Different agonists induce distinct single-channel conductance states in TRPV1 channels.
The TRPV1 ion channel is a membrane protein that is expressed in primary afferent nociceptors, where it is activated by a diverse array of stimuli. Our prior work has shown that this channel is activated by lysophosphatidic acid (LPA), an unsaturated lysophospholipid that is produced endogenously and released under certain pathophysiological conditions, resulting in the sensation of pain. Macroscopic currents activated by saturating concentrations of LPA applied to excised membrane patches are larger in magnitude than those activated by saturating concentrations of capsaicin, which causes near-maximal TRPV1 open probability. Here we show that activation of TRPV1 by LPA is associated with a higher single-channel conductance than activation by capsaicin. We also observe that the effects of LPA on TRPV1 are not caused by an increase in the surface charge nor are they mimicked by a structurally similar lipid, ruling out the contribution of change in membrane properties. Finally, we demonstrate that the effects of LPA on the unitary conductance of TRPV1 depend upon the presence of a positively charged residue in the C terminus of the channel, suggesting that LPA induces a distinct conformational change.


Quantitative network signal combinations downstream of TCR activation can predict IL-2 production response.
Proximal signaling events activated by TCR-peptide/MHC (TCR-pMHC) binding have been the focus of intense ongoing study, but understanding how the consequent downstream signaling networks integrate to govern ultimate avidity-appropriate TCR-pMHC T cell responses remains a crucial next challenge. We hypothesized that a quantitative combination of key downstream network signals across multiple pathways must encode the information generated by TCR activation, providing the basis for a quantitative model capable of interpreting and predicting T cell functional responses. To this end, we measured 11 protein nodes across six downstream pathways, along five time points from 10 min to 4 h, in a 1B6 T cell hybridoma stimulated by a set of three myelin proteolipid protein 139-151 altered peptide ligands. A multivariate regression model generated from this data compendium successfully comprehends the various IL-2 production responses and moreover successfully predicts a priori the response to an additional peptide treatment, demonstrating that TCR binding information is quantitatively encoded in the downstream network. Individual node and/or time point measurements less effectively accounted for the IL-2 responses, indicating that signals must be integrated dynamically across multiple pathways to adequately represent the encoded TCR signaling information. Of further importance, the model also successfully predicted a priori direct experimental tests of the effects of individual and combined inhibitors of the MEK/ERK and PI3K/Akt pathways on this T cell response. Together, our findings show how multipathway network signals downstream of TCR activation quantitatively integrate to translate pMHC stimuli into functional cell responses.


Modeling Staphylococcus epidermidis-Induced Non-Unions: Subclinical and Clinical Evidence in Rats.
S. epidermidis is one of the leading causes of orthopaedic infections associated with biofilm formation on implant devices. Open fractures are at risk of S. epidermidis transcutaneous contamination leading to higher non-union development compared to closed fractures. Although the role of infection in delaying fracture healing is well recognized, no in vivo models investigated the impact of subclinical low-grade infections on bone repair and non-union. We hypothesized that the non-union rate is directly related to the load of this commonly retrieved pathogen and that a low-grade contamination delays the fracture healing without clinically detectable infection. Rat femurs were osteotomized and stabilized with plates. Fractures were infected with a characterized clinical-derived methicillin-resistant S. epidermidis (10(3), 10(5), 10(8) colony forming units) and compared to uninfected controls. After 56 days, bone healing and osteomyelitis were clinically assessed and further evaluated by micro-CT, microbiological and histological analyses. The biofilm formation was visualized by scanning electron microscopy. The control group showed no signs of infection and a complete bone healing. The 10(3) group displayed variable response to infection with a 67% of altered bone healing and positive bacterial cultures, despite no clinical signs of infection present. The 10(5) and 10(8) groups showed severe signs of osteomyelitis and a non-union rate of 83-100%, respectively. The cortical bone reaction related to the periosteal elevation in the control group and the metal scattering detected by micro-CT represented limitations of this study. Our model showed that an intra-operative low-grade S. epidermidis contamination might prevent the bone healing, even in the absence of infectious signs. Our findings also pointed out a dose-dependent effect between the S. epidermidis inoculum and non-union rate. This pilot study identifies a relevant preclinical model to assess the role of subclinical infections in orthopaedic and trauma surgery and to test specifically designed diagnostic, prevention and therapeutic strategies.


Cytokine and Antibody Based Diagnostic Algorithms for Sputum Culture-Positive Pulmonary Tuberculosis.
Tuberculosis (TB) is one of the most serious infectious diseases globally and has high mortality rates. A variety of diagnostic tests are available, yet none are wholly reliable. Serum cytokines, although significantly and frequently induced by different diseases and thus good biomarkers for disease diagnosis and prognosis, are not sufficiently disease-specific. TB-specific antibody detection, on the other hand, has been reported to be highly specific but not sufficiently sensitive. In this study, our aim was to improve the sensitivity and specificity of TB diagnosis by combining detection of TB-related cytokines and TB-specific antibodies in peripheral blood samples. TB-related serum cytokines were screened using a human cytokine array. TB-related cytokines and TB-specific antibodies were detected in parallel with microarray technology. The diagnostic performance of the new protocol for active TB was systematically compared with other traditional methods. Here, we show that cytokines I-309, IL-8 and MIG are capable of distinguishing patients with active TB from healthy controls, patients with latent TB infection, and those with a range of other pulmonary diseases, and that these cytokines, and their presence alongside antibodies for TB-specific antigens Ag14-16kDa, Ag32kDa, Ag38kDa and Ag85B, are specific markers for active TB. The diagnostic protocol for active TB developed here, which combines the detection of three TB-related cytokines and TB-specific antibodies, is highly sensitive (91.03%), specific (90.77%) and accurate (90.87%). Our results show that combining detection of TB-related cytokines and TB-specific antibodies significantly enhances diagnostic accuracy for active TB, providing greater accuracy than conventional diagnostic methods such as interferon gamma release assays (IGRAs), TB antibody Colloidal Gold Assays and microbiological culture, and suggest that this diagnostic protocol has potential for clinical application.


High throughput modifications of single-strand conformation polymorphism analysis : mutation detection in familial hypercholesterolemia.
In most patients with familial hypercholesterolemia (FH) the disorder is caused by a mutation in the gene coding for the low density lipoprotein receptor (LDL-R) (1). The variety of different defects observed in receptor function at the cellular level reflects mutations in different domains of the gene, and there is an increasing number of pointers to suggest that genetic factors influence clinical severity. The diagnosis of FH on clinical grounds is not 100% accurate, and some hypercholesterolemic individuals may not have a mutation in the LDL-R gene, whereas some individuals who would not be included in the clinical criteria do have such a mutation. The purpose of this chapter is to Illustrate the use of the single-strand conformational polymorphism (SSCP) technique for mutation screening in the LDL-R gene and to discuss several adaptations of published methods that improve throughput, and that we believe are appropriate for a disorder such as FH. In the next few years such techniques will help to tackle molecular diagnosis and family tracing in the large number of FH patients present in Europe and North America.


Evaluation of the CHUMS Child Bereavement Group: A Pilot Study Examining Statistical and Clinical Change.
This article describes the largest evaluation of a UK child bereavement service to date. Change was assessed using conventional statistical tests as well as clinical significance methodology. Consistent with the fact that the intervention was offered on a universal, preventative basis, bereaved young people experienced a statistically significant, small to medium-sized decrease in symptoms over time. This change was equivalent across child age and gender. Type of bereavement had a slight impact on change when rated by parents. Potential clinical implications are highlighted, and various limitations are discussed that we hope to address using an experimental design in future research.


Modular detergents tailor the purification and structural analysis of membrane proteins including G-protein coupled receptors.
Detergents enable the purification of membrane proteins and are indispensable reagents in structural biology. Even though a large variety of detergents have been developed in the last century, the challenge remains to identify guidelines that allow fine-tuning of detergents for individual applications in membrane protein research. Addressing this challenge, here we introduce the family of oligoglycerol detergents (OGDs). Native mass spectrometry (MS) reveals that the modular OGD architecture offers the ability to control protein purification and to preserve interactions with native membrane lipids during purification. In addition to a broad range of bacterial membrane proteins, OGDs also enable the purification and analysis of a functional G-protein coupled receptor (GPCR). Moreover, given the modular design of these detergents, we anticipate fine-tuning of their properties for specific applications in structural biology. Seen from a broader perspective, this represents a significant advance for the investigation of membrane proteins and their interactions with lipids.


Development of a fall-risk self-assessment for community-dwelling seniors.
To determine seniors' beliefs about falls and design a fall-risk self-assessment and educational materials to promote early identification of evidence-based fall risks and encourage prevention behaviors. Focus groups with community-dwelling seniors, conducted in two phases to identify perceptions about fall risks and risk reduction and to assess face validity of the fall-risk self-assessment and acceptability of educational materials. Lay perception of fall risks was in general concordance with evidence-based research. Maintaining independence and positive tone were perceived as key motivators for fall prevention. Seniors intended to use information in the educational tool to stimulate discussions about falls with health care providers. An evidence-based, educational fall-risk self-assessment acceptable to older adults can build on existing lay knowledge about fall risks and perception that falls are a relevant problem and can educate seniors about their specific risks and how to minimize them.


