia-targeted release) and triple therapy (ROS scavenging, macrophage polarization, and the anti-inflammatory effect of Rb1). The spontaneous assembly and recognition of ManAC4A, with its precise structure and molecular weight, facilitated the simple and straightforward preparation of Rb1@ManAC4A, leading to excellent batch consistency. Progress in simplicity and reproducibility, as directed by this research, will catalyze the clinical translation of multifunctional materials.


Post-sepsis immunosuppression depends on NKT cell regulation of mTOR/IFN-γ in NK cells.
As treatment of the early, inflammatory phase of sepsis improves, post-sepsis immunosuppression and secondary infection have increased in importance. How early inflammation drives immunosuppression remains unclear. Although IFN-γ typically helps microbial clearance, we found that increased plasma IFN-γ in early clinical sepsis was associated with the later development of secondary Candida infection. Consistent with this observation, we found that exogenous IFN-γ suppressed macrophage phagocytosis of zymosan in vivo, and antibody blockade of IFN-γ after endotoxemia improved survival of secondary candidemia. Transcriptomic analysis of innate lymphocytes during endotoxemia suggested that NKT cells drove IFN-γ production by NK cells via mTORC1. Activation of invariant NKT (iNKT) cells with glycolipid antigen drove immunosuppression. Deletion of iNKT cells in Cd1d-/- mice or inhibition of mTOR by rapamycin reduced immunosuppression and susceptibility to secondary Candida infection. Thus, although rapamycin is typically an immunosuppressive medication, in the context of sepsis, rapamycin has the opposite effect. These results implicated an NKT cell/mTOR/IFN-γ axis in immunosuppression following endotoxemia or sepsis. In summary, in vivo iNKT cells activated mTORC1 in NK cells to produce IFN-γ, which worsened macrophage phagocytosis, clearance of secondary Candida infection, and mortality.


["Doctor please, grant me some sick leave"!: medical certificates for psychological reasons].
General practitioners are regularly called to evaluate the psychological work capacity of patients. The implicit motivation behind the explicit reason for requesting a sick leave is linked to the subject's history and the way he transfers it in his professional life. An incapacity to work harbours a variety of challenges for the patient, the physician and their relationship. In order to get a better understanding of all the issues at stake, the doctor should understand the significances that represents the work to the patient and the consequences of a sick leave and its associated transference and countertransference issues.


Influences of human and livestock density on winter habitat selection of Mongolian gazelle (Procapra gutturosa).
Human and livestock related disturbances of habitat selection by ungulates are topics of global concern, as they have profound impacts on ungulate survival, population density, fitness, and management; however, differences in ungulate habitat use under different human and livestock densities are not fully understood. Mongolian gazelle (Procapra gutturosa), an endemic ungulate species on the Asia-European steppe, faces varying intensities of human and livestock disturbances in the area around Dalai Lake, China. To investigate how habitat selection strategies vary as disturbance intensity changes, we randomly set 20 transects containing 1486 plots, on which we conducted repeated surveys of 21 ecological factors during the winters in the period of 2005-2008. We aimed to: 1) determine the critical factors underlying habitat selection of the gazelles; 2) determine the gazelles' habitat preferences in this area; 3) determine how habitat selection varies with disturbance intensity and explore the primary underlying mechanism. We used binary-logistic regressions and information theoretic approaches to build best-fit habitat selection models, and calculated resource selection functions. Sixty-six herds, 522 individuals, and 499 tracks were recorded. Our results indicate that snow depth and aboveground biomass are the main factors affecting habitat selection by Mongolian gazelle throughout the district in winter. Thin snow cover and abundant aboveground biomass are preferred. Avoiding disturbance was the primary factor accounting for habitat selection in low disturbance areas, although with increasing human or live-stock-related disturbance, gazelle maintained a reduced distance to the source of the disturbance. Presumably owing to that shift, movement costs were more important as disturbance increased. In addition, Mongolian gazelle selected habitats based on topographical features promoting greater visibility where disturbance was lower. We suggest several management implications of our findings for this ungulate species will contribute to the effective conservation of Mongolian gazelle in the Dalai Lake area.


Introducing Pharmaceutical Care to Primary Care in Iceland-An Action Research Study.
Even though pharmaceutical care is not a new concept in pharmacy, its introduction and development has proved to be challenging. In Iceland, general practitioners are not familiar with pharmaceutical care and additionally no such service is offered in pharmacies or primary care settings. Introducing pharmaceutical care in primary care in Iceland is making great efforts to follow other countries, which are bringing the pharmacist more into patient care. General practitioners are key stakeholders in this endeavor. The aim of this study was to introduce pharmacist-led pharmaceutical care into primary care clinics in Iceland in collaboration with general practitioners by presenting different setting structures. Action research provided the framework for this research. Data was collected from pharmaceutical care interventions, whereby the pharmaceutical care practitioner ensures that each of a patient's medications is assessed to determine if it is appropriate, effective, safe, and that the patient can take medicine as expected. Sources of data included pharmaceutical care notes on patients, researcher's notes, meetings, and interviews with general practitioners over the period of the study. The study ran from September 2013 to October 2015. Three separate semi-structured in-depth interviews were conducted with five general practitioners from one primary health care clinic in Iceland at different time points throughout the study. Pharmaceutical care was provided to elderly patients (n = 125) before and between general practitioners' interviews. The study setting was a primary care clinic in the Reykjavik area and the patients' homes. Results showed that the GPs' knowledge about pharmacist competencies as healthcare providers and their potential in patient care increased. GPs would now like to have access to a pharmacist on a daily basis. Direct contact between the pharmacist and GPs is better when working in the same physical space. Pharmacist's access to medical records is necessary for optimal service. Pharmacist-led clinical service was deemed most needed in dose dispensing polypharmacy patients. This research indicated that it was essential to introduce Icelandic GPs to the potential contribution of pharmacists in patient care and that action research was a useful methodology to promote and develop a relationship between those two health care providers in primary care in Iceland.


Automatic Positive and Negative Emotion Regulation in Adolescents with Major Depressive Disorder.
Adolescents with major depressive disorder (MDD) exhibit hypoactivity to positive stimuli and hyperactivity to negative stimuli in terms of neural responses. Automatic emotion regulation (AER) activates triple networks (i.e., the central control network, default mode network, and salience network). Based on previous studies, we hypothesized that adolescents with MDD exhibit dissociable spatiotemporal deficits during positive and negative AER. We first collected EEG data from 32 adolescents with MDD and 35 healthy adolescents while they performed an implicit emotional Go/NoGo task. Then, we characterized the spatiotemporal dynamics of cortical activity during AER. In Go trials, MDD adolescents exhibited reduced N2 amplitudes, enhanced theta power for positive pictures, and stronger bottom-up information flow from the left orbitofrontal cortex (OFC) to the right superior frontal gyrus compared to top-down information flow than the controls. In contrast, in NoGo trials, MDD adolescents exhibited elevated P3 amplitudes, enhanced theta power, and stronger top-down information flows from the right middle frontal gyrus to the right OFC and the left insula than the controls. Overall, adolescents with MDD exhibited impaired automatic attention to positive emotions and impaired automatic response inhibition. These findings have potential implications for the clinical treatment of adolescents with MDD.


Effects of two infectious bursal disease vaccine virus strains on hepatic microsomal enzyme activities in chickens.
The influence of two infectious bursal disease vaccines on the activities of hepatic microsomal enzymes aniline hydroxylase, ethylmorphine N-demethylase, NADPH-cytochrome c reductase, aryl sulphotransferase and p-nitrophenol UDP-glucuronyltransferase was investigated in chickens. The vaccines contained attenuated Winterfield 2512 and VMG-91 strains, respectively. The activities of enzymes were determined on postvaccination days 0, 2, 5 and 7. At the same time, post-mitochondrial supernatant, cytosolic and microsomal pellet protein concentrations were determined. As expected, the antibody titres against infectious bursal disease virus in the serum were increased in both tested groups in relation to each administered vaccine. Using RT-PCR, the presence of the VP2 gene fragment of virus in the liver of chicken was demonstrated 4 and 6 h after vaccination. The results of this study suggest that the two commercial vaccines modulate the activities of five enzymes tested, and that the two attenuated vaccines applied triggered induction and/or inhibition of phases I and II of biotransformation enzyme activities.


A modeling approach integrating microbial activity, mass transfer, and geochemical processes to interpret biological assays: An example for PCE degradation in a multi-phase batch setup.
The rate at which organic contaminants can be degraded in aquatic environments is not only dependent upon specific degrading bacteria, but also upon the composition of the microbial community, mass transfer of the contaminant, and abiotic processes that occur in the environment. In this study, we present three-phase batch experiments of tetrachloroethene (PCE) degradation by a consortium of organohalide-respiring bacteria, cultivated alone or in communities with iron- and/or sulfate-reducers. We developed a modeling approach to quantitatively evaluate the experimental results, comprised of chemical and biomolecular time series data. The model utilizes the IPhreeqc module to couple multi-phase mass transfer between gaseous, organic and aqueous phases with microbial and aquatic geochemical processes described using the geochemical code PHREEQC. The proposed approach is able to capture the contaminant degradation, the microbial population dynamics, the effects of multi-phase kinetic mass transfer and sample removal, and the geochemical reactions occurring in the aqueous phase. The model demonstrates the importance of aqueous speciation and abiotic reactions on the bioavailability of the substrates. The model-based interpretation allowed us to quantify the reaction kinetics of the different bacterial guilds. The model further revealed that the inclusion of sulfate-reducing bacteria lowers the rate of PCE degradation and that this effect is moderated in the presence of iron-reducing bacteria.


Risk factors and characteristics of youth living with, or at high risk for, HIV.
Over 8,000 adolescents and young adults (4,111 males; 4,085 females) reported on several HIV-related risk behaviors during enrollment into 10 service demonstration projects targeted to youth living with, or at risk for, HIV. Distinct risk patterns emerged by gender when predicting HIV serostatus (versus unknown serostatus/negative serostatus). Males who had injection drug risk histories, had sex with an HIV positive partner, had sexually transmitted diseases, had sex with males, and/or were homeless had an inflated risk of being HIV positive. Females who engaged in sex with an HIV partner, had sex with an injection drug user, and/or had sexually transmitted diseases, were at the highest HIV risk. For both samples, engaging in sex with women reduced the likelihood of HIV positive status. Very basic information about risk factors obtained at service intake offers important information about HIV status of "high risk" youth presenting for care in community programs, as well as suggests clear risk factors for targeted preventive efforts.


