Combined Unilateral Blockade of Cholinergic, Peptidergic, And Serotonergic Receptors in The Ventral Respiratory Column Does Not Affect Breathing in Awake Or Sleeping Goats

Previous work in intact awake and sleeping goats has found that unilateral blockade of excitatory inputs in the ventral respiratory column (VRC) elicits changes in the concentrations of multiple neurochemicals, including serotonin (5-HT), substance P, glycine, and GABA, while increasing or having no effect on breathing. These findings are consistent with the concept of interdependence between neuromodulators, whereby attenuation of one modulator elicits compensatory changes in other modulators to maintain breathing. Because there is a large degree of redundancy and multiplicity of excitatory inputs to the VRC, we herein tested the hypothesis that combined unilateral blockade of muscarinic acetylcholine (mACh), neurokinin-1 (NK1, the receptor for substance P), and 5-HT2A receptors would elicit changes in multiple neurochemicals, but would not change breathing. We unilaterally reverse-dialyzed a cocktail of antagonists targeting these receptors into the VRC of intact adult goats. Breathing was continuously monitored while effluent fluid from dialysis was collected for quantification of neurochemicals. We found that neither double blockade of mACh and NK1 receptors, nor triple blockade of mACh, NK1, and 5-HT2A receptors significantly affected breathing (P ≥ 0.05) in goats that were awake or in non-rapid eye movement (NREM) sleep. However, both double and triple blockade increased the effluent concentration of substance P (P \u3c 0.001) and decreased GABA concentrations. These findings support our hypothesis and, together with past data, suggest that both in wakefulness and NREM sleep, multiple neuromodulator systems collaborate to stabilize breathing when a deficit in one or multiple excitatory neuromodulators exists

Effects on Breathing of Agonists to μ-opioid or GABA\u3csub\u3eA\u3c/sub\u3e Receptors Dialyzed into the Ventral Respiratory Column of Awake and Sleeping Goats

Pulmonary ventilation (V̇I) in awake and sleeping goats does not change when antagonists to several excitatory G protein-coupled receptors are dialyzed unilaterally into the ventral respiratory column (VRC). Concomitant changes in excitatory neuromodulators in the effluent mock cerebral spinal fluid (mCSF) suggest neuromodulatory compensation. Herein, we studied neuromodulatory compensation during dialysis of agonists to inhibitory G protein-coupled or ionotropic receptors into the VRC. Microtubules were implanted into the VRC of goats for dialysis of mCSF mixed with agonists to either μ-opioid (DAMGO) or GABAA (muscimol) receptors. We found: (1) V̇I decreased during unilateral but increased during bilateral dialysis of DAMGO, (2) dialyses of DAMGO destabilized breathing, (3) unilateral dialysis of muscimol increased V̇I, and (4) dialysis of DAMGO decreased GABA in the effluent mCSF. We conclude: (1) neuromodulatory compensation can occur during altered inhibitory neuromodulator receptor activity, and (2) the mechanism of compensation differs between G protein-coupled excitatory and inhibitory receptors and between G protein-coupled and inotropic inhibitory receptors

State-Dependent and -Independent Effects of Dialyzing Excitatory Neuromodulator Receptor Antagonists into the Ventral Respiratory Column

Unilateral dialysis of the broad-spectrum muscarinic receptor antagonist atropine (50 mM) into the ventral respiratory column [(VRC) including the pre-Bötzinger complex region] of awake goats increased pulmonary ventilation (V̇i) and breathing frequency (f), conceivably due to local compensatory increases in serotonin (5-HT) and substance P (SP) measured in effluent mock cerebral spinal fluid (mCSF). In contrast, unilateral dialysis of a triple cocktail of antagonists to muscarinic (atropine; 5 mM), neurokinin-1, and 5-HT receptors does not alter V̇i or f, but increases local SP. Herein, we tested hypotheses that 1) local compensatory 5-HT and SP responses to 50 mM atropine dialyzed into the VRC of goats will not differ between anesthetized and awake states; and 2) bilateral dialysis of the triple cocktail of antagonists into the VRC of awake goats will not alter V̇i or f, but will increase local excitatory neuromodulators. Through microtubules implanted into the VRC of goats, probes were inserted to dialyze mCSF alone (time control), 50 mM atropine, or the triple cocktail of antagonists. We found 1) equivalent increases in local 5-HT and SP with 50 mM atropine dialysis during wakefulness compared with isoflurane anesthesia, but V̇i and f only increased while awake; and 2) dialyses of the triple cocktail of antagonists increased V̇i, f, 5-HT, and SP

