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Search Results: 1 - 10 of 308054 matches for " Eric J Cavanaugh "
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Pore dilation occurs in TRPA1 but not in TRPM8 channels
Jun Chen, Donghee Kim, Bruce R Bianchi, Eric J Cavanaugh, Connie R Faltynek, Philip R Kym, Regina M Reilly
Molecular Pain , 2009, DOI: 10.1186/1744-8069-5-3
Abstract: Abundantly expressed in sensory neurons, TRPV1, TRPA1 and TRPM8 are involved in sensory function, pain and neurogenic inflammation [1]. The function of these ion channels has been attributed to their ability to pass certain ion species across the plasma membrane. Once activated, TRPV1, TRPA1 and TRPM8 are permeable to small cations such as Ca2+, K+, Na+; hence, channel activation simultaneously depolarizes the plasma membrane and raises intracellular Ca2+, which subsequently triggers a variety of physiological processes. By analogy to voltage-gated K+ channels, it is assumed that ion selectivity of TRP channels should be an invariant signature to the respective channel. However, this notion has been challenged recently. When activated, TRPV1 exhibits time and agonist-dependent changes in ion selectivity [2]. In fact, TRPV1 undergoes pore dilation and allows permeation of large organic cations, including spermine (202.3 Da), NMDG (195.2 Da), Yo-Pro (376 Da), gentamycin (477.6 Da) and QX-314 [3-7]. Here we explored whether TRPA1 and TRPM8 undergo pore dilation by examining Yo-Pro uptake and changes in ion selectivity upon channel activation.Yo-Pro is a divalent cation impermeable to the plasma membrane. However, under certain conditions, it can enter cells, bind nucleic acids and emit fluorescence. Hence the uptake of Yo-Pro has been used previously as an indicator of pore dilation [2,8,9]. In HEK293-F cells transiently expressing rat TRPA1, allyl isothiocyanate (AITC) evoked robust increases in intracellular Ca2+ (Fig. 1A). Concomitantly, AITC also induced Yo-Pro uptake in a concentration-dependent manner (Fig. 1B). At higher concentrations of AITC (100 or 300 μM), the increase in fluorescence was immediately noticeable and continued to increase for about 50 min. In addition, AITC also induced Ca2+ influx and Yo-Pro uptake in cells expressing human TRPA1 and mouse TRPA1, but not in untransfected cells (data not shown). In cells expressing human TRPM8, menthol activat
Cutaneous nociception evoked by 15-delta PGJ2 via activation of ion channel TRPA1
Lillian Cruz-Orengo, Ajay Dhaka, Robert J Heuermann, Timothy J Young, Michael C Montana, Eric J Cavanaugh, Donghee Kim, Gina M Story
Molecular Pain , 2008, DOI: 10.1186/1744-8069-4-30
Abstract: Our search for endogenous chemical activators utilizing a bioactive lipid library screen identified a cyclopentane PGD2 metabolite, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), as a TRPA1 agonist. Similar to CA and AITC, this electrophilic molecule is known to modify cysteines of cellular target proteins. Electophysiological recordings verified that 15d-PGJ2 specifically activates TRPA1 and not TRPV1 or TRPM8 (thermoTRPs also enriched in DRG). Accordingly, we identified a population of mouse DRG neurons responsive to 15d-PGJ2 and AITC that is absent in cultures derived from TRPA1 knockout mice. The irritant molecules that activate TRPA1 evoke nociceptive responses. However, 15d-PGJ2 has not been correlated with painful sensations; rather, it is considered to mediate anti-inflammatory processes via binding to the nuclear peroxisome proliferator-activated receptor gamma (PPARγ). Our in vivo studies revealed that 15d-PGJ2 induced acute nociceptive responses when administered cutaneously. Moreover, mice deficient in the TRPA1 channel failed to exhibit such behaviors.In conclusion, we show that 15d-PGJ2 induces acute nociception when administered cutaneously and does so via a TRPA1-specific mechanism.The prostaglandins (PGs) are a class of biomolecules derived from arachidonic acid (AA) that are involved in a variety of signaling processes including inflammation. For example, PGE2 and PGI2 are produced during inflammation and contribute to the direct sensitization of nociceptive neurons of the dorsal root ganglia (DRG). Downstream of binding to its G protein-coupled receptor (GPCR), PGE2 sensitizes nociceptive neurons to thermal stimuli via PKA-dependent phosphorylation of the heat- and capsaicin-gated Transient Receptor Potential (TRP) ion channel TRPV1 [1]. TRPV1 is the founding mammalian member of a subfamily of TRP channels gated by temperature (dubbed thermoTRPs)[2].TRPA1, first characterized as a thermoTRP channel gated by noxious cold (although this finding is con
Metatranscriptomic Analysis of Sulfur Oxidation Genes in the Endosymbiont of Solemya Velum
Frank J. Stewart,Colleen M. Cavanaugh
Frontiers in Microbiology , 2011, DOI: 10.3389/fmicb.2011.00134