The Micronemal Plasmodium Proteins P36 and P52 Act in Concert to Establish the Replication-Permissive Compartment Within Infected Hepatocytes.
Within the liver, Plasmodium sporozoites traverse cells searching for a "suitable" hepatocyte, invading these cells through a process that results in the formation of a parasitophorous vacuole (PV), within which the parasite undergoes intracellular replication as a liver stage. It was previously established that two members of the Plasmodium s48/45 protein family, P36 and P52, are essential for productive invasion of host hepatocytes by sporozoites as their simultaneous deletion results in growth-arrested parasites that lack a PV. Recent studies point toward a pathway of entry possibly involving the interaction of P36 with hepatocyte receptors EphA2, CD81, and SR-B1. However, the relationship between P36 and P52 during sporozoite invasion remains unknown. Here we show that parasites with a single P52 or P36 gene deletion each lack a PV after hepatocyte invasion, thereby pheno-copying the lack of a PV observed for the P52/P36 dual gene deletion parasite line. This indicates that both proteins are equally important in the establishment of a PV and act in the same pathway. We created a Plasmodium yoelii P36mCherry tagged parasite line that allowed us to visualize the subcellular localization of P36 and found that it partially co-localizes with P52 in the sporozoite secretory microneme organelles. Furthermore, through co-immunoprecipitation studies in vivo, we determined that P36 and P52 form a protein complex in sporozoites, indicating a concerted function for both proteins within the PV formation pathway. However, upon sporozoite stimulation, only P36 was released as a secreted protein while P52 was not. Our results support a model in which the putatively glycosylphosphatidylinositol (GPI)-anchored P52 may serve as a scaffold to facilitate the interaction of secreted P36 with the host cell during sporozoite invasion of hepatocytes.


Extensive variation in the density and distribution of DNA polymorphism in sorghum genomes.
Sorghum genotypes currently used for grain production in the United States were developed from African landraces that were imported starting in the mid-to-late 19(th) century. Farmers and plant breeders selected genotypes for grain production with reduced plant height, early flowering, increased grain yield, adaptation to drought, and improved resistance to lodging, diseases and pests. DNA polymorphisms that distinguish three historically important grain sorghum genotypes, BTx623, BTx642 and Tx7000, were characterized by genome sequencing, genotyping by sequencing, genetic mapping, and pedigree-based haplotype analysis. The distribution and density of DNA polymorphisms in the sequenced genomes varied widely, in part because the lines were derived through breeding and selection from diverse Kafir, Durra, and Caudatum race accessions. Genomic DNA spanning dw1 (SBI-09) and dw3 (SBI-07) had identical haplotypes due to selection for reduced height. Lower SNP density in genes located in pericentromeric regions compared with genes located in euchromatic regions is consistent with background selection in these regions of low recombination. SNP density was higher in euchromatic DNA and varied >100-fold in contiguous intervals that spanned up to 300 Kbp. The localized variation in DNA polymorphism density occurred throughout euchromatic regions where recombination is elevated, however, polymorphism density was not correlated with gene density or DNA methylation. Overall, sorghum chromosomes contain distal euchromatic regions characterized by extensive, localized variation in DNA polymorphism density, and large pericentromeric regions of low gene density, diversity, and recombination.


Vitamin K Supplementation for the Prevention of Cardiovascular Disease: Where Is the Evidence? A Systematic Review of Controlled Trials.
Matrix gla protein (MGP) is an important vitamin K-dependent inhibitor of vascular calcification. High levels of uncarboxylated, dephosphorylated MGP have been associated with vascular calcification and are responsive to vitamin K treatment. In this systematic review, we summarize the available evidence examining whether vitamin K supplementation improves surrogate measures of cardiovascular disease including artery and valve calcification, atherosclerosis and artery stiffening. Data from controlled trials of adults were obtained by searching Ovid MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and the Web of Science Core Collection. We identified nine randomized controlled trials for review, including trials of vitamin K1 or vitamin K2 supplementation, that assessed a surrogate measure of cardiovascular disease including arterial calcification, atherosclerosis or arterial stiffening. For each trial, the risk of bias was assessed applying Cochrane Collaboration methodology. The findings indicate that vitamin K does not consistently prevent progression of calcification, atherosclerosis or arterial stiffness. There may be some benefit in people with calcification at study entry. Studies were heterogenous, with relatively short follow-up and outcome measures were varied. While vitamin K supplementation clearly improves the carboxylation of dephosphoylated MGP, its role in mitigating vascular calcification is uncertain, based on current evidence.


Identifying intracellular Staphylococcus aureus in chronic rhinosinusitis: a direct comparison of techniques.
The emerging concept of intracellular pathogens such as Staphylococcus aureus playing a role in chronic rhinosinusitis (CRS) has led to the development of numerous imaging techniques for their identification. Traditional methods of bacterial culture are not effective at localizing bacteria to the surface or within tissue samples. The aim of this study was to develop and validate a novel imaging technique using confocal scanning laser microscopy (CSLM) coupled with a fluorescence in situ hybridization (FISH) probe and nucleic acid counterstain (propidium iodide [PI]) that allows for simultaneous analysis of S. aureus intracellular status and surface biofilm within whole mucosal samples. A prospective study was performed including 17 patients undergoing endoscopic sinus surgery for CRS. Tissue samples were analyzed with both CSLM-FISH/PI and immunohistochemistry (IHC) for intracellular S. aureus status. Using CSLM-FISH/PI intracellular S. aureus was identified in 9/17 (47%) patients and in 7/17 (39%) using IHC. Surface biofilm can be identified with CSLM-FISH/PI in the same piece of tissue; however, deeper imaging to the submucosa is impossible. IHC showed submucosal bacteria in three patients. Both CSLM-FISH/PI and IHC are complementary techniques that can be used to identify intracellular S. aureus. CSLM-FISH/PI allows for the simultaneous detection of intracellular status and surface biofilm within the tissue analyzed. IHC has a role in the identification of intracellular and submucosal S. aureus within these tissues. Additional investigation is required to identify the true pathogenic nature of intracellular organisms as well as any relationship to surface biofilm status.


Photosynthesis without β-carotene.
Carotenoids are essential in oxygenic photosynthesis: they stabilize the pigment-protein complexes, are active in harvesting sunlight and in photoprotection. In plants, they are present as carotenes and their oxygenated derivatives, xanthophylls. While mutant plants lacking xanthophylls are capable of photoautotrophic growth, no plants without carotenes in their photosystems have been reported so far, which has led to the common opinion that carotenes are essential for photosynthesis. Here, we report the first plant that grows photoautotrophically in the absence of carotenes: a tobacco plant containing only the xanthophyll astaxanthin. Surprisingly, both photosystems are fully functional despite their carotenoid-binding sites being occupied by astaxanthin instead of β-carotene or remaining empty (i.e. are not occupied by carotenoids). These plants display non-photochemical quenching, despite the absence of both zeaxanthin and lutein and show that tobacco can regulate the ratio between the two photosystems in a very large dynamic range to optimize electron transport.


Comparison of the Septi-Chek AFB and BACTEC systems and conventional culture for recovery of mycobacteria.
The performance of the Septi-Chek AFB system was compared with that of the BACTEC radiometric system and that of Lowenstein-Jensen agar slants (LJ) for detection of mycobacteria in clinical specimens. A total of 642 specimens were cultured; 61 (9.5%) yielded mycobacteria. Mycobacterium tuberculosis (34 isolates) and Mycobacterium avium complex (25 isolates) were the predominant species isolated. Of the 61 culture-positive specimens, 30 were smear positive and 31 were smear negative. Overall, 95% of the positive specimens were detected by Septi-Chek and BACTEC (100% of M. tuberculosis isolates) and 75% by LJ (82% of M. tuberculosis isolates). The mean times to detection were 15 days for BACTEC, 23 days for Septi-Chek, and 27 days for LJ. Of the 30 smear-positive specimens, 100% were recovered by Septi-Chek and BACTEC and 90% were recovered by LJ. Of the 31 smear-negative specimens, 90% were detected by Septi-Chek and BACTEC and 61% were detected by LJ. The Septi-Chek and BACTEC systems are superior to the conventional (LJ) mycobacterial culture method. Although Septi-Chek requires more time for the detection of mycobacteria than BACTEC, it is comparable in terms of overall recovery.


Changes in Influenza Vaccination Rates After Withdrawal of Live Vaccine.
Before the start of the 2016-2017 influenza season, the Advisory Committee on Immunization Practices withdrew its recommendation promoting the use of live attenuated influenza vaccines (LAIVs). There was concern that this might lessen the likelihood that those with a previous LAIV would return for an injectable influenza vaccine (IIV) and that child influenza immunization rates would decrease overall. Using Oregon's statewide immunization registry, the ALERT Immunization Information System, child influenza immunization rates were compared across the 2012-2013 through 2016-2017 seasons. Additionally, matched cohorts of children were selected based on receipt of either an LAIV or an IIV during the 2015-2016 season. Differences between the IIV and LAIV cohorts in returning for the IIV in the 2016-2017 season were assessed. Overall, influenza immunization rates for children aged 2 to 17 years were unchanged between the 2015-2016 and 2016-2017 seasons. Children aged 3 to 10 with a previous IIV were 1.03 (95% confidence interval, 1.02 to 1.04) times more likely to return for an IIV in 2016-2017 than those with a previous LAIV, whereas children aged 11 to 17 years with a previous IIV were 1.08 (95% confidence interval, 1.05 to -1.09) times more likely to return. Withdrawal of the LAIV recommendation was not associated with an overall change in child influenza immunization rates across seasons. Children with a previous (2015-2016) IIV were slightly more likely to return during the 2016-2017 season for influenza immunization than those with a previous LAIV.


