Preparation of hollow TiO2 nanoparticles through TiO2 deposition on polystyrene latex particles and characterizations of their structure and photocatalytic activity.
In a mixed solvent of water and ethanol, polystyrene/titanium dioxide (PSt/TiO2) composite particles of core-shell structure were prepared by hydrolysis of tetrabutyl titanate in the presence of cationic PSt particles or anionic PSt particles surface-treated using γ-aminopropyl triethoxysilane. Hollow TiO2 particles were obtained through calcination of the PSt/TiO2 core-shell particles to burn off the PSt core or through dissolution of the core by tetrahydrofuran (THF). An alternative process constituted of preheating the PSt/TiO2 particles at 200°C to allow partial crystallization followed by calcination or PSt dissolution by THF. The outcome TiO2 particles thus prepared were examined by TEM, and hollow TiO2 particles were observed. The crystalline phase structure and phase transformation were characterized, which revealed that preheating before the removal of the PSt core was useful to achieve the desired hollow TiO2 particles, and the calcination process was beneficial to the formation of anatase and rutile structures. The tests of TiO2 particles as catalyst in the photodegradation of Rhodamine B demonstrated that a much higher catalytic activity was observed with the TiO2 hollow particles prepared through calcination combined with preheating.


Effect of disease and recovery on functional anatomy in brain tumor patients: insights from functional MRI and diffusion tensor imaging.
Patients with brain tumors provide a unique opportunity to understand functional brain plasticity. Using advanced imaging techniques, such as functional MRI and diffusion tensor imaging, we have gained tremendous knowledge of brain tumor behavior, transformation, infiltration and destruction of nearby structures. Using these advanced techniques as an adjunct with more proven techniques, such as direct cortical stimulation, intraoperative navigation and advanced microsurgical techniques, we now are able to better formulate safer resection trajectories, perform larger resections at reduced risk and better counsel patients and their families about possible complications. Brain mapping in patients with brain tumors and other lesions has shown us that the old idea of fixed function of the adult cerebral cortex is not entirely true. Improving care for patients with brain lesions in the future will depend on better understanding of the functional organization and plasticity of the adult brain. Advanced noninvasive brain imaging will undoubtedly play a role in advancing this understanding.


Structure-activity-dependent regulation of cell communication by perfluorinated fatty acids using in vivo and in vitro model systems.
Perfluoroalkanoates, [e.g., perfluorooctanoate (PFOA)], are known peroxisome proliferators that induce hepatomegaly and hepatocarcinogenesis in rodents, and are classic non-genotoxic carcinogens that inhibit in vitro gap-junctional intercellular communication (GJIC). This inhibition of GJIC is known to be a function of perfluorinated carbon lengths ranging from 7 to 10. The aim of this study was to determine if the inhibition of GJIC by PFOA but not perfluoropentanoate (PFPeA) observed in F344 rat liver cells in vitro also occurs in F344 rats in vivo and to determine mechanisms of PFOA dysregulation of GJIC using in vitro assay systems. We used an incision load/dye transfer technique to assess GJIC in livers of rats exposed to PFOA and PFPeA. We used in vitro assays with inhibitors of cell signaling enzymes and antioxidants known to regulate GJIC to identify which enzymes regulated PFOA-induced inhibition of GJIC. PFOA inhibited GJIC and induced hepatomegaly in rat livers, whereas PFPeA had no effect on either end point. Serum biochemistry of liver enzymes indicated no cytotoxic response to these compounds. In vitro analysis of mitogen-activated protein kinase (MAPK) indicated that PFOA, but not PFPeA, can activate the extracellular receptor kinase (ERK). Inhibition of GJIC, in vitro, by PFOA depended on the activation of both ERK and phosphatidylcholine-specific phospholipase C (PC-PLC) in the dysregulation of GJIC in an oxidative-dependent mechanism. The in vitro analysis of GJIC, an epigenetic marker of tumor promoters, can also predict the in vivo activity of PFOA, which dysregulated GJIC via ERK and PC-PLC.


Reduced White Matter Integrity in Antisocial Personality Disorder: A Diffusion Tensor Imaging Study.
Emerging neuroimaging research suggests that antisocial personality disorder (ASPD) may be linked to abnormal brain anatomy, but little is known about possible impairments of white matter microstructure in ASPD, as well as their relationship with impulsivity or risky behaviors. In this study, we systematically investigated white matter abnormalities of ASPD using diffusion tensor imaging (DTI) measures: fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD). Then, we further investigated their correlations with the scores of impulsivity or risky behaviors. ASPD patients showed decreased FA in multiple major white matter fiber bundles, which connect the fronto-parietal control network and the fronto-temporal network. We also found AD/RD deficits in some additional white matter tracts that were not detected by FA. More interestingly, several regions were found correlated with impulsivity or risky behaviors in AD and RD values, although not in FA values, including the splenium of corpus callosum, left posterior corona radiate/posterior thalamic radiate, right superior longitudinal fasciculus, and left inferior longitudinal fasciculus. These regions can be the potential biomarkers, which would be of great interest in further understanding the pathomechanism of ASPD.


Preparation and characterization of biodegradable PLA polymeric blends.
The purpose of this study was to fine-tune the mechanical properties of high molecular-weight poly-L-lactic acid (PLLA), especially to increase its toughness without sacrificing too much of its original strength. Besides of its long degradation time, PLLA is usually hard and brittle, which hinders its usage in medical applications, i.e., orthopedic and dental surgery. Some modifications, such as the addition of plasticizers or surfactants/compatibilizers, are usually required to improve its original properties. PDLLA can degrade quickly due to its amorphous structure, thus shortening the degradation time of PLLA/PDLLA blends. Blends of biodegradable poly-L-lactic acid (PLLA) and poly-DL-lactic acid (PDLLA) or polycaprolactone (PCL), in addition to a third component, the surfactant-a copolymer of ethylene oxide and propylene oxide, were prepared by blending these three polymers at various ratios using dichloromethane as a solvent. The weight percentages of PLLA/PDLLA (or PCL) blends were 100%/0%, 80%/20%, 60%/40%, 50%/50%, 40%/60%, 20%/80% and 0%/100%, respectively. Physical properties such as the crystalline melting point, glass transition point (T(g)), phase behavior, degradation behavior, and other mechanical properties were characterized by thermogravimetric analysis, differential scanning calorimetry (DSC), infrared spectroscopy, gel permeation chromatography, and dynamic mechanical analysis (DMA). DSC data indicate that PLLA/PDLLA blends without the surfactant had two T(g)'s. With the addition of the surfactant, there was a linear shift of the single T(g) as a function of composition, with lower percentages of PLLA producing lower glass transition temperatures indicating that better miscibility had been achieved. DMA data show that the 40/60 PLLA/PDLLA blends without the surfactant had high elastic modulus and elongation, and similar results were observed after adding 2% surfactant into the blends. The 50/50 PLLA/PDLLA/2% surfactant blend had the highest elastic modulus, yield strength, and break strength compared with other ratios of PLLA/PDLLA/2% surfactant blends. The elongation at break of 50/50 PLLA/PDLLA was similar to that of PLLA. Again, the elongation at break of 50/50 PLLA/PDLLA/2% surfactant was almost 1.2-1.9 times higher than that of 50/50 PLLA/PDLLA and PLLA. Elongation of PLLA increased with the addition of PCL, but the strength decreased at the same time. In conclusions, adding PDLLA and surfactant to PLLA via solution-blending may be an effective way to make PLLA tougher and more suitable to use in orthopedic or dental applications.


The association between rural-urban continuum, maternal education and adverse birth outcomes in Québec, Canada.
Rural relative to urban area and low socioeconomic status (SES) are associated with adverse birth outcomes. Whether a graded association of increasing magnitude is present across the urban-rural continuum, accounting for SES, is unclear. We examined the association between rural-urban continuum, SES and adverse birth outcomes. Singleton births from 1999 to 2003 (n = 356,147) were linked to Québec municipalities ranked on a continuum of 3 urban and 4 rural areas based on population and economic base. Maternal education was used to represent SES. Odds ratios (OR) were calculated for preterm birth (PTB), low birth weight (LBW), and small-for-gestational-age (SGA) birth, accounting for municipality and individual-level covariates. We used stratified analyses to examine interaction between SES and rural-urban continuum. Relative to metropolitan area residence, living in small urban or rural areas was associated with adverse birth outcomes. Living in rural areas was associated with SGA birth (OR 1.11, 95% CI 1.05-1.17) and LBW (OR 1.15, 95% CI 1.05-1.26), and living in small urban areas was associated with PTB (OR 1.14, 95% CI 1.08-1.20). Upon stratification by education, living in remote rural relative to metropolitan areas was associated with adverse birth outcomes among university educated mothers only, and living in small urban areas was associated with adverse birth outcomes among mothers with lesser but not higher education. An SES gradient was present in all rural-urban areas, particularly for SGA birth. Differences in perinatal health exist across the rural-urban continuum, and maternal education has a modifying influence.


Trial and error: evaluating and refining a community model of HIV testing in Australia.
The 2012 regulatory approval of HIV rapid point of care (RPOC) tests in Australia and a national strategic focus on HIV testing provided a catalyst for implementation of non-clinical HIV testing service models. PRONTO! opened in 2013 as a two-year trial delivering peer-led community-based HIV RPOC tests targeting gay, bisexual and other men who have sex with men (GBM), with the aim of increasing HIV testing frequency. Initial data suggested this aim was not achieved and, as part of a broader service evaluation, we sought to explore client acceptability and barriers to testing at PRONTO! to refine the service model. We present descriptive and thematic analyses of data from two in-depth evaluation surveys and four focus groups with PRONTO! clients focused on service acceptability, client testing history, intentions to test and barriers to testing for HIV and other sexually transmitted infections (STIs). The three novel aspects of the PRONTO! model, testing environment, rapid-testing, peer-staff, were reported to be highly acceptable among survey and focus group participants. Focus group discussions revealed that the PRONTO! model reduced anxiety associated with HIV testing and created a comfortable environment conducive to discussing sexual risk and health. However, an absence of STI testing at PRONTO!, driven by restrictions on medical subsidies for STI testing and limited funds available at the service level created a barrier to HIV testing. An overwhelming majority of PRONTO! clients reported usually testing for STIs alongside HIV and most reported plans to seek STI testing after testing for HIV at PRONTO!. When deciding where, when and what to test for, clients reported balancing convenience and relative risk and consequences for each infection as guiding their decision-making. A community-based and peer-led HIV testing model reduced previously reported barriers to HIV testing, while introducing new barriers. The absence of STI testing at PRONTO! and the need to access multiple services for comprehensive sexual health screening, created a significant service engagement barrier for some clients. Understanding client motivations to access testing and ensuring novel service models meet client needs is crucial for developing acceptable sexual health services for high-risk populations.


