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Genetic assessment of inbred chicken lines indicates genomic signatures of resistance to Marek's disease

Journal of Animal Science and Biotechnology 2018年