Quality versus accuracy: result of a reanalysis of protein-binding microarrays from the DREAM5 challenge by using BayesPI2 including dinucleotide interdependence.
Computational modeling transcription factor (TF) sequence specificity is an important research topic in regulatory genomics. A systematic comparison of 26 algorithms to learn TF-DNA binding specificity in in vitro protein-binding microarray (PBM) data was published recently, but the quality of those examined PBMs was not evaluated completely. Here, new quality-control parameters such as principal component analysis (PCA) ellipse is proposed to assess the data quality for either single or paired PBMs. Additionally, a biophysical model of TF-DNA interactions including adjacent dinucleotide interdependence was implemented in a new program - BayesPI2, where sparse Bayesian learning and relevance vector machine are used to predict unknown model parameters. Then, 66 mouse TFs from the DREAM5 challenge were classified into two groups (i.e. good vs. bad) based on the paired PBM quality-control parameters. Subsequently, computational methods to model TF sequence specificity were evaluated between the two groups. Results indicate that both the algorithm performance and the predicted TF-binding energy-level of a motif are significantly influenced by PBM data quality, where poor PBM data quality is linked to specific protein domains (e.g. C2H2 DNA-binding domain). Especially, the new dinucleotide energy-dependent model (BayesPI2) offers great improvement in testing prediction accuracy over the simple energy-independent model, for at least 21% of analyzed the TFs.


Removal of phenol and phosphate from aqueous solutions using activated carbons prepared from oily sludge through physical and chemical activation.
Preparation and characterization of activated carbons (ACs) from oily sludge by physical and chemical activation using steam, ZnCl2 and FeCl3 were investigated. The characteristics of produced adsorbents were determined by iodine number, Brunauer-Emmett-Teller (BET) equation, Fourier transform infrared spectrometry and scanning electron microscopy analyses. Batch adsorption experiments for phenol and phosphate were performed to evaluate the efficiency of adsorbents. The optimum porous structure of adsorbents with a BET surface area of 1,259 m2 g-1, total pore volume of 1.22 cm3 g-1 and iodine number of 994 mg g-1 was achieved by ZnCl2 activation at 500 °C and impregnation ratio of 1:1. The adsorption data were well fitted to the pseudo-second-order kinetic model (R2>0.99) and Freundlich isotherm (R2>0.99). The maximum adsorption capacity of phenol (238 mg g-1) and phosphate (102 mg g-1) based on the Langmuir model was achieved at pH of 6.0 and adsorbent dose of 1 g L-1. Thermodynamic parameters were negative and showed that adsorption of phenol and phosphate onto the AC was feasible, spontaneous and exothermic. The results suggested that prepared AC was an effective adsorbent for removal of phenol and phosphate ions from the polluted water.


Classification of mental tasks in the prefrontal cortex using fNIRS.
Functional near infrared spectroscopy (fNIRS) is rapidly gaining interest in both the Neuroscience, as well as the Brain-Computer-Interface (BCI) community. Despite these efforts, most single-trial analysis of fNIRS data is focused on motor-imagery, or mental arithmetics. In this study, we investigate the suitability of different mental tasks, namely mental arithmetics, word generation and mental rotation for fNIRS based BCIs. We provide the first systematic comparison of classification accuracies achieved in a sample study. Data was collected from 10 subjects performing these three tasks.


Understanding the conflicts of patient empowerment.
In line with the emphasis placed by nursing development units on critical scrutiny and practice evaluation, the authors review the patient empowerment nursing literature to identify its practical implications for their clinical area and staff. This article presents some early conclusions arising out of this process and highlights the conflicts which nurses face in ensuring that patients are empowered while maintaining their rights and privacy.


Characterization and chromosome assignment of the human homolog of int-2, a potential proto-oncogene.
int-2 is one of two cellular genes (int-1 and int-2) currently implicated in the genesis of mammary carcinomas by mouse mammary tumor virus and may constitute a novel cellular proto-oncogene. Using low-stringency hybridization with mouse int-2 probes, we established that homologous genes exist in a variety of mammalian species, including humans, but failed to detect related sequences in other classes and phyla. Recombinant bacteriophage clones and a single cosmid encompassing the human int-2 gene were isolated and characterized by restriction enzyme mapping. A survey of nine primary human breast tumors, three breast tumor cell lines, and three normal individuals revealed no evidence for gross amplification or rearrangement of the int-2 locus. Three distinct restriction fragment length polymorphisms were observed which could prove useful in future linkage studies. By a combination of in situ hybridization of metaphase chromosomes and somatic cell genetics, the human int-2 gene was mapped to chromosome 11, band q13.


Examining subjective wellbeing and health-related quality of life in women with endometriosis.
The purpose of this study was to explore the subjective wellbeing, health-related quality of life and lived experience of women living with endometriosis. In 2015 five hundred participants between the ages of 18-63 (M = 30.5, SD = 7.46) were recruited through Endometriosis Australia and social media, completing an online questionnaire comprising the Personal Wellbeing Index, the Endometriosis Health Profile-30 and various open-ended questions. Results found that women with endometriosis reported low levels of subjective wellbeing (mean PWI total scores of 51.5 ± 2.03), considerably below the normative range of 70-80 for western populations. The mean Endometriosis Health Profile total score indicated a very low health-related quality of life amongst the women in this sample (78.9, ±13.14). There was also a significant relationship between scores on the Endometriosis Health Profile and Personal Wellbeing Index. The findings from the qualitative data suggest that endometriosis impacts negatively on women's lives in several areas such as; social life, relationships and future plans, this in turn affects women's overall life quality. The study highlights the strong negative impact that endometriosis can have on women's subjective wellbeing and health related quality of life, contributing to productivity issues, relationship difficulties and social dissatisfaction and increasing the risk of psychological comorbidities.


The comparisons of inhibitory control and post-error behaviors between different types of athletes and physically inactive adults.
To properly behave and correct mistakes, individuals must inhibit inappropriate actions and detect errors for future behavioral adjustment. Increasing evidence has demonstrated that athletes are superior in cognitive functions and this benefit varied dependent on the types of sport that individuals involved in, but less is known on whether athletes have a different error-related behavioral pattern. The purpose of this study was to compare the behavioral performance of inhibition and error monitoring between individuals who participated in an open-skill sport (n = 12), a closed-skill sport (n = 12), and a sedentary lifestyle (n = 16). A combined flanker/stop signal task was presented and the derived stop signal reaction time (SSRT), post-correct accuracy and reaction time (RT), as well as post-error accuracy and RT were compared across groups. Our findings indicated there was no difference in SSRT between groups. Surprisingly, significant post-error slowing (PES) was observed only in controls but not in sport groups, the controls also exhibited significantly longer post-error RT compared with the open-skill group. However, there was no difference in the post-error accuracy between groups, indicating a higher efficiency in the post-error processing among open- and closed-skill groups by requiring comparatively less time for behavioral adjustments. The present study is the first to disclose the discrepancies in PES between different types of athletes and controls. The findings suggest that sport training along with higher amounts of physical activity is associated with a more efficient behavioral pattern for error processing especially when the sport requires open skills in nature.


Defect mediated magnetic transitions in Fe and Mn doped MoS2.
We report single-phase syntheses of undoped 2H-MoS2 as well as Mn and Fe doped MoS2 by a facile hydrothermal route. The formation of the 2H-MoS2 phase was confirmed by XRD and was corroborated with Raman spectra. The morphology of the doped and undoped MoS2 nanostructures comprised sheets, as revealed by TEM and STEM images. The fine granular structure was observed by high resolution TEM micrographs. The STEM-EDS results show dopant concentrations of ∼1 atom% corresponding to Mn and Fe in doped MoS2. The undoped MoS2 revealed diamagnetic behavior at room temperature and paramagnetic behavior in the range (100 to 300 K). The Mn-MoS2 sample displayed ferromagnetism below 20 K with a coercive field of ∼50 Oe. Such a sample may be utilized for magnetic switching purposes at low temperatures. The onset of the antiferromagnetic interaction was observed below 145 K in Fe-MoS2 samples. They have been understood in terms of long-range magnetic interactions amongst the dipole moments mediated via surface defects as well as the interaction between the dipoles and the surface charges. The findings are corroborated with the help of EPR studies.


Pretransplant donor-specific and non-specific immune parameters associated with early acute rejection.
New immunosuppression protocols have resulted in decreased rates of biopsy-proven acute rejection; however, it is unclear whether recipients without biopsy-proven acute rejection are still at risk for immune complication and chronic allograft dysfunction. The aim of our studies was to determine whether pretransplant immune parameters were associated with posttransplant early acute rejection, unstable creatinine courses, and poor graft outcome. Immune parameters, including human leukocyte antigen (HLA) mismatch, HLA-specific antibodies, global CD4+ cellular response as measured by intracellular adenosine triphosphate (iATP) synthesis, and IFN-gamma precursor frequencies to donor or third-party cells as measured by ELISPOT were determined for a total of 126 kidney recipients treated with a protocol, including rapid discontinuation of prednisone. The donor specific pretransplant parameters of HLA class I mismatches (P=0.04) and total HLA mismatches (P=0.04) with the donor as well as the pretransplant HLA-donor specific antibodies (P=0.002) were associated with biopsy-proven acute rejection. Higher pretransplant iATP levels, a donor nonspecific parameter, were found associated with biopsy proven acute rejection (P=0.04). Pretransplant iATP levels were significantly greater for recipients with early unstable creatinine levels (P=0.01). Recipients with a pretransplant iATP value greater than 375 ng/ml were 3.67 times more likely to experience acute rejection (P=0.03). Pretransplant assessment of donor specific and nonspecific immune parameters may identify recipients who can benefit from closer clinical and immunological surveillance to allow for tailored immunsuppression and selective intervention aimed at optimizing both short and long-term graft outcome.


From SARS to strategic actions reframing systems.
The developed world responds to new and re-emerging diseases through the discovery of medications. Disease can be transmitted around the world in a day, but the development of medications does not occur at this rate. The world has one environment and the focus in health care must be on identifying factors in this environment that coalesce to produce disease. The aim of this paper is to introduce the integrative model of environmental health and explore its potential to illuminate the Toronto SARS experience. SARS affected people on three continents in a matter of days. Response to this new disease varied from one area to another and was dependent upon the level of integration of health services and communication across services. The present focus of the health care system is on treating the results of disease rather than the causative factors. Reacting to a new disease had grave social and economic consequences. The time for a new global environmental approach to health is now. The Toronto SARS experience was examined using the integrative model of environmental health and the upstream perspective as exemplars to interrupt the traditional approach to disease. All health care providers share the responsibility to learn about and to understand how our environment creates disease. This knowledge comes through research on topics such as; chemicals, pesticides, soil erosion, killing of forests, contamination of water, destabilization of climate, and social disruption from wars. Health care systems in the developed world continue to focus on the treatment of disease. A global ecological initiative for an integrated disease prevention system must be negotiated among nations.