Sex Differences in Nonalcoholic Fatty Liver Disease: State of the Art and Identification of Research Gaps.
Despite tremendous research advancements in nonalcoholic fatty liver disease (NAFLD), our understanding of sex differences in NAFLD remains insufficient. This review summarizes the current knowledge on sex differences in NAFLD, identifies gaps, and discusses important considerations for future research. The prevalence and severity of NAFLD are higher in men than in women during the reproductive age. However, after menopause, NAFLD occurs at a higher rate in women, suggesting that estrogen is protective. Sex differences also exist for the major risk factors of NAFLD. In general, animal models of NAFLD recapitulate the sex differences observed in patients, with more severe steatosis and steatohepatitis, more proinflammatory/profibrotic cytokines, and a higher incidence of hepatic tumors in male than female subjects. Based on computer modeling, female and male livers are metabolically distinct with unique regulators modulating sex-specific metabolic outcomes. Analysis of the literature reveals that most published clinical and epidemiological studies fail to examine sex differences appropriately. Considering the paucity of data on sex differences and the knowledge that regulators of pathways relevant to current therapeutic targets for NAFLD differ by sex, clinical trials should be designed to test drug efficacy and safety according to sex, age, reproductive stage (i.e., menopause), and synthetic hormone use. Conclusion: Sex differences do exist in the prevalence, risk factors, fibrosis, and clinical outcomes of NAFLD, suggesting that, while not yet incorporated, sex will probably be considered in future practice guidelines; adequate consideration of sex differences, sex hormones/menopausal status, age, and other reproductive information in clinical investigation and gene association studies of NAFLD are needed to fill current gaps and implement precision medicine for patients with NAFLD.


A logical analysis of the Drosophila gap-gene system.
This manuscript focuses on the formal analysis of the gap-gene network involved in Drosophila segmentation. The gap genes are expressed in defined domains along the anterior-posterior axis of the embryo, as a response to asymmetric maternal information in the oocyte. Though many of the individual interactions among maternal and gap genes are reasonably well understood, we still lack a thorough understanding of the dynamic behavior of the system as a whole. Based on a generalized logical formalization, the present analysis leads to the delineation of: (1) the minimal number of distinct, qualitative, functional levels associated with each of the key regulatory factors (the three maternal Bcd, Hb and Cad products, and the four gap Gt, Hb, Kr and Kni products); (2) the most crucial interactions and regulatory circuits of the earliest stages of the segmentation process; (3) the ordering of different regulatory interactions governed by each of these products according to corresponding concentration scales; and (4) the role of gap-gene cross-interactions in the transformation of graded maternal information into discrete gap-gene expression domains. The proposed model allows not only the qualitative reproduction of the patterns of gene expression characterized experimentally, but also the simulation and prediction of single and multiple mutant phenotypes.


Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies.
The complement system plays a paradoxical role in the development and expression of autoimmunity in humans. The activation of complement in systemic lupus erythematosus (SLE) contributes to tissue injury. In contrast, inherited deficiency of classical pathway components, particularly C1q (ref. 1), is powerfully associated with the development of SLE. This leads to the hypothesis that a physiological action of the early part of the classical pathway protects against the development of SLE (ref. 2) and implies that C1q may play a key role in this respect. C1q-deficient (C1qa-/-) mice were generated by gene targeting and monitored for eight months. C1qa-/- mice had increased mortality and higher titres of autoantibodies, compared with strain-matched controls. Of the C1qa-/- mice, 25% had glomerulonephritis with immune deposits and multiple apoptotic cell bodies. Among mice without glomerulonephritis, there were significantly greater numbers of glomerular apoptotic bodies in C1q-deficient mice compared with controls. The phenotype associated with C1q deficiency was modified by background genes. These findings are compatible with the hypothesis that C1q deficiency causes autoimmunity by impairment of the clearance of apoptotic cells.


Conductivity of solvated electrons in hexane investigated with terahertz time-domain spectroscopy.
We present investigations of the transient photoconductivity and recombination dynamics of quasifree electrons in liquid n-hexane and cyclohexane performed using terahertz time-domain spectroscopy (THz-TDS). Quasifree electrons are generated by two-photon photoionization of the liquid using a femtosecond ultraviolet pulse, and the resulting changes in the complex conductivity are probed by a THz electromagnetic pulse at a variable delay. The detection of time-domain wave forms of the THz electric field permits the direct determination of both the real and the imaginary part of the conductivity of the electrons over a wide frequency range. The change in conductivity can be described by the Drude model, thus yielding the quasifree electron density and scattering time. The electron density is found to decay on a time scale of a few hundred picoseconds, which becomes shorter with increasing excitation density. The dynamics can be described by a model that assumes nongeminate recombination between electrons and positive ions. In addition, a strong dependence of the quasifree electron density on temperature is observed, in agreement with a two-state model in which the electron may exist in either a quasifree or a bound state.


Checklists in the operating room: Help or hurdle? A qualitative study on health workers' experiences.
Checklists have been used extensively as a cognitive aid in aviation; now, they are being introduced in many areas of medicine. Although few would dispute the positive effects of checklists, little is known about the process of introducing this tool into the health care environment. In 2008, a pre-induction checklist was implemented in our anaesthetic department; in this study, we explored the nurses' and physicians' acceptance and experiences with this checklist. Focus group interviews were conducted with a purposeful sample of checklist users (nurses and physicians) from the Department of Anaesthesia and Intensive Care in a tertiary teaching hospital. The interviews were analysed qualitatively using systematic text condensation. Users reported that checklist use could divert attention away from the patient and that it influenced workflow and doctor-nurse cooperation. They described senior consultants as both sceptical and supportive; a head physician with a positive attitude was considered crucial for successful implementation. The checklist improved confidence in unfamiliar contexts and was used in some situations for which it was not intended. It also revealed insufficient equipment standardisation. Our findings suggest several issues and actions that may be important to consider during checklist use and implementation.


Invited review: Sustainability of the US dairy industry.
The US dairy industry has realized tremendous improvements in efficiencies and milk production since the 1940s. During this time, farm and total cow numbers have decreased and average herd size has increased. This intensification, combined with the shift to a largely urban public, has resulted in increased scrutiny of the dairy industry by social and environmental movements and increased concern regarding the dairy industry's sustainability. In response to these concerns, a group of scientists specializing in animal welfare, nutrient management, greenhouse gas emissions, animal science, agronomy, agricultural engineering, microbiology, and economics undertook a critical review of the US dairy industry. Although the US dairy system was identified as having significant strengths, the consensus was that the current structure of the industry lacks the resilience to adapt to changing social and environmental landscapes. We identified several factors affecting the sustainability of the US dairy industry, including climate change, rapid scientific and technological innovation, globalization, integration of societal values, and multidisciplinary research initiatives. Specific challenges include the westward migration of milk production in the United States (which is at odds with projected reductions in precipitation and associated limitations in water availability for cattle and crops), and the growing divide between industry practices and public perceptions, resulting in less public trust. Addressing these issues will require improved alignment between industry practices and societal values, based upon leadership from within the industry and sustained engagement with other interested participants, including researchers, consumers, and the general public.


Considering the culture of disability in cultural competence education.
Cultural competence extends beyond understanding those values, beliefs, and needs that are associated with patients' age or gender or with their racial, ethnic, or religious backgrounds. People hold many simultaneous cultural associations, and each have implications for the care process. The "culture of disability" is a pan-ethnic culture for which a set of physician competencies are required to ensure appropriate, culturally sensitive care to persons with congenital or acquired disabilities. Such competencies include communicating with patients who have deficits in verbal communication and avoidance of infantilizing speech; understanding the values and needs of persons with disabilities; the ability to encourage self-advocacy skills of patients and families; acknowledging the core values of disability culture including the emphasis on interdependence rather than independence; and feeling comfortable with patients with complex disabilities. Medical schools have developed programs to increase students' exposure to persons with disabilities and it is suggested that such programs are most effective when they are the result of collaboration with community-based facilities or organizations that serve persons with disabilities in the natural environment. Combining lecture-based instruction and structured experiences with the opportunity for students to interact with patients in their natural environments may facilitate development of competencies with respect to patients with disabilities. The culture of disability should be included as one of the many cultures addressed in cultural competence initiatives in medical school and residency curricula.


Viral packaging ATPases utilize a glutamate switch to couple ATPase activity and DNA translocation.
Many viruses utilize ringed packaging ATPases to translocate double-stranded DNA into procapsids during replication. A critical step in the mechanochemical cycle of such ATPases is ATP binding, which causes a subunit within the motor to grip DNA tightly. Here, we probe the underlying molecular mechanism by which ATP binding is coupled to DNA gripping and show that a glutamate-switch residue found in AAA+ enzymes is central to this coupling in viral packaging ATPases. Using free-energy landscapes computed through molecular dynamics simulations, we determined the stable conformational state of the ATPase active site in ATP- and ADP-bound states. Our results show that the catalytic glutamate residue transitions from an active to an inactive pose upon ATP hydrolysis and that a residue assigned as the glutamate switch is necessary for regulating this transition. Furthermore, we identified via mutual information analyses the intramolecular signaling pathway mediated by the glutamate switch that is responsible for coupling ATP binding to conformational transitions of DNA-gripping motifs. We corroborated these predictions with both structural and functional experimental measurements. Specifically, we showed that the crystal structure of the ADP-bound P74-26 packaging ATPase is consistent with the structural coupling predicted from simulations, and we further showed that disrupting the predicted signaling pathway indeed decouples ATPase activity from DNA translocation activity in the φ29 DNA packaging motor. Our work thus establishes a signaling pathway that couples chemical and mechanical events in viral DNA packaging motors.