Associations between ozone and morbidity using the Spatial Synoptic Classification system.
Synoptic circulation patterns (large-scale tropospheric motion systems) affect air pollution and, potentially, air-pollution-morbidity associations. We evaluated the effect of synoptic circulation patterns (air masses) on the association between ozone and hospital admissions for asthma and myocardial infarction (MI) among adults in North Carolina. Daily surface meteorology data (including precipitation, wind speed, and dew point) for five selected cities in North Carolina were obtained from the U.S. EPA Air Quality System (AQS), which were in turn based on data from the National Climatic Data Center of the National Oceanic and Atmospheric Administration. We used the Spatial Synoptic Classification system to classify each day of the 9-year period from 1996 through 2004 into one of seven different air mass types: dry polar, dry moderate, dry tropical, moist polar, moist moderate, moist tropical, or transitional. Daily 24-hour maximum 1-hour ambient concentrations of ozone were obtained from the AQS. Asthma and MI hospital admissions data for the 9-year period were obtained from the North Carolina Department of Health and Human Services. Generalized linear models were used to assess the association of the hospitalizations with ozone concentrations and specific air mass types, using pollutant lags of 0 to 5 days. We examined the effect across cities on days with the same air mass type. In all models we adjusted for dew point and day-of-the-week effects related to hospital admissions. Ozone was associated with asthma under dry tropical (1- to 5-day lags), transitional (3- and 4-day lags), and extreme moist tropical (0-day lag) air masses. Ozone was associated with MI only under the extreme moist tropical (5-day lag) air masses. Elevated ozone levels are associated with dry tropical, dry moderate, and moist tropical air masses, with the highest ozone levels being associated with the dry tropical air mass. Certain synoptic circulation patterns/air masses in conjunction with ambient ozone levels were associated with increased asthma and MI hospitalizations.


Numerical Simulation of a Passive Control of the Flow Around an Aerofoil Using a Flexible, Self Adaptive Flaplet.
Self-activated feathers are used by almost all birds to adapt their wing characteristics to delay stall or to moderate its adverse effects (e.g., during landing or sudden increase in angle of attack due to gusts). Some of the feathers are believed to pop up as a consequence of flow separation and to interact with the flow and produce beneficial modifications of the unsteady vorticity field. The use of self adaptive flaplets in aircrafts, inspired by birds feathers, requires the understanding of the physical mechanisms leading to the mentioned aerodynamic benefits and the determination of the characteristics of optimal flaps including their size, positioning and ideal fabrication material. In this framework, this numerical study is divided in two parts. Firstly, in a simplified scenario, we determine the main characteristics that render a flap mounted on an aerofoil at high angle of attack able to deliver increased lift and improved aerodynamic efficiency, by varying its length, position and its natural frequency. Later on, a detailed direct numerical simulation analysis is used to understand the origin of the aerodynamic benefits introduced by the flaplet movement induced by the interaction with the flow field. The parametric study that has been carried out, reveals that an optimal flap can deliver a mean lift increase of about 20% on a NACA0020 aerofoil at an incidence of 20 o degrees. The results obtained from the direct numerical simulation of the flow field around the aerofoil equipped with the optimal flap at a chord Reynolds number of 2 × 104 shows that the flaplet movement is mainly induced by a cyclic passage of a large recirculation bubble on the aerofoil suction side. In turns, when the flap is pushed downward, the induced plane jet displaces the trailing edge vortices further downstream, away from the wing, moderating the downforce generated by those vortices and regularising the shedding cycle that appears to be much more organised when the optimal flaplet configuration is selected.


Associations between Genetically Predicted Blood Protein Biomarkers and Pancreatic Cancer Risk.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with few known risk factors and biomarkers. Several blood protein biomarkers have been linked to PDAC in previous studies, but these studies have assessed only a limited number of biomarkers, usually in small samples. In this study, we evaluated associations of circulating protein levels and PDAC risk using genetic instruments. To identify novel circulating protein biomarkers of PDAC, we studied 8,280 cases and 6,728 controls of European descent from the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium, using genetic instruments of protein quantitative trait loci. We observed associations between predicted concentrations of 38 proteins and PDAC risk at an FDR of < 0.05, including 23 of those proteins that showed an association even after Bonferroni correction. These include the protein encoded by ABO, which has been implicated as a potential target gene of PDAC risk variant. Eight of the identified proteins (LMA2L, TM11D, IP-10, ADH1B, STOM, TENC1, DOCK9, and CRBB2) were associated with PDAC risk after adjusting for previously reported PDAC risk variants (OR ranged from 0.79 to 1.52). Pathway enrichment analysis showed that the encoding genes for implicated proteins were significantly enriched in cancer-related pathways, such as STAT3 and IL15 production. We identified 38 candidates of protein biomarkers for PDAC risk. This study identifies novel protein biomarker candidates for PDAC, which if validated by additional studies, may contribute to the etiologic understanding of PDAC development.


[Our experience of spinal anesthesia for transurethral resection of the bladder and prostate. Retrospective study of 334 patients operated in 1986].
Retrospective study of one years is performed on 334 patients who undergo transurethral surgery. Spinal anesthesia is used in 263 cases, general anesthesia in 71. Spinal administration of local anesthetics (lidocaine hyperbaric 5% or bupivacaine 0.5%) or opioid (Pethidine 1 mg/kg) have been used in old patients without any complication. The advantages are less blood uses, early stand up, no discontinuity in oral nutrition. For our team there are only few contra-indications for spinal anesthesia: blood coagulation abnormalities or some very rare heart diseases.


An enigmatic decoupling between heat stress and coral bleaching on the Great Barrier Reef.
Ocean warming threatens the functioning of coral reef ecosystems by inducing mass coral bleaching and mortality events. The link between temperature and coral bleaching is now well-established based on observations that mass bleaching events usually occur when seawater temperatures are anomalously high. However, times of high heat stress but without coral bleaching are equally important because they can inform an understanding of factors that regulate temperature-induced bleaching. Here, we investigate the absence of mass coral bleaching on the Great Barrier Reef (GBR) during austral summer 2004. Using four gridded sea surface temperature data products, validated with in situ temperature loggers, we demonstrate that the summer of 2004 was among the warmest summers of the satellite era (1982-2017) on the GBR. At least half of the GBR experienced temperatures that were high enough to initiate bleaching in other years, yet mass bleaching was not reported during 2004. The absence of bleaching is not fully explained by wind speed or cloud cover. Rather, 2004 is clearly differentiated from bleaching years by the slow speed of the East Australian Current (EAC) offshore of the GBR. An anomalously slow EAC during summer 2004 may have dampened the upwelling of nutrient-rich waters onto the GBR shelf, potentially mitigating bleaching due to the lower susceptibility of corals to heat stress in low-nutrient conditions. Although other factors such as irradiance or acclimatization may have played a role in the absence of mass bleaching, 2004 remains a key case study for demonstrating the dynamic nature of coral responses to marine heatwaves.


Sample matching by inferred agonal stress in gene expression analyses of the brain.
Gene expression patterns in the brain are strongly influenced by the severity and duration of physiological stress at the time of death. This agonal effect, if not well controlled, can lead to spurious findings and diminished statistical power in case-control comparisons. While some recent studies match samples by tissue pH and clinically recorded agonal conditions, we found that these indicators were sometimes at odds with observed stress-related gene expression patterns, and that matching by these criteria still sometimes results in identifying case-control differences that are primarily driven by residual agonal effects. This problem is analogous to the one encountered in genetic association studies, where self-reported race and ethnicity are often imprecise proxies for an individual's actual genetic ancestry. We developed an Agonal Stress Rating (ASR) system that evaluates each sample's degree of stress based on gene expression data, and used ASRs in post hoc sample matching or covariate analysis. While gene expression patterns are generally correlated across different brain regions, we found strong region-region differences in empirical ASRs in many subjects that likely reflect inter-individual variabilities in local structure or function, resulting in region-specific vulnerability to agonal stress. Variation of agonal stress across different brain regions differs between individuals, revealing a new level of complexity for gene expression studies of brain tissues. The Agonal Stress Ratings quantitatively assess each sample's extent of regulatory response to agonal stress, and allow a strong control of this important confounder.


Imprinted-like biopolymeric micelles as efficient nanovehicles for curcumin delivery.
To enhance the solubility and improve the bioavailability of hydrophobic curcumin, a new kind of imprinted-like biopolymeric micelles (IBMs) was designed. The IBMs were prepared via co-assembly of gelatin-dextran conjugates with hydrophilic tea polyphenol, then crosslinking the assembled micelles and finally removing the template tea polyphenol by dialysis. The obtained IBMs show selective binding for polyphenol analogous drugs over other drugs. Furthermore, curcumin can be effectively encapsulated into the IBMs with 5×10(4)-fold enhancement of aqueous solubility. We observed the sustained drug release behavior from the curcumin-loaded IBMs (CUR@IBMs) in typical biological buffers. In addition, we found the cell uptake of CUR@IBMs is much higher than that of free curcumin. The cell cytotoxicity results illustrated that CUR@IBMs can improve the growth inhibition of HeLa cells compared with free curcumin, while the blank IBMs have little cytotoxicity. The in vivo animal study demonstrated that the IBMs could significantly improve the oral bioavailability of curcumin.


Conservation of a CD1 multigene family in the guinea pig.
CD1 is a family of cell-surface molecules capable of presenting microbial lipid Ags to specific T cells. Here we describe the CD1 gene family of the guinea pig (Cavia porcellus). Eight distinct cDNA clones corresponding to CD1 transcripts were isolated from a guinea pig thymocyte cDNA library and completely sequenced. The guinea pig CD1 proteins predicted by translation of the cDNAs included four that can be classified as homologues of human CD1b, three that were homologues of human CD1c, and a single CD1e homologue. These guinea pig CD1 protein sequences contain conserved amino acid residues and hydrophobic domains within the putative Ag binding pocket. A mAb specific for human CD1b cross-reacted with multiple guinea pig CD1 isoforms, thus allowing direct analysis of the structure and expression of at least a subset of guinea pig CD1 proteins. Cell-surface expression of CD1 was detected on cortical thymocytes, dermal dendritic cells in the skin, follicular dendritic cells of lymph nodes, and in the B cell regions within the lymph nodes and spleen. CD1 proteins were also detected on a subset of PBMCs consistent with expression on circulating B cells. This distribution of CD1 staining in guinea pig tissues was thus similar to that seen in other mammals. These data provide the foundation for the development of the guinea pig as an animal model to study the in vivo function of CD1.