Abstract: Thioautotrophic endosymbionts in the Domain Bacteria mediate key sulfur transformations in marine reducing environments. However, the molecular pathways underlying symbiont metabolism and the extent to which these pathways are expressed in situ are poorly characterized for almost all symbioses. This is largely due to the difficulty of culturing symbionts apart from their hosts. Here, we use pyrosequencing of community RNA transcripts (i.e., the metatranscriptome) to characterize enzymes of dissimilatory sulfur metabolism in the model symbiosis between the coastal bivalve Solemya velum and its intracellular thioautotrophic symbionts. High-throughput sequencing of total RNA from the symbiont-containing gill of a single host individual generated 1.6 million sequence reads (500 Mbp). Of these, 43,735 matched Bacteria protein-coding genes in BLASTX searches of the NCBI database. The taxonomic identities of the matched genes indicated relatedness to diverse species of sulfur-oxidizing Gammaproteobacteria, including other thioautotrophic symbionts and the purple sulfur bacterium Allochromatium vinosum. Manual querying of these data identified 28 genes from diverse pathways of sulfur energy metabolism, including the dissimilatory sulfite reductase (Dsr) pathway for sulfur oxidation to sulfite, the APS pathway for sulfite oxidation, and the Sox pathway for thiosulfate oxidation. In total, reads matching sulfur energy metabolism genes represented 7% of the Bacteria mRNA pool. Together, these data highlight the dominance of thioautotrophy in the context of symbiont community metabolism, identify the likely pathways mediating sulfur oxidation, and illustrate the utility of metatranscriptome sequencing for characterizing community gene transcription of uncultured symbionts.
Safety and efficacy of glycopyrrolate oral solution for management of pathologic drooling in pediatric patients with cerebral palsy and other neurologic conditions
Zeller RS, Davidson J, Lee HM, Cavanaugh PF
Therapeutics and Clinical Risk Management , 2012, DOI: http://dx.doi.org/10.2147/TCRM.S27362
Abstract: fety and efficacy of glycopyrrolate oral solution for management of pathologic drooling in pediatric patients with cerebral palsy and other neurologic conditions Original Research (2601) Total Article Views Authors: Zeller RS, Davidson J, Lee HM, Cavanaugh PF Published Date January 2012 Volume 2012:8 Pages 25 - 32 DOI: http://dx.doi.org/10.2147/TCRM.S27362 Received: 15 October 2011 Accepted: 11 November 2011 Published: 25 January 2012 Robert S Zeller1, Jennifer Davidson2, Hak-Myung Lee2, Paul F Cavanaugh2 1Texas Children's Hospital, Baylor College of Medicine, Houston, TX; 2Shionogi Inc, Florham Park, NJ, USA Background: The purpose of this study was to assess the safety and efficacy of oral glycopyrrolate solution 1 mg/5 mL for 24 weeks in pediatric patients with chronic moderate-to-severe drooling associated with cerebral palsy and other neurologic conditions. Methods: In this multicenter, open-label, 24-week study, males and females aged 3–18 years weighing at least 27 lb received oral glycopyrrolate solution, starting at 0.02 mg/kg three times daily and titrated in increments of 0.02 mg/kg every 5–7 days for 4 weeks to an optimal maintenance dose or a maximum dose of 0.1 mg/kg, but not exceeding 3 mg three times daily. Safety was assessed by description and tabulation of all adverse events. The primary efficacy endpoint was response, defined as at least a three-point change from baseline to week 24 on the modified Teacher's Drooling Scale. Results: Of 137 intent-to-treat participants, 10 (7.3%) received the maximum dose of 0.1 mg/kg three times daily; 122 (89%) had at least one treatment-emergent adverse event, 47% related to oral glycopyrrolate solution, with most being mild-to-moderate in intensity. The most commonly reported treatment-emergent adverse events were constipation (20.4%), vomiting (17.5%), diarrhea (17.5%), pyrexia (14.6%), dry mouth (10.9%), flushing (10.9%), and nasal congestion (10.9%). Nineteen patients (13.9%) discontinued treatment due to an adverse event, but no adverse event was specifically associated with discontinuation. Two patients had clinically significant toxicity grade shifts, one each in platelet count and calcium concentration. No deaths occurred on treatment; deaths of three patients (multisystem organ failure, anoxic encephalopathy, and aspiration pneumonia) within 30 days of their last dose were not considered to be treatment-related. At 24 weeks, 52.3% (95% confidence interval 43.7–60.9) of patients were responders, with at least a three-point decrease in modified Teacher's Drooling Scale from baseline, with 83.5% of parents/caregivers and 85.8% of investigators rating oral glycopyrrolate solution as being worthwhile. Conclusion: Oral glycopyrrolate solution 1 mg/5 mL for chronic moderate-to-severe drooling associated with cerebral palsy or other neurologic conditions was well tolerated over 24 weeks by pediatric patients aged 3–18 years.