Speed Determines Leadership and Leadership Determines Learning during Pigeon Flocking.
A key question in collective behavior is how individual differences structure animal groups, affect the flow of information, and give some group members greater weight in decisions. Depending on what factors contribute to leadership, despotic decisions could either improve decision accuracy or interfere with swarm intelligence. The mechanisms behind leadership are therefore important for understanding its functional significance. In this study, we compared pigeons' relative influence over flock direction to their solo flight characteristics. A pigeon's degree of leadership was predicted by its ground speeds from earlier solo flights, but not by the straightness of its previous solo route. By testing the birds individually after a series of flock flights, we found that leaders had learned straighter homing routes than followers, as we would expect if followers attended less to the landscape and more to conspecifics. We repeated the experiment from three homing sites using multiple independent flocks and found individual consistency in leadership and speed. Our results suggest that the leadership hierarchies observed in previous studies could arise from differences in the birds' typical speeds. Rather than reflecting social preferences that optimize group decisions, leadership may be an inevitable consequence of heterogeneous flight characteristics within self-organized flocks. We also found that leaders learn faster and become better navigators, even if leadership is not initially due to navigational ability. The roles that individuals fall into during collective motion might therefore have far-reaching effects on how they learn about the environment and use social information.


T1 and T2 mapping cardiovascular magnetic resonance imaging techniques reveal unapparent myocardial injury in patients with myocarditis.
This study evaluated the ability of T1 and T2 mapping cardiovascular magnetic resonance (CMR) to detect myocardial injury in apparently normal myocardium of patients with myocarditis. We included 20 patients with "infarct-like" acute myocarditis who had typical focal myocardial lesions on late gadolinium enhancement (LGE) images as well as 20 healthy controls. The CMR protocol consisted of a standard myocarditis protocol which was combined with T1 (modified Look-Locker inversion recovery (MOLLI) with a 3(3)5 scheme and T2 mapping (hybrid gradient- and spin-echo multi-echo sequence, GraSE). First, LGE images were used to depict focal myocardial injury and apparently normal, remote myocardium. Second, native T1, T2 and ECV values were obtained in focal lesions but also in apparently normal myocardium. Third, native T1, T2 and ECV values ≥2 standard deviations above reference values obtained in healthy volunteers were used to quantify myocardial injury in patients with myocarditis. Apparently normal myocardium had significantly higher median native T1 [1095 (1055-1148) ms] and ECV [34 (32-35) %] values compared to reference values from healthy volunteers, which were 1051 (1021-1064) ms (p < 0.01) and 26 (24-27) % (p < 0.0001). Furthermore, a nonsignificant increase in median myocardial T2 was detected in apparently normal myocardium of patients with myocarditis compared to healthy volunteers [59 (55-65) vs. 56 (54-60) ms; p = 0.18]. Consequently, the amount of myocardial injury was significantly larger on native T1 [48 (32-56) %; p < 0.01] and ECV maps [58 (50-66) %; p < 0.01] compared to LGE [14 (9-20) %]. Native T1 and ECV maps reveal hidden myocardial injury in normal appearing myocardium of patients with myocarditis. The amount of myocardial injury in myocarditis was underestimated by conventional LGE imaging.


Development of the Modified Yale Food Addiction Scale Version 2.0.
The Yale Food Addiction Scale (YFAS) operationalizes indicators of addictive-like eating, originally based on the Diagnostic and Statistical Manual of Mental Disorders 4th edition Text Revision (DSM-IV-TR) criteria for substance-use disorders. The YFAS has multiple adaptations, including a briefer scale (mYFAS). Recently, the YFAS 2.0 was developed to reflect changes to diagnostic criteria in the DSM-5. The current study developed a briefer version of the YFAS 2.0 (mYFAS 2.0) using the participant sample from the YFAS 2.0 validation paper (n = 536). Then, in an independent sample recruited from Mechanical Turk, 213 participants completed the mYFAS 2.0, YFAS 2.0, and measures of eating-related constructs in order to evaluate the psychometric properties of the mYFAS 2.0, relative to the YFAS 2.0. The mYFAS 2.0 and YFAS 2.0 performed similarly on indexes of reliability, convergent validity with related constructs (e.g. weight cycling), discriminant validity with distinct measures (e.g. dietary restraint) and incremental validity evidenced by associations with frequency of binge eating beyond a measure of disinhibited eating. The mYFAS 2.0 may be an appropriate choice for studies prioritizing specificity when assessing for addictive-like eating or when a briefer measurement of food addiction is needed. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association.


Caveolae and calcium handling, a review and a hypothesis.
Caveolae are associated with molecules crucial for calcium handling. This review considers the roles of caveolae in calcium handling for smooth muscle and interstitial cells of Cajal (ICC). Structural studies showed that the plasma membrane calcium pump (PMCA), a sodium-calcium exchanger (NCX1), and a myogenic nNOS appear to be colocalized with caveolin 1, the main constituent of these caveolae. Voltage dependent calcium channels (VDCC) are associated but not co-localized with caveolin 1, as are proteins of the peripheral sarcoplasmic reticulum (SR) such as calreticulin. Only the nNOS is absent from caveolin 1 knockout animals. Functional studies in calcium free media suggest that a source of calcium in tonic smooth muscles exists, partly sequestered from extracellular EGTA. This source supported sustained contractions to carbachol using VDCC and dependent on activity of the SERCA pump. This source is postulated to be caveolae, near peripheral SR. New evidence, presented here, suggests that a similar source exists in phasic smooth muscle of the intestine and its ICC. These results suggest that caveolae and peripheral SR are a functional unit recycling calcium through VDCC and controlling its local concentration. Calcium handling molecules associated with caveolae in smooth muscle and ICC were identified and their possible functions also reviewed.


Endothelial senescence is induced by phosphorylation and nuclear export of telomeric repeat binding factor 2-interacting protein.
The interplay among signaling events for endothelial cell (EC) senescence, apoptosis, and activation and how these pathological conditions promote atherosclerosis in the area exposed to disturbed flow (d-flow) in concert remain unclear. The aim of this study was to determine whether telomeric repeat-binding factor 2-interacting protein (TERF2IP), a member of the shelterin complex at the telomere, can regulate EC senescence, apoptosis, and activation simultaneously, and if so, by what molecular mechanisms. We found that d-flow induced p90RSK and TERF2IP interaction in a p90RSK kinase activity-dependent manner. An in vitro kinase assay revealed that p90RSK directly phosphorylated TERF2IP at the serine 205 (S205) residue, and d-flow increased TERF2IP S205 phosphorylation as well as EC senescence, apoptosis, and activation by activating p90RSK. TERF2IP phosphorylation was crucial for nuclear export of the TERF2IP-TRF2 complex, which led to EC activation by cytosolic TERF2IP-mediated NF-κB activation and also to senescence and apoptosis of ECs by depleting TRF2 from the nucleus. Lastly, using EC-specific TERF2IP-knockout (TERF2IP-KO) mice, we found that the depletion of TERF2IP inhibited d-flow-induced EC senescence, apoptosis, and activation, as well as atherosclerotic plaque formation. These findings demonstrate that TERF2IP is an important molecular switch that simultaneously accelerates EC senescence, apoptosis, and activation by S205 phosphorylation.


Is there an association between clinical features, response to diagnostic analgesia and radiological findings in horses with a magnetic resonance imaging diagnosis of navicular disease or other injuries of the podotrochlear apparatus?
Previous descriptions of the clinical features of navicular disease occurred before the widespread use of magnetic resonance imaging (MRI) allowed a more definitive diagnosis of foot pain. The objective of this study was to compare the clinical features of horses with lesions of the podotrochlear apparatus with those with other causes of foot pain. It was hypothesised that primary navicular bone disease would be associated with more advanced radiological findings than other diagnoses. A retrospective study was performed of all horses examined at a referral centre with a definitive diagnosis of foot pain based on MRI ± post-mortem examination. Clinical examination findings, response to diagnostic analgesia and radiological grading of the navicular bone were compared among five diagnosis groups: (1) primary navicular bone pathology (NB); (2) lesions of the collateral sesamoidean ligament and/or distal sesamoidean impar ligament (CSL + DSIL); (3) primary deep digital flexor tendon injury (DDFT); (4) navicular bone pathology and other lesions of the podotrochlear apparatus ± DDFT (PTA) and (5) Other. There were 702 horses (NB, 62; CSL + DSIL, 180; DDFT, 69; PTA, 92; Other, 299). Horses with PTA injuries were more frequently unilaterally lame than other groups (P = 0.04). Horses with DDFT injury were more likely to exhibit pain on turning than other groups (P <0.01). There were no associations between response to diagnostic analgesia and diagnostic group, and no association between radiological grade and diagnostic group. Clinical examination findings generally did not discriminate between diseases of the PTA and other causes of foot pain. Overall radiological scores of the navicular bone did not accurately predict navicular bone pathology.


The effect of tibial component sizing on patient reported outcome measures following uncemented total knee replacement.
When performing total knee replacement (TKR), surgeons are required to decide on the most appropriate size of tibial component. As implants are predominantly selected from incremental sizes of a preferred design, it may be necessary for a surgeon to slightly under or oversize the component. There are concerns that overhang could lead to pain from irritation of soft tissues, and an undersized component could lead to subsidence and failure. Patient reported outcome measures were recorded in 154 TKRs at one year postoperatively (in 100 TKRs) and five years post-operatively (in 54 TKRs) in 138 patients. The Oxford Knee Score (OKS), WOMAC and SF-12 were recorded, and a composite pain score was derived from the OKS and WOMAC pain questions. Tibial component size and position were assessed on scaled radiographs and implants were grouped into anatomic sized tibial component (78 TKRs), undersized component (48 TKRs), minor overhang one to three mm (10 TKRs) or major overhang ≥ 3 mm (18 TKRs). There was no statistically significant difference between the mean post-operative OKS, WOMAC, SF-12 or composite pain score of each group. Furthermore, localisation of the site of pain did not correlate with medial or lateral overhang of the tibial component. Our results suggest that tibial component overhang or undersizing is not detrimental to outcome measures or pain. II.


