Characterization of Rock Types at Meridiani Planum, Mars using MER 13-Filter Pancam Spectra

The Mars Exploration Rover Opportunity has traversed more than 13 km across Meridiani Planum, finding evidence of ancient aqueous environments that, in the past, may have been suitable for life. Meridiani bedrock along the rover traverse is a mixture in composition and bulk mineralogy between a sulfate-rich sedimentary rock and hematite spherules ("blueberries"). On top of the bedrock, numerous loose rocks exist. These rocks consist of both local bedrock and "cobbles" of foreign origin. The cobbles provide a window into lithologic diversity and a chance to understand other types of martian rocks and meteorites. This study was also an attempt to establish a method to expand upon those of Mini-TES to remotely identify rocks of interest to make efficient use of the rover s current resources

Discharge Identity of Medullary Inspiratory Neurons is Altered during Repetitive Fictive Cough

This study investigated the stability of the discharge identity of inspiratory decrementing (I-Dec) and augmenting (I-Aug) neurons in the caudal (cVRC) and rostral (rVRC) ventral respiratory column during repetitive fictive cough in the cat. Inspiratory neurons in the cVRC (n = 23) and rVRC (n = 17) were recorded with microelectrodes. Fictive cough was elicited by mechanical stimulation of the intrathoracic trachea. Approximately 43% (10 of 23) of I-Dec neurons shifted to an augmenting discharge pattern during the first cough cycle (C1). By the second cough cycle (C2), half of these returned to a decrementing pattern. Approximately 94% (16 of 17) of I-Aug neurons retained an augmenting pattern during C1 of a multi-cough response episode. Phrenic burst amplitude and inspiratory duration increased during C1, but decreased with each subsequent cough in a series of repetitive coughs. As a step in evaluating the model-driven hypothesis that VRC I-Dec neurons contribute to the augmentation of inspiratory drive during cough via inhibition of VRC tonic expiratory neurons that inhibit premotor inspiratory neurons, cross-correlation analysis was used to assess relationships of tonic expiratory cells with simultaneously recorded inspiratory neurons. Our results suggest that reconfiguration of inspiratory-related sub-networks of the respiratory pattern generator occurs on a cycle-by-cycle basis during repetitive coughing

Efficacy and safety of trimodulin, a novel polyclonal antibody preparation, in patients with severe community-acquired pneumonia: a randomized, placebo-controlled, double-blind, multicenter, phase II trial (CIGMA study)

Purpose The CIGMA study investigated a novel human polyclonal antibody preparation (trimodulin) containing ~ 23% immunoglobulin (Ig) M, ~ 21% IgA, and ~ 56% IgG as add-on therapy for patients with severe community-acquired pneumonia (sCAP). Methods In this double-blind, phase II study (NCT01420744), 160 patients with sCAP requiring invasive mechanical ventilation were randomized (1:1) to trimodulin (42 mg IgM/kg/day) or placebo for five consecutive days. Primary endpoint was ventilator-free days (VFDs). Secondary endpoints included 28-day all-cause and pneumonia-related mortality. Safety and tolerability were monitored. Exploratory post hoc analyses were performed in subsets stratified by baseline C-reactive protein (CRP; ≥ 70 mg/L) and/or IgM (≤ 0.8 g/L). Results Overall, there was no statistically significant difference in VFDs between trimodulin (mean 11.0, median 11 [n = 81]) and placebo (mean 9.6; median 8 [n = 79]; p = 0.173). Twenty-eight-day all-cause mortality was 22.2% vs. 27.8%, respectively (p = 0.465). Time to discharge from intensive care unit and mean duration of hospitalization were comparable between groups. Adverse-event incidences were comparable. Post hoc subset analyses, which included the majority of patients (58–78%), showed significant reductions in all-cause mortality (trimodulin vs. placebo) in patients with high CRP, low IgM, and high CRP/low IgM at baseline. Conclusions No significant differences were found in VFDs and mortality between trimodulin and placebo groups. Post hoc analyses supported improved outcome regarding mortality with trimodulin in subsets of patients with elevated CRP, reduced IgM, or both. These findings warrant further investigation

Anti-infectives in Drug Delivery-Overcoming the Gram-Negative Bacterial Cell Envelope.