Nanoparticle-Delivered Multimeric Soluble CD40L DNA Combined with Toll-Like Receptor Agonists as a Treatment for Melanoma

Stimulation of CD40 or Toll-Like Receptors (TLR) has potential for tumor immunotherapy. Combinations of CD40 and TLR stimulation can be synergistic, resulting in even stronger dendritic cell (DC) and CD8+ T cell responses. To evaluate such combinations, established B16F10 melanoma tumors were injected every other day X 5 with plasmid DNA encoding a multimeric, soluble form of CD40L (pSP-D-CD40L) either alone or combined with an agonist for TLR1/2 (Pam3CSK4 ), TLR2/6 (FSL-1 and MALP2), TLR3 (polyinosinic-polycytidylic acid, poly(I:C)), TLR4 ( monophosphoryl lipid A, MPL), TLR7 (imiquimod), or TLR9 (Class B CpG phosphorothioate oligodeoxynucleotide, CpG). When used by itself, pSP-D-CD40L slowed tumor growth and prolonged survival, but did not lead to cure. Of the TLR agonists, CpG and poly(I:C) also slowed tumor growth, and the combination of these two TLR agonists was more effective than either agent alone. The triple combination of intratumoral pSP-D-CD40L + CpG + poly(I:C) markedly slowed tumor growth and prolonged survival. This treatment was associated with a reduction in intratumoral CD11c+ dendritic cells and an influx of CD8+ T cells. Since intratumoral injection of plasmid DNA does not lead to efficient transgene expression, pSP-D-CD40L was also tested with cationic polymers that form DNA-containing nanoparticles which lead to enhanced intratumoral gene expression. Intratumoral injections of pSP-D-CD40L-containing nanoparticles formed from polyethylenimine (PEI) or C32 (a novel biodegradable poly(B-amino esters) polymer) in combination with CpG + poly(I:C) had dramatic antitumor effects and frequently cured mice of B16F10 tumors. These data confirm and extend previous reports that CD40 and TLR agonists are synergistic and demonstrate that this combination of immunostimulants can significantly suppress tumor growth in mice. In addition, the enhanced effectiveness of nanoparticle formulations of DNA encoding immunostimulatory molecules such as multimeric, soluble CD40L supports the further study of this technology for tumor immunotherapy

Empirical Challenges in Organizational Aesthetics Research: Towards a Sensual Methodology

Despite growing scholarly interest in aesthetic dimensions of organizational life, there is a lack of literature expressly engaging with the methodological mechanics of 'doing aesthetics research'. This article addresses that gap. It begins with an overview of the conceptual idiosyncrasies of 'aesthetics' as a facet of human existence and maps out the challenges these pose for empirical research methodology. A review of methodological approaches adopted to date in empirical studies of organizational aesthetics is then presented. The remainder of the article draws on the author's experiences and suggests methods and techniques to address both conceptual and practical challenges encountered during the execution of an organizational aesthetics research project. The article calls for a firmer focus on the aesthetic experiences of organizational members in addition to those of researchers and concludes with some suggestions as to the future of such 'sensual methodologies' </jats:p

Impact of Morphine Treatment on Infarct Size and Reperfusion Injury in Acute Reperfused ST-Elevation Myocardial Infarction