Brightness-equalized quantum dots.
As molecular labels for cells and tissues, fluorescent probes have shaped our understanding of biological structures and processes. However, their capacity for quantitative analysis is limited because photon emission rates from multicolour fluorophores are dissimilar, unstable and often unpredictable, which obscures correlations between measured fluorescence and molecular concentration. Here we introduce a new class of light-emitting quantum dots with tunable and equalized fluorescence brightness across a broad range of colours. The key feature is independent tunability of emission wavelength, extinction coefficient and quantum yield through distinct structural domains in the nanocrystal. Precise tuning eliminates a 100-fold red-to-green brightness mismatch of size-tuned quantum dots at the ensemble and single-particle levels, which substantially improves quantitative imaging accuracy in biological tissue. We anticipate that these materials engineering principles will vastly expand the optical engineering landscape of fluorescent probes, facilitate quantitative multicolour imaging in living tissue and improve colour tuning in light-emitting devices.


Postural sway in single-limb and bilateral quiet standing after unilateral total knee arthroplasty.
To investigate whether total knee arthroplasty (TKA) was associated with stability in single-limb stance and whether reduced stability in single-limb stance was associated with increased postural sway in bilateral quiet standing. 3D kinematics for center of mass was used to assess postural sway in 23 subjects with TKA and 23 controls. Tests included bilateral quiet standing with and without vision and on a compliant surface, and single-limb stance. 30% of the subjects in the TKA group were unable to maintain single-limb stance for 20s on any leg. Of the 70% in the TKA group able to stand on one leg, mean sway velocity in the medio-lateral direction was marginally higher for the prosthetic side (p=.02), but no differences were found between the TKA and the control group in single-limb stance. Performance in bilateral quiet standing was similar in TKA-subjects, able as well as unable to stand on one leg, and controls. Reduced quadriceps strength in the contralateral leg, higher BMI, and older age predicted failure to maintain single-limb stance. In subjects able to stand on one leg, performance was considered comparable between the prosthetic and contralateral side and between groups. Inability to stand on one leg did not affect postural sway in bilateral quiet standing. The results suggest that inability to maintain single-limb stance is explained by reduced physical capacity rather than the knee condition in itself. The present study emphasizes the importance of physical activity to improve strength and functional capacity.


Modelling lipid competition dynamics in heterogeneous protocell populations.
Recent experimental work in the field of synthetic protocell biology has shown that prebiotic vesicles are able to 'steal' lipids from each other. This phenomenon is driven purely by asymmetries in the physical state or composition of the vesicle membranes, and, when lipid resource is limited, translates directly into competition amongst the vesicles. Such a scenario is interesting from an origins of life perspective because a rudimentary form of cell-level selection emerges. To sharpen intuition about possible mechanisms underlying this behaviour, experimental work must be complemented with theoretical modelling. The aim of this paper is to provide a coarse-grain mathematical model of protocell lipid competition. Our model is capable of reproducing, often quantitatively, results from core experimental papers that reported distinct types vesicle competition. Additionally, we make some predictions untested in the lab, and develop a general numerical method for quickly solving the equilibrium point of a model vesicle population.


Paenibacillus ihbetae sp. nov., a cold-adapted antimicrobial producing bacterium isolated from high altitude Suraj Tal Lake in the Indian trans-Himalayas.
The assessment of bacterial diversity and bioprospection of the high-altitude lake Suraj Tal microorganisms for potent antimicrobial activities revealed the presence of two Gram-stain-variable, endospore-forming, rod-shaped, aerobic bacteria, namely IHBB 9852T and IHBB 9951. Phylogenetic analysis based on 16S rRNA gene sequence showed the affiliation of strains IHBB 9852T and IHBB 9951 within the genus Paenibacillus, exhibiting the highest sequence similarity to Paenibacillus lactis DSM 15596T (97.8% and 97.7%) and less than 95.9% similarity to other species of the genus Paenibacillus. DNA-DNA relatedness among strains IHBB 9852T and IHBB 9951 was 90.2%, and with P. lactis DSM 15596T, was 52.7% and 52.4%, respectively. The novel strains contain anteiso-C15:0, iso-C15:0, C16:0 and iso-C16:0 as major fatty acids, and phosphatidylglycerol, phosphatidylethanolamine and diphosphatidylglycerol were predominant polar lipids. The DNA G+C content for IHBB 9852T and IHBB 9951 was 52.1 and 52.2mol%. Based on the results of phenotypic and genomic characterisations, we concluded that strains IHBB 9852T and IHBB 9951 belong to a novel Paenibacillus species, for which the name Paenibacillus ihbetae sp. nov. is proposed. The type strain is IHBB 9852T (=MTCC 12459T=MCC 2795T=JCM 31131T=KACC 19072T; DPD TaxonNumber TA00046) and IHBB 9951 (=MTCC 12458=MCC 2794=JCM 31132=KACC 19073) is a reference strain.


The Generalized Matrix Decomposition Biplot and Its Application to Microbiome Data.
Exploratory analysis of human microbiome data is often based on dimension-reduced graphical displays derived from similarities based on non-Euclidean distances, such as UniFrac or Bray-Curtis. However, a display of this type, often referred to as the principal-coordinate analysis (PCoA) plot, does not reveal which taxa are related to the observed clustering because the configuration of samples is not based on a coordinate system in which both the samples and variables can be represented. The reason is that the PCoA plot is based on the eigen-decomposition of a similarity matrix and not the singular value decomposition (SVD) of the sample-by-abundance matrix. We propose a novel biplot that is based on an extension of the SVD, called the generalized matrix decomposition biplot (GMD-biplot), which involves an arbitrary matrix of similarities and the original matrix of variable measures, such as taxon abundances. As in a traditional biplot, points represent the samples, and arrows represent the variables. The proposed GMD-biplot is illustrated by analyzing multiple real and simulated data sets which demonstrate that the GMD-biplot provides improved clustering capability and a more meaningful relationship between the arrows and points.IMPORTANCE Biplots that simultaneously display the sample clustering and the important taxa have gained popularity in the exploratory analysis of human microbiome data. Traditional biplots, assuming Euclidean distances between samples, are not appropriate for microbiome data, when non-Euclidean distances are used to characterize dissimilarities among microbial communities. Thus, incorporating information from non-Euclidean distances into a biplot becomes useful for graphical displays of microbiome data. The proposed GMD-biplot accounts for any arbitrary non-Euclidean distances and provides a robust and computationally efficient approach for graphical visualization of microbiome data. In addition, the proposed GMD-biplot displays both the samples and taxa with respect to the same coordinate system, which further allows the configuration of future samples.


The relationship between experiential deficits of negative symptoms and subjective quality of life in schizophrenia.
Understanding the link between quality of life and symptoms in schizophrenia is important in enhancing the prospect of patient recovery. Only weak associations have been found between subjective quality of life (SQOL) and negative symptoms. However, this may be because many existing symptom assessment scales inadequately assess the experiential deficits of negative symptoms. This study aimed to re-evaluate these findings using the Clinical Assessment Interview for Negative Symptoms (CAINS), which as been designed to capture both the expressive and experiential subdomains of negative symptoms as separate constructs. In this observational study 275 participants with at least moderate negative symptoms were assessed three times over nine months using the CAINS, the Positive and Negative Syndrome Scale (PANSS), and the Manchester Short Assessment of Quality of Life (MANSA). A significant negative association between SQOL and the CAINS experiential subscale was found in the cross-sectional analysis (adj. B=-0.28, 95% CI=-0.44 to -0.12, P=0.001), and in the change scores (adj. B=-0.13, 95% CI=-0.26 to -0.01, P=0.032). No associations between SQOL and expressive symptoms, or negative symptoms measured using the PANSS were detected in the multivariable models. These findings suggest that the association between negative symptoms and SQOL is related primarily to experiential deficits, and highlights the importance of measuring the separate subdomains of negative symptoms as distinct constructs. The findings also highlight the impact of negative symptoms and experiential deficits in particular on social outcomes, further emphasising the need to develop new treatments for these symptoms.


Avoiding 40% of the premature deaths in each country, 2010-30: review of national mortality trends to help quantify the UN sustainable development goal for health.
The UN will formulate ambitious Sustainable Development Goals for 2030, including one for health. Feasible goals with some quantifiable, measurable targets can influence governments. We propose, as a quatitative health target, "Avoid in each country 40% of premature deaths (under-70 deaths that would be seen in the 2030 population at 2010 death rates), and improve health care at all ages". Targeting overall mortality and improved health care ignores no modifiable cause of death, nor any cause of disability that is treatable (or also causes many deaths). 40% fewer premature deaths would be important in all countries, but implies very different priorities in different populations. Reinforcing this target for overall mortality in each country are four global subtargets for 2030: avoid two-thirds of child and maternal deaths; two-thirds of tuberculosis, HIV, and malaria deaths; a third of premature deaths from non-communicable diseases (NCDs); and a third of those from other causes (other communicable diseases, undernutrition, and injuries). These challenging subtargets would halve under-50 deaths, avoid a third of the (mainly NCD) deaths at ages 50-69 years, and so avoid 40% of under-70 deaths. To help assess feasibility, we review mortality rates and trends in the 25 most populous countries, in four country income groupings, and worldwide. UN sources yielded overall 1970-2010 mortality trends. WHO sources yielded cause-specific 2000-10 trends, standardised to country-specific 2030 populations; decreases per decade of 42% or 18% would yield 20-year reductions of two-thirds or a third. Throughout the world, except in countries where the effects of HIV or political disturbances predominated, mortality decreased substantially from 1970-2010, particularly in childhood. From 2000-10, under-70 age-standardised mortality rates decreased 19% (with the low-income and lower-middle-income countries having the greatest absolute gains). The proportional decreases per decade (2000-10) were: 34% at ages 0-4 years; 17% at ages 5-49 years; 15% at ages 50-69 years; 30% for communicable, perinatal, maternal, or nutritional causes; 14% for NCDs; and 13% for injuries (accident, suicide, or homicide). Moderate acceleration of the 2000-10 proportional decreases in mortality could be feasible, achieving the targeted 2030 disease-specific reductions of two-thirds or a third. If achieved, these reductions avoid about 10 million of the 20 million deaths at ages 0-49 years that would be seen in 2030 at 2010 death rates, and about 17 million of the 41 million such deaths at ages 0-69 years. Such changes could be achievable by 2030, or soon afterwards, at least in areas free of war, other major effects of political disruption, or a major new epidemic. UK Medical Research Council, Norwegian Agency for Development Cooperation, Centre for Global Health Research, and Bill & Melinda Gates Foundation.