Nurses and subordination: a historical study of mental nurses' perceptions on administering aversion therapy for 'sexual deviations'.
This study aimed to examine the meanings that nurses attached to the 'treatments' administered to cure 'sexual deviation' (SD) in the UK, 1935-1974. In the UK, homosexuality was considered a classifiable mental illness that could be 'cured' until 1992. Nurses were involved in administering painful and distressing treatments. The study is based on oral history interviews with fifteen nurses who had administered treatments to cure individuals of their SD. The interviews were transcribed for historical interpretation. Some nurses believed that their role was to passively follow any orders they had been given. Other nurses limited their culpability concerning administering these treatments by adopting dehumanising and objectifying language and by focussing on administrative tasks, rather than the human beings in need of their care. Meanwhile, some nurses genuinely believed that they were acting beneficently by administering these distinctly unpleasant treatments. It is envisaged that this study might act to reiterate the need for nurses to ensure their interventions have a sound evidence base and that they constantly reflect on the moral and value base of their practice and the influence that science and societal norms can have on changing views of what is considered 'acceptable practice'.


Cyclic adenosine monophosphate: potassium-dependent action on vascular smooth muscle membrane potential.
Dibutyryl cyclic adenosine monophosphate and theophylline hyperpolarize smooth muscle of rabbit main pulmonary artery in low concentrations of potassium (1 millimole per liter) but do not have a significant effect on the membrane potential in the presence of high concentrations of potassium (10 millimoles per liter). The dependence of the hyperpolarizing effect on a low external concentration of potassium is similar to that observed with isoproterenol. Prior treatment with theophylline potentiated the hyperpolarizing action of isoproterenol. These findings are compatible with the assumption that potassium-dependent, beta-adrenergic hyperpolarization is mediated by cyclic adenosine monophosphate.


Family-wide analysis of poly(ADP-ribose) polymerase activity.
The poly(adenosine diphosphate (ADP)-ribose) polymerase (PARP) protein family generates ADP-ribose (ADPr) modifications onto target proteins using NAD(+) as substrate. Based on the composition of three NAD(+) coordinating amino acids, the H-Y-E motif, each PARP is predicted to generate either poly(ADPr) (PAR) or mono(ADPr) (MAR). However, the reaction product of each PARP has not been clearly defined, and is an important priority since PAR and MAR function via distinct mechanisms. Here we show that the majority of PARPs generate MAR, not PAR, and demonstrate that the H-Y-E motif is not the sole indicator of PARP activity. We identify automodification sites on seven PARPs, and demonstrate that MAR and PAR generating PARPs modify similar amino acids, suggesting that the sequence and structural constraints limiting PARPs to MAR synthesis do not limit their ability to modify canonical amino-acid targets. In addition, we identify cysteine as a novel amino-acid target for ADP-ribosylation on PARPs.


Accepting leadership responsibility: preparing yourself to lead honestly, humanely, and effectively.
Many who enter management are ready and willing to accept the benefits of their positions, but not all are readily accepting of the full responsibilities of leadership. All too frequently, modern leadership appears self-serving, with the needs and desires of the leaders taking precedence over the needs of the followers and even the needs of the clients or customers. True leadership, however, should primarily benefit the followers rather than the leader. Leaders lead and followers follow for essentially the same reason, fulfillment of needs, so leaders and followers are fundamentally little different from each other. Every manager at every level has organizational superiors, so every leader is a follower as well. A true leader among managers is one who subordinates personal needs to the organization's needs, places employees well above self in importance, models appropriate behavior for employees, and functions as a facilitator in the employees' continuing efforts to get the necessary work done efficiently and effectively.


On the optical theory of photoelastic tomography.
In recent years many authors have considered the possibility of using tomography for nondestructive determination of three-dimensional stress fields. A natural starting point for this is integrated photoelasticity. The problem is complicated since the stress field is a tensor field, and in the general case in integrated photoelasticity the relationships between the measurement data and the parameters of the stress field are non-linear. To elucidate these relationships, we have systematically studied the propagation of polarized light in an inhomogeneous birefringent medium. The inverse problem of integrated photoelasticity is formulated in the general form, and particular cases in which the polarization transformation matrix is exactly determined by integrals of the stress tensor components are considered. The possibility of using the Radon inversion for approximate determination of the normal stress field in an arbitrary section of the test object is outlined.


HSV-1 clinical isolates with unique in vivo and in vitro phenotypes and insight into genomic differences.
Strain-specific factors contribute in significant but undefined ways to the variable incidence of herpes simplex virus (HSV) recrudescence. Studies that investigate these strain-specific factors are needed. Here, we used qPCR, in vitro assays, and genomic sequencing to identify important relationships between in vitro and clinical phenotypes of unique HSV-1 clinical isolates. Nine HSV-1 isolates from individuals displaying varying reactivation patterns were studied. Isolates associated with frequent recurrent herpes labialis (RHL) (1) displayed higher rates of viral shedding in the oral cavity than those associated with rare RHL and (2) tended to replicate more efficiently at 33 °C than 39 °C. HSV-1 isolates also displayed a more stable phenotype during propagation in U2OS cells than in Vero cells. Draft genome sequences of four isolates and one variant spanning 95.6 to 97.2 % of the genome were achieved, and whole-genome alignment demonstrated that the majority of these isolates clustered with known North American/European isolates. These findings revealed procedures that could help identify unique genotypes and phenotypes associated with HSV-1 isolates, which can be important for determining viral factors critical for regulating HSV-1 reactivation.


Premature ventricular complexes in the absence of identifiable heart disease.
To define the prevalence, frequency and characteristics of premature ventricular complexes (PVCs) in adults free of recognizable heart disease, we performed 24-hour ambulatory electrocardiography on 101 subjects (51 men and 50 women, mean age 48.8 years) in whom physical examination, chest x-ray, ECG, echocardiogram, maximal exercise stress test, right- and left-heart catheterization and coronary arteriography were normal. Thirty-nine subjects had at least 1 PVC/24 hours, but only four had more than 100 PVCs/24 hours and fewer than five had more than five PVCs in any given hour. The probability of having at least 1 PVC/24 hours increased with age (chi square = 11.789, p = 0.019). The number of PVCs/24 hours was also positively associated with age (4 = 0.33, p = 0.001). These was no consistent relationship between the presence or number of PVCs/24 hours and sex, blood pressure, weight, height, body mass index, serum potassium or calcium, cholesterol and triglyceride, hemoglobin, the ingestion of coffee, tea or alcohol, and cigarette smoking. Four subjects had multiform PVCs, two of whom had early PVCs.


Transmission and lineage displacement drive rapid population genomic flux in cystic fibrosis airway infections of a Pseudomonas aeruginosa epidemic strain.
Pseudomonas aeruginosa chronic infections of cystic fibrosis (CF) airways are a paradigm for within-host evolution with abundant evidence for rapid evolutionary adaptation and diversification. Recently emerged transmissible strains have spread globally, with the Liverpool Epidemic Strain (LES) the most common strain infecting the UK CF population. Previously we have shown that highly divergent lineages of LES can be found within a single infection, consistent with super-infection among a cross-sectional cohort of patients. However, despite its clinical importance, little is known about the impact of transmission on the genetic structure of these infections over time. To characterize this, we longitudinally sampled a meta-population of 15 genetic lineages within the LES over 13 months among seven chronically infected CF patients by genome sequencing. Comparative genome analyses of P. aeruginosa populations revealed that the presence of coexisting lineages contributed more to genetic diversity within an infection than diversification in situ. We observed rapid and substantial shifts in the relative abundance of lineages and replacement of dominant lineages, likely to represent super-infection by repeated transmissions. Lineage dynamics within patients led to rapid changes in the frequencies of mutations across suites of linked loci carried by each lineage. Many loci were associated with important infection phenotypes such as antibiotic resistance, mucoidy and quorum sensing, and were repeatedly mutated in different lineages. These findings suggest that transmission leads to rapid shifts in the genetic structure of CF infections, including in clinically important phenotypes such as antimicrobial resistance, and is likely to impede accurate diagnosis and treatment.


Resting-State Functional Connectivity and Network Analysis of Cerebellum with Respect to [corrected] IQ and Gender.
During the last years, it has been established that the prefrontal and posterior parietal brain lobes, which are mostly related to intelligence, have many connections to cerebellum. However, there is a limited research investigating cerebellum's relationship with cognitive processes. In this study, the network of cerebellum was analyzed in order to investigate its overall organization in individuals with low and high fluid [corrected] Intelligence Quotient (IQ). Functional magnetic resonance imaging (fMRI) data were selected from 136 subjects in resting-state from the Human Connectome Project (HCP) database and were further separated into two IQ groups composed of 69 low-IQ and 67 high-IQ subjects. Cerebellum was parcellated into 28 lobules/ROIs (per subject) using a standard cerebellum anatomical atlas. Thereafter, correlation matrices were constructed by computing Pearson's correlation coefficients between the average BOLD time-series for each pair of ROIs inside the cerebellum. By computing conventional graph metrics, small-world network properties were verified using the weighted clustering coefficient and the characteristic path length for estimating the trade-off between segregation and integration. In addition, a connectivity metric was computed for extracting the average cost per network. The concept of the Minimum Spanning Tree (MST) was adopted and implemented in order to avoid methodological biases in graph comparisons and retain only the strongest connections per network. Subsequently, six global and three local metrics were calculated in order to retrieve useful features concerning the characteristics of each MST. Moreover, the local metrics of degree and betweenness centrality were used to detect hubs, i.e., nodes with high importance. The computed set of metrics gave rise to extensive statistical analysis in order to examine differences between low and high-IQ groups, as well as between all possible gender-based group combinations. Our results reveal that both male and female networks have small-world properties with differences in females (especially in higher IQ females) indicative of higher neural efficiency in cerebellum. There is a trend toward the same direction in men, but without significant differences. Finally, three lobules showed maximum correlation with the median response time in low-IQ individuals, implying that there is an increased effort dedicated locally by this population in cognitive tasks.


