Recruitment of Gr-1+ monocytes is essential for control of acute toxoplasmosis

Circulating murine monocytes comprise two largely exclusive subpopulations that are responsible for seeding normal tissues (Gr-1−/CCR2−/CX3CR1high) or responding to sites of inflammation (Gr-1+/CCR2+/CX3CR1lo). Gr-1+ monocytes are recruited to the site of infection during the early stages of immune response to the intracellular pathogen Toxoplasma gondii. A murine model of toxoplasmosis was thus used to examine the importance of Gr-1+ monocytes in the control of disseminated parasitic infection in vivo. The recruitment of Gr-1+ monocytes was intimately associated with the ability to suppress early parasite replication at the site of inoculation. Infection of CCR2−/− and MCP-1−/− mice with typically nonlethal, low doses of T. gondii resulted in the abrogated recruitment of Gr-1+ monocytes. The failure to recruit Gr-1+ monocytes resulted in greatly enhanced mortality despite the induction of normal Th1 cell responses leading to high levels of IL-12, TNF-α, and IFN-γ. The profound susceptibility of CCR2−/− mice establishes Gr-1+ monocytes as necessary effector cells in the resistance to acute toxoplasmosis and suggests that the CCR2-dependent recruitment of Gr-1+ monocytes may be an important general mechanism for resistance to intracellular pathogens

Ambulatory monitoring of activity levels of individuals in the sub-acute stage following stroke: a case series

<p>Abstract</p> <p>Background</p> <p>There is an important need to better understand the activities of individual patients with stroke outside of structured therapy since this activity is likely to have a profound influence on recovery. A case-study approach was used to examine the activity levels and associated physiological load of patients with stroke throughout a day.</p> <p>Methods</p> <p>Activities and physiologic measures were recorded during a continuous 8 hour period from 4 individuals in the sub-acute stage following stroke (ranging from 49 to 80 years old; 4 to 8 weeks post-stroke) in an in-patient rehabilitation hospital.</p> <p>Results</p> <p>Both heart rate (p = 0.0207) and ventilation rate (p < 0.0001) increased as intensity of activity increased. Results revealed individual differences in physiological response to daily activities, and large ranges in physiological response measures during 'moderately' and 'highly' therapeutic activities.</p> <p>Conclusion</p> <p>Activity levels of individuals with stroke during the day were generally low, though task-related changes in physiologic measures were observed. Large variability in the physiological response to even the activities deemed to be greatest intensity suggests that inclusion of such extended measurement of physiologic measures may improve understanding of physiological profile that could guide elements of the physical therapy prescription.</p

Do functional walk tests reflect cardiorespiratory fitness in sub-acute stroke?

BACKGROUND AND PURPOSE: The Six-Minute Walk Test (6MWT) has been employed as a measure of functional capacity, but its relationship to cardiorespiratory fitness in stroke is not well established. Gait speed measured over short distances is commonly used as an index of walking competency following stroke. We evaluated the relationship between the 6MWT, aerobic fitness (VO(2)peak) and walking competency in sub-acute stroke. METHODS: Thirty-six individuals (mean age ± SD, 64.6 ± 14.4 years; time post-stroke 16.2 ± 13.3 days) were evaluated using the 6MWT (distance, speed, heart rate), a maximal exercise test (VO(2)peak, heart rate, exercise test duration), and walking competency using a five meter walk (speed, symmetry ratio). Correlation analyses were used to examine the relationships between these outcomes. RESULTS: There was a strong correlation between the 6MWT and five meter walk velocity for preferred (r = 0.79) and fast (r = 0.82) speed (p < 0.001). On average, the 6MWT speed was faster than the preferred gait speed (94.9 cm/s vs. 83.8 cm/s, p = 0.003), but slower than the fast-paced walk (115.1 cm/s, p < 0.001). There was significant though more moderate association between 6MWT distance and VO(2)peak (r = 0.56, p < 0.001) and exercise test duration (r = 0.60, p < 0.001). CONCLUSION: The speed selected during the 6MWT was strongly related to the velocities selected during the five meter walk distance (intermediate to the selected preferred and fast speeds). Although the 6MWT may be challenging to the cardiorespiratory system, it appears to be more strongly influenced by potential limits to walking speed rather than cardiorespiratory capacity. As a result, this test is not, by itself, an adequate measure of aerobic fitness early after stroke

Changes in spatiotemporal gait variables over time during a test of functional capacity after stroke