Current evidence regarding the effect of intravenous morphine administration on reperfusion injury and/or cardioprotection in patients with myocardial infarction is conflicting. The aim of this study was to evaluate the impact of morphine administration, on infarct size and reperfusion injury assessed by cardiac magnetic resonance imaging (CMR) in a large multicenter ST-elevation myocardial infarction (STEMI) population. In total, 734 STEMI patients reperfused by primary percutaneous coronary intervention <12 h after symptom onset underwent CMR imaging at eight centers for assessment of myocardial damage. Intravenous morphine administration was recorded in all patients. CMR was completed within one week after infarction using a standardized protocol. The clinical endpoint of the study was the occurrence of major adverse cardiac events (MACE) within 12 months after infarction. Intravenous morphine was administered in 61.8% (n = 454) of all patients. There were no differences in infarct size (17%LV, interquartile range [IQR] 8–25%LV versus 16%LV, IQR 8–26%LV, p = 0.67) and microvascular obstruction (p = 0.92) in patients with versus without morphine administration. In the subgroup of patients with early reperfusion within 120 min and reduced flow of the infarcted vessel (TIMI-flow ≤2 before PCI) morphine administration resulted in significantly smaller infarcts (12%LV, IQR 12–19 versus 19%LV, IQR 10–29, p = 0.035) and reduced microvascular obstruction (p = 0.003). Morphine administration had no effect on hard clinical endpoints (log-rank test p = 0.74) and was not an independent predictor of clinical outcome in Cox regression analysis. In our large multicenter CMR study, morphine administration did not have a negative effect on myocardial damage or clinical prognosis in acute reperfused STEMI. In patients, presenting early ( ≤120 min) morphine may have a cardioprotective effect as reflected by smaller infarcts; but this finding has to be assessed in further well-designed clinical studie

A First Look at White Dwarf - M Dwarf Pairs in the Sloan Digital Sky Survey (SDSS)

We have identified 109 White Dwarf (WD) - M dwarf pairs in the Sloan Digital Sky Survey (SDSS) with g < 20th magnitude. For each system we determined the temperature of the WD primary and the spectral type of the M dwarf secondary. Using H-alpha emission as a proxy for the chromospheric activity level of the M dwarf, we investigated correlations between the activity level and properties of the system. Compared with field M dwarfs (Hawley et al. 1996), we see a slightly higher active fraction of early-type stars, with activity levels similar to the field. We have conducted followup observations at the ARC 3.5m telescope to obtain radial velocity information and to search for short period binaries, which may be on the verge of interacting. We report on one system with a 4.1 hour period, and several additional systems with significant velocity variations.Comment: 23 pages with 10 figures. Accepted by AJ, to appear in May 2003 issu

Does hypoglycemia following a glucose challenge test identify a high risk pregnancy?

<p>Abstract</p> <p>Objective</p> <p>An association between maternal hypoglycemia during pregnancy with fetal growth restriction and overall perinatal mortality has been reported. In a retrospective pilot study we found that hypoglycemia was linked with a greater number of special care/neonatal intensive care unit admissions and approached significance in the number of women who developed preeclampsia. That study was limited by its retrospective design, a narrow patient population and the inability to perform multivariate analysis because of the limitations in the data points collected. This study was undertaken to compare the perinatal outcome in pregnancies with hyoglycemia following a glucose challenge test (GCT) to pregnancies with a normal GCT.</p> <p>Methods</p> <p>Obstetric patients (not pre-gestational diabetics or gestational diabetes before 24 weeks were eligible. Women with a 1 hour glucose ≤ 88 mg/dL (4.8 m/mol) following a 50-gram oral GCT were matched with the next patient with a 1 hour glucose of 89–139 mg/dL. Pregnancy outcomes were evaluated.</p> <p>Results</p> <p>Over 22 months, 436 hypoglycemic patients and 434 normal subjects were identified. Hypoglycemia was increased in women < 25 (p = 0.003) and with pre-existing medical conditions (p < 0.001). Hypoglycemia was decreased if pre-pregnancy BMI ≥ 30 (p = 0.008).</p> <p>Preeclampsia/eclampsia was more common in hypoglycemic women. (OR = 3.13, 95% CI 1.51 – 6.51, p = 0.002) but not other intrapartum and perinatal outcomes.</p> <p>Conclusion</p> <p>Hypoglycemic patients are younger, have reduced pre-pregnancy weight, lower BMIs, and are more likely to develop preeclampsia than normoglycemic women.</p