Bone material properties in premenopausal women with idiopathic osteoporosis.
Idiopathic osteoporosis (IOP) in premenopausal women is characterized by fragility fractures at low or normal bone mineral density (BMD) in otherwise healthy women with normal gonadal function. Histomorphometric analysis of transiliac bone biopsy samples has revealed microarchitectural deterioration of cancellous bone and thinner cortices. To examine bone material quality, we measured the bone mineralization density distribution (BMDD) in biopsy samples by quantitative backscattered electron imaging (qBEI), and mineral/matrix ratio, mineral crystallinity/maturity, relative proteoglycan content, and collagen cross-link ratio at actively bone forming trabecular surfaces by Raman microspectroscopy and Fourier transform infrared microspectroscopy (FTIRM) techniques. The study groups included: premenopausal women with idiopathic fractures (IOP, n = 45), or idiopathic low BMD (Z-score ≤ -2.0 at spine and/or hip) but no fractures (ILBMD, n = 19), and healthy controls (CONTROL, n = 38). BMDD of cancellous bone showed slightly lower mineral content in IOP (both the average degree of mineralization of cancellous bone [Cn.Ca(Mean) ] and mode calcium concentration [Cn.Ca(Peak) ] are 1.4% lower) and in ILBMD (both are 1.6% lower, p < 0.05) versus CONTROL, but no difference between IOP and ILBMD. Similar differences were found when affected groups were combined versus CONTROL. The differences remained significant after adjustment for cancellous mineralizing surface (MS/BS), suggesting that the reduced mineralization of bone matrix cannot be completely accounted for by differences in bone turnover. Raman microspectroscopy and FTIRM analysis at forming bone surfaces showed no differences between combined IOP/ILBMD groups versus CONTROL, with the exceptions of increased proteoglycan content per mineral content and increased collagen cross-link ratio. When the two affected subgroups were considered individually, mineral/matrix ratio and collagen cross-link ratio were higher in IOP than ILBMD. In conclusion, our findings suggest that bone material properties differ between premenopausal women with IOP/ILBMD and normal controls. In particular, the altered collagen properties at sites of active bone formation support the hypothesis that affected women have osteoblast dysfunction that may play a role in bone fragility.


Partially Defective Store Operated Calcium Entry and Hem(ITAM) Signaling in Platelets of Serotonin Transporter Deficient Mice.
Serotonin (5-hydroxytryptamin, 5-HT) is an indolamine platelet agonist, biochemically derived from tryptophan. 5-HT is secreted from the enterochromaffin cells into the gastrointestinal tract and blood. Blood 5-HT has been proposed to regulate hemostasis by acting as a vasoconstrictor and by triggering platelet signaling through 5-HT receptor 2A (5HTR2A). Although platelets do not synthetize 5-HT, they take 5-HT up from the blood and store it in their dense granules which are secreted upon platelet activation. To identify the molecular composite of the 5-HT uptake system in platelets and elucidate the role of platelet released 5-HT in thrombosis and ischemic stroke. 5-HT transporter knockout mice (5Htt-/-) were analyzed in different in vitro and in vivo assays and in a model of ischemic stroke. In 5Htt-/- platelets, 5-HT uptake from the blood was completely abolished and agonist-induced Ca2+ influx through store operated Ca2+ entry (SOCE), integrin activation, degranulation and aggregation responses to glycoprotein VI (GPVI) and C-type lectin-like receptor 2 (CLEC-2) were reduced. These observed in vitro defects in 5Htt-/- platelets could be normalized by the addition of exogenous 5-HT. Moreover, reduced 5-HT levels in the plasma, an increased bleeding time and the formation of unstable thrombi were observed ex vivo under flow and in vivo in the abdominal aorta and carotid artery of 5Htt-/- mice. Surprisingly, in the transient middle cerebral artery occlusion (tMCAO) model of ischemic stroke 5Htt-/- mice showed nearly normal infarct volume and the neurological outcome was comparable to control mice. Although secreted platelet 5-HT does not appear to play a crucial role in the development of reperfusion injury after stroke, it is essential to amplify the second phase of platelet activation through SOCE and plays an important role in thrombus stabilization.


Switch of CD8 T cells to noncytolytic CD8-CD4- cells that make TH2 cytokines and help B cells.
CD8+ T cells are a major defense against viral infections and intracellular parasites. Their production of interferon-gamma (IFN-gamma) and their cytolytic activity are key elements in the immune response to these pathogens. Mature mouse CD8+ T cells that were activated in the presence of interleukin-4 (IL-4) developed into a CD8-CD4- population that was not cytolytic and did not produce IFN-gamma. However, these CD8- cells produced large amounts of IL-4, IL-5, and IL-10 and helped activate resting B cells. Thus, CD8 effector functions are potentially diverse and could be exploited by infectious agents that switch off host protective cytolytic responses.


Concomitant aneurysm detection in an intracranial dolichoectasia mouse model using a MicroFil polymer perfusion technique.
To assess the feasibility of using MicroFil polymer perfusion to detect concomitant saccular aneurysms in an intracranial arterial dolichoectasia (IADE) model in mice, and to report detailed histomorphometric features of these aneurysms. IADE models were created in C57/BL6 mice via microsurgical injection of 25 mU elastase into the cisterna magna. The cerebral vasculature was perfused with MicroFil polymer and harvested at 1, 3, and 7 days, and 2 and 4 weeks (n=8 for each group). IADE was defined by a tortuosity index >10 combined with a 25% increase in diameter of the A1 segment of the anterior cerebral artery (ACA), internal carotid artery (ICA), or basilar artery compared with the baseline of controls, which received heat-inactivated elastase. Saccular aneurysm occurrence rate, location, and morphological parameters were investigated using macroscopic and microscopic analysis. IADE was present in 95% (36/38) of the subjects, with a mortality rate of 5% (2/40). Fifteen concomitant saccular aneurysms were detected in 8 (21%) of the 38 surviving mice, including 6 at the posterior communicating artery, 1 along the ACA, 2 along the anterior communicating artery complex, 3 along the ICA, and 3 along the middle cerebral artery. Rupture was confirmed in two aneurysms. Histological examination indicated that the aneurysms develop via arterial-wall remodelling, which is characterized by internal elastic lamina disruptions and muscular layer discontinuity in the media. The proportion of subjects developing saccular aneurysms in addition to IADE in our mouse model is similar to the 15% of patients with IADE who have concomitant saccular aneurysms.


Melatonin administration attenuates depressed immune functions trauma-hemorrhage.
The pineal hormone melatonin has been used in clinical trials in patients suffering from AIDS and also as an adjuvant for cancer therapy. Although melatonin has been reported to have beneficial effects in some animal models of immune dysfunction, it remains unknown whether this hormone has any salutary effects on immunity following soft-tissue trauma and/or major blood loss. To study this, soft-tissue trauma (2.5-cm midline laparotomy) and hemorrhagic shock (arterial BP 35 +/- 5 mm Hg) were induced in C3H/HeN mice. The mice were resuscitated after 90 min of hypotension with the shed blood and lactated Ringer's solution. Treatment with saline, vehicle, or melatonin (10 mg/kg BW) subcutaneously was administered in the evening of the day of surgery and again on the following evening. All animals were sacrificed at 48 hr following trauma-hemorrhage and resuscitation to obtain plasma, splenocytes, as well as splenic and peritoneal macrophages (Mphi). The results indicate that melatonin administration after trauma-hemorrhage significantly improved the depressed immune functions, as evidenced by the restoration of Mphi IL-1 and IL-6 release, as well as significantly improved splenocyte IL-2 and IL-3 release and splenocyte proliferative capacity. No differences in circulating corticosterone levels between vehicle- and melatonin-treated animals were observed. This is the first study to show that melatonin, which is reported to be free of adverse side effects, can be considered a safe and effective therapeutic agent for restoring the depressed immunological function after soft-tissue trauma and hemorrhagic shock.


Dissociating neural correlates of action monitoring and metacognition of agency.
Judgments of agency refer to people's self-reflective assessments concerning their own control: their assessments of the extent to which they themselves are responsible for an action. These self-reflective metacognitive judgments can be distinguished from action monitoring, which involves the detection of the divergence (or lack of divergence) between observed states and expected states. Presumably, people form judgments of agency by metacognitively reflecting on the output of their action monitoring and then consciously inferring the extent to which they caused the action in question. Although a number of previous imaging studies have been directed at action monitoring, none have assessed judgments of agency as a potentially separate process. The present fMRI study used an agency paradigm that not only allowed us to examine the brain activity associated with action monitoring but that also enabled us to investigate those regions associated with metacognition of agency. Regarding action monitoring, we found that being "out of control" during the task (i.e., detection of a discrepancy between observed and expected states) was associated with increased brain activity in the right TPJ, whereas being "in control" was associated with increased activity in the pre-SMA, rostral cingulate zone, and dorsal striatum (regions linked to self-initiated action). In contrast, when participants made self-reflective metacognitive judgments about the extent of their own control (i.e., judgments of agency) compared with when they made judgments that were not about control (i.e., judgments of performance), increased activity was observed in the anterior PFC, a region associated with self-reflective processing. These results indicate that action monitoring is dissociable from people's conscious self-attributions of control.


Implication of a Novel Function of Sar1 in the Nucleus.
The coat protein complex II (COPII) generates transport carriers that deliver newly synthesized proteins from the endoplasmic reticulum (ER) to the Golgi apparatus. The small GTPase Sar1 is a well-known regulator of the assembly of the COPII coat. In the present study, we demonstrate that, besides its well-established role in ER-to-Golgi trafficking, the nuclear localization of Sar1 is essential for the viability of Saccharomyces cerevisiae. Inhibition of either the nuclear entry or retention of Sar1 leads to a severe growth defect. Additionally, in vivo deletion of Sar1, by using conditional genetic depletion, further demonstrates that the loss of nuclear localization of Sar1 results in an abnormal nuclear envelope shape. Our findings highlighted a possible novel role of Sar1 within the nucleus, which may relate to the proper formation of the nuclear envelope.Key words: Sar1, COPII, small GTPase, nuclear envelope, membrane traffic.


Mind-Wandering Tends to Occur under Low Perceptual Demands during Driving.
Fluctuations in attention behind the wheel poses a significant risk for driver safety. During transient periods of inattention, drivers may shift their attention towards internally-directed thoughts or feelings at the expense of staying focused on the road. This study examined whether increasing task difficulty by manipulating involved sensory modalities as the driver detected the lane-departure in a simulated driving task would promote a shift of brain activity between different modes of processing, reflected by brain network dynamics on electroencephalographic sources. Results showed that depriving the driver of salient sensory information imposes a relatively more perceptually-demanding task, leading to a stronger activation in the task-positive network. When the vehicle motion feedback is available, the drivers may rely on vehicle motion to perceive the perturbations, which frees attentional capacity and tends to activate the default mode network. Such brain network dynamics could have major implications for understanding fluctuations in driver attention and designing advance driver assistance systems.


