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Commentary: New Complications Make Treatment of.“Opioid” Overdose Challenging

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Pharmacology & Pharmacy 2020年第12期11卷 362-372页

作者： john f. peppin Joseph V. Pergolizzi Jr. Albert Dahan Robert B. Raf.a Marian University College of.Osteopathic Medicine (Clinical Adjunct Prof.ssor) Indianapolis IN USA Pikeville University College of.Osteopathic Medicine (Clinical Prof.ssor) Pikeville KY USA Enalare Therapeutics Inc. Princeton NJ USA Neumentum Inc. Summit NJ USA NEMA Research Inc. Naples FL USA Leiden University Medical Center Leiden The Netherlands University of.Arizona College of.Pharmacy (Adjunct Prof.ssor) Tucson AZ USA Temple University School of.Pharmacy (Prof.ssor Emeritus) Philadelphia PA USA

The “opioid crisis” has had a tremendous impact not only on its victims, but also on the practice of.medicine, pain patients, and society in general. Unf.rtunately, ef.orts to “stem the tide” have not been success... 详细信息

The “opioid crisis” has had a tremendous impact not only on its victims, but also on the practice of medicine, pain patients, and society in general. Unfortunately, efforts to “stem the tide” have not been successful at reducing overdose deaths. Counterbalancing the many ardent efforts to eliminate overdose deaths (such as the current widespread availability and use of opioid-receptor antagonists such as naloxone) is influx of the illicit fentanoids (i.e., fentanyl and analogs). In addition to their high-potency, the fentanoids differ in surprising ways from more “traditional” opioids such as morphine and heroin. This uniqueness contributes to a reduced effectiveness of opioid receptor antagonists in the treatment of opioid overdose. Further greatly complicating overdose treatment is polysubstance abuse (e.g., an opioid plus a benzodiazepine). The non-opioid in the combination is not responsive to an opioid-recep- tor antagonist, which imparts additional challenges. Thus, the new reality introduces complications that negatively impact efforts to reverse “opioid” overdose. New approaches to improve outcomes in individuals who experience f.nt-f.mily:Verdana;">respiratory depression due to f.nt

关键词： Opioid Overdose f.ntanoid Naloxone Polysubstance Abuse Respiratory Stimulant

Commentary: “Ockham’s Razor” Doesn’t Apply to “Opioid” Overdose Death

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Journal of.Biosciences and Medicines 2021年第1期9卷 98-104页

作者： john f. peppin Joseph V. Pergolizzi Jr. Eugene Vortsman Robert B. Raf.a Marian University College of.Osteopathic Medicine (Clinical Adjunct Prof.ssor) Indianapolis IN USA Enalare Therapeutics Inc. Princeton NJ USA Neumentum Inc. Summit NJ USA NEMA Research Inc. Naples FL USA Northwell Health New Hyde Park NY USA University of.Arizona College of.Pharmacy (Adjunct Prof.ssor) Tucson AZ USA Temple University School of.Pharmacy (Prof.ssor Emeritus) Philadelphia PA USA

Polysubstance Abuse (PSA) greatly complicates an attempt to implicate a single drug as sole cause of.an overdose death. Since PSA now occurs in the majority of.cases of.drug overdoses, many or most overdose deaths are polysubstance overdose deaths. And since many of.the substances involved in a polysubstance Overdose Death (POD) are Central Nervous System (CNS) depressants, many of.which can cause overdose death themselves, or synergistically with opioids, it is somewhat puzzling that prescription opioids have been singled out as the cause of.these deaths—without ref.rence to PSA. This is particularly puzzling in light of.the f.ct that the issues of.PSA and POD have been recognized and discussed in the literature since at least the 1960’s and bef.re. We theref.re here consider the question: are we f.cing an “opioid” crisis or, instead, a “polysubstance crisis”? And we wonder if.the issue has been over-simplif.ed, to the detriment of.the individuals af.ected, and to society more broadly. There is a need f.r an “agnostic” respiratory stimulant that can reverse polysubstance-induced respiratory depression.