Randomized Phase III evaluation of the efficacy and safety of a novel glycopyrrolate oral solution for the management of chronic severe drooling in children with cerebral palsy or other neurologic conditions
Zeller RS, Lee HM, Cavanaugh PF, Davidson J
Therapeutics and Clinical Risk Management , 2012, DOI: http://dx.doi.org/10.2147/TCRM.S26893
Abstract: ndomized Phase III evaluation of the efficacy and safety of a novel glycopyrrolate oral solution for the management of chronic severe drooling in children with cerebral palsy or other neurologic conditions Original Research (2257) Total Article Views Authors: Zeller RS, Lee HM, Cavanaugh PF, Davidson J Published Date January 2012 Volume 2012:8 Pages 15 - 23 DOI: http://dx.doi.org/10.2147/TCRM.S26893 Received: 06 October 2011 Accepted: 04 November 2011 Published: 25 January 2012 Robert S Zeller1, Hak-Myung Lee2, Paul Cavanaugh2, Jennifer Davidson2 1Blue Bird Circle Clinic for Pediatric Neurology at Texas Children's Hospital and Baylor College of Medicine, Houston, TX, USA; 2Shionogi Inc, Florham Park, NJ, USA Aim: To evaluate the efficacy of glycopyrrolate oral solution (1 mg/5 mL) in managing problem drooling associated with cerebral palsy and other neurologic conditions. Method: Thirty-eight patients aged 3–23 years weighing at least 27 lb (12.2 kg) with severe drooling (clothing damp 5–7 days/week) were randomized to glycopyrrolate (n = 20), 0.02–0.1 mg/kg three times a day, or matching placebo (n = 18). Primary efficacy endpoint was responder rate, defined as percentage showing ≥3-point change on the modified Teacher's Drooling Scale (mTDS). Results: Responder rate was significantly higher for the glycopyrrolate (14/19; 73.7%) than for the placebo (3/17; 17.6%) group (P = 0.0011), with improvements starting 2 weeks after treatment initiation. Mean improvements in mTDS at week 8 were significantly greater in the glycopyrrolate than in the placebo group (3.94 ± 1.95 vs 0.71 ± 2.14 points; P < 0.0001). In addition, 84% of physicians and 100% of parents/caregivers regarded glycopyrrolate as worthwhile compared with 41% and 56%, respectively, for placebo (P ≤ 0.014). Most frequently reported treatment-emergent adverse events (glycopyrrolate vs placebo) were dry mouth, constipation, and vomiting. Interpretation: Children aged 3–16 years with problem drooling due to neurologic conditions showed a significantly better response, as assessed by mTDS, to glycopyrrolate than to placebo. ClinicalTrials.gov identifier: NCT00425087.
Is there an association between immunosuppressant therapy medication adherence and depression, quality of life, and personality traits in the kidney and liver transplant population?