Hypofractionated stereotactic body radiotherapy for primary and metastatic liver tumors using the novalis image-guided system: preliminary results regarding efficacy and toxicity.
www.tcrt.org The purpose of this study was to evaluate the efficacy and toxicity of stereotactic body radiotherapy (SBRT) for primary and metastatic liver tumors using the Novalis image-guided radiotherapy system. After preliminarily treating liver tumors using the Novalis system from July 2006, we started a protocol-based study in February 2008. Eighteen patients (6 with primary hepatocellular carcinoma and 12 with metastatic liver tumor) were treated with 55 or 50 Gy, depending upon their planned dose distribution and liver function, delivered in 10 fractions over 2 weeks. Four non-coplanar and three coplanar static beams were used. Patient age ranged from 54 to 84 years (median: 72 years). The Child-Pugh classification was Grade A in 17 patients and Grade B in 1. Tumor diameter ranged from 12 to 35 mm (median: 23 mm). Toxicities were evaluated according to the Common Terminology Criteria of Adverse Events version 4.0, and radiation-induced liver disease (RILD) was defined by Lawrence's criterion. The median follow-up period was 14.5 months. For all patients, the 1-year overall survival and local control rates were 94% and 86%, respectively. A Grade 1 liver enzyme change was observed in 5 patients, but no RILD or chronic liver dysfunction was observed. SBRT using the Novalis image-guided system is safe and effective for treating primary and metastatic liver tumors. Further investigation of SBRT for liver tumors is warranted. In view of the acceptable toxicity observed with this protocol, we have moved to a new protocol to shorten the overall treatment time and escalate the dose.


Range image segmentation by an effective jump-diffusion method.
This paper presents an effective jump-diffusion method for segmenting a range image and its associated reflectance image in the Bayesian framework. The algorithm works on complex real-world scenes (indoor and outdoor), which consist of an unknown number of objects (or surfaces) of various sizes and types, such as planes, conics, smooth surfaces, and cluttered objects (like trees and bushes). Formulated in the Bayesian framework, the posterior probability is distributed over a solution space with a countable number of subspaces of varying dimensions. The algorithm simulates Markov chains with both reversible jumps and stochastic diffusions to traverse the solution space. The reversible jumps realize the moves between subspaces of different dimensions, such as switching surface models and changing the number of objects. The stochastic Langevin equation realizes diffusions within each subspace. To achieve effective computation, the algorithm precomputes some importance proposal probabilities over multiple scales through Hough transforms, edge detection, and data clustering. The latter are used by the Markov chains for fast mixing. The algorithm is tested on 100 1D simulated data sets for performance analysis on both accuracy and speed. Then, the algorithm is applied to three data sets of range images under the same parameter setting. The results are satisfactory in comparison with manual segmentations.


DTI and MTR abnormalities in schizophrenia: analysis of white matter integrity.
Diffusion tensor imaging (DTI) studies in schizophrenia demonstrate lower anisotropic diffusion within white matter due either to loss of coherence of white matter fiber tracts, to changes in the number and/or density of interconnecting fiber tracts, or to changes in myelination, although methodology as well as localization of such changes differ between studies. The aim of this study is to localize and to specify further DTI abnormalities in schizophrenia by combining DTI with magnetization transfer imaging (MTI), a technique sensitive to myelin and axonal alterations in order to increase specificity of DTI findings. 21 chronic schizophrenics and 26 controls were scanned using Line-Scan-Diffusion-Imaging and T1-weighted techniques with and without a saturation pulse (MT). Diffusion information was used to normalize co-registered maps of fractional anisotropy (FA) and magnetization transfer ratio (MTR) to a study-specific template, using the multi-channel daemon algorithm, designed specifically to deal with multidirectional tensor information. Diffusion anisotropy was decreased in schizophrenia in the following brain regions: the fornix, the corpus callosum, bilaterally in the cingulum bundle, bilaterally in the superior occipito-frontal fasciculus, bilaterally in the internal capsule, in the right inferior occipito-frontal fasciculus and the left arcuate fasciculus. MTR maps demonstrated changes in the corpus callosum, fornix, right internal capsule, and the superior occipito-frontal fasciculus bilaterally; however, no changes were noted in the anterior cingulum bundle, the left internal capsule, the arcuate fasciculus, or inferior occipito-frontal fasciculus. In addition, the right posterior cingulum bundle showed MTR but not FA changes in schizophrenia. These findings suggest that, while some of the diffusion abnormalities in schizophrenia are likely due to abnormal coherence, or organization of the fiber tracts, some of these abnormalities may, in fact, be attributed to or coincide with myelin/axonal disruption.


Effect of improper scan alignment on retinal nerve fiber layer thickness measurements using Stratus optical coherence tomograph.
Misalignment of the Stratus optical coherence tomograph scan circle placed by the operator around the optic nerve head (ONH) during each retinal nerve fiber layer (RNFL) examination can affect the instrument reproducibility and its theoretical ability to detect true structural changes in the RNFL thickness over time. We evaluated the effect of scan circle placement on RNFL measurements. Observational clinical study. Sixteen eyes of 8 normal participants were examined using the Stratus optical coherence tomograph Fast RNFL thickness acquisition protocol (software version 4.0.7; Carl Zeiss Meditec, Dublin, CA). Four consecutive images were taken by the same operator with the circular scan centered on the optic nerve head. Four images each with the scan displaced superiorly, inferiorly, temporally, and nasally were also acquired. Differences in average and sectoral RNFL thicknesses were determined. For the centered scans, the coefficients of variation (CV) and the intraclass correlation coefficient for the average RNFL thickness measured were calculated. When the average RNFL thickness of the centered scans was compared with the average RNFL thickness of the displaced scans individually using analysis of variance with post-hoc analysis, no difference was found between the average RNFL thickness of the nasally (105.2 microm), superiorly (106.2 microm), or inferiorly (104.1 microm) displaced scans and the centered scans (106.4 microm). However, a significant difference (analysis of variance with Dunnett's test: F=8.82, P<0.0001) was found between temporally displaced scans (115.8 microm) and centered scans. Significant differences in sectoral RNFL thickness measurements were found between centered and each displaced scan. The coefficient of variation for average RNFL thickness was 1.75% and intraclass correlation coefficient was 0.95. In normal eyes, average RNFL thickness measurements are robust and similar with significant superior, inferior, and nasal scan displacement, but average RNFL thickness is greater when scans are displaced temporally. Parapapillary scan misalignment produces significant changes in RNFL assessment characterized by an increase in measured RNFL thickness in the quadrant in which the scan is closer to the disc, and a significant decrease in RNFL thickness in the quadrant in which the scan is displaced further from the optic disc.


Neurogenic muscarinic vasodilation in the cat. An example of endothelial cell-independent cholinergic relaxation.
Nerve-mediated and acetylcholine-induced dilator behavior of feline posterior auricular arteries was studied in vitro. We evaluated the muscarinic nature and endothelial cell-dependence of the vasodilations and attempted to determine if there are inhibitory muscarinic receptors located directly on the smooth muscle cells in this artery. Transmural nerve stimulation of arteries which were pretreated with guanethidine (5 X 10(-6)M) and constricted with prostaglandin F2 alpha (3 X 10(-6)M) caused a frequency-dependent, tetrodotoxin-sensitive relaxation of up to 50% of induced tone. Atropine (10(-7)M) blocked more than 95% of this response at all frequencies. Removal of the endothelium by rubbing the intimal surface did not affect the magnitude of the response, but prolonged it slightly. Neurogenic relaxations in rubbed preparations were atropine-sensitive, although less so than control at higher stimulation frequencies. Relaxation of this artery to the calcium ionophore A23187 was completely endothelial cell-dependent. However, exogenous acetylcholine caused dose-dependent relaxations both in control and rubbed preparations. We conclude that the posterior auricular artery is an example of a blood vessel which has muscarinic receptors located directly on its smooth muscle cells which, when activated by acetylcholine released from perivascular nerves, mediate a smooth muscle cell relaxation. This finding contrasts with models of the vascular smooth muscle cell which indicates an excitatory role for muscarinic receptors.


Mycobacterium bovis infection in North American elk (Cervus elaphus).
A naturally occurring outbreak of Mycobacterium bovis infection in captive wild elk (wapiti) in Montana was confirmed by mycobacteriologic examination. Twenty-eight of 143 elk responded to M. bovis purified protein derivative (PPD) tuberculin injected intradermally in the cervical region (SCT). The results of comparative cervical tuberculin skin tests conducted within 9 days of SCT revealed greater responses to M. bovis PPD tuberculin than to M. avium PPD tuberculin in 23 of 28 elk responding. At necropsy, several grossly visible tuberculous lesions were observed in the parenchyma of the lung, thoracic lymph nodes, and submandibular lymph nodes. Microscopic examination of appropriately stained tissue sections revealed the presence of granulomatous lesions containing acid-fast bacilli. An enzyme-linked immunosorbent assay (ELISA) was developed using a sarkosyl extract of M. bovis (antigen) and peroxidase-labeled protein G (conjugate); reactions were detected in the sera of 8 of 9 elk responding to M. bovis PPD tuberculin. Lymphocyte blastogenic assay responses were detected using M. bovis antigens in 7 of 9 elk positive on skin tests using M. bovis PPD.


Power, trust, and risk: some reflections on an absent issue.
In modern discussions among health professionals there is a strange lack of discussions of power. This is most notably true for the discussions about proper physician-patient relations and the discussions about trust. This article explores some of the consequences of this absence. It is argued that the absence of the issue of power hampers a serious and open moral discussion of important institutional forms in the health care system. It is also argued that some of the proposals for how to organize physician-patient interaction are rather unrealistic, mainly because the issue of power is neglected. Finally, the article develops some ideas about how power ought to be approached in modern health care.