<p>Abstract</p> <p>Background</p> <p>Gait dysfunction and fatigue are common post-stroke, though it is unclear how extended walking activity, as would be performed during activities of daily living, may change over time. The purpose of this study was to examine if spatial and temporal gait variables deteriorate during an extended bout of walking in a test of functional capacity after stroke.</p> <p>Methods</p> <p>24 community dwelling, independently ambulating individuals greater than 3 months after stroke performed the Six-Minute Walk Test (6MWT). Participants walked over a pressure-sensitive mat on each pass of the 30 m course which recorded spatial and temporal parameters of gait. Mean gait speed and temporal symmetry ratio during each two-minute interval of the 6MWT were examined. Additional post hoc analyses examined the incidence of rests during the 6MWT and changes in gait speed and symmetry.</p> <p>Results</p> <p>On average, participants demonstrated a 3.4 ± 6.5 cm/s decrease in speed over time (p= 0.02). Participants who rested were also characterized by increased asymmetry in the final two minutes (p= 0.05). 30% of participants rested at some point during the test, and if a rest was taken, duration increased in the final two minutes (p= 0.001). Examination of factors which may have been associated with resting indicated that resters had poorer balance (p= 0.006) than non-resting participants.</p> <p>Conclusion</p> <p>This study supports previous findings establishing that walking performance after stroke declines over relatively short bouts of functionally-relevant ambulation. Such changes may be associated with both cardiorespiratory and muscular fatigue mechanisms that influence performance. The findings also indicate that rest duration should be routinely quantified during the 6MWT after stroke, and consequently, further research is necessary to determine how to interpret 6MWT scores when resting occurs.</p

Implementation of a reference standard and proficiency testing programme by the World Wide Antimalarial Resistance Network (WWARN)

<p>Abstract</p> <p>Background</p> <p>The Worldwide Antimalarial Resistance Network (WWARN) is a global collaboration to support the objective that anyone affected by malaria receives effective and safe drug treatment. The Pharmacology module aims to inform optimal anti-malarial drug selection. There is an urgent need to define the drug exposure - effect relationship for most anti-malarial drugs. Few anti-malarials have had their therapeutic blood concentration levels defined. One of the main challenges in assessing safety and efficacy data in relation to drug concentrations is the comparability of data generated from different laboratories. To explain differences in anti-malarial pharmacokinetics in studies with different measurement laboratories it is necessary to confirm the accuracy of the assay methods. This requires the establishment of an external quality assurance process to assure results that can be compared. This paper describes this process.</p> <p>Methods</p> <p>The pharmacology module of WWARN has established a quality assurance/quality control (QA/QC) programme consisting of two separate components:</p> <p indent="1">1. A proficiency testing programme where blank human plasma spiked with certified reference material (CRM) in different concentrations is sent out to participating bioanalytical laboratories.</p> <p indent="1">2. A certified reference standard programme where accurately weighed amounts of certified anti-malarial reference standards, metabolites, and internal standards are sent to participating bioanalytical and in vitro laboratories.</p> <p>Conclusion</p> <p>The proficiency testing programme is designed as a cooperative effort to help participating laboratories assess their ability to carry out drug analysis, resolve any potential problem areas and to improve their results - and, in so doing, to improve the quality of anti-malarial pharmacokinetic data published and shared with WWARN.</p> <p>By utilizing the same source of standards for all laboratories, it is possible to minimize bias arising from poor quality reference standards. By providing anti-malarial drug standards from a central point, it is possible to lower the cost of these standards.</p

F901318 represents a novel class of antifungal drug that inhibits dihydroorotate dehydrogenase

There is an important medical need for new antifungal agents with novel mechanisms of action to treat the increasing number of patients with life-threatening systemic fungal disease and to overcome the growing problem of resistance to current therapies. F901318, the leading representative of a novel class of drug, the orotomides, is an antifungal drug in clinical development that demonstrates excellent potency against a broad range of dimorphic and filamentous fungi. In vitro susceptibility testing of F901318 against more than 100 strains from the four main pathogenic Aspergillus spp. revealed minimal inhibitory concentrations of ≤0.06 µg/mL—greater potency than the leading antifungal classes. An investigation into the mechanism of action of F901318 found that it acts via inhibition of the pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH) in a fungal-specific manner. Homology modeling of Aspergillus fumigatus DHODH has identified a predicted binding mode of the inhibitor and important interacting amino acid residues. In a murine pulmonary model of aspergillosis, F901318 displays in vivo efficacy against a strain of A. fumigatus sensitive to the azole class of antifungals and a strain displaying an azole-resistant phenotype. F901318 is currently in late Phase 1 clinical trials, offering hope that the antifungal armamentarium can be expanded to include a class of agent with a mechanism of action distinct from currently marketed antifungals