Gorevski E,Succop P,Sachdeva J,Cavanaugh TM
Patient Preference and Adherence , 2013,
Abstract: Elizabeth Gorevski,1 Paul Succop,1 Jyoti Sachdeva,1 Teresa M Cavanaugh,1 Paul Volek,1 Pamela Heaton,1 Marie Chisholm-Burns,2 Jill E Martin-Boone1 1University of Cincinnati, Cincinnati, OH, USA, 2University of Tennessee College of Pharmacy, Memphis, TN, USA Objectives: To measure the association of transplant patients' personality, depression, and quality of life with medication adherence in kidney and liver transplant recipients. Methods: A cross-sectional study of liver and kidney transplant recipients greater than 1 year post-transplant was conducted. Patients’ adherence with medications was assessed using the Immunosuppressive Therapy Adherence Scale. Personality and depression were assessed using the NEO Five-Factor Inventory Scale and Patient Health Questionnaire 9, respectively. Quality of life was assessed using the Short Form-36, and functional status was determined using the Karnofsky Performance Status Scale. Results: A total of 86 kidney and 50 liver transplant patients completed the surveys. Logistic regression analysis demonstrated an association between depression and adherence with immunosuppressive medications in kidney transplant recipients. Kidney transplant patients who exhibited “low openness” scores were 91% more likely to be nonadherent. Kidney transplant patients’ physical functional status was strongly associated with nonadherence, and for each point increase in functionality the patients adherence increased by 4%. In the liver sample, age was associated with adherence. For every year increase in age, adherence increased by 7%. Conclusion: The presence of low openness as a personality trait, poor physical functional status, and depression were associated with adherence in the kidney transplant population. In the liver transplant population, younger age was associated with nonadherence. Keywords: adherence, transplant, liver, kidney
Randomized Phase III evaluation of the efficacy and safety of a novel glycopyrrolate oral solution for the management of chronic severe drooling in children with cerebral palsy or other neurologic conditions
Zeller RS,Lee HM,Cavanaugh PF,Davidson J
Therapeutics and Clinical Risk Management , 2012,
Abstract: Robert S Zeller1, Hak-Myung Lee2, Paul Cavanaugh2, Jennifer Davidson21Blue Bird Circle Clinic for Pediatric Neurology at Texas Children's Hospital and Baylor College of Medicine, Houston, TX, USA; 2Shionogi Inc, Florham Park, NJ, USAAim: To evaluate the efficacy of glycopyrrolate oral solution (1 mg/5 mL) in managing problem drooling associated with cerebral palsy and other neurologic conditions.Method: Thirty-eight patients aged 3–23 years weighing at least 27 lb (12.2 kg) with severe drooling (clothing damp 5–7 days/week) were randomized to glycopyrrolate (n = 20), 0.02–0.1 mg/kg three times a day, or matching placebo (n = 18). Primary efficacy endpoint was responder rate, defined as percentage showing ≥3-point change on the modified Teacher's Drooling Scale (mTDS).Results: Responder rate was significantly higher for the glycopyrrolate (14/19; 73.7%) than for the placebo (3/17; 17.6%) group (P = 0.0011), with improvements starting 2 weeks after treatment initiation. Mean improvements in mTDS at week 8 were significantly greater in the glycopyrrolate than in the placebo group (3.94 ± 1.95 vs 0.71 ± 2.14 points; P < 0.0001). In addition, 84% of physicians and 100% of parents/caregivers regarded glycopyrrolate as worthwhile compared with 41% and 56%, respectively, for placebo (P ≤ 0.014). Most frequently reported treatment-emergent adverse events (glycopyrrolate vs placebo) were dry mouth, constipation, and vomiting.Interpretation: Children aged 3–16 years with problem drooling due to neurologic conditions showed a significantly better response, as assessed by mTDS, to glycopyrrolate than to placebo.ClinicalTrials.gov identifier: NCT00425087.Keywords: sialorrhea, randomized controlled trial, cholinergic antagonists
Safety and efficacy of glycopyrrolate oral solution for management of pathologic drooling in pediatric patients with cerebral palsy and other neurologic conditions
Zeller RS,Davidson J,Lee HM,Cavanaugh PF
Therapeutics and Clinical Risk Management , 2012,
Abstract: Robert S Zeller1, Jennifer Davidson2, Hak-Myung Lee2, Paul F Cavanaugh21Texas Children's Hospital, Baylor College of Medicine, Houston, TX; 2Shionogi Inc, Florham Park, NJ, USABackground: The purpose of this study was to assess the safety and efficacy of oral glycopyrrolate solution 1 mg/5 mL for 24 weeks in pediatric patients with chronic moderate-to-severe drooling associated with cerebral palsy and other neurologic conditions.Methods: In this multicenter, open-label, 24-week study, males and females aged 3–18 years weighing at least 27 lb received oral glycopyrrolate solution, starting at 0.02 mg/kg three times daily and titrated in increments of 0.02 mg/kg every 5–7 days for 4 weeks to an optimal maintenance dose or a maximum dose of 0.1 mg/kg, but not exceeding 3 mg three times daily. Safety was assessed by description and tabulation