HIV-1 reverse transcriptase is a target for cytotoxic T lymphocytes in infected individuals.
Characterization of the host immune response to human immunodeficiency virus type 1 (HIV-1) is critical to the rational design of an effective AIDS vaccine. In this study, cytotoxic T lymphocytes (CTL) specific for HIV-1 reverse transcriptase (RNA-dependent DNA polymerase) were found in blood samples from HIV-1-infected individuals. CTL targets were prepared by immortalizing B cells from ten seropositive and six seronegative individuals, and then infecting these cells with recombinant vaccinia viruses containing HIV-1 genes. CTL directed against autologous B lymphoblasts expressing HIV-1 reverse transcriptase were detected in fresh blood samples from eight HIV-1 seropositive subjects, but in no seronegative controls. The effector cells were identified as major histocompatibility complex-restricted CD3+CD8+ lymphocytes. Because the HIV-1 pol gene is highly conserved among different isolates and generates both humoral and cellular immune responses, it bears consideration for inclusion in a candidate AIDS vaccine.


ON THE PRESENCE OF CHOLIN AND NEURIN IN THE INTESTINAL CANAL DURING ITS COMPLETE OBSTRUCTION : A RESEARCH ON AUTOINTOXICATION.
My experiments lead me to believe that complete occlusion of the small intestine at its lower end will give rise to the occurrence of cholin, neurin and perhaps other bases, provided the food taken contains any considerable quantity of lecithin. It is not improbable that still other poisons are formed by bacterial action from other constituents of the food in cases of intestinal obstruction. While cholin would have to be absorbed in relatively large amounts to exert a marked toxic action in human beings it is otherwise with neurin, which is many times more intense in its action and must be classed with the exceedingly active poisons. It has been shown both by the experiments of Schmidt and Weiss and also by those recorded in this paper that the poisonous neurin may be formed from cholin by bacteria. In its physiological action neurin agrees closely with muscarin; especially to be noted here is the paralytic action on the heart and its power to increase the intestinal movements to such an extent that continual evacuations occur. Whether the ptomaine which was found by me is poisonous 1 cannot yet say. It must be considered proved, however, that highly toxic substances may arise in the intestinal canal during its complete occlusion. The method of treating cases of intestinal obstruction, before surgical means are resorted to, namely, washing out the stomach and as much of the gut as possible often reduces the violent paristalsis and this is due, perhaps, to the removal of substances out of which irritating and toxic products are formed by bacteria. In conclusion, I would remark that our knowledge of the fate of lecithin in the digestive canal under normal conditions is very deficient. The assumption that it is saponified by the fat-splitting enzyme of the pancreatic juice, thus yielding cholin, glycero-phosphoric acid and fatty acids, rests on the work of Bókai in 1877 and, as that investigator himself admits, without excluding bacterial action. This omission throws grave doubts on the results. If the assumption of Bókai be correct, caution must be observed in the use of some foods that have been considered most nutritious and healthful; for instance, the ingestion of a meal made up largely of eggs would hardly be without danger because of the poisonous action of the large quantity of cholin liberated from the lecithin and the probability of the formation of the highly poisonous neurin. It is my purpose in the near future to examine this question with the help of modern methods.


Prevalence of allergic disease in foreign-born American children.
Improved understanding of allergic disease epidemiology lead to novel therapeutic and prevention strategies. To study the association between US birthplace and prevalence of childhood allergic disease and to determine the effects of prolonged US residence on allergic disease. Cross-sectional questionnaire distributed to 91, 642 children aged 0 to 17 years enrolled in the 2007-2008 National Survey of Children's Health. Place of birth. Prevalence of allergic disease, including asthma, eczema, hay fever, and food allergies. Children born outside the United States had significantly lower odds of any atopic disorders than those born in the United States (logistic regression OR, 0.48; 95% CI, 0.38-0.61), including ever-asthma (0.53; 0.39-0.72), current-asthma (0.34; 0.23-0.51), eczema (0.43; 0.30-0.61), hay fever (0.39; 0.27-0.55), and food allergies (0.60; 0.37-0.99). The associations between child's birthplace and atopic disorders remained significant in multivariate models including age, sex, race/ethnicity, annual household income, residence in metropolitan areas, and history of child moving to a new address. Children born outside the United States whose parents were also born outside the United States had significantly lower odds of any atopic disorders than those whose parents were born in the United States (P = .005). Children born outside the United States who lived in the United States for longer than 10 years when compared with those who resided for only 0 to 2 years had significantly higher odds of developing any allergic disorders (adjusted OR, 3.04; 95% CI, 1.08-8.60), including eczema (4.93; 1.18-20.62; P = .03) and hay fever (6.25; 1.70-22.96) but not asthma or food allergies (P ≥ .06). Children born outside the United States have a lower prevalence allergic disease that increases after residing in the United States for 1 decade.


First Record of Barley yellow striate mosaic virus Affecting Wheat Summer-Nurseries in Syria.
A limited survey to identify virus diseases affecting wheat in summer nurseries in agricultural stations in southern Syria was conducted during October 2002. A total of 94 bread and durum wheat samples with symptoms suggestive of virus infection (stripping, stunting, and yellowing) were collected. All samples were tested for the presence of four viruses by tissue-blot immunoassay (2) at the Virology Laboratory of ICARDA, Aleppo, Syria using the following polyclonal antibodies: Barley stripe mosaic virus (BSMV); Barley yellow dwarf virus-PAV (BYDV-PAV) and Wheat streak mosaic virus (WSMV) from the Virology Laboratory at ICARDA; and Barley yellow striate mosaic virus (BYSMV) isolated from Italy (BYSMV-Italy) and provided by M. Conti, Instituto di Fitovirologia applicata, Turino, Italy. Serological results obtained indicated that BYSMV was the most commonly encountered virus (78.7%) followed by BYDV-PAV (22.3%), whereas, BSMV and WSMV were not detected in any of the samples tested. In sodium dodecyl sulfate-polyacrylamide gel electrophoresis, followed by western blots, purified BYSMV preparations were observed to contain a 47-kDa structural protein typical of the N protein of Rhabdoviruses that reacted strongly with three BYSMV antisera (BYSMV-Italy, BYSMV-Lebanon [4], and BYSMV-Morocco [1]). Samples that reacted with BYSMV antisera were transmitted from wheat to wheat, barley, and oat plants by the planthopper Laodelphax striatella (Fallen) (Hemiptera: family Delphacidae) in a persistent manner, and the major symptoms of BYSMV on cereal crops were stripping and stunting. BYDV-PAV has been reported from Syria earlier (3) but to our knowledge, this is the first report of BYSMV affecting wheat in Syria. References: (1) B. E. Lockhart et al. Plant Dis. 70:1113, 1986. (2) K. M. Makkouk and A. Comeau. Eur. J. Plant Pathol. 100:71, 1994. (3) K. M. Makkouk et al. Phytopathol. Mediterr. 28:164, 1989. (4) K. M. Makkouk et al. Plant Dis. 85:446, 2001.


Longitudinal Study of Oral Microbiome Variation in Twins.
Humans are host to a multitude of microorganisms that rapidly populate the body at birth, subject to a complex interplay that is dependent on host genetics, lifestyle, and environment. The host-associated microbiome, including the oral microbiome, presents itself in a complex ecosystem important to health and disease. As the most common chronic disease globally, dental caries is induced by host-microbial dysbiosis in children and adults. Multiple biological and environmental factors are likely to impact disease predisposition, onset, progression, and severity, yet longitudinal studies able to capture these influences are missing. To investigate how host genetics and environment influenced the oral microbial communities over time, we profiled supragingival plaque microbiomes of dizygotic and monozygotic twins during 3 visits over 12-months. Dental plaque DNA samples were amplified by targeting the 16S rRNA gene V4 region, and microbial findings were correlated with clinical, diet and genetic metadata. We observed that the oral microbiome variances were shaped primarily by the environment when compared to host genetics. Among the environmental factors shaping microbial changes of our subjects, significant metadata included age of the subject, and the age by which subjects initiated brushing habits, and the types of actions post-brushing. Relevant heritability of the microbiome included Actinomyces and Capnocytophaga in monozygotic twins and Kingella in dizygotic twins. Corynebacterium and Veillonella abundances were associated with age, whereas Aggregatibacter was associated with younger subjects. Streptococcus abundance showed an inverse association over time, and Selenomonas abundances increased with brushing frequency per day. Unraveling the exact biological mechanisms in caries has the potential to reveal novel host-microbial biomarkers, pathways, and targets important to effective preventive measures, and early disease control in children.


Differences in Pornography Use Among Couples: Associations with Satisfaction, Stability, and Relationship Processes.
The present study utilized a sample of 1755 adult couples in heterosexual romantic relationships to examine how different patterns of pornography use between romantic partners may be associated with relationship outcomes. While pornography use has been generally associated with some negative and some positive couple outcomes, no study has yet explored how differences between partners may uniquely be associated with relationship well-being. Results suggested that greater discrepancies between partners in pornography use were related to less relationship satisfaction, less stability, less positive communication, and more relational aggression. Mediation analyses suggested that greater pornography use discrepancies were primarily associated with elevated levels of male relational aggression, lower female sexual desire, and less positive communication for both partners which then predicted lower relational satisfaction and stability for both partners. Results generally suggest that discrepancies in pornography use at the couple level are related to negative couple outcomes. Specifically, pornography differences may alter specific couple interaction processes which, in turn, may influence relationship satisfaction and stability. Implications for scholars and clinicians interested in how pornography use is associated with couple process are discussed.