Commentary: the role of the chiropractor: .
Chiropractors in Australia face some challenges that are unique in their history. The value of their primary treatment modality is now widely recognised. The process of professionalisation of this occupation is well advanced. Yet the integration of chiropractic services within the mainstream Australian health care system remains problematic. It is contended in this paper that chiropractors' integration will be facilitated by two genuine and strategic moves by the medically minded segment of, or the entire, profession. One is to abandon metaphysical notions as part of the 'philosophy of chiropractic' and the other is to pursue limited prescription rights allowing chiropractors to play fully the role of the primary contact practitioners of neuromusculoskeletal medicine. This development is deemed to be beneficial and appropriate for the profession as well as the patients served by this profession.


Managing the cancer-work interface: the effect of cancer survivorship on unemployment.
This study assessed differences in employment outcomes among cancer survivors using data from a nationally representative sample. The 2011 Medical Expenditure Panel Survey (MEPS) data and the 2011 MEPS Experiences with Cancer Survivorship Supplement representing 3,360,465 people in the US population were analyzed to evaluate factors associated with unemployment among cancer survivors during the 5 years following diagnosis and treatment. The sample included adults 1) diagnosed with cancer within 5 years prior to survey completion and 2) engaged in paid employment since diagnosis. Individuals diagnosed with nonmelanoma skin cancer (n=33) were excluded from analyses. Data of 221 cancer survivors were used to identify factors associated with employment status at the time respondents were employed (n=155) vs unemployed (n=66). Results of bivariate analyses indicated that unemployed survivors were older, more likely to be women, more likely to be uninsured at the time of cancer diagnosis, and to report lower incomes than cancer survivors who continue to be employed. Unemployed survivors were more likely than employed survivors to have had anxiety about being forced to retire or quit early when they were employed because of cancer and to report cancer-related interference with physical and mental aspects of their job tasks; unemployed survivors also took less paid time off and were less likely to change to a flexible job schedule when they were employed. In multiple logistic regression analyses, worry about being forced to retire (protective), worry that cancer recurrence will interfere with home or work responsibilities (risk), and change to a flexible work schedule (risk) following cancer diagnosis were associated with unemployment after controlling for demographic differences between employed and unemployed cancer survivors. Findings of this study highlight the extent to which the challenges of managing the cancer-work interface create challenges to employment among cancer survivors and may lead to long-term unemployment among cancer survivors. Future studies should evaluate the strategies that the survivors could use to manage the cancer-work interface during cancer treatment to attain medical, psychological, social, and employment outcomes.


Effect of genotypic resistance on the virological response to highly active antiretroviral therapy in cerebrospinal fluid.
Paired plasma and cerebrospinal fluid (CSF) specimens drawn from 15 HIV-infected patients with neurological disease before and after a median 6-week duration of highly active antiretroviral therapy (HAART) were studied to assess the short-term virological response of CSF and whether this can be predicted on the basis of baseline resistance mutations. After treatment, the median plasma and CSF viral load (VL) decreased by, respectively, 2.08 log10 (p = 0.0001) and 0.91 log10 copies/ml (p = 0.007) in comparison with baseline. A plasma virological response was observed in all but one patient, whereas the posttreatment CSF VL increased, remained unchanged, or decreased at a substantial lower rate than in plasma of six "CSF non/slow responders" (40%). Direct sequencing of baseline specimens showed that none of these patients had reverse transcriptase (RT) or primary protease resistance mutations in the CSF alone, but two had RT mutations conferring high-level resistance to drugs included in the HAART regimen in both CSF and plasma. The other four patients had no RT or primary protease resistance mutations. There was no significant difference in the nucleotide diversity of the CSF and plasma RT sequences, baseline plasma or CSF VL, the CSF-to-plasma VL ratio, the number of CSF cells, the CD4+ cell counts, or the history of antiretroviral treatment between the CSF non-slow responders and the other patients. During this short-term follow-up and despite a plasma response, a significant proportion of HAART-treated patients with neurological symptoms showed a slow or absent CSF response. Most of these cases were not associated with the presence of resistant HIV strains in the CSF.


Bipolaron formation in organic solar cells observed by pulsed electrically detected magnetic resonance.
We report the observation of a spin-dependent dark transport current, exhibiting spin coherence at room temperature, in a π-conjugated polymer-fullerene blend using pulsed electrically detected magnetic resonance. The resonance at g = 2.0028(3) is due to polarons in the polymer, and exhibits spin locking at high microwave fields. The presence of an excess of fullerene, and the operating voltage (1 V) used, suppresses negative polaron formation in the polymer. It is concluded that spin-dependent transport is due to the formation of positive bipolarons.


Photodynamic therapy in vitro and in vivo with hematoporphyrin derivative and laser light.
Photodynamic therapy is currently under investigation as a new form of treatment for solid malignant tumors in animals and in humans. The method involves photosensitization of drugs and fluorescent dyes, such as hematoporphyrin derivative (Hpd), after preferential incorporation by neoplastic cells. In in vitro experiments laser light activation completely destroys Hpd-pretreated EL4 cells. Mice bearing MS-2 fibrosarcoma treated with Hpd and laser light survived indefinitely, in comparison with control animals that were untreated or treated only with Hpd or laser light. In mice bearing the highly metastatic tumors B16 melanoma and Lewis lung carcinoma (LLC) treated with Hpd and laser light delivered through a quartz fiber optic significantly prolonged the median survival time. This therapy was compared with surgical excision of primary tumors and, for superficial nonmetastatic neoplasma MS-2, the photodynamic therapy was more effective than surgery, while for metastatic tumors B16 and LLC, there was no significant difference between the two methodologies. However, phototherapy is much less traumatic to the animals.


Percutaneous cystogastrostomy for treatment of pancreatic pseudocysts.
Cystogastrostomy or cystojejunostomy at open operation has been the usual treatment for symptomatic pancreatic pseudocyst. The aim of this study was to assess prospectively the results of percutaneous cystogastrostomy (PCG) for the treatment of symptomatic pseudocysts. The technique of PCG comprised initially of drainage of the pseudocyst with a 10 Fr percutaneous, transgastric catheter. This initial drainage catheter had two components; the first, between the pseudocyst and the stomach, drained the pseudocyst and the second, between the stomach and exterior, acted as a percutaneous gastrostomy. The initial drain was left in situ for 14 days, at which time it was exchanged percutaneously for the definitive PCG; a double ended Mallecot type catheter that drained between the pseudocyst and the stomach. The latter catheter was left in situ until there was no residual pseudocyst demonstrated on computerized tomography scan and was removed endoscopically. Eleven patients with large (> 6 cm), symptomatic pseudocysts have been treated with PCG. All patients were treated successfully without the need for surgical intervention. The median time to radiological resolution was 24 days. There were four episodes of sepsis, two related to central venous line infections nad two related to catheter blockage. Percutaneous, cystogastrostomy blockage was managed by either replacing the initial drain or inserting a second catheter. The median follow up after successful treatment was 9 months (range 2-17). There were no symptomatic recurrences and one small (2 cm) asymptomatic recurrent pseudocyst. This preliminary experience with PCG demonstrates the efficacy of this procedure for treating symptomatic pancreatic pseudocysts.


Evolutionary game theory in growing populations.
Existing theoretical models of evolution focus on the relative fitness advantages of different mutants in a population while the dynamic behavior of the population size is mostly left unconsidered. We present here a generic stochastic model which combines the growth dynamics of the population and its internal evolution. Our model thereby accounts for the fact that both evolutionary and growth dynamics are based on individual reproduction events and hence are highly coupled and stochastic in nature. We exemplify our approach by studying the dilemma of cooperation in growing populations and show that genuinely stochastic events can ease the dilemma by leading to a transient but robust increase in cooperation.


Preclinical endodontic teaching. A survey of Saudi dental schools.
To provide an overview of the general curricula in preclinical endodontic training from 6 established dental schools in Saudi Arabia. This study was conducted in January 2014 including only schools that had more than 2 groups of student graduates prior to the study. We included 2 dental schools from the Central region, one from Qassim region, one from the Makkah region (west), one from Abha region (south west), and one from the eastern region. An internet-based questionnaire was sent to the course directors of preclinical endodontics department of the 6 schools. The survey comprised 20 questions that examined various aspects of preclinical endodontics. It was demonstrated that a significant number of faculty members had Doctor of Philosophy (PhD) degrees (n=21), Master's degrees (n=15), and Saudi board certifications (n=8). We determined that the faculty to student ratio varied from 2:1 to 8: 1 among the colleges. The participating dental schools were found to teach the Step Back, as well as the Step Down techniques for root canal preparation. Five of the 6 schools implemented the use of nickel titanium rotary instruments. All dental schools predominantly used radiographs as the means of the working length determination. The curriculum for preclinical endodontics in Saudi Arabia is comparable to that followed in most European countries. A more comprehensive survey is needed that would involve more schools to formulate generalized guidelines for preclinical endodontic training in Saudi Arabia.


Systematic care for caregivers of patients with dementia: a multicenter, cluster-randomized, controlled trial.
To evaluate the effectiveness of the Systematic Care Program for Dementia (SCPD) on patient institutionalization and to determine the predictors of institutionalization. Single-blind, multicenter, cluster-randomized, controlled trial. Six community mental health services (CMHSs) across the Netherlands. A total of 295 patient-caregiver dyads referred to a CMHS with suspected patient dementia. Training of health professionals in the SCPD and its subsequent use. The SCPD consists of a systematic assessment of caregiver problems and alerts health professionals in flexible, connecting, proactive interventions to them. The intensity of the SCPD depends on the judgment of the health professional, based on individual caregiver needs. Institutionalization in long-term care facilities at 12 months of follow-up. No main intervention effect on institutionalization was found. However, a better sense of competence in the control group reduced the chance of institutionalization but not in the intervention group. The caregiver's sense of competence and depressive symptoms and the patient's behavioral problems and severity of dementia were the strongest predictors of institutionalization. The intensity of the program was low, even for dyads exposed to the SCPD. Although no main effect was found, the results suggest that the SCPD might prevent a deterioration of the sense of competence in the intervention group. The intensity of a program is crucial and should be prescribed on the basis of evidence rather than left to the discretion of health professionals. Future controlled trials in daily clinical practice should use a process analysis to control for compliance.