Infectious diseases are becoming a major menace to the state of health worldwide, with difficulties in effective treatment especially of nosocomial infections caused by Gram-negative bacteria being increasingly reported. Inadequate permeation of anti-infectives into or across the Gram-negative bacterial cell envelope, due to its intrinsic barrier function as well as barrier enhancement mediated by resistance mechanisms, can be identified as one of the major reasons for insufficient therapeutic effects. Several in vitro, in silico, and in cellulo models are currently employed to increase the knowledge of anti-infective transport processes into or across the bacterial cell envelope; however, all such models exhibit drawbacks or have limitations with respect to the information they are able to provide. Thus, new approaches which allow for more comprehensive characterization of anti-infective permeation processes (and as such, would be usable as screening methods in early drug discovery and development) are desperately needed. Furthermore, delivery methods or technologies capable of enhancing anti-infective permeation into or across the bacterial cell envelope are required. In this respect, particle-based carrier systems have already been shown to provide the opportunity to overcome compound-related difficulties and allow for targeted delivery. In addition, formulations combining efflux pump inhibitors or antimicrobial peptides with anti-infectives show promise in the restoration of antibiotic activity in resistant bacterial strains. Despite considerable progress in this field however, the design of carriers to specifically enhance transport across the bacterial envelope or to target difficult-to-treat (e.g., intracellular) infections remains an urgently needed area of improvement. What follows is a summary and evaluation of the state of the art of both bacterial permeation models and advanced anti-infective formulation strategies, together with an outlook for future directions in these fields

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Neurogenic mechanisms in bladder and bowel ageing

The prevalence of both urinary and faecal incontinence, and also chronic constipation, increases with ageing and these conditions have a major impact on the quality of life of the elderly. Management of bladder and bowel dysfunction in the elderly is currently far from ideal and also carries a significant financial burden. Understanding how these changes occur is thus a major priority in biogerontology. The functions of the bladder and terminal bowel are regulated by complex neuronal networks. In particular neurons of the spinal cord and peripheral ganglia play a key role in regulating micturition and defaecation reflexes as well as promoting continence. In this review we discuss the evidence for ageing-induced neuronal dysfunction that might predispose to neurogenic forms of incontinence in the elderly

Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function

BACKGROUND: Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function. METHODS: A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function. RESULTS: The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue. CONCLUSION: The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies. FUNDING: For detailed information per study, see Acknowledgments.This work was supported by a grant from the US National Heart, Lung, and Blood Institute (N01-HL-25195; R01HL 093328 to RSV), a MAIFOR grant from the University Medical Center Mainz, Germany (to PSW), the Center for Translational Vascular Biology (CTVB) of the Johannes Gutenberg-University of Mainz, and the Federal Ministry of Research and Education, Germany (BMBF 01EO1003 to PSW). This work was also supported by the research project Greifswald Approach to Individualized Medicine (GANI_MED). GANI_MED was funded by the Federal Ministry of Education and Research and the Ministry of Cultural Affairs of the Federal State of Mecklenburg, West Pomerania (contract 03IS2061A). We thank all study participants, and the colleagues and coworkers from all cohorts and sites who were involved in the generation of data or in the analysis. We especially thank Andrew Johnson (FHS) for generation of the gene annotation database used for analysis. We thank the German Center for Cardiovascular Research (DZHK e.V.) for supporting the analysis and publication of this project. RSV is a member of the Scientific Advisory Board of the DZHK. Data on CAD and MI were contributed by CARDIoGRAMplusC4D investigators. See Supplemental Acknowledgments for consortium details. PSW, JFF, AS, AT, TZ, RSV, and MD had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis

Peripheral Chemoreceptors Tune Inspiratory Drive via Tonic Expiratory Neuron Hubs in the Medullary Ventral Respiratory Column Network