Transfection of thrombospondin 1 complementary DNA into a human breast carcinoma cell line reduces primary tumor growth, metastatic potential, and angiogenesis.
Previous studies demonstrated that metastatic MDA-MB-435 breast carcinoma cells synthesized and secreted less of the extracellular matrix protein thrombospondin 1 (TSP1) than nonmetastatic breast carcinoma cell lines, a trend also observed for melanoma and lung carcinoma cell lines. To directly examine the effect of tumor cell TSP1 expression on tumor growth and metastasis. MDA-MB-435 cells were transfected with full length THBS-1 cDNA linked to a constitutive cytomegalovirus promoter, or with the cytomegalovirus vector alone. Injection of transfected clones that overexpressed TSP1 into the mammary fat pad of nude mice resulted in a dose-dependent inhibition of primary tumor size and an inhibition of spontaneous pulmonary metastases, which occurred in 21-30% of THBS-1 transfectants compared to 44-49% of controls (P = 0.007). An additional clone was identified that overexpressed a COOH-terminally truncated TSP1. This clone produced larger primary tumors and an increase in the occurrence of metastases relative to control transfectants, suggesting the participation of a previously understudied region of TSP1 in the regulation of tumor progression. The THBS-1 and control transfectants did not exhibit significant differences in growth, colonization, or motility in vitro. However, a relative reduction in capillary densities in primary tumors formed by the wild-type THBS-1 transfectants was observed, suggestive of an angiostatic effect. The data indicate that tumor cell production of TSP1 can exert a significant inhibitory effect on tumor progression in the MDA-MB-435 breast carcinoma cell line, which may be attributable in part to a reduction in angiogenesis.


Osteology of Galeamopus pabsti sp. nov. (Sauropoda: Diplodocidae), with implications for neurocentral closure timing, and the cervico-dorsal transition in diplodocids.
Diplodocids are among the best known sauropod dinosaurs. Numerous specimens of currently 15 accepted species belonging to ten genera have been reported from the Late Jurassic to Early Cretaceous of North and South America, Europe, and Africa. The highest diversity is known from the Upper Jurassic Morrison Formation of the western United States: a recent review recognized 12 valid, named species, and possibly three additional, yet unnamed ones. One of these is herein described in detail and referred to the genus Galeamopus. The holotype specimen of Galeamopus pabsti sp. nov., SMA 0011, is represented by material from all body parts but the tail, and was found at the Howe-Scott Quarry in the northern Bighorn Basin in Wyoming, USA. Autapomorphic features of the new species include a horizontal canal on the maxilla that connects the posterior margin of the preantorbital and the ventral margin of the antorbital fenestrae, a vertical midline groove marking the sagittal nuchal crest, the presence of a large foramen connecting the postzygapophyseal centrodiapophyseal fossa and the spinopostzygapophyseal fossa of mid- and posterior cervical vertebrae, a very robust humerus, a laterally placed, rugose tubercle on the concave proximal portion of the anterior surface of the humerus, a relatively stout radius, the absence of a distinct ambiens process on the pubis, and a distinctly concave posteroventral margin of the ascending process of the astragalus. In addition to the holotype specimen SMA 0011, the skull USNM 2673 can also be referred to Galeamopus pabsti. Histology shows that the type specimen SMA 0011 is sexually mature, although neurocentral closure was not completed at the time of death. Because SMA 0011 has highly pneumatized cervical vertebrae, the development of the lamination appears a more important indicator for individual age than neurocentral fusion patterns. SMA 0011 is one of very few sauropod specimens that preserves the cervico-dorsal transition in both vertebrae and ribs. The association of ribs with their respective vertebrae shows that the transition between cervical and dorsal vertebrae is significantly different in Galeamopus pabsti than in Diplodocus carnegii or Apatosaurus louisae, being represented by a considerable shortening of the centra from the last cervical to the first dorsal vertebra. Diplodocids show a surprisingly high diversity in the Morrison Formation. This can possibly be explained by a combination of geographical and temporal segregation, and niche partitioning.


Selecting Appropriate Toys for Young Children in the Digital Era.
Play is essential to optimal child development because it contributes to the cognitive, physical, social, and emotional well-being of children and youth. It also offers an ideal and significant opportunity for parents and other caregivers to engage fully with children using toys as an instrument of play and interaction. The evolution of societal perceptions of toys from children's playthings to critical facilitators of early brain and child development has challenged caregivers in deciding which toys are most appropriate for their children. This clinical report strives to provide pediatric health care providers with evidence-based information that can be used to support caregivers as they choose toys for their children. The report highlights the broad definition of a toy; consideration of potential benefits and possible harmful effects of toy choices on child development; and the promotion of positive caregiving and development when toys are used to engage caregivers in play-based interactions with their children that are rich in language, pretending, problem-solving, and creativity. The report aims to address the evolving replacement of more traditional toys with digital media-based virtual "toys" and the lack of evidence for similar benefits in child development. Furthermore, this report briefly addresses the role of toys in advertising and/or incentive programs and aims to bring awareness regarding safety and health hazards associated with toy availability and accessibility in public settings, including some health care settings.


Questionnaire reliability and validity for aluminum potroom workers.
As a part of a study on the respiratory symptoms of aluminum potroom workers, the reliability of a self-administered questionnaire and an interview questionnaire was studied with the use of 261 and 49 employees, respectively. The validity of the self-administered questionnaire (134 persons examined) and the interview questionnaire (90 persons examined) was assessed in a comparison of the statements with the case histories. The reliability of the self-administered questionnaire was fairly high, the kappa coefficient ranging from 0.58 to 0.83, while the reliability of the interview questionnaire varied from -0.03 to 0.45. The same pattern was present with regard to validity, as the self-administered questionnaire showed the highest mean sensitivity, specificity, and agreement in a comparison with the case histories. The self-administered questionnaire seemed to discriminate well between symptomatic and asymptomatic individuals, whereas supplemental information about symptoms, as obtained by a standardized interview questionnaire, appeared to be less valid.


Based on regular expression matching of evaluation of the task performance in WSN: a queue theory approach.
Due to the limited resources of wireless sensor network, low efficiency of real-time communication scheduling, poor safety defects, and so forth, a queuing performance evaluation approach based on regular expression match is proposed, which is a method that consists of matching preprocessing phase, validation phase, and queuing model of performance evaluation phase. Firstly, the subset of related sequence is generated in preprocessing phase, guiding the validation phase distributed matching. Secondly, in the validation phase, the subset of features clustering, the compressed matching table is more convenient for distributed parallel matching. Finally, based on the queuing model, the sensor networks of task scheduling dynamic performance are evaluated. Experiments show that our approach ensures accurate matching and computational efficiency of more than 70%; it not only effectively detects data packets and access control, but also uses queuing method to determine the parameters of task scheduling in wireless sensor networks. The method for medium scale or large scale distributed wireless node has a good applicability.


Dynamic regimes and bifurcations in a model of actin-based motility.
Propulsion by actin polymerization is widely used in cell motility. Here, we investigate a model of the brush range of an actin gel close to a propelled object, describing the force generation and the dynamics of the propagation velocity. We find transitions between stable steady states and relaxation oscillations when the attachment rate of actin filaments to the obstacle is varied. The oscillations set in at small values of the attachment rate via a homoclinic bifurcation. A second transition from a stable steady state to relaxation oscillations, found for higher values of the attachment rate, occurs via a supercritical Hopf bifurcation. The behavior of the model near the second transition is similar that of a system undergoing a canard explosion. Consequently, we observe excitable dynamics also. The model further exhibits bistability between stationary states or stationary states and limit cycles. Therefore, the brush of actin filament ends appears to have a much richer dynamics than was assumed until now.


Singlet exciton fission in thin films of tert-butyl-substituted terrylenes.
Two terrylene chromophores, 2,5,10,13-tetra(tert-butyl)terrylene (1) and 2,5-di(tert-butyl)terrylene (2), were synthesized and studied to determine their singlet exciton fission (SF) efficiencies. Compound 1 crystallizes in one-dimensional stacks, whereas 2 packs in a slip-stacked, herringbone pattern of dimers motif. Strongly quenched fluorescence and rapid singlet exciton decay dynamics are observed in vapor-deposited thin films of 1 and 2. Phosphorescence measurements on thin films of 1 and 2 show that SF is only 70 meV endoergic for these chromophores. Femtosecond transient absorption experiments using low laser fluences on these films reveal rapid triplet exciton formation for both 1 (τ = 120 ± 10 ps) and 2 (τ = 320 ± 20 ps) that depends strongly on film crystallinity. The transient absorption data are consistent with formation of an excimer state prior to SF. Triplet exciton yield measurements indicate nearly quantitative SF in thin films of both chromophores in highly crystalline solvent-vapor-annealed films: 170 ± 20% for 1 and 200 ± 30% for 2. These results show that significantly different crystal morphologies of the same chromophore can both result in high-efficiency SF provided that the energetics are favorable.


Effects of maternal cigarette smoking on ultrasonic measurements of fetal growth and on Doppler flow velocity waveforms.
Serial ultrasound biometry and Doppler flow velocity waveform analysis were used to measure the effects of maternal smoking in a prospective study of 535 pregnancies. Smoking was associated with significant reductions in maternal weight gain, birthweights and placental weights. Decreased fetal biparietal diameter measurements were observed in pregnancies of smoking women; this effect was maximal at 24 weeks' gestation, was restricted to male fetuses and was not associated with altered head circumferences after birth. Umbilical artery and uteroplacental systolic/diastolic ratios were similar in pregnancies of smoking and non-smoking women, indicating that the effects of smoking on placental vascular resistance are periodic rather than continuous. The findings of this study confirm the need for studies of fetal growth to include prenatal measurements obtained by high resolution ultrasound imaging, rather than relying on findings obtainable by examination of the infant after birth.