GRIPS - Gamma-Ray Imaging, Polarimetry and Spectroscopy

We propose to perform a continuously scanning all-sky survey from 200 keV to 80 MeV achieving a sensitivity which is better by a factor of 40 or more compared to the previous missions in this energy range. The Gamma-Ray Imaging, Polarimetry and Spectroscopy (GRIPS) mission addresses fundamental questions in ESA's Cosmic Vision plan. Among the major themes of the strategic plan, GRIPS has its focus on the evolving, violent Universe, exploring a unique energy window. We propose to investigate $\gamma$-ray bursts and blazars, the mechanisms behind supernova explosions, nucleosynthesis and spallation, the enigmatic origin of positrons in our Galaxy, and the nature of radiation processes and particle acceleration in extreme cosmic sources including pulsars and magnetars. The natural energy scale for these non-thermal processes is of the order of MeV. Although they can be partially and indirectly studied using other methods, only the proposed GRIPS measurements will provide direct access to their primary photons. GRIPS will be a driver for the study of transient sources in the era of neutrino and gravitational wave observatories such as IceCUBE and LISA, establishing a new type of diagnostics in relativistic and nuclear astrophysics. This will support extrapolations to investigate star formation, galaxy evolution, and black hole formation at high redshifts.Comment: to appear in Exp. Astron., special vol. on M3-Call of ESA's Cosmic Vision 2010; 25 p., 25 figs; see also www.grips-mission.e

The Pine River Statement: Human Health Consequences of DDT Use

Objectives: Dichlorodiphenyltrichloroethane (DDT) was used worldwide until the 1970s, when concerns about its toxic effects, its environmental persistence, and its concentration in the food supply led to use restrictions and prohibitions. In 2001, more than 100 countries signed the Stockholm Convention on Persistent Organic Pollutants (POPs), committing to eliminate the use of 12 POPs of greatest concern. However, DDT use was allowed for disease vector control. In 2006, the World Health Organization and the U.S. Agency for International Development endorsed indoor DDT spraying to control malaria. To better inform current policy, we reviewed epidemiologic studies published from 2003 to 2008 that investigated the human health consequences of DDT and/or DDE (dichlorodiphenyldichloroethylene) exposure. Data sources and extraction: We conducted a PubMed search in October 2008 and retrieved 494 studies. Data synthesis: Use restrictions have been successful in lowering human exposure to DDT, but blood concentrations of DDT and DDE are high in countries where DDT is currently being used or was more recently restricted. The recent literature shows a growing body of evidence that exposure to DDT and its breakdown product DDE may be associated with adverse health outcomes such as breast cancer, diabetes, decreased semen quality, spontaneous abortion, and impaired neurodevelopment in children. Conclusions: Although we provide evidence to suggest that DDT and DDE may pose a risk to human health, we also highlight the lack of knowledge about human exposure and health effects in communities where DDT is currently being sprayed for malaria control. We recommend research to address this gap and to develop safe and effective alternatives to DDT.Dichlorodiphenyltrichloroethane (DDT) was used worldwide until the 1970s, when concerns about its toxic effects, its environmental persistence, and its concentration in the food supply led to use restrictions and prohibitions. In 2001, more than 100 countries signed the Stockholm Convention on Persistent Organic Pollutants (POPs), committing to eliminate the use of 12 POPs of greatest concern. However, DDT use was allowed for disease vector control. In 2006, the World Health Organization and the U.S. Agency for International Development endorsed indoor DDT spraying to control malaria. To better inform current policy, we reviewed epidemiologic studies published from 2003 to 2008 that investigated the human health consequences of DDT and/or DDE (dichlorodiphenyldichloroethylene) exposure. Data sources and extraction We conducted a PubMed search in October 2008 and retrieved 494 studies. Data synthesis Use restrictions have been successful in lowering human exposure to DDT, but blood concentrations of DDT and DDE are high in countries where DDT is currently being used or was more recently restricted. The recent literature shows a growing body of evidence that exposure to DDT and its breakdown product DDE may be associated with adverse health outcomes such as breast cancer, diabetes, decreased semen quality, spontaneous abortion, and impaired neurodevelopment in children. Conclusions Although we provide evidence to suggest that DDT and DDE may pose a risk to human health, we also highlight the lack of knowledge about human exposure and health effects in communities where DDT is currently being sprayed for malaria control. We recommend research to address this gap and to develop safe and effective alternatives to DDThttp://dx.doi.org/10.1289/ehp.1174