Patterns of Vertebrate Diversity and Protection in Brazil.
Most conservation decisions take place at national or finer spatial scales. Providing useful information at such decision-making scales is essential for guiding the practice of conservation. Brazil is one of the world's megadiverse countries, and consequently decisions about conservation in the country have a disproportionate impact on the survival of global biodiversity. For three groups of terrestrial vertebrates (birds, mammals, and amphibians), we examined geographic patterns of diversity and protection in Brazil, including that of endemic, small-ranged, and threatened species. To understand potential limitations of the data, we also explored how spatial bias in collection localities may influence the perceived patterns of diversity. The highest overall species richness is in the Amazon and Atlantic Forests, while the Atlantic Forest dominates in terms of country endemics and small-ranged species. Globally threatened species do not present a consistent pattern. Patterns for birds were similar to overall species richness, with higher concentrations of threatened species in the Atlantic Forest, while mammals show a more generalized pattern across the country and a high concentration in the Amazon. Few amphibians are listed as threatened, mostly in the Atlantic Forest. Data deficient mammals occur across the country, concentrating in the Amazon and southeast Atlantic Forest, and there are no data deficient birds in Brazil. In contrast, nearly a third of amphibians are data deficient, widespread across the country, but with a high concentration in the far southeast. Spatial biases in species locality data, however, possibly influence the perceived patterns of biodiversity. Regions with low sampling density need more biological studies, as do the many data deficient species. All biomes except the Amazon have less than 3% of their area under full protection. Reassuringly though, rates of protection do correlate with higher biodiversity, including higher levels of threatened and small-ranged species. Our results indicate a need for expanded formal protection in Brazil, especially in the Atlantic forest, and with an emphasis on fully protected areas.


Upper limb posture estimation in robotic and virtual reality-based rehabilitation.
New motor rehabilitation therapies include virtual reality (VR) and robotic technologies. In limb rehabilitation, limb posture is required to (1) provide a limb realistic representation in VR games and (2) assess the patient improvement. When exoskeleton devices are used in the therapy, the measurements of their joint angles cannot be directly used to represent the posture of the patient limb, since the human and exoskeleton kinematic models differ. In response to this shortcoming, we propose a method to estimate the posture of the human limb attached to the exoskeleton. We use the exoskeleton joint angles measurements and the constraints of the exoskeleton on the limb to estimate the human limb joints angles. This paper presents (a) the mathematical formulation and solution to the problem, (b) the implementation of the proposed solution on a commercial exoskeleton system for the upper limb rehabilitation, (c) its integration into a rehabilitation VR game platform, and (d) the quantitative assessment of the method during elbow and wrist analytic training. Results show that this method properly estimates the limb posture to (i) animate avatars that represent the patient in VR games and (ii) obtain kinematic data for the patient assessment during elbow and wrist analytic rehabilitation.


Intact but less accessible phonetic representations in adults with dyslexia.
Dyslexia is a severe and persistent reading and spelling disorder caused by impairment in the ability to manipulate speech sounds. We combined functional magnetic resonance brain imaging with multivoxel pattern analysis and functional and structural connectivity analysis in an effort to disentangle whether dyslexics' phonological deficits are caused by poor quality of the phonetic representations or by difficulties in accessing intact phonetic representations. We found that phonetic representations are hosted bilaterally in primary and secondary auditory cortices and that their neural quality (in terms of robustness and distinctness) is intact in adults with dyslexia. However, the functional and structural connectivity between the bilateral auditory cortices and the left inferior frontal gyrus (a region involved in higher-level phonological processing) is significantly hampered in dyslexics, suggesting deficient access to otherwise intact phonetic representations.


Leptin: cutting the fat off the bone.
Leptin was initially proposed to be the antiobesity hormone. Now it is realised that leptin is more a signal molecule that communicates nutritional status to the brain, and that it is involved in bone formation by having an antiosteogenic action. Recently, Florent Elefteriou and colleagues (Endocrinology 2003; 144: 3842-47) found that hypothalamic neurons control bone mass. These researchers used monosodium glutamate to obliterate neurons in the arcuate nucleus. Previously, this group (Cell 2002; 101: 305-17) had shown that leptin inhibits bone formation by modulating the sympathetic nervous system. Although leptin influences both energy balance and bone mass by acting on the hypothalamus, the two processes involve different proteins and neurons. WHERE NEXT? Leptin has antiosteogenic activity in mice, mediated by hypothalamic nervous pathways and the sympathetic nervous system. Yet some human studies dispute leptin's antiosteogenic role. Large clinical studies are necessary to consolidate leptin's role in the physiology of human bone. In mice the beta blocker propranolol, a widely used drug with no major deleterious effects, significantly increases bone formation and bone mass without affecting bodyweight, a finding that may provide novel opportunities to design efficient bone-forming drugs for human beings.


Involvement of alpha1-adrenoceptors in conditioned place preference supported by nicotine in rats.
The noradrenergic system might be a critical mediator of psychostimulants and opiates hedonic value. The objective of this study is to evaluate the involvement of alpha1-adrenoceptors (alpha1-ARs) in nicotine incentive learning. Rats, subjected to an unbiased conditioned place preference (CPP) procedure, received eight 30-min alternating nicotine (0.06 mg/kg) and saline pairings with distinct floor textures. The alpha1-AR antagonist, prazosin (0.125, 0.25, 0.5, or 1 mg/kg), was administered 30 min before nicotine pairings (acquisition) or one of the two 20-min test sessions conducted 24 h and 3 weeks after conditioning (expression). Pre-pairing injections of prazosin (0.5-1 mg/kg) prevented the acquisition of nicotine-CPP. On pre-test administration, prazosin (0.5 mg/kg) abolished the short-term expression of nicotine-CPP; whereas, none of the tested doses impaired its long-term expression. During a drug-free 3-week test session, nicotine-CPP was also weakened in rats given prazosin (0.5 mg/kg) before the 24-h test, while nicotine-CPP was reduced neither in animals given prazosin immediately after the first test session nor in those not subjected to the 24-h test. The activation of alpha1-ARs is one of the mechanisms that code for the incentive motivational value of nicotine. It participates also in the short-term, but not the long-term, control of behavior by nicotine-paired stimuli. The latter effect does not result from disruption by prazosin of either memory for the nicotine-cue association or reconsolidation processes at recall. Thus, differences exist in the neurobiological mechanisms that contribute to the incentive motivational value of nicotine and the short- and long-term "memory" of the incentive salience acquired by nicotine-paired cues.


Multivessel coronary artery bypass grafting versus percutaneous coronary intervention in ESRD.
Thirty to sixty percent of patients with ESRD on dialysis have coronary heart disease, but the optimal strategy for coronary revascularization is unknown. We used data from the United States Renal Data System to define a cohort of 21,981 patients on maintenance dialysis who received initial coronary revascularization with either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) between 1997 and 2009 and had at least 6 months of prior Medicare coverage as their primary payer. The primary outcome was death from any cause, and the secondary outcome was a composite of death or myocardial infarction. Overall survival rates were consistently poor during the study period, with unadjusted 5-year survival rates of 22%-25% irrespective of revascularization strategy. Using multivariable-adjusted proportional hazards regression, we found that CABG compared with PCI associated with significantly lower risks for both death (HR=0.87, 95% CI=0.84-0.90) and the composite of death or myocardial infarction (HR=0.88, 95% CI=0.86-0.91). Results were similar in analyses using a propensity score-matched cohort. In the absence of data from randomized trials, these results suggest that CABG may be preferred over PCI for multivessel coronary revascularization in appropriately selected patients on maintenance dialysis.


Diabetes education: the experiences of young adults with type 1 diabetes.
Clinician-led diabetes education is a fundamental component of care to assist people with Type 1 diabetes (T1D) self-manage their disease. Recent initiatives to incorporate a more patient-centered approach to diabetes education have included recommendations to make such education more individualized. Yet there is a dearth of research that identifies patients' perceptions of clinician-led diabetes education. We aimed to describe the experience of diabetes education from the perspective of young adults with T1D. We designed a self-reported survey for Australian adults, aged 18-35 years, with T1D. Participants (n = 150) were recruited by advertisements through diabetes consumer-organizations. Respondents were asked to rate aspects of clinician-led diabetes education and identify sources of self-education. To expand on the results of the survey we interviewed 33 respondents in focus groups. The majority of respondents (56.0%) were satisfied with the amount of continuing clinician-led diabetes education; 96.7% sought further self-education; 73.3% sourced more diabetes education themselves than that provided by their clinicians; 80.7% referred to diabetes organization websites for further education; and 30.0% used online chat-rooms and blogs for education. Focus groups: The three key themes that emerged from the interview data were deficiencies related to the pedagogy of diabetes education; knowledge deficiencies arising from the gap between theoretical diabetes education and practical reality; and the need for and problems associated with autonomous and peer-led diabetes education. Our findings indicate that there are opportunities to improve clinician led-diabetes education to improve patient outcomes by enhancing autonomous health-literacy skills and to incorporate peer-led diabetes education and support with clinician-led education. The results provide evidence for the potential value of patient engagement in quality improvement and health-service redesign.


In vitro interaction between resistin and peroxisome proliferator-activated receptor γ in porcine ovarian follicles.
In the present study, using real-time polymerase chain reaction and immunoblotting methods, we quantified the expression of peroxisome proliferator-activated receptor (PPAR) γ, PPARα and PPARβ in different sized ovarian follicles (small (SF), medium (MF) and large (LF) follicles) in prepubertal and adult pigs. In prepubertal pigs, PPARγ and PPARα expression was highest in LF; however, PPARβ expression did not differ among SF, MF and LF. In mature pigs, only protein expression of PPARγ and PPARα increased during ovarian follicle development. Following identification of very high levels of PPARγ expression in LF in prepubertal and adult pigs, using in vitro culture of ovarian follicles, we determined the effect of resistin at 0.1, 1 and 10ngmL(-1) on PPARγ mRNA and protein expression and the effect of rosiglitazone at 25 and 50µM (a PPARγ agonist) on resistin mRNA and protein expression. Resistin increased PPARγ expression in ovarian follicles in both prepubertal and adult pigs, whereas rosiglitazone had an inhibitory effect on resistin expression. The role of PPARγ in regulating the effects of resistin on ovarian steroidogenesis was investigated using GW9662 (a PPARγ antagonist at dose of 1μM). In these studies, GW9662 reversed the effect of resistin on steroid hormone secretion. The data suggest that there is local cooperation between resistin and PPARγ expression in the porcine ovary. Resistin significantly increased the expression of PPARγ, whereas PPARγ decreased resistin expression; thus, PPARγ is a new key regulator of resistin expression and function.