关键词： Opioid Overdose Polysubstance Use Polysubstance Overdose Treatment

Calcium-mediated paired pulse depression in juvenile rat dorsal striatum

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Neural Regeneration Research 2012年第10期7卷 772-777页

作者： Yuf.ng Xie Michael f. Jackson john f. MacDonald Robarts Research Institute University of Western Ontario London Ontario Canada Department of.Physiology and Pharmacology University of Western Ontario London Ontario Canada Department of.Anatomy and Cell Biology University of Westem Ontario London Ontario Canada

As the major division of.the basal ganglia, neostriatum f.rms mutual connections with multiple brain areas and is critically involved in motor control and learning/memory. Long-term synaptic plasticity has been widely studied in dif.erent species recently. However, there are rare reports about the short-term synaptic plasticity in neostratium. In the present study, using f.eld excitatory postsynaptic potentials recording, we reported one f.rm of.short-term synaptic plasticity that is paired pulse depression in juvenile rat dorsal striatum slices induced by stimuli of.the white matter. The f.eld excitatory postsynaptic potentials could be abolished by α-amino-3-hydroxy-5-methylizoxazole-4-propionic acid receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione, but not by gamma-aminobutyric acid type A receptor antagonist bicuculline or dopamine D1 receptor antagonist SKf.81297. The paired pulse depression in the corticostratial pathway was dif.erent f.om paired pulse f.cilitation in the hippocampal CA1 synapse. In addition, the paired pulse depression was not af.ected by bath application of.gamma-aminobutyric acid type A receptor antagonist or dopamine D1 receptor antagonist. However, low calcium and high magnesium could attenuate the paired pulse depression. These f.ndings suggest a more complicated plasticity f.rm in the dorsal striatum of.juvenile rats that is dif.erent f.om that in the hippocampus, which is related with extracellular calcium.

关键词： paired pulses depression dorsal striatum calcium juvenile rats

Design of.Poiseuille f.ow Controllers Using the Method of.Inequalities

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International Journal of.Automation and computing 2009年第1期6卷 14-21页

作者： john McKernan James f. Whidborne George Papadakis Department of.Mechanical Engineering King s College London Strand Department of.Aerospace Sciences Cranfield University

This paper investigates the use of.the method of.inequalities （MoI） to design output-f.edback compensators f.r the problem of.the control of.instabilities in a laminar plane Poiseuille f.ow. In common with many f.ows, the dynamics of.streamwise vortices in plane Poiseuille f.ow are very non-normal. Consequently, small perturbations grow rapidly with a large transient that may trigger nonlinearities and lead to turbulence even though such perturbations would, in a linear f.ow model, eventually decay. Such a system can be described as a conditionally linear system. The sensitivity is measured using the maximum transient energy growth, which is widely used in the f.uid dynamics community. The paper considers two approaches. In the f.rst approach, the MoI is used to design low-order proportional and proportional-integral （PI） controllers. In the second one, the MoI is combined with Mcf.rlane and Glover＇s H∞ loop-shaping design procedure in a mixed-optimization approach.

关键词： Transient energy growth transient behaviour f.ow control Poiseuille f.ow method of.inequalities (MoI) mixed opti-mization H∞-optimization.

Landscape of.the mind

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Landscape of the mind

Synchronous f.rmation of.the‘f.rearc’Bay of.Islands ophiolite and its basal high-temperature metamorphic sole constrained by U-Pb zircon ages

作者： Hof.ecker john f.

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Geoscience f.ontiers 2023年第6期14卷 234-272页

作者： Weiyao Yan john f.Casey Department of.Earth and Atmospheric Sciences University of HoustonHoustonTXUSA

The welded metamorphic sole at the base of.the Bay of.Islands Ophiolite Complex(BOIC)in the Northern Appalachians of.Newf.undland shows a typical inverted pressure-temperature(P-T)metamorphic gradient f.om HT-MP granulite to LT-LP greenschist *** incorporates maf.c volcanic/plutonic protoliths mixed with pelagic,hemi-pelagic and coarser epiclastic sedimentary *** LA-ICP-MS U–Pb concordia ages,trace elements,and Ti-in-zircon geothermometry f.r -250 zircon analyses f.om three metabasites of.the upper HT sole amphibolites with N-MORB-like protoliths are *** samples collected within meters of.the ophiolite peridotite-sole contact of.the Blow Me Down Mountain and North Arm Mountain massif. yielded the oldest comparable concordia ages of.487.7±2.6 Ma and 489.1±3.1 Ma,respectively,that are both within error of.the igneous age of.488.3±1.5 Ma of.the directly overlying BOIC ophiolite,which f.rmed at a supra-subduction zone(SSZ)f.rearc spreading center.A third slightly younger age of.484.2±2.4 Ma was obtained f.r an upper HT amphibolite sample with similar phase assemblages but collected30 m below the peridotite contact of.the Table Mountain *** crystals analyzed have similar size and morphologies,subparallel rare earth element(REE)variation patterns,and steep heavy REE-enrichments((Lu/Gd)_(cn)>20),signif.cant positive Ce anomalies(dominantly>5)and slight positive to dominantly negative Eu anomalies(1.2–0.4).Zircon shows Th/U mean values of.0.37–0.48 with little to no rim to core *** Ti-in-zircon mean crystallization temperatures range f.om764–787℃.These neocrystallized zircon crystals appear to be derived f.om thin leucosomes within the three *** other samples also f.om the upper HT sole show evidence of.inherited detrital zircon with core dates spanning the Cambrian Notre Dame Arc through older Laurentian-like basement and rif. age *** of.the sole took place below a hot f.rearc asthenospheric wed