Distance to Healthy Metabolic and Cardiovascular Dynamics From Fetal Heart Rate Scale-Dependent Features in Pregnant Sheep Model of Human Labor Predicts the Evolution of Acidemia and Cardiovascular Decompensation.
The overarching goal of the present work is to contribute to the understanding of the relations between fetal heart rate (FHR) temporal dynamics and the well-being of the fetus, notably in terms of predicting the evolution of lactate, pH and cardiovascular decompensation (CVD). It makes uses of an established animal model of human labor, where 14 near-term ovine fetuses subjected to umbilical cord occlusions (UCO) were instrumented to permit regular intermittent measurements of metabolites lactate and base excess, pH, and continuous recording of electrocardiogram (ECG) and systemic arterial blood pressure (to identify CVD) during UCO. ECG-derived FHR was digitized at the sampling rate of 1,000 Hz and resampled to 4 Hz, as used in clinical routine. We focused on four FHR variability features which are tunable to temporal scales of FHR dynamics, robustly computable from FHR sampled at 4 Hz and within short-time sliding windows, hence permitting a time-dependent, or local, analysis of FHR which helps dealing with signal noise. Results show the sensitivity of the proposed features for early detection of CVD, correlation to metabolites and pH, useful for early acidosis detection and the importance of coarse time scales (2.5-8 s) which are not disturbed by the low FHR sampling rate. Further, we introduce the performance of an individualized self-referencing metric of the distance to healthy state, based on a combination of the four features. We demonstrate that this novel metric, applied to clinically available FHR temporal dynamics alone, accurately predicts the time occurrence of CVD which heralds a clinically significant degradation of the fetal health reserve to tolerate the trial of labor.


Yttrium-90 ibritumomab tiuxetan plus busulfan, cyclophosphamide, and etoposide (BuCyE) versus BuCyE alone as a conditioning regimen for non-Hodgkin lymphoma.
Radioimmunotherapy agents have a highly significant role in autologous stem cell transplantation as they improve tolerability and increase the efficacy of the conditioning regimen. We retrospectively analyzed the efficacy and toxicity of yttrium-90 ibritumomab tiuxetan (Zevalin) combined with intravenous busulfan, cyclophosphamide, and etoposide (Z-BuCyE) compared with those of BuCyE alone followed by autologous stem cell transplantation in patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL). The efficacy, toxicity, and engraftment characteristics were compared between 19 patients who received Z-BuCyE and 19 historical controls who received BuCyE. The 2 treatment groups shared similar baseline characteristics. The median time to platelet engraftment (>20×10(9)/L) and neutrophil engraftment (>0.5×10(9)/L) did not significantly differ between the Z-BuCyE group (12 days and 10 days, respectively) and the BuCyE group (12 days and 10 days, respectively). No significant differences were observed between the groups with respect to toxicities and treatment-related mortality. The median follow-up period was 30.4 months, and median event-free survival was generally better in the Z-BuCyE group (12.5 months) vs. the BuCyE group (6.2 months, P=0.236). No significant difference in overall survival between the groups was noted. Adding ibritumomab tiuxetan to BuCyE high-dose chemotherapy may benefit patients with relapsed or refractory B-cell NHL with no risk of additional toxicity.


Stent-graft placement for wide-neck aneurysm of the vertebrobasilar junction.
We present a case in which a stent-graft was used to treat an aneurysm of the vertebrobasilar junction. According to our literature search, this is one of the first cases involving the intracranial placement of a stent-graft and the first case in which an aneurysm of the vertebrobasilar junction was treated in this manner. A stent-graft can be useful device for the neuroendovascular treatment of aneurysms in select patients.


Speed Training Practices of Brazilian Olympic Sprint and Jump Coaches: Toward a Deeper Understanding of Their Choices and Insights (Part II).
This is the second article in a three-article collection regarding the plyometric, speed, and resistance training practices of Brazilian Olympic sprint and jump coaches. Here, we list and describe six out of the ten speed training methods most commonly employed by these experts to enhance the sprinting capabilities of their athletes. Maximum speed sprinting, form running, resisted sprinting, overspeed running, uphill and downhill running, and sport-specific movement methods are critically examined with reference to their potential application in different sport contexts. In an era when sprint speed is of critical importance across numerous sports, practitioners can employ the methods outlined here to design efficient training programs for their athletes.


[Systemic artery-pulmonary vein fistula. Apropos of a case].
Fistulas between a systemic artery arising from the aorta and the pulmonary vein with absence of a branch of the pulmonary artery and without abnormality of the bronchial tree are very seldom. We report the case of a child which had a continuous vascular murmur with heart failure secondary to a left-left shunt. A left inferior lobectomy was performed. The inferior lobe was the site of a huge arterio-venous fistula between an artery arising, from the aorta and the pulmonary veins.


Malaria profiles and challenges in artemisinin resistance containment in Myanmar.
This study examined evolving malaria profiles from January, 2010 to December, 2014 to evaluate achievements and challenges of implementing measures to prevent and control spread of artemisinin resistance in Myanmar. Using National Malaria Control Programme (NMCP) data, a cross-sectional descriptive study of 52 townships in artemisinin-resistant containment areas in Myanmar was conducted. Annual program data were analysed, and trends over time are graphically presented. In the 52 study townships populated by 8.7 million inhabitants, malaria incidence showed a decreasing trend from 10.54 per 1 000 population in 2010 to 2.53 in 2014, and malaria mortalities also decreased from 1.83 per 100 000 population in 2010 to 0.17 in 2014. The proportion of confirmed to total tested malaria cases also decreased from 6 to 1%, while identification of cases improved. All cases from all parasites species, including Plasmodium falciparum, decreased. Coverage of LLIN (long-lasting insecticidal net)/ITN (insecticide-treated mosquito nets) and indoor residual spraying (IRS) was high in targeted areas with at-risk persons, even though the total population was not covered. In addition to passive case detection (PCD), active case detection (ACD) was conducted in hard-to-reach areas and worksites where mobile migrant populations were present. ACD improved in most areas from 2012 to 2014, but continues to need to be strengthened. The findings provide useful data on the malaria situation in artemisinin-resistant initiative areas, which may be useful for the NMCP to meet its elimination goal. These profiles could contribute to better planning, implementation, and evaluation of intervention activities.


Laser acceleration of absorbing particles.
A Yb-doped fiber laser is used to accelerate and evaporate absorbing particles in air. Optical intensities of 1MW/cm2 and 2MW/cm2 illuminate stainless steel particles. These particles are accelerated to velocities of tens of meters per second before evaporating within a few tenths of a millisecond. Position measurements are made using direct imaging with a high-speed camera. A fundamental system of coupled differential equations to track particle momentum, velocity, mass, radius, temperature, vapor opacity, and temperature distribution is developed and shown to accurately model the trajectories and lifetimes of laser heated particles. Atoms evaporating from the particle impart momentum to the larger particle, which accelerates until it is slowed by drag forces. Heat transfer within the evaporating particles is dominated by radiation diffusion, a process that usually only dominates in astrophysical objects, for example in the photospheres of stars.


AT13148 is a novel, oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity.
Deregulated phosphatidylinositol 3-kinase pathway signaling through AGC kinases including AKT, p70S6 kinase, PKA, SGK and Rho kinase is a key driver of multiple cancers. The simultaneous inhibition of multiple AGC kinases may increase antitumor activity and minimize clinical resistance compared with a single pathway component. We investigated the detailed pharmacology and antitumor activity of the novel clinical drug candidate AT13148, an oral ATP-competitive multi-AGC kinase inhibitor. Gene expression microarray studies were undertaken to characterize the molecular mechanisms of action of AT13148. AT13148 caused substantial blockade of AKT, p70S6K, PKA, ROCK, and SGK substrate phosphorylation and induced apoptosis in a concentration and time-dependent manner in cancer cells with clinically relevant genetic defects in vitro and in vivo. Antitumor efficacy in HER2-positive, PIK3CA-mutant BT474 breast, PTEN-deficient PC3 human prostate cancer, and PTEN-deficient MES-SA uterine tumor xenografts was shown. We show for the first time that induction of AKT phosphorylation at serine 473 by AT13148, as reported for other ATP-competitive inhibitors of AKT, is not a therapeutically relevant reactivation step. Gene expression studies showed that AT13148 has a predominant effect on apoptosis genes, whereas the selective AKT inhibitor CCT128930 modulates cell-cycle genes. Induction of upstream regulators including IRS2 and PIK3IP1 as a result of compensatory feedback loops was observed. The clinical candidate AT13148 is a novel oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity, which shows a distinct mechanism of action from other AKT inhibitors. AT13148 will now be assessed in a first-in-human phase I trial.


[Inhibitory action of Fenton systems on topoisomerase I from Trypanosoma cruzi and Crithidia fasciculata]].
Fenton systems (H2O2/Fe(II) or H2O2/Cu(II)) inhibited Trypanosoma cruzi and Crithidia fasciculata topoisomerase I activity. About 61-71% inactivation was produced by 25 mM Fe(II) or Cu(II) with 3 mM H2O2. Thiol compounds and free radicals scavengers prevented the Fenton systems effects, depending on the topoisomerase assayed. With the T. cruzi enzyme, reduced glutathione, DL-dithiothreitol, cysteine and N-acetyl-L-cysteine entirely prevented the effect of the H2O2/Fe(II) system, mannitol protected 37%, whereas histidine and ethanol were ineffective. With C. fasciculata topoisomerase, reduced glutathione, DL-dithiothreitol and N-acetyl-L-cysteine protected 100%, cysteine, histidine and mannitol protected 28, 34 and 48% respectively, whereas ethanol was ineffective. With the H2O2/Cu(II) system and T. cruzi topoisomerase, DL-dithiothreitol and histidine protected 100% and 60%, respectively but the other assayed protectors were less effective. Similar results were obtained with the C. fasciculata enzyme. Topoisomerase inactivation by H2O2/Fe(II) or H2O2/Cu(II) systems was irreversible since they were not reverted by the more effective enzyme protectors. It is suggested that topoisomerases could act either as scavengers of "reactive oxygen species" (ROS) generated by Fenton systems or bind the corresponding metal ions, whose redox cycling would generate reactive oxygen species "in situ".


Prediction of Depression Scores From Aerobic Fitness, Body Fatness, Physical Activity, and Vagal Indices in Non-exercising, Female Workers.
Background: Depression is associated with a decreased cardiorespiratory fitness, and physical activity [PA] levels, higher rates of obesity, and dysfunction in autonomic control of heart rate [HR]. However, these parameters were mostly recorded with indirect methods. Thus, the aim of the current study was to investigate the relationships between depression scores and objective measures of body fatness, autonomic indices (i.e. HRV and HRR), cardiorespiratory fitness and PA levels; and subsequently to present the best predictive models of depression scores for this population, based on these variables. Methods: Thirty-five non-exercising women (26-43 years; maximal oxygen consumption [VO2max] ~ 17.4-38.3 mL/kg/min) volunteered for participation in this study. All participants responded to the Beck Depression Inventory [DBI] and were evaluated for body mass index [BMI], percentage of body fat, sum of skinfolds, and VO2max. Subsequently, over four consecutive days, an orthostatic test and a submaximal exercise on a cycle ergometer were performed to record HRV and HRR, respectively. In addition, incidental PA was recorded during 5 consecutive days using accelerometers. Results: depression scores were related to VO2max (r = -0.446, p = 0.007) and the sum of skinfolds (r = 0.434, p = 0.009). Several stepwise multiple linear regression models were performed and only VO2max was revealed as an independent predictor of the Beck scores (ß = -0.446, R 2 = 0.199, p = 0.007). Conclusion: The present study revealed that VO2max and the sum of skinfolds were moderately related to depression scores, while VO2max was the only independent predictor of depression scores in female workers.


Skin α-Synuclein Aggregation Seeding Activity as a Novel Biomarker for Parkinson Disease.
Deposition of the pathological α-synuclein (αSynP) in the brain is the hallmark of synucleinopathies, including Parkinson disease (PD), Lewy body dementia (LBD), and multiple system atrophy (MSA). Whether real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA) assays can sensitively detect skin biomarkers for PD and non-PD synucleinopathies remains unknown. To develop sensitive and specific skin biomarkers for antemortem diagnosis of PD and other synucleinopathies. This retrospective and prospective diagnostic study evaluated autopsy and biopsy skin samples from neuropathologically and clinically diagnosed patients with PD and controls without PD. Autopsy skin samples were obtained at 3 medical centers from August 2016 to September 2019, and biopsy samples were collected from 3 institutions from August 2018 to November 2019. Based on neuropathological and clinical diagnoses, 57 cadavers with synucleinopathies and 73 cadavers with nonsynucleinopathies as well as 20 living patients with PD and 21 living controls without PD were included. Specifically, cadavers and participants had PD, LBD, MSA, Alzheimer disease, progressive supranuclear palsy, or corticobasal degeneration or were nonneurodegenerative controls (NNCs). A total of 8 approached biopsy participants either refused to participate in or were excluded from this study due to uncertain clinical diagnosis. Data were analyzed from September 2019 to April 2020. Skin αSynP seeding activity was analyzed by RT-QuIC and PMCA assays. A total of 160 autopsied skin specimens from 140 cadavers (85 male cadavers [60.7%]; mean [SD] age at death, 76.8 [10.1] years) and 41 antemortem skin biopsies (27 male participants [66%]; mean [SD] age at time of biopsy, 65.3 [9.2] years) were analyzed. RT-QuIC analysis of αSynP seeding activity in autopsy abdominal skin samples from 47 PD cadavers and 43 NNCs revealed 94% sensitivity (95% CI, 85-99) and 98% specificity (95% CI, 89-100). As groups, RT-QuIC also yielded 93% sensitivity (95% CI, 85-97) and 93% specificity (95% CI, 83-97) among 57 cadavers with synucleinopathies (PD, LBD, and MSA) and 73 cadavers without synucleinopathies (Alzheimer disease, progressive supranuclear palsy, corticobasal degeneration, and NNCs). PMCA showed 82% sensitivity (95% CI, 76-88) and 96% specificity (95% CI, 85-100) with autopsy abdominal skin samples from PD cadavers. From posterior cervical and leg skin biopsy tissues from patients with PD and controls without PD, the sensitivity and specificity were 95% (95% CI, 77-100) and 100% (95% CI, 84-100), respectively, for RT-QuIC and 80% (95% CI, 49-96) and 90% (95% CI, 60-100) for PMCA. This study provides proof-of-concept that skin αSynP seeding activity may serve as a novel biomarker for antemortem diagnoses of PD and other synucleinopathies.


Treatment of Plasmodium falciparum merozoites with the protease inhibitor E64 and mechanical filtration increases their susceptibility to complement activation.
Plasmodium falciparum malaria killed 451,000 people in 2017. Merozoites, the stage of the parasite that invades RBCs, are a logical target for vaccine development. Treatment with the protease inhibitor E64 followed by filtration through a 1.2 μm filter is being used to purify merozoites for immunologic assays. However, there have been no studies to determine the effect of these treatments on the susceptibility of merozoites to complement or antibodies. To address this gap, we purified merozoites with or without E64 followed by filtration through either a 1.2 or 2.7 μm filter, or no filtration. Merozoites were then incubated in either 10% fresh or heat-inactivated serum followed by surface staining and flow cytometry with monoclonal antibodies against the complement effector molecules C3b or C5b9. To determine the effect of anti-merozoite antibodies, we incubated merozoites with MAb5.2, a mouse monoclonal antibody that targets the merozoite surface protein 1. We used an amine-reactive fluorescent dye to measure membrane integrity. Treatment with E64 resulted in an insignificant increase in the proportion of merozoites that were C3b positive but in a significant increase in the proportion that were C5b9 positive. Filtration increased the proportion of merozoites that were either C3b or C5b9-positive. The combination of filtration and E64 treatment resulted in marked deposition of C3b and C5b9. MAb5.2 induced greater complement deposition than serum alone or an IgG2b isotype control. The combination of E64 treatment, filtration, and MAb5.2 resulted in very rapid and significant deposition of C5b9. Filtration through the 1.2 μm filter selected a population of merozoites with greater membrane integrity, but their integrity deteriorated rapidly upon exposure to serum. We conclude that E64 treatment and filtration increase the susceptibility of merozoites to complement and antibody. Filtered or E64-treated merozoites are not suitable for immunologic studies that address the efficacy of antibodies in vitro.


Dementia and Hip Fractures: A Comprehensive Review of Management Approaches.
» The elderly population is the fastest growing demographic, and the number of dementia cases in the United States is expected to double to 10 million by 2050.» Patients with dementia are at 3× higher risk of hip fractures and have higher morbidity and mortality after hip fractures.» Hip fracture patients with dementia benefit from early analgesia and timely surgical fixation of fracture.» Early and intensive inpatient rehabilitation is associated with improved postoperative outcomes in patients with dementia.» Coordination of care within a "orthogeriatric" team decreases mortality, and fracture liaison services show potential for improving long-term outcomes in hip fracture patients with dementia.


The specificity of targeted vaccines for APC surface molecules influences the immune response phenotype.
Different diseases require different immune responses for efficient protection. Thus, prophylactic vaccines should prime the immune system for the particular type of response needed for protection against a given infectious agent. We have here tested fusion DNA vaccines which encode proteins that bivalently target influenza hemagglutinins (HA) to different surface molecules on antigen presenting cells (APC). We demonstrate that targeting to MHC class II molecules predominantly induced an antibody/Th2 response, whereas targeting to CCR1/3/5 predominantly induced a CD8(+)/Th1 T cell response. With respect to antibodies, the polarizing effect was even more pronounced upon intramuscular (i.m) delivery as compared to intradermal (i.d.) vaccination. Despite these differences in induced immune responses, both vaccines protected against a viral challenge with influenza H1N1. Substitution of HA with ovalbumin (OVA) demonstrated that polarization of immune responses, as a consequence of APC targeting specificity, could be extended to other antigens. Taken together, the results demonstrate that vaccination can be tailor-made to induce a particular phenotype of adaptive immune responses by specifically targeting different surface molecules on APCs.


Photoemission studies of high-tc superconductors: the superconducting gap.
Over the last several years there have been great improvements in the energy resolution and detection efficiency of angle-resolved photoemission spectroscopy. These improvements have made it possible to discover a number of fascinating features in the electronic structure of the high transition temperature (T(c)) superconductors: apparently bandlike Fermi surfaces, flat-band saddle points, and nested Fermi surface sections. Recent work suggests that these features, previously thought explainable only by one-electron band theory, may be better understood with a many-body approach. Furthermore, other properties of the high-T(c) superconductors, which are difficult to understand with band theory, are well described using a many-body picture. Angle-resolved photoemission spectroscopy has also been used to investigate the nature of the superconducting pairing state, revealing an anisotropic gap consistent with a d-wave order parameter and fueling the current debate over s-wave versus d-wave superconductivity.


CLCN7 and TCIRG1 mutations differentially affect bone matrix mineralization in osteopetrotic individuals.
Osteopetrosis is an inherited disorder of impaired bone resorption, with the most commonly affected genes being CLCN7 and TCIRG1, encoding the Cl(-) /H(+) exchanger CLC-7 and the a3 subunit of the vacuolar H(+) -ATPase, respectively. We and others have previously shown that the disease is frequently accompanied by osteomalacia, and that this additional pathology is also found in Tcirg1-deficient oc/oc mice. The remaining question was whether osteoid enrichment is specifically associated with TCIRG1 inactivation, or whether CLCN7 mutations would also cause skeletal mineralization defects. Here we describe a complete osteologic assessment of one family carrying a novel mutation in CLCN7 (D145G), which impairs the activation and relaxation kinetics of the CLC-7 ion transporter. The two siblings carrying the mutation in the homozygous state displayed high bone mass, increased serum levels of bone formation markers, but no impairment of calcium homeostasis when compared to the other family members. Most importantly, however, undecalcified processing of an iliac crest biopsy from one of the affected children clearly demonstrated a pathological increase of trabecular bone mass, but no signs of osteomalacia. Given the potential relevance of these findings we additionally performed undecalcified histology of iliac crest biopsies from seven additional cases with osteopetrosis caused by a mutation in TNFRSF11A (n=1), CLCN7 (n=3), or TCIRG1 (n=3). Here we observed that all cases with TCIRG1-dependent osteopetrosis displayed severe osteoid accumulation and decreased calcium content within the mineralized matrix. In contrast, there was no detectable bone mineralization defect in the cases with TNFRSF11A-dependent or CLCN7-dependent osteopetrosis. Taken together, our analysis demonstrates that CLCN7 and TCIRG1 mutations differentially affect bone matrix mineralization, and that there is a need to modify the current classification of osteopetrosis.


Rescuer fatigue in the elderly: standard vs. hands-only CPR.
Hands-only cardiopulmonary resuscitation (HO-CPR) is recommended as an alternative to standard CPR (STD-CPR). Studies have shown a degradation of adequate compressions with HO-CPR after 2 min when performed by young, healthy medical students. Elderly rescuers' ability to maintain an adequate compression rate and depth until emergency medical services (EMS) arrives is unknown. The specific aim of this study was to compare elderly rescuers' ability to maintain adequate compression rate and depth during HO-CPR and STD-CPR in a manikin model. In this prospective, randomized crossover study, 17 elderly volunteers performed both HO-CPR and STD-CPR, separated by at least 2 days, on a manikin model for 9 min each. The primary endpoint was the number of adequate chest compressions (> 38 mm) delivered per minute. Secondary endpoints were total compressions, compression rate, and the number of breaks taken for rest. There was no difference in the number of adequate compressions between groups in the first minute; however, the STD-CPR group delivered significantly more adequate chest compressions in minutes 2-9 (p<0.05). The total number of compressions delivered was significantly greater in the HO-CPR than STD-CPR group when considering the entire resuscitation period. A significantly greater number of rescuers took breaks for rest during HO-CPR than STD-CPR. Although HO-CPR resulted in a greater number of overall compressions than STD-CPR, STD-CPR resulted in a greater number of adequate compressions in all but the first minute of resuscitation.


Expression of brain-derived neurotrophic factors, neurotrophin-3, and neurotrophin-4 in the nucleus accumbens during heroin dependency and withdrawal.
Neurotrophins, brain-derived neurotrophic factors (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4), have been implicated in the modulation of heroin dependency. This study was designed to explore the expression alterations of BDNF, NT-3, and NT-4 in the context of heroin dependence and withdrawal in the rat nucleus accumbens (NAc). Heroin dependence was induced by a progressive intraperitoneal treatment of heroin. The results showed that the expression levels of BDNF and NT-4 were significantly decreased in the NAc of rats with heroin addiction in comparison with the control group, whereas there was a significant increase in BDNF and NT-4 expressions in the groups of rats with both naloxone-induced and spontaneous withdrawal. Moreover, NT-3 expression was markedly increased in the NAc of rats with heroin addiction and spontaneous withdrawal in comparison with the control group, but decreased in the NAc of rats with naloxone-induced withdrawal. These results indicated that chronic administration of heroin results in the alterations of BDNF, NT-3, and NT-4 expressions in the rat NAc. BDNF, NT-3, and NT-4 may play a critical role in the development of heroin dependency and withdrawal.


Capsaicin for non-allergic rhinitis.
There are many forms of rhinitis. Patients are diagnosed with non-allergic rhinitis when anatomic, infectious and allergic aetiologies have been excluded. The symptoms, including nasal congestion, blockage or obstruction, clear rhinorrhoea, sneezing and, less frequently, nasal itching, can range from mild to debilitating. It affects between 25% and 50% of patients with rhinitis. Several medications are widely used in the treatment of non-allergic rhinitis, including oral and topical nasal antihistamines, intranasal and (rarely) systemic corticosteroids, and anticholinergics. Capsaicin, the active component of chili peppers, delivered intranasally, is considered a treatment option for non-allergic rhinitis. To assess the effectiveness of capsaicin in the management of non-allergic rhinitis compared with no therapy, placebo or other topical or systemic medications, or two or more of the above therapies in combination, or different capsaicin regimens. We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 5); PubMed; EMBASE; CINAHL; Web of Science; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the search was 24 June 2015. Randomised controlled trials in adult patients with non-allergic rhinitis comparing intranasal capsaicin with no therapy, placebo or other topical or systemic medications, or their combinations. We used the standard methodological procedures expected by The Cochrane Collaboration. We included four studies (five publications) involving 302 participants with idiopathic non-allergic rhinitis. All the included studies described patients with moderately severe, idiopathic non-allergic rhinitis who were between the ages of 16 and 65. Studies had follow-up periods ranging from four to 38 weeks. The overall risk of bias in the studies was either high or unclear (two studies had overall high risk of bias, while two others had low to unclear risk of bias). Using the GRADE system we assessed the evidence as being of low to moderate quality. A meta-analysis was not possible, given lack of similarity of the reported outcomes.Two studies compared capsaicin with placebo. One study reported that capsaicin resulted in an improvement of overall nasal symptoms (a primary outcome) measured on a visual analogue scale (VAS) of 0 to 10. There was a mean difference (MD) of -3.34 (95% confidence interval (CI) -5.24 to -1.44), MD -3.73 (95% CI -5.45 to -2.01) and MD -3.52 (95% CI -5.55 to -1.48) at two, 12 and 36 weeks post-treatment, respectively. Another study reported that, compared to placebo, capsaicin (at 4 µg/puff) was more likely to produce overall symptom resolution (reduction in nasal blockage, sneezing/itching/coughing and nasal secretion measured with a daily record chart) at four weeks post-treatment (a primary outcome). The risk ratio (RR) was 3.17 (95% CI 1.38 to 7.29).One study compared capsaicin to budesonide (an intranasal corticosteroid). This study found that patients treated with capsaicin had a better overall symptom score compared to those treated with budesonide (MD 2.50, 95% CI 1.06 to 3.94, VAS of 0 to 10). However, there were no differences in the individual symptom scores for headache, postnasal drip, rhinorrhoea, nasal blockage, sneezing and sore throat assessed during the last three days of a four-week treatment.One study compared two different regimens of capsaicin administration: five treatments in one day versus five treatments given every two to three days during two weeks. Using daily record charts, the study reported significant improvement of individual symptom scores for rhinorrhoea in patients treated five times per day, however numerical data were not presented. There were no improvements in the other outcomes: rhinorrhoea, nasal obstruction, sneezing and overall nasal symptoms, measured on a VAS.Finally, one of these studies also compared three doses of capsaicin (to placebo). Patients treated with a 1 µg versus 4 µg per puff dose of capsaicin had a worse daily record chart overall symptom score resolution (RR 0.63, 95% CI 0.34 to 1.16).Only one study attempted to measure adverse effects (a primary outcome), however due to methodological issues with the assessment we are unable to draw any conclusions.We sought to include other secondary outcomes (e.g. quality of life measures, treatment dropouts, endoscopic scores, turbinate or mucosal size, cost of therapy), but none of these were measured or reported in the included studies. Capsaicin may be an option in the treatment of idiopathic non-allergic rhinitis. It is given in the form of brief treatments, usually during the same day. It appears to have beneficial effects on overall nasal symptoms up to 36 weeks after treatment, based on a few, small studies (low-quality evidence). Well-conducted randomised controlled trials are required to further advance our understanding of the effectiveness of capsaicin in non-allergic rhinitis, especially in patients with non-allergic rhinitis of different types and severity, and using different methods of capsaicin application.


Continuing competency in orthopaedics: the future of recertification.
The American Board of Orthopaedic Surgery implemented a recertification program in 1986. This process has expanded to include a number of examination pathways that take into account subspecialty practices. Over the past two decades, general competencies of physicians have been defined and programs for evaluation and maintenance of these competencies developed. In an effort to have a more continuous process rather than episodic examinations only, and stimulate lifelong learning and practice improvement, recertification is now undergoing transformation to a Maintenance of Certification program. Maintenance of Certification as a process will emphasize ongoing self-assessment and lifelong learning, with required components occurring more frequently during the 10 year recertification cycle. Patient satisfaction and communication surveys will be incorporated to provide feedback to physicians to improve practice performance. Case list reviews, with a focus on patient safety measures, will also be a new addition to the process.


A Quality by Experimental Design Approach to Assess the Effect of Formulation and Process Variables on the Extrusion and Spheronization of Drug-Loaded Pellets Containing Polyplasdone® XL-10.
Successful pellet production has been reported in literature with cross-linked poly(vinylpyrrolidone), Polyplasdone® XL-10 and INF-10. In the present study, a quality by experimental design approach was used to assess several formulation and process parameter effects on the characteristics of Polyplasdone® XL-10 pellets, including pellet size, shape, yield, usable yield, friability, and number of fines. The hypothesis is that design of experiments and appropriate data analysis allow optimization of the Polyplasdone product. High drug loading was achieved using caffeine, a moderately soluble drug to allow in vitro release studies. A five-factor, two-level, half-fractional factorial design (Resolution V) with center point batches allowed mathematical modeling of the influence of the factors and their two-factor interactions on five of the responses. The five factors were Polyplasdone® level in the powder blend, volume of water in the wet massing step, wet mixing time, spheronizer speed, and spheronization time. Each factor and/or its two-factor interaction with another factor influenced pellet characteristics. The behavior of these materials under various processing conditions and component levels during extrusion-spheronization have been assessed, discussed, and explained based on the results. Numerical optimization with a desirability of 0.974 was possible because curvature and lack of fit were not significant with any of the model equations. The values predicted by the optimization described well the observed responses. The hypothesis was thus supported.