Outbreak of eczema and rhinitis in a group of office workers in Greenland.
Disturbed indoor climate may in some cases be associated with illness. In the present paper, we report the results from a thorough investigation of office workers in Greenland, who developed skin and/or airway problems after moving into renewed offices. In 2009 the office of the Bank of Greenland had a total renovation of the building, including new furniture and carpets. Symptoms developed within the first year after moving back into the renewed buildings. After removal of carpets in the building, symptoms significantly improved. Workers were examined in 2009 and re-examined in 2013, including clinical examination, patch test and when relevant also skin prick tests and histamine release test. Isothiazolinones and fumarates, both able to cause airway as well as skin symptoms, were isolated from carpets before testing, and included in the test series. In total, 32 out of 80 workers (40%) developed symptoms; 27 reported eczema, 20 rhinitis and 4 urticaria. Eczema was located on the hands and/or lower arms in 18 workers, on the face in 10 workers and on legs/trunk in 12 workers. After intervention in the office, 22 workers with eczema reported significant improvement, all cases of hand eczema cleared and 16 workers with rhinitis also improved. Positive patch tests to carpet extracts were found significantly more frequent in the worker cohort than in a control group comprising 47 dermatitis patients (p<0.001). Only few workers reacted with a positive response to skin prick test or in the HR test, no obvious pattern in reactions was found, and no conclusions can be made from these reactions. The results indicate that the reported symptoms are related to exposures from the building after renovation in 2009. A specific triggering exposure could not be identified, although chemicals from the glued carpets are suspected. The study is an example of a work place investigation, and illustrates the diversity of symptoms and exposures involved in "Sick Building" cases.


Regulation of immune response by Plasmodium-infected red blood cells.
During the asexual blood stage infection of the human malaria parasite, Plasmodium falciparum, parasite-derived proteins are inserted onto the surface of the host red blood cell membrane. These proteins are highly variable and were originally thought only to mediate antigenic variation, and sequestration of parasites from peripheral circulation, thus enabling immune evasion. Recent studies have revealed that PfEMP-1 and other molecules on the P. falciparum-infected red blood cell (PfRBC) activate and modulate the immune response. In this review, we discuss how PfRBCs interact with antigen-presenting cells (APCs) and other cells of the immune system, and how such interactions could modulate the host response to Plasmodium infections.


Effect of dietary supplementation with conjugated linoleic acid on markers of calcium and bone metabolism in healthy adult men.
Conjugated linoleic acid (CLA) has been shown to positively influence calcium and bone metabolism in experimental animals and cells in culture, but there are limited human data available. To investigate the effect of CLA supplementation on biomarkers of calcium and bone metabolism in healthy adult males. The study consisted of a double-blind, placebo-controlled trial in which 60 healthy adult males (aged 39-64 y) were randomly assigned to receive daily either 3.0 g CLA isomer blend (50:50% cis-9,trans-11:trans-10,cis-12 isomers) or a palm/bean oil blend (placebo) for 8 weeks. Urine and blood samples were collected at weeks 0 and 8 and were analysed for biomarkers of calcium and bone metabolism. Supplementation with CLA or placebo for 8 weeks had no significant effects on markers of bone formation (serum osteocalcin and bone-specific alkaline phosphatase) or bone resorption (serum C-telopeptide-related fraction of type 1 collagen degradation products, urinary N-telopeptide-related fraction of type 1 collagen degradation products, urinary pyridinoline and deoxypyridinoline), or on serum or urinary calcium levels. Baseline levels of these biochemical parameters were similar in both groups of subjects. While the placebo had no effect, CLA supplementation resulted in a three-fold increase (P<0.00001) in cis-9,trans-11 CLA isomer in total plasma lipids. Under the conditions tested in this double-blind, placebo-controlled trial in adult men, a CLA supplement of mixed isomers did not affect markers of calcium or bone metabolism. Further investigation of the effects of CLA on calcium and bone metabolism in other gender- and age-groups is warranted.


Reentrant synchronization and pattern formation in pacemaker-entrained Kuramoto oscillators.
We study phase entrainment of Kuramoto oscillators under different conditions on the interaction range and the natural frequencies. In the first part the oscillators are entrained by a pacemaker acting like an impurity or a defect. We analytically derive the entrainment frequency for arbitrary interaction range and the entrainment threshold for all-to-all couplings. For intermediate couplings our numerical results show a reentrance of the synchronization transition as a function of the coupling range. The origin of this reentrance can be traced back to the normalization of the coupling strength. In the second part we consider a system of oscillators with an initial gradient in their natural frequencies, extended over a one-dimensional chain or a two-dimensional lattice. Here it is the oscillator with the highest natural frequency that becomes the pacemaker of the ensemble, sending out circular waves in oscillator-phase space. No asymmetric coupling between the oscillators is needed for this dynamical induction of the pacemaker property nor need it be distinguished by a gap in the natural frequency.


Context-dependent minimisation of prediction errors involves temporal-frontal activation.
According to the predictive coding model of perception, the brain constantly generates predictions of the upcoming sensory inputs. Perception is realised through a hierarchical generative model which aims at minimising the discrepancy between predictions and the incoming sensory inputs (i.e., prediction errors). Notably, prediction errors are weighted depending on precision of prior information. However, it remains unclear whether and how the brain monitors prior precision when minimising prediction errors in different contexts. The current study used magnetoencephalography (MEG) to address this question. We presented participants with repetition of two non-predicted probes embedded in context of high and low precision, namely mispredicted and unpredicted probes. Non-parametric permutation statistics showed that the minimisation of precision-weighted prediction errors started to dissociate on early components of the auditory responses (including the P1m and N1m), indicating that the brain can differentiate between these scenarios at an early stage of the auditory processing stream. Permutation statistics conducted on the depth-weighted statistical parametric maps (dSPM) source solutions of the repetition difference waves between the two non-predicted probes further revealed a cluster extending from the frontal areas to the posterior temporal areas in the left hemisphere. Overall, the results suggested that context precision not only changes the weighting of prediction errors but also modulates the dynamics of how prediction errors are minimised upon the learning of statistical regularities (achieved by stimulus repetition), which likely involves differential activation at temporal-frontal regions.


Inflammatory Myeloradiculitis Secondary to Pembrolizumab: A Case Report and Literature Review.
Immune checkpoint inhibitors are the most important new medications in oncology and include inhibitors of programmed cell death protein-1 (PD-1) such as Pembrolizumab, Nivolumab, and Cemiplimab. These anticancer agents prevent tumour immune evasion and have been associated with a range of immune-related adverse events (irAEs) including those involving the nervous system. In this case report and literature review, we present the first case of inflammatory myeloradiculitis secondary to Pembrolizumab. We also summarise the characteristics, treatment, and outcomes of other cases reported in the literature which include a component of myelitis. Finally, we make general recommendations on management.


The spatial and temporal domains of modern ecology.
To understand ecological phenomena, it is necessary to observe their behaviour across multiple spatial and temporal scales. Since this need was first highlighted in the 1980s, technology has opened previously inaccessible scales to observation. To help to determine whether there have been corresponding changes in the scales observed by modern ecologists, we analysed the resolution, extent, interval and duration of observations (excluding experiments) in 348 studies that have been published between 2004 and 2014. We found that observational scales were generally narrow, because ecologists still primarily use conventional field techniques. In the spatial domain, most observations had resolutions ≤1 m2 and extents ≤10,000 ha. In the temporal domain, most observations were either unreplicated or infrequently repeated (>1 month interval) and ≤1 year in duration. Compared with studies conducted before 2004, observational durations and resolutions appear largely unchanged, but intervals have become finer and extents larger. We also found a large gulf between the scales at which phenomena are actually observed and the scales those observations ostensibly represent, raising concerns about observational comprehensiveness. Furthermore, most studies did not clearly report scale, suggesting that it remains a minor concern. Ecologists can better understand the scales represented by observations by incorporating autocorrelation measures, while journals can promote attentiveness to scale by implementing scale-reporting standards.


Comparison of the Mycobacterium tuberculosis molecular bacterial load assay, microscopy and GeneXpert versus liquid culture for viable bacterial load quantification before and after starting pulmonary tuberculosis treatment.
Molecular bacterial load assay (MBLA) rapidly quantifies viable Mycobacterium tuberculosis (Mtb) and may be useful for monitoring treatment response and treatment efficacy. We conducted a prospective study in 56 adults with pulmonary tuberculosis from whom 244 sputum samples were collected before and during the first month of treatment. We evaluated MBLA for early monitoring of bacterial burden and investigated bactericidal activities of first-line therapy in patients infected with drug susceptible and resistant isolates. Mtb loads measured by MBLA and culture were correlated after one-week (r = 0.56) and one-month (r = 0.73) of treatment. Correlations between culture and GeneXpert or microscopy were weaker during treatment. Mtb load by MBLA declined more rapidly than GeneXpert after one-week (2.73 Ct, P < 0.001; 0.95 Ct, P = 0.297, respectively) and one-month (8.94 Ct, P < 0.001; 6.78 Ct, P < 0.001). Mtb loads in multidrug resistant (MDR) infections were significantly greater than in both sensitive and poly/mono-resistance after one-week (P < 0.02) and one-month treatment (P = 0.001). MBLA performed better than GeneXpert and microscopy in comparison to culture for quantifying viable Mtb during treatment. It can be used for monitoring bacterial load during TB treatment, facilitating early detection of treatment failure thus improving outcomes.


Effect of influenza vaccination on viral replication and immune response in persons infected with human immunodeficiency virus receiving potent antiretroviral therapy.
Nineteen patients infected with human immunodeficiency virus (HIV) with varying levels of viral suppression achieved with antiretroviral therapy were evaluated to determine whether trivalent influenza vaccine activated HIV replication. Humoral immune responses and CD4+ lymphocyte subsets were compared in 5 HIV-uninfected vaccinated subjects. Transient elevations of plasma HIV RNA levels (76-89 copies/mL) appeared within 2 weeks in 3 of 11 patients with <50 copies/mL at baseline. Sustained elevation in HIV plasma RNA was observed in 7 of 8 patients with baseline HIV RNA of >50 copies/mL. HIV DNA decreased in patients with <400 RNA copies/mL at baseline and showed an HIV RNA increase after vaccination (n=8) when compared with 8 patients with <50 copies/mL at baseline who lacked viral response to vaccination. Concurrent decreases in proviral DNA and memory phenotype CD4+ cells in association with increased plasma HIV RNA after vaccination in patients with <400 RNA copies/mL at baseline suggest that in vivo mobilization of the latently infected cell reservoir may occur during potent antiretroviral therapy.