of all adverse events. The primary efficacy endpoint was response, defined as at least a three-point change from baseline to week 24 on the modified Teacher's Drooling Scale.Results: Of 137 intent-to-treat participants, 10 (7.3%) received the maximum dose of 0.1 mg/kg three times daily; 122 (89%) had at least one treatment-emergent adverse event, 47% related to oral glycopyrrolate solution, with most being mild-to-moderate in intensity. The most commonly reported treatment-emergent adverse events were constipation (20.4%), vomiting (17.5%), diarrhea (17.5%), pyrexia (14.6%), dry mouth (10.9%), flushing (10.9%), and nasal congestion (10.9%). Nineteen patients (13.9%) discontinued treatment due to an adverse event, but no adverse event was specifically associated with discontinuation. Two patients had clinically significant toxicity grade shifts, one each in platelet count and calcium concentration. No deaths occurred on treatment; deaths of three patients (multisystem organ failure, anoxic encephalopathy, and aspiration pneumonia) within 30 days of their last dose were not considered to be treatment-related. At 24 weeks, 52.3% (95% confidence interval 43.7–60.9) of patients were responders, with at least a three-point decrease in modified Teacher's Drooling Scale from baseline, with 83.5% of parents/caregivers and 85.8% of investigators rating oral glycopyrrolate solution as being worthwhile.Conclusion: Oral glycopyrrolate solution 1 mg/5 mL for chronic moderate-to-severe drooling associated with cerebral palsy or other neurologic conditions was well tolerated over 24 weeks by pediatric patients aged 3–18 years.Keywords: sialorrhea, randomized controlled trial, cholinergic antagonists
Practical Applications of Cosmology to Human Society  [PDF]
Eric J. Chaisson
Natural Science (NS) , 2014, DOI: 10.4236/ns.2014.610077
Abstract: Complex systems throughout Nature display structures and functions that are built and maintained, at least in part, by optimal energies flowing through them—not specific, ideal values, rather ranges in energy rate density below which systems are starved and above which systems are destroyed. Cosmic evolution, as a physical cosmology that notably includes life, is rich in empirical findings about many varied systems that can potentially help assess global problems facing us here on Earth. Despite its grand and ambitious objective to unify theoretical understanding of all known complex systems from big bang to humankind, cosmic evolution does have useful, practical applications from which humanity could benefit. Cosmic evolution’s emphasis on quantitative data analyses might well inform our attitudes toward several serious issues now challenging 21st-century society, including global warming, smart machines, world economics, and cancer research. This paper comprises one physicist’s conjectures about each of these applied topics, suggesting how energy-flow modeling can guide our search for viable solutions to real-world predicaments confronting civilization today.


Association between Mycobacterium tuberculosis Complex Phylogenetic Lineage and Acquired Drug Resistance
Courtney M. Yuen, Ekaterina V. Kurbatova, Eleanor S. Click, J. Sean Cavanaugh, J. Peter Cegielski
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0083006
Abstract: Background Development of resistance to antituberculosis drugs during treatment (i.e., acquired resistance) can lead to emergence of resistant strains and consequent poor clinical outcomes. However, it is unknown whether Mycobacterium tuberculosis complex species and lineage affects the likelihood of acquired resistance. Methods We analyzed data from the U.S. National Tuberculosis Surveillance System and National Tuberculosis Genotyping Service for tuberculosis cases during 2004–2011 with assigned species and lineage and both initial and final drug susceptibility test results. We determined univariate associations between species and lineage of Mycobacterium tuberculosis complex bacteria and acquired resistance to isoniazid, rifamycins, fluoroquinolones, and second-line injectables. We used Poisson regression with backward elimination to generate multivariable models for acquired resistance to isoniazid and rifamycins. Results M. bovis was independently associated with acquired resistance to isoniazid (adjusted prevalence ratio = 8.46, 95% CI 2.96–24.14) adjusting for HIV status, and with acquired resistance to rifamycins (adjusted prevalence ratio = 4.53, 95% CI 1.29–15.90) adjusting for homelessness, HIV status, initial resistance to isoniazid, site of disease, and administration of therapy. East Asian lineage was associated with acquired resistance to fluoroquinolones (prevalence ratio = 6.10, 95% CI 1.56–23.83). Conclusions We found an association between mycobacterial species and lineage and acquired drug resistance using U.S. surveillance data. Prospective clinical studies are needed to determine the clinical significance of these findings, including whether rapid genotyping of isolates at the outset of treatment may benefit patient management.
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