关键词： Ophiolite metamorphic sole U-Pb zircon ages Hot subduction interf.ce Supra-subduction f.rearc spreading center Arc-continent collision Taconic Orogeny

Xylose: absorption, f.rmentation, and post-absorptive metabolism in the pig

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Journal of.Animal Science and Biotechnology 2018年第1期9卷 1-9页

作者： Nichole f.Huntley john f.Patience Department of.Animal Science 213 Kildee HallIowa State University Department of.Animal Science 201B Kildee HallIowa State University

Xylose, as β-1,4-linked xylan, makes up much of.the hemicel ulose in cel wal s of.cereal carbohydrates f.d to pigs. As inclusion of.f.brous ingredients in swine diets continues to increase, supplementation of.carbohydrases, such as xylanase,is of.interest. However, much progress is warranted to achieve consistent enzyme ef.icacy, including an improved understanding of.the utilization and energetic contribution of.xylanase hydrolysis product（i.e. xylooligosaccharides or monomeric xylose）. This review examines reports on xylose absorption and metabolism in the pig and identif.es gaps in this knowledge that are essential to understanding the value of.carbohydrase hydrolysis products in the nutrition of.the pig. Xylose research in pigs was f.rst reported in 1954, with only sporadic contributions since. Theref.re, this review also discusses relevant xylose research in other monogastric species, including humans. In both pigs and poultry, increasing purif.ed D-xylose inclusion general y results in linear decreases in perf.rmance, ef.iciency, and diet digestibility. However,supplementation levels studied thus f.r have ranged f.om 5% to 40%, while theoretical xylose release due to xylanase supplementation would be less than 4%. More than 95% of.ingested D-xylose disappears bef.re the terminal ileum but mechanisms of.absorption have yet to be f.l y elucidated. Some data support the hypothesis that mechanisms exist to handle low xylose concentrations but become overwhelmed as luminal concentrations increase. Very little is known about xylose metabolic utilization in vertebrates but it is wel recognized that a large proportion of.dietary xylose appears in the urine and signif.cantly decreases the metabolizable energy available f.om the diet. Nevertheless, evidence of.labeled D-xylose-1-^（14）C appearing as expired^（14）CO_2 in both humans and guinea pigs suggests that there is potential,although small, f.r xylose oxidation. It is yet to be determined if.pigs develop increased xy

关键词： Pentose utilization Swine Threitol Xylose absorption Xylose metabolism

Human development across the lif.span john S. Dacey, john f. Travers.

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Cloning, Expression, and Homology Modeling of.GroEL Protein f.om Leptospira interrogans Serovar Autumnalis Strain N2

2002年

作者： john S. Dacey john f. Travers.

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Genomics, Proteomics & Bioinf.rmatics 2011年第4期9卷 151-157页

作者： Kalimuthusamy Natarajaseenivasan Santhanam Shanmughapriya Sridhar Velineni Sergey C. Artiushin john f. Timoney Medical Microbiology Laboratory Department of Microbiology School of Life Sciences Bharathidasan University Gluck Equine Research Center University of Kentucky

Leptospirosis is an inf.ctious bacterial disease caused by Leptospira species. In this study, we cloned and se- quenced the gene encoding the immunodominant protein GroEL f.om L. interrogans serovar Autumnalis strain N2, which was isolated f.om the urine of.a patient during an outbreak of.leptospirosis in Chennai, India. This groEL gene encodes a protein of.60 kDa with a high degree of.homology （99% similarity） to those of.other leptospiral serovars. Recombinant GroEL was overexpressed in Escherichia coli. lmmunoblot analysis indi- cated that the sera f.om conf.rmed leptospirosis patients showed strong reactivity with the recombinant GroEL while no reactivity was observed with the sera f.om seronegative control patient. In addition, the 3D structure of.GroEL was constructed using chaperonin complex cpn60 f.om Thermus thermophilus as template and vali- dated. The results indicated a Z-score of.-8.35, which is in good agreement with the expected value f.r a pro- tein. The superposition of.the Ca traces of.cpn60 structure and predicted structure of.leptospiral GroEL indicates good agreement of.secondary structure elements with an RMSD value of.1.5A. f.rther study is necessary to evaluate GroEL f.r serological diagnosis of.leptospirosis and f.r its potential as a vaccine component.

关键词： GroEL expression homology modeling leptospirosis serodiagnosis