A network model for plant-pollinator community assembly.
Community assembly models, usually constructed for food webs, are an important component of our understanding of how ecological communities are formed. However, models for mutualistic community assembly are still needed, especially because these communities are experiencing significant anthropogenic disturbances that affect their biodiversity. Here, we present a unique network model that simulates the colonization and extinction process of mutualistic community assembly. We generate regional source pools of species interaction networks on the basis of statistical properties reported in the literature. We develop a dynamic synchronous Boolean framework to simulate, with few free parameters, the dynamics of new mutualistic community formation from the regional source pool. This approach allows us to deterministically map out every possible trajectory of community formation. This level of detail is rarely observed in other analytic approaches and allows for thorough analysis of the dynamical properties of community formation. As for food web assembly, we find that the number of stable communities is quite low, and the composition of the source pool influences the abundance and nature of community outcomes. However, in contrast to food web assembly, stable mutualistic communities form rapidly. Small communities with minor fluctuations in species presence/absence (self-similar limit cycles) are the most common community outcome. The unique application of this Boolean network approach to the study of mutualistic community assembly offers a great opportunity to improve our understanding of these critical communities.


Retransplantation for hepatitis C: results of a U.S. multicenter retransplant study.
It is widely perceived that outcomes are relatively poor following retransplantation (reTX) for recurrent of hepatitis C virus (HCV) infection. Transplant centers debate the utility of offering another liver to these patients. A U.S. study group was formed to retrospectively compare survival after reTX in patients with recurrent HCV (histologically proven) and those transplanted for other indications greater than 90 days after first transplantation, from 1996 to 2004. Patients were divided into 3 groups; group 1: HCV reTX (n = 43), group 2: non-HCV reTX (n = 73), and group 3: recurrent HCV but no reTX (n = 156). They were predominantly male, Caucasian, with mean age of 47.2 yr. The commonest indications for non-HCV reTX were chronic rejection (36%), hepatic artery thrombosis (31%) and recurrent primary sclerosing cholangitis (17%). Duration of hospitalization, number of intensive care unit (ICU) days, and time interval from listing to transplantation or reTX were similar between reTX groups. The 1-yr and 3-yr survival rates after reTX were also similar for HCV reTX and non-HCV reTX groups (1 yr, 69% vs. 73%; 3 yr, 49% vs. 55%). Model for End-Stage Liver Disease (MELD) scores were not predictive of survival from reTX. However, with a MELD score of >30 in the non HCV group, survival was <50%. In the recurrent HCV not undergoing reTX group, 30% were reevaluated for reTX but only 15% were listed for reTX and the 3-yr survival was 47%. The most common reasons for not listing for reTX were recurrent HCV within 6 months (22%), fibrosing cholestatic hepatitis (19%), and renal dysfunction (9%). In conclusion, patients retransplanted for recurrent HCV had similar 1-yr and 3-yr survival when compared to patients undergoing reTX for other indications. MELD scores were not predictive of post-reTX survival. Survival was <50% in the non-HCV reTx group with MELD score of >30. Many patients with recurrent HCV are not considered for reTX and die from recurrent disease.


Practical challenges in the conduct of pragmatic trials embedded in health plans: Lessons of IMPACT-AFib, an FDA-Catalyst trial.
IMPACT-AFib was an 80,000-patient randomized clinical trial implemented by five US insurance companies (health plans) aimed at increasing the use of oral anticoagulants by individuals with atrial fibrillation who were at high risk of stroke and not on treatment. The underlying thesis was that patients could be change agents to initiate prescribing discussions with their providers. We tested the effect of mailing information to both patients and their providers. We used administrative medical claims and pharmacy dispensing data to identify eligible patients, to randomize them to an early or delayed intervention, and to assess clinical outcomes. The core data were analysis-ready datasets each site had created and curated for the FDA's Sentinel System, supplemented by updated "fresh" pharmacy and enrollment data to ensure eligibility at the time of intervention. Following mutually agreed upon procedures, sites linked to additional internal source data to implement the intervention-educational information mailed to patients and their providers in the early intervention arm, and to providers of patients in the delayed intervention arm approximately 12 months later. The primary analysis compares the early intervention arm to the delayed intervention arm, prior to the delayed intervention being conducted (i.e. compares intervention to non-intervention). The endpoints of interest were evidence of initiation of anticoagulation (primary) as well as clinical endpoints, including stroke and hospitalization for bleeding. Major challenges, some unanticipated, identified during the planning phase include convening multi-stakeholder investigator teams and advisors, addressing ethical concerns about not intervening in a usual care comparison group, and identifying and avoiding interference with sites' routine programs that were similar to the intervention. Needs and challenges during the implementation phase included the fact that even limited site-specific programming greatly increased time and effort, the need to refresh research data extracts immediately before outreach to patients and providers, potential difficulty identifying low-cost medications such as warfarin that may not be reimbursed by health plans and so not discoverable in dispensing data, the need to develop workarounds when "providers" in claims data were facilities, difficulty addressing clustering of patients by provider because providers can have multiple identifiers within and between health plans, and the need to anticipate loss to follow up because of health plan disenrollment or change in benefits. As pragmatic trials begin to shape evidence generation within clinical practice, investigators should anticipate issues inherent to claims data and working with multiple large sites. In IMPACT-AFib, we found that investing in collaboration and communication among all parties throughout all phases of the study helped ensure common understanding, early identification of challenges, and streamlined actual implementation.


Kinetic and inhibition studies of dihydroxybenzoate-AMP ligase from Escherichia coli.
Inhibition of siderophore biosynthetic pathways in pathogenic bacteria represents a promising strategy for antibacterial drug development. Escherichia coli synthesize and secrete the small molecule iron chelator siderophore, enterobactin, in response to intracellular iron depletion. Here we describe a detailed kinetic analysis of EntE, one of six enzymes in the enterobactin synthetase gene cluster. EntE catalyzes the ATP-dependent condensation of 2,3-dihydroxybenzoic acid (DHB) and phosphopantetheinylated EntB (holo-EntB) to form covalently arylated EntB, a product that is vital for the final assembly of enterobactin. Initial velocity studies show that EntE proceeds via a bi-uni-uni-bi ping-pong kinetic mechanism with a k(cat) equal to 2.8 s(-1) and K(m) values of 2.5, 430, and 2.9 microM for DHB, ATP, and holo-EntB-ArCP, respectively. Inhibition and direct binding experiments suggest that, during the first half-reaction (adenylation), DHB binds first to the free enzyme, followed by ATP and the release of pyrophosphate to form the adenylate intermediate. During the second half-reaction (ligation), phosphopantetheinylated EntB binds to the enzyme followed by the release of products, AMP and arylated EntB. Two hydrolytically stable adenylate analogues, 5'-O-[N-(salicyl)sulfamoyl]adenosine (Sal-AMS) and 5'-O-[N-(2,3-dihydroxybenzoyl)sulfamoyl]adenosine (DHB-AMS), are shown to act as slow-onset tight-binding inhibitors of the enzyme with (app)K(i) values of 0.9 and 3.8 nM, respectively. Direct binding experiments, via isothermal titration calorimetry, reveal low picomolar dissociation constants for both analogues with respect to EntE. The tight binding of Sal-AMS and DHB-AMS to EntE suggests that these compounds may be developed further as effective antibiotics targeted to this enzyme.


A Mouse Model of Hepatic Ischemia-Reperfusion Injury Demonstrates Potentially Reversible Effects on Hippocampal Neurons and Postoperative Cognitive Function.
BACKGROUND This study aimed to investigate cognitive function, hippocampal neuronal changes, and the expression of inflammatory cytokines in a mouse model of hepatic ischemia-reperfusion injury. MATERIAL AND METHODS Sixty mice were divided into the sham group, which underwent surgery without vascular occlusion; the I/R1 group, with occlusion of the left hepatic artery and portal vein for 20 min, and reperfusion for 30 min; and the I/R2 group, with occlusion of the left hepatic artery and portal vein for 40 min, and reperfusion for 30 min. At postoperative day 4 and 11, ten mice from each group underwent the Morris water maze (MWM) task. Hippocampal tissues were stained for Nissl bodies. Expression of nuclear factor-κB (NF-κB) and choline acetyltransferase (ChAT) were quantified by immunohistochemistry. Serum tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS Groups I/R1 and I/R2 showed a significantly increased latency in the MWM test between days 5-9, compared with the sham group (P<0.05), with no difference by day 11; the I/R2 group had an initial lower crossing frequency (P<0.05), with no difference by day 18. The I/R2 group showed reduced numbers of Nissl bodies in hippocampal neurons. The I/R1 and I/R2 groups had increased expression of NF-κB, TNF-α, and IL-1β and decreased ChAT. No differences between the groups were found in levels of NF-κB, TNF-α, IL-1β, or ChAT by day 18. CONCLUSIONS A mouse model of hepatic ischemia-reperfusion injury showed transient and reversible cognitive dysfunction, changes in hippocampal neurons, and expression of inflammatory cytokines.


Dolichoectasia and multifocal simultaneous intracranial haemorrhages.
Dolichoectasia is found primarily in aged individual with atherosclerotic disease. It presents with brain stem compression and stroke, which could be ischaemic or haemorrhagic. Even if severe atherosclerosis is thought to play a pivotal role, new evidence suggest that the internal elastic laminae is disrupted, intracranially and extracranially, so multiorganic involvement with various clinical presentations can occur. We present a rare association of multiorganic dolichoectasia debuting with multiple intracranial haemorrhages. A 79-year-old woman presented with altered mental status and left hemiplegia. The work up demonstrated brain arteries dolichoectasia and an abdominal aortic aneurysm with multiple site intraparenchymal haemorrhages. In this case, the presentation of multiple site dolichoectasia and multiple haemorrhages is probably linked to a systemic "media disease" that affected the media of small, medium and large arteries rather than a coincidental finding.