Models of brain stem ventral respiratory column (VRC) circuits typically emphasize populations of neurons, each active during a particular phase of the respiratory cycle. We have proposed that “tonic” pericolumnar expiratory (t-E) neurons tune breathing during baroreceptor-evoked reductions and central chemoreceptor-evoked enhancements of inspiratory (I) drive. The aims of this study were to further characterize the coordinated activity of t-E neurons and test the hypothesis that peripheral chemoreceptors also modulate drive via inhibition of t-E neurons and disinhibition of their inspiratory neuron targets. Spike trains of 828 VRC neurons were acquired by multielectrode arrays along with phrenic nerve signals from 22 decerebrate, vagotomized, neuromuscularly blocked, artificially ventilated adult cats. Forty-eight of 191 t-E neurons fired synchronously with another t-E neuron as indicated by cross-correlogram central peaks; 32 of the 39 synchronous pairs were elements of groups with mutual pairwise correlations. Gravitational clustering identified fluctuations in t-E neuron synchrony. A network model supported the prediction that inhibitory populations with spike synchrony reduce target neuron firing probabilities, resulting in offset or central correlogram troughs. In five animals, stimulation of carotid chemoreceptors evoked changes in the firing rates of 179 of 240 neurons. Thirty-two neuron pairs had correlogram troughs consistent with convergent and divergent t-E inhibition of I cells and disinhibitory enhancement of drive. Four of 10 t-E neurons that responded to sequential stimulation of peripheral and central chemoreceptors triggered 25 cross-correlograms with offset features. The results support the hypothesis that multiple afferent systems dynamically tune inspiratory drive in part via coordinated t-E neurons. understanding the connectivity and functions of oscillating networks in the brain is a major goal in neuroscience (e.g., Akam and Kullmann 2014). Brain stem circuit mechanisms that control the drive to breathe are of particular interest not only because of their vital functions in maintaining ventilation and cardiovascular coupling (Nicholls and Paton 2009). The brain stem respiratory network can concurrently express multiple rhythms, in addition to the basic breathing rhythm, with frequencies spanning several orders of magnitude (Dick et al. 2005; Funk and Parkis 2002; Morris et al. 2010). These circuits for breathing have remarkable adaptive and emergent properties (Devinney et al. 2013; Lindsey et al. 1992, 2012; Ramirez et al. 2012) and participate in the generation of numerous other behaviors (Bartlett and Leiter 2012), including vocal communication (McLean et al. 2013), coughing and swallowing, and their coordinated expression as a metabehavioral response to aspiration (Pitts et al. 2013; Shannon et al. 2000). Breathing may also bind orofacial sensations (Kleinfeld et al. 2014) and be involved in hippocampal processes for learning and memory (Lockmann and Belchior 2014). Core circuits for generating the respiratory motor pattern are found in the ventral respiratory column (VRC; Richter and Smith 2014) and are embedded in a larger pontomedullary respiratory network (Nuding et al. 2009a; Segers et al. 2008). Models of the VRC typically emphasize interactions among populations of neurons, each active only during a particular phase of the respiratory cycle or at a phase transition (Lindsey et al. 2012). However, pericolumnar “tonic” neurons with or without respiratory-modulated discharge patterns have also been identified and proposed to serve as intermediaries in the regulation of breathing by sensory (e.g., baroreceptor, chemoreceptor) systems and by internal state-dependent drives (Orem 1989). We have proposed that the VRC includes an excitatory inspiratory (I) neuron chain tuned by feedforward and recurrent inhibition from other I neurons and by the inspiratory-phase inhibitory actions of tonically firing expiratory (t-E) neurons, i.e., cells that are active predominantly during the expiratory (E) phase but also discharge during the I phase under eupneic-like normocapnic conditions (O\u27Connor et al. 2012; Segers et al. 1987). Several observations support the hypothesis that t-E neurons serve as a downstream network “hub” (van den Heuvel and Sporns 2013) where signals from multiple afferent systems functionally converge for modulation of inspiratory drive. First, baroreceptor-evoked reductions in inspiratory drive are associated with increased firing rates in t-E neurons that have inhibitory functional connections with inspiratory premotor or motor neurons (Lindsey et al. 1998). Second, central chemoreceptor-evoked enhancement of inspiratory drive occurs during suppressed inspiratory-phase activity in t-E neurons (Ott et al. 2012). Third, such disinhibitory amplification of inspiratory drive also occurs during a bout of coughing (Segers et al. 2012). In the course of these prior studies, we identified cross-correlation feature sets indicative of distributed functional inhibitory connectivity of t-E neurons within the column (Ott et al. 2012; Segers et al. 2012) and noted that some pairs of t-E neurons exhibited short-timescale spike synchrony. One aim of the present work was to confirm and extend that result. Such coordinated firing would be consistent with the hub concept and cooperative behavior among t-E neurons that could influence the efficacy or duration of their collective actions on common targets. Peripheral chemoreceptors of the carotid body rapidly sense changes in arterial O2 and CO2-pH and also modulate the drive to breathe (Kumar and Prabhakar 2012), although the functional connections through which they act upon VRC circuits remain incompletely understood (Nuding et al. 2009b; Spyer and Gourine 2009). Having previously identified differential peripheral chemoreceptor modulation of inspiratory neurons in the pre-Bötzinger region and more caudal medullary domains (Morris et al. 1996, 2001), we had the second objective of testing the hypothesis that carotid chemoreceptors enhance inspiratory drive via downstream disinhibitory actions of t-E neurons upon caudal columnar inspiratory neurons. Numerous disorders of breathing and cardio-respiratory coupling are associated with dysfunctional chemoreceptor drive mechanisms (Dempsey and Smith 2014; Garcia et al. 2013; Perez and Keens 2013; Plataki et al. 2013). Brain mechanisms that mediate the separate and joint actions of central chemoreceptors, sensors of brain CO2 and pH, and the peripheral chemoreceptors are topics of active research and debate (Duffin and Mateika 2013; Nuding et al. 2009b; Teppema and Smith 2013; Wilson and Day 2013). Thus a related third aim was to determine whether t-E neurons are dually modulated by both central and peripheral chemoreceptor influences. We employed electrode arrays with individual submicrometer electrode depth adjustments to monitor VRC neurons at multiple sites simultaneously. Acquired data sets were screened for short-timescale correlations indicative of paucisynaptic functional connectivity and altered firing rates during chemoreceptor perturbation