Quantitative proteomics analysis of sporadic parathyroid adenoma tissue samples.
Molecular pathogenesis of parathyroid tumors is incompletely understood. Identification of novel molecules and understanding their role in parathyroid tumorigenesis by proteomics approach would be informative with potential clinical implications. Adenomatous (n = 5) and normal (n = 2) parathyroid tissue lysates were analyzed for protein profile by LC-MS/MS method and the proteins were classified using bioinformatics tools such as PANTHER and toppfun functional enrichment tool. Identified proteins were further validated by western blotting and qRT-PCR (n = 20). Comparative proteomics analysis revealed that a total of 206 proteins (74 upregulated and 132 downregulated) were differentially expressed (≥ twofold change) in adenomas. Bioinformatics analysis revealed that 48 proteins were associated with plasma membrane, 49 with macromolecular complex, 39 were cytoplasm, 38 were organelle related, 21 were cell junction and 10 were extracellular proteins. These proteins belonged to a diverse protein family such as enzymes, transcription factors, cell signalling, cell adhesion, cytoskeleton proteins, receptors, and calcium-binding proteins. The major biological processes predicted for the proteins were a cellular, metabolic and developmental process, cellular localization, and biological regulation. The differentially expressed proteins were found to be associated with MAPK, phospholipase C (PLC) and phosphatidylinositol (PI) signalling pathways, and with chromatin organization. Western blot and qRT-PCR analysis of three proteins (DNAJC2, ACO2, and PRDX2) validated the LC-MS/MS findings. This exploratory study demonstrates the feasibility of proteomics approach in finding the dysregulated proteins in benign parathyroid adenomas, and our preliminary results suggest that MAPK, PLC and PI signalling pathways and chromatin organization are involved in parathyroid tumorigenesis.


Genomic region detection via Spatial Convex Clustering.
Several modern genomic technologies, such as DNA-Methylation arrays, measure spatially registered probes that number in the hundreds of thousands across multiple chromosomes. The measured probes are by themselves less interesting scientifically; instead scientists seek to discover biologically interpretable genomic regions comprised of contiguous groups of probes which may act as biomarkers of disease or serve as a dimension-reducing pre-processing step for downstream analyses. In this paper, we introduce an unsupervised feature learning technique which maps technological units (probes) to biological units (genomic regions) that are common across all subjects. We use ideas from fusion penalties and convex clustering to introduce a method for Spatial Convex Clustering, or SpaCC. Our method is specifically tailored to detecting multi-subject regions of methylation, but we also test our approach on the well-studied problem of detecting segments of copy number variation. We formulate our method as a convex optimization problem, develop a massively parallelizable algorithm to find its solution, and introduce automated approaches for handling missing values and determining tuning parameters. Through simulation studies based on real methylation and copy number variation data, we show that SpaCC exhibits significant performance gains relative to existing methods. Finally, we illustrate SpaCC's advantages as a pre-processing technique that reduces large-scale genomics data into a smaller number of genomic regions through several cancer epigenetics case studies on subtype discovery, network estimation, and epigenetic-wide association.


Histologic types of breast carcinoma in relation to international variation and breast cancer risk factors. WHO Collaborative Study of Neoplasia and Steroid Contraceptives.
Associations between breast cancer risk factors and histologic types of invasive breast carcinoma were studied in 2,728 patients. Lobular and tubular carcinomas occurred with increased relative frequency in most high-risk groups. The proportion of these types increased with age to a maximum at 45-49 years and decreased in the following decade. Significantly increased proportions of lobular and tubular carcinomas were also associated with high-risk countries, prior benign breast biopsy, bilateral breast cancer, concurrent mammary dysplasia, high age at first live birth, never-pregnant patients compared to those with a first live birth before age 20, private pay status, and length of education. Nonsignificant increases were associated with family history of breast cancer, less than 5 live births, less than 25 months total of breast feeding, use of oral contraceptives or IUD, and high occupational class. As a general trend, the higher the overall relative risk, the higher the proportion of lobular and tubular carcinomas. The occurrence of other histologic types also increased with increased breast cancer risk, but to a smaller degree than for lobular/tubular carcinomas. It is suggested that all hormonally related, socio-economic and geographic risk factors exert their effect by selectively increasing number of lobular cells at risk. Family history of breast carcinoma and age over 49 years did not follow the general trend parallel increases in the proportion of lobular/tubular carcinomas and breast cancer risk, and may operate through other mechanisms.


High-Throughput Screening Using a Whole-Cell Virus Replication Reporter Gene Assay to Identify Inhibitory Compounds against Rift Valley Fever Virus Infection.
Rift Valley fever virus (RVFV) is an emerging virus that causes serious illness in humans and livestock. There are no approved vaccines or treatments for humans. The purpose of the study was to identify inhibitory compounds of RVFV infection without any preconceived idea of the mechanism of action. A whole-cell-based high-throughput drug screening assay was developed to screen 28,437 small chemical compounds targeting RVFV infection. To accomplish both speed and robustness, a replication-competent NSs-deleted RVFV expressing a fluorescent reporter gene was developed. Inhibition of fluorescence intensity was quantified by spectrophotometry and related to virus infection in human lung epithelial cells (A549). Cell toxicity was assessed by the Resazurin cell viability assay. After primary screening, 641 compounds were identified that inhibited RVFV infection by ≥80%, with ≥50% cell viability at 50 µM concentration. These compounds were subjected to a second screening regarding dose-response profiles, and 63 compounds with ≥60% inhibition of RVFV infection at 3.12 µM compound concentration and ≥50% cell viability at 25 µM were considered hits. Of these, six compounds with high inhibitory activity were identified. In conclusion, the high-throughput assay could efficiently and safely identify several promising compounds that inhibited RVFV infection.


Introducing clinical laboratory science: CLS students help shape the future.
The profession of clinical laboratory science (CLS) is in dire need of increased exposure to young people. By introducing the clinical laboratory sciences to students at a critical point in their science education and by making it relevant to their lives, more choices are made available to them when considering future career options. With this in mind, the CLS faculty at Texas Tech University Health Sciences Center (TTUHSC) redesigned a recruitment program and developed it into one making use of CLS student knowledge, enthusiasm, and professionalism. CLS students were given the assignment of designing an entire curriculum for a ten day presentation of clinical laboratory science topics to middle and secondary school students. Following the presentations, participants in the program were asked to provide feedback regarding CLS student performance and overall opinion of their interest in clinical laboratory science. The objectives of this study were twofold: 1) to determine if educational methodologies could be appropriately applied by CLS students to present CLS disciplines to middle and high school students; and 2) to determine if the student presentation was successful in initiating interest in the CLS profession based on outcome measures. As a component of the CLS laboratory management course, CLS students were instructed in education methodologies including objective writing, teaching-unit preparation, and evaluation tool design. In the following semester, these students were divided into groups and assigned a specific CLS discipline that would then be presented to middle and secondary school students in a two week, 30 hour educational program. This program was offered by the TTUHSC CLS program in cooperation with the Institute for the Development and Enrichment of Advanced Learners (IDEAL) at Texas Tech University. The curriculum prepared by the CLS students (with faculty supervision) provided the framework for the present study. Didactic instruction of the CLS students regarding objective writing, curriculum design, and preparation of evaluations was included as a component of a CLS laboratory management course. The educational program presented by IDEAL in conjunction with the TTUHSC CLS program within the School of Allied Health Sciences occurred in the CLS student laboratories located in Lubbock, Texas. TTUHSC senior CLS students in a 2 + 2 baccalaureate level CLS program acted as instructors in the educational program which was presented to middle and secondary school students from around the region. CLS program faculty served as supervisors of this program. Questionnaires with Likert-scaled responses were used to evaluate outcomes. These questionnaires regarded 1) faculty assessment of CLS student performance relative to instruction in education methods; 2) participant feedback on the effectiveness and competence of the CLS student instructors and overall appeal of the presented subject material; and 3) peer evaluations of attitude, contribution, and effort of the group members. CLS faculty strongly agreed that the CLS students demonstrated a high level of competence when writing objectives, planning age-appropriate curriculum and activities, and demonstrating a positive image of the profession. Regarding satisfaction of the IDEAL student participant, questionnaire responses demonstrated a high rate (84% or greater for middle school participants and 85% for high school students). The program design has been so successful that it has been implemented for several other programs offered by TTU and IDEAL. The education methods used in presenting the IDEAL program mirror those found in clinical and academic settings and is an effective technique to introduce CLS students to the varied aspects of educational methodology. The presentation by the CLS students also demonstrated that introduction of clinical laboratory science disciplines early in the education of middle and secondary school students leads to an interest in the CLS profession and to the desire to learn more about it.


Quantitative Fourier analysis of schlieren masks: the transition from shadowgraph to schlieren.
In a schlieren setup, a lens system forms an image of the refractive index fluctuations of a transparent sample onto a matrix detector while an intensity mask is positioned in the Fourier plane of a collecting lens to perform the required spatial filtering. In the absence of the mask, the resulting technique is that of a shadowgraph. The two methods provide different information about the refractive index of transparent fluids and can be used both for visualization purposes and scattering measurements. Here, we describe the effect of the intensity mask on the technique transfer function, i.e., its ability to detect different spatial frequencies and show how the special cases of shadowgraph, schlieren, and the transition between the two can be derived. We also present experimental data that agree well with our predictions.