Contribution of primary motor cortex to compensatory balance reactions

<p>Abstract</p> <p>Background</p> <p>Rapid compensatory arm reactions represent important response strategies following an unexpected loss of balance. While it has been assumed that early corrective actions arise largely from sub-cortical networks, recent findings have prompted speculation about the potential role of cortical involvement. To test the idea that cortical motor regions are involved in early compensatory arm reactions, we used continuous theta burst stimulation (cTBS) to temporarily suppress the hand area of primary motor cortex (M1) in participants prior to evoking upper limb balance reactions in response to whole body perturbation. We hypothesized that following cTBS to the M1 hand area evoked EMG responses in the stimulated hand would be diminished. To isolate balance reactions to the upper limb participants were seated in an elevated tilt-chair while holding a stable handle with both hands. The chair was held vertical by a magnet and was triggered to fall backward unpredictably. To regain balance, participants used the handle to restore upright stability as quickly as possible with both hands. Muscle activity was recorded from proximal and distal muscles of both upper limbs.</p> <p>Results</p> <p>Our results revealed an impact of cTBS on the amplitude of the EMG responses in the stimulated hand muscles often manifest as inhibition in the stimulated hand. The change in EMG amplitude was specific to the target hand muscles and occasionally their homologous pairs on the non-stimulated hand with no consistent effects on the remaining more proximal arm muscles.</p> <p>Conclusions</p> <p>Present findings offer support for cortical contributions to the control of early compensatory arm reactions following whole-body perturbation.</p

Age and gender differences in narcissism: A comprehensive study across eight measures and over 250,000 participants

Age and gender differences in narcissism have been studied often. However, considering the rich history of narcissism research accompanied by its diverging conceptualizations, little is known about age and gender differences across various narcissism measures. The present study investigated age and gender differences and their interactions across eight widely used narcissism instruments (i.e., Narcissistic Personality Inventory, Hypersensitive Narcissism Scale, Dirty Dozen, Psychological Entitlement Scale, Narcissistic Personality Disorder Symptoms from the Diagnostic and Statistical Manual of Mental Disorders, Version IV, Narcissistic Admiration and Rivalry Questionnaire-Short Form, Single-Item Narcissism Scale, and brief version of the Pathological Narcissism Inventory). The findings of Study 1 (N = 5,736) revealed heterogeneity in how strongly the measures are correlated. Some instruments loaded clearly on one of the three factors proposed by previous research (i.e., Neuroticism, Extraversion, Antagonism), while others cross-loaded across factors and in distinct ways. Cross-sectional analyses using each measure and meta-analytic results across all measures (Study 2) with a total sample of 270,029 participants suggest consistent linear age effects (random effects meta-analytic effect of r = -.104), with narcissism being highest in young adulthood. Consistent gender differences also emerged (random effects meta-analytic effect was -.079), such that men scored higher in narcissism than women. Quadratic age effects and Age × Gender effects were generally very small and inconsistent. We conclude that despite the various conceptualizations of narcissism, age and gender differences are generalizable across the eight measures used in the present study. However, their size varied based on the instrument used. We discuss the sources of this heterogeneity and the potential mechanisms for age and gender differences

The Seventh Data Release of the Sloan Digital Sky Survey

This paper describes the Seventh Data Release of the Sloan Digital Sky Survey (SDSS), marking the completion of the original goals of the SDSS and the end of the phase known as SDSS-II. It includes 11663 deg^2 of imaging data, with most of the roughly 2000 deg^2 increment over the previous data release lying in regions of low Galactic latitude. The catalog contains five-band photometry for 357 million distinct objects. The survey also includes repeat photometry over 250 deg^2 along the Celestial Equator in the Southern Galactic Cap. A coaddition of these data goes roughly two magnitudes fainter than the main survey. The spectroscopy is now complete over a contiguous area of 7500 deg^2 in the Northern Galactic Cap, closing the gap that was present in previous data releases. There are over 1.6 million spectra in total, including 930,000 galaxies, 120,000 quasars, and 460,000 stars. The data release includes improved stellar photometry at low Galactic latitude. The astrometry has all been recalibrated with the second version of the USNO CCD Astrograph Catalog (UCAC-2), reducing the rms statistical errors at the bright end to 45 milli-arcseconds per coordinate. A systematic error in bright galaxy photometr is less severe than previously reported for the majority of galaxies. Finally, we describe a series of improvements to the spectroscopic reductions, including better flat-fielding and improved wavelength calibration at the blue end, better processing of objects with extremely strong narrow emission lines, and an improved determination of stellar metallicities. (Abridged)Comment: 20 pages, 10 embedded figures. Accepted to ApJS after minor correction