Biocompatible conjugation of Tris base to 2-acetyl and 2-formyl phenylboronic acid.
We describe the biocompatible conjugation of the Tris base to 2-formyl and 2-acetylphenylboronic acid (abbreviated as 2-FPBA and 2-APBA respectively), which have emerged as a versatile chemotype for fast biocompatible conjugation reactions. Tris base was found to react with 2-FPBA/APBA to give oxazolidinoboronate (OzB) complexes, analogous to the thiazolidinoboronate (TzB) and imidazolidinoboronate (IzB) complex formation that we recently reported. The Tris conjugations proceed well in complex biological media, and in contrast to the TzB/IzB complexes, the Tris conjugates exhibit superior kinetic stability (dissociation over days) as well as chemical stability against oxidation. We demonstrate the utility of such conjugation chemistries via a small molecule-induced peptide cyclization in blood serum.


[Exponential growth of cell numbers. II. Cell death immediately after mitosis].
A mathematical model was examined of the exponential growth state of the cell number (N) with the proliferative pool Pc greater than or equal to 1, the non-zero variability of the phase duration of the mitotic cycle and with the cell death immediately after mitosis. At this state it is impossible to calculate the cell loss factor phi from Steel's formula (1968). A method was proposed for calculation of phi, Pc and the potential doubling time (tDpot) of N (and the mean duration of mitosis, tM), provided the doubling time of N, the indexes of S- and M-phase, the mean durations of mitotic cycle and of S, G2- and M-phases (or G2 + 0.5 M)-phase) are known from experimental data. The approximate values of phi, Pc, tDpot and tM were calculated for six solid transplanted tumors. It is noticed that using this mathematical model the cell kinetics was described satisfactory for not all the tumours examined.


Introducing a digital portal that enables patients to access their health records.
People manage many aspects of their lives online through digital devices such as smartphones. However, the ability for people to manage their healthcare digitally has not yet been fully realised. Patient portals are secure online links that offer patients convenient and constant access to their personal health records. Evidence has suggested that patient portals can enhance patients' engagement in their own care and support them to manage any long-term conditions. This article describes the introduction of a patient portal at Cambridge University Hospitals NHS Foundation Trust. The article outlines the process of implementation and discusses the lessons learned, which may be of value to other organisations.


Impact on behavioral changes due to chronic use of sertraline in Wistar albino rats.
Despite having better tolerability and a wide range of clinical applications over other antidepressants, selective serotonin reuptake inhibitors (SSRIs) are also known to be associated with serious adverse effects like suicidal ideation on chronic use. The present study had explored the impact of the chronic use of sertraline, an SSRI, on the behavioral changes in Wistar albino rats. The study was conducted on 30 Wistar albino rats of either sex; divided into five groups. Four groups were subjected to chronic mild stress induced by using various stressors randomly scheduled in a week and continued for a period of 3 weeks. The stressed rodents were subjected to sertraline treatment for 9 weeks in different human therapeutic doses extrapolated to animal doses. Behavioral changes were monitored, assessed, and evaluated throughout the treatment phase with the help of tests such as locomotor activity test, forced swim test, tail suspension test, antianxiety test, and sucrose preference test (SPT). All tests except SPT, demonstrated significant (P < 0.05) reduction in depressive-like activity in the stressed rodents by the mid-treatment phase, followed by an abrupt onset of the depressive state by the end of the treatment phase. SPT showed a significant (P < 0.05) increase in sucrose consumption throughout the treatment phase. Behavioral changes following chronic sertraline administration conferred gradual remission of depression state on initial treatment phase, followed by a reversal of effect on chronic use.


Functional source separation from magnetoencephalographic signals.
We propose a novel cerebral source extraction method (functional source separation, FSS) starting from extra-cephalic magnetoencephalographic (MEG) signals in humans. It is obtained by adding a functional constraint to the cost function of a basic independent component analysis (ICA) model, defined according to the specific experiment under study, and removing the orthogonality constraint, (i.e., in a single-unit approach, skipping decorrelation of each new component from the subspace generated by the components already found). Source activity was obtained all along processing of a simple separate sensory stimulation of thumb, little finger, and median nerve. Being the sources obtained one by one in each stage applying different criteria, the a posteriori "interesting sources selection" step is avoided. The obtained solutions were in agreement with the homuncular organization in all subjects, neurophysiologically reacting properly and with negligible residual activity. On this basis, the separated sources were interpreted as satisfactorily describing highly superimposed and interconnected neural networks devoted to cortical finger representation. The proposed procedure significantly improves the quality of the extraction with respect to a standard BSS algorithm. Moreover, it is very flexible in including different functional constraints, providing a promising tool to identify neuronal networks in very general cerebral processing.


The role of beta-lactam/beta-lactamase inhibitors in the management of mixed infections.
Microbiological studies show that the in vitro antimicrobial activity of sulbactam-ampicillin encompasses not only gram-positive and gram-negative aerobes, but also anaerobes. Such a broad spectrum of activity suggests its suitability as monotherapy for the empiric management of polymicrobial infections. Typical mixed infections, which are frequently life-threatening, include those occurring in the abdomen or pelvis, diabetic foot infections, and brain abscess. Numerous comparative clinical studies have revealed the clinical and bacteriological efficacy of sulbactam-ampicillin to be comparable to that of imipenem cilastatin and the second-generation cephalosporins cefoxitin and cefotetan. In addition, other studies have demonstrated that sulbactam-ampicillin monotherapy is cost-beneficial. A reduction in the duration of hospitalization, the lack of potentially toxic side-effects, and lower drug costs associated with monotherapy all contribute to the cost-effectiveness of sulbactam-ampicillin.


[Skin temperature and the hot water test in the diagnosis of injuries to the median, ulnar and tibial nerves].
In 289 patients with a complete anatomical interruption of the median, ulnar and tibial nerves from 1 month to 2 years following the trauma the author determined the skin temperature in the autonomous zone and in the one of a maximum drop of sensibility. Anesthesia, a temperature drop on the average from 1.4 +/- 0.5--2.2 +/-0.5 degrees C, the absence of skin folds and a pinck color in thermal tests clarify the diagnosis of a complete anatomical interruption of the median or ulnar nerve. In lesions of both nerves, especially in combination with lesions of the arteries, the skin temperature is lower than that in an isolated damage of one of the neves. In most of the patients with an interruption of the tibial nerve the skin temperature in the autonomous zone is higher and there are no skin folds in the autonomous zones in thermal tests. Skin temperature measurements and thermal tests are simple objective methods in the diagnosis of nerve lesions.


Why is the measurement of jugular venous pressure discredited?
Every doctor should be able to make a probable diagnosis of congestive heart failure by clinical examination. The most revealing clinical sign is an elevated jugular venous pressure. The measurement of this pressure was introduced by Lewis in 1930 and refined and standardised by Borst and Molhuysen in 1952. Still, this method has fallen into disuse and is thought to be not very sensitive for diagnosing congestive heart failure. A study of the methods described in the literature reveals that variations in technique are responsible for great differences in normal values. It is argued that smaller elevations of jugular venous pressure can only be measured reliably by adhering strictly to the conditions put forward by Borst and Molhuysen. In this way the sensitivity will improve considerably. A plea is made for an intensive training in this method for doctors and medical students.


Synergistic Combination of Polymyxin B and Enrofloxacin Induced Metabolic Perturbations in Extensive Drug-Resistant Pseudomonas aeruginosa.
Polymyxins are used as a last-resort class of antibiotics against multidrug-resistant (MDR) Gram-negative Pseudomonas aeruginosa. As polymyxin monotherapy is associated with potential development of resistance, combination therapy is highly recommended. This study investigated the mechanism underlying the synergistic killing of polymyxin B and enrofloxacin against extensive drug-resistant (XDR) P. aeruginosa. An XDR isolate P. aeruginosa 12196 was treated with clinically relevant concentrations of polymyxin B (2 mg/L) and enrofloxacin (1 mg/L) alone or in combination. Metabolome profiles were investigated from bacterial samples collected at 1-and 4-h posttreatment using liquid chromatography with tandem mass spectrometry (LC-MS/MS), and data were analyzed using univariate and multivariate statistics. Significantly perturbed metabolites (q < 0.05, fold change ≥ 2) were subjected to pathway analysis. The synergistic killing by polymyxin B-enrofloxacin combination was initially driven by polymyxin B as indicated by the perturbation of lipid metabolites at 1 h in particular. The killing was subsequently driven by enrofloxacin via the inhibition of DNA replication, resulting in the accumulation of nucleotides at 4 h. Furthermore, the combination uniquely altered levels of metabolites in energy metabolism and cell envelope biogenesis. Most importantly, the combination significantly minimized polymyxin resistance via the inhibition of lipid A modification pathway, which was most evident at 4 h. This is the first study to elucidate the synergistic mechanism of polymyxin B-enrofloxacin combination against XDR P. aeruginosa. The metabolomics approach taken in this study highlights its power to elucidate the mechanism of synergistic killing by antibiotic combinations at the systems level.


Characterization of rat kidney proximal tubule brush border membrane-associated phosphatidylinositol phosphodiesterase.
Isolated rat kidney proximal tubule brush border membrane vesicles exhibit an increase in diacylglycerol levels (20- to 30-fold) and a concomitant decrease in phosphatidylinositol when incubated with [3H]arachidonate-labeled lipids, Ca2+, and deoxycholate. Levels of free arachidonate, triglyceride, and noninositol phospholipids are not altered. These results suggest phosphatidylinositol phosphodiesterase activity is associated with rat proximal tubule brush border membrane. Presence of both deoxycholate and certain divalent cations was necessary to demonstrate enzyme activity. Optimum pH ranged from 7.0 to 8.5. Ca2+, Mg2+, and Mn2+ stimulated diglyceride production while Ba2+, Zn2+, Hg2+, and K+ were ineffective. HgCl2 inhibited Ca2+-stimulated phosphatidylinositol phosphodiesterase. Mg2+ and deoxycholate-dependent enzyme activity was shown to be phosphatidylinositol specific. Sodium lauryl sulfate, tetradecyltrimethylammonium bromide, and Triton X-100 did not activate phosphatidylinositol phosphodiesterase in the presence of Ca2+. In combination with deoxycholate, diglyceride formation was not affected by sodium lauryl sulfate, partially inhibited by Triton X-100, and completely abolished by tetradecyltrimethylammonium bromide. Diglyceride kinase activity was not found associated with brush border membrane phosphatidylinositol phosphodiesterase. ATP (1-5 mM) inhibited Ca2+- or Mg2+-stimulated, deoxycholate-dependent phosphatidylinositol hydrolysis by chelating the required divalent cation.