Template CoMFA: the 3D-QSAR Grail?
Template CoMFA, a novel alignment methodology for training or test set structures in 3D-QSAR, is introduced. Its two most significant advantages are its complete automation and its ability to derive a single combined model from multiple structural series affecting a biological target. Its only two inputs are one or more "template" structures having 3D coordinates that share some Cartesian space, as may result from X-ray crystallography or pharmacophoric hypothesis, and one or more connectivity-only SAR tables associated with a common target. Template CoMFA also overcomes the major disadvantages of both existing 3D-QSAR alignment methodologies, specifically the tedium and subjectivity of familiar ad hoc approaches, and the awkwardness, occasional physicochemical heresies, and structural scope limitations of the purely topomer approach. The template CoMFA algorithms are described, and two of its application classes are presented. The first class, general models of binding to factor Xa and P38 map kinase, uses crystallographic structures as templates, with the encouraging result that the statistical qualities of each of these two combined models are equivalent to those of their constituent individual series models. The second, 15 data sets originally collected for validation of topomer CoMFA, with arbitrary structures as templates, confirms that the modeling power of template CoMFA resembles that of its predecessors.


Reclassification of Thiomicrospira hydrogeniphila (Watsuji et al. 2016) to Thiomicrorhabdus hydrogeniphila comb. nov., with emended description of Thiomicrorhabdus (Boden et al., 2017).
The genus Thiomicrorhabdus (Tmr) in the Piskirickettsiaceae in the Thiotrichales of the Gammaproteobacteria contains four species of sulfur-oxidising obligate chemolithoautotroph with validly published names, all previously classified as Thiomicrospira (Tms) species. Here we demonstrate that Thiomicrospira hydrogeniphila, a recently published hydrogen-utilising chemolithoautotroph closely related to Thiomicrorhabdus frisia (type species of Thiomicrorhabdus) should be classified as a member of the genus Thiomicrorhabdus and not Thiomicrospira, as Thiomicrorhabdus hydrogeniphila comb. nov., on the basis of comparative physiology and morphology as well as 16S rRNA (rrs) gene identity of Tms. hydrogeniphila MAS2T being closer to that of Tmr. frisia JB-A2T (99.1 %) than to Tms. pelophila DSM 1534T (90.5 %) or Hydrogenovibrio marinus MH-110T (94.1 %), and on the basis of the topology of 16S rRNA gene maximum likelihood trees, which clearly place Tms. hydrogeniphila within the genus Thiomicrorhabdus. It was also noted that thiosulfate-grown Thiomicrorhabdus spp. can be distinguished from Thiomicrospira spp. or Hydrogenovibrio spp. on the basis of the 3 dominant fatty acids (C16 : 1, C18 : 1 and C16 : 0), and from other Thiomicrorhabdus spp. on the basis of the fourth dominant fatty acid, which varies between the species of this genus - which could provide a useful diagnostic method. We provide an emended description of Thiomicrorhabdus (Boden R, Scott KM, Williams J, Russel S, Antonen K et al.Int J Syst Evol Microbiol 2017;67:1140-1151) to take into account the properties of Thiomicrorhabdus hydrogeniphila comb. nov.


Food security: increasing yield and improving resource use efficiency.
Food production and security will be a major issue for supplying an increasing world population. The problem will almost certainly be exacerbated by climate change. There is a projected need to double food production by 2050. In recent times, the trend has been for incremental modest yield increases for most crops. There is an urgent need to develop integrated and sustainable approaches that will significantly increase both production per unit land area and the resource use efficiency of crops. This review considers some key processes involved in plant growth and development with some examples of ways in which molecular technology, plant breeding and genetics may increase the yield and resource use efficiency of wheat. The successful application of biotechnology to breeding is essential to provide the major increases in production required. However, each crop and each specific agricultural situation presents specific requirements and targets for optimisation. Some increases in production will come about as new varieties are developed which are able to produce satisfactory crops on marginal land presently not considered appropriate for arable crops. Other new varieties will be developed to increase both yield and resource use efficiency on the best land.


Late relapses in patients successfully treated for thrombotic thrombocytopenic purpura. Canadian Apheresis Group.
To determine the incidence and timing of relapses in patients who have recovered from an acute episode of thrombotic thrombocytopenic purpura. Clinical follow-up for 3 to 10 years. General community outpatient study; patients who had relapse were hospitalized. 63 of 72 surviving patients who had participated in a randomized study that compared plasma exchange and plasma infusion as treatments for thrombotic thrombocytopenic purpura and for whom continued clinical follow-up was obtained. Recurrence of thrombotic thrombocytopenic purpura as defined by a decrease in platelet count to less than 100 x 10(9)/L and by the onset of microangiopathic hemolytic anemia as identified by erythrocyte fragmentation in a peripheral blood film. 37 of the 63 patients have not had recurrence of thrombotic thrombocytopenic purpura and have remained completely well; 6 patients have not had recurrence but have developed other medical problems; 3 patients have not had recurrence but have residual neurologic defects from the original episode; and 17 patients have had one or more recurrences, occurring 7 months to 8 years after the original episode. As determined by Kaplan-Meier analysis, the projected recurrence rate after 10 years in all surviving patients is 36% (95% CI, 23% to 59%). More than one third of patients who survive an acute episode of thrombotic thrombocytopenic purpura will have at least one relapse during the following 10 years.


Case-control study on cellular and cordless telephones and the risk for acoustic neuroma or meningioma in patients diagnosed 2000-2003.
We performed a case-control study on the use of cellular and cordless telephones and the risk for brain tumors. We report the results for benign brain tumors with data from 413 cases (89% response rate), 305 with meningioma, 84 with acoustic neuroma, 24 with other types and 692 controls (84% response rate). For meningioma, analogue phones yielded odds ratio (OR) = 1.7, 95% confidence interval (CI) = 0.97-3.0, increasing to OR = 2.1, 95% CI = 1.1-4.3 with a >10-year latency period. Also digital cellular phones and cordless phones increased the risk to some extent. For acoustic neuroma, analogue phones gave OR = 4.2, 95% CI = 1.8-10 increasing to OR = 8.4, 95% CI = 1.6-45 with a >15-year latency period, but based on low numbers. Digital phones yielded OR = 2.0, 95% CI = 1.05-3.8, whereas for cordless phones OR was not significantly increased. In the multivariate analysis, analogue phones represented a significant risk factor for acoustic neuroma.


General trend for pressurized superconducting hydrogen-dense materials.
The long-standing prediction that hydrogen can assume a metallic state under high pressure, combined with arguments put forward more recently that this state might even be superconducting up to high temperatures, continues to spur tremendous research activities toward the experimental realization of metallic hydrogen. These efforts have however so far been impeded by the enormous challenges associated with the exceedingly large required pressure. Hydrogen-dense materials, of the MH(4) form (where M can be, e.g., Si, Ge, or Sn) or of the MH(3) form (with M being, e.g., Al, Sc, Y, or La), allow for the rather exciting opportunity to carry out a proxy study of metallic hydrogen and associated high-temperature superconductivity at pressures within the reach of current techniques. At least one experimental report indicates that a superconducting state might have been observed already in SiH(4), and several theoretical studies have predicted superconductivity in pressurized hydrogen-rich materials; however, no systematic dependence on the applied pressure has yet been identified so far. In the present work, we have used first-principles methods in an attempt to predict the superconducting critical temperature (T(c)) as a function of pressure (P) for three metal-hydride systems of the MH(3) form, namely ScH(3), YH(3), and LaH(3). By comparing the obtained results, we are able to point out a general trend in the T(c)-dependence on P. These gained insights presented here are likely to stimulate further theoretical studies of metallic phases of hydrogen-dense materials and should lead to new experimental investigations of their superconducting properties.


Constructive or cruel? Positive or patronizing? Reactions to expressions of positive and negative stereotypes of the mentally ill.
Previous research has shown that people respond with greater sensitivity to negative stereotypical comments about a group that are made from someone outside the group in question than from someone who belongs to the group. In this paper, we investigated if the same effect occurs in response to comments made about stigmatized groups. Specifically, we examined how people react to comments made about the mentally ill. The conditions under which people accept or reject stereotypes of the mentally ill may shed light on the conditions necessary for effective anti-discrimination campaigns. In the current study, participants responded to positive or negative stereotypes of the mentally ill voiced by either someone who has, or has not, suffered from a mental illness. Participants were more sensitive, agreed less, and evaluated the speaker less favourably when comments came from the out-group rather than the in-group source. The effects were strongest for negative comments, however contrary to previous research participants also responded less favourably to positive comments from the out-group source. These reactions were mediated by the perceived constructiveness of the speaker's motives. Implications for the effectiveness of anti-discrimination campaigns are discussed.


The Changing Therapeutic Landscape of Metastatic Renal Cancer.
The practising clinician treating a patient with metastatic clear cell renal cell carcinoma (CCRCC) faces a difficult task of choosing the most appropriate therapeutic regimen in a rapidly developing field with recommendations derived from clinical trials. NCCN guidelines for kidney cancer initiated a major shift in risk categorization and now include emerging treatments in the neoadjuvant setting. Updates of European Association of Urology clinical guidelines also include immune checkpoint inhibition as the first-line treatment. Randomized trials have demonstrated a survival benefit for ipilimumab and nivolumab combination in the intermediate and poor-risk group, while pembrolizumab plus axitinib combination is recommended not only for unfavorable disease but also for patients who fit the favorable risk category. Currently vascular endothelial growth factor (VEGF) targeted therapy based on tyrosine kinase inhibitors (TKI), sunitinib and pazopanib is the alternative regimen for patients who cannot tolerate immune checkpoint inhibitors (ICI). Cabozantinib remains a valid alternative option for the intermediate and high-risk group. For previously treated patients with TKI with progression, nivolumab, cabozantinib, axitinib, or the combination of ipilimumab and nivolumab appear the most plausible alternatives. For patients previously treated with ICI, any VEGF-targeted therapy, not previously used in combination with ICI therapy, seems to be a valid option, although the strength of this recommendation is weak. The indication for cytoreductive nephrectomy (CN) is also changing. Neoadjuvant systemic therapy does not add perioperative morbidity and can help identify non-responders, avoiding unnecessary surgery. However, the role of CN should be investigated under the light of new immunotherapeutic interventions. Also, markers of response to ICI need to be identified before the optimal selection of therapy could be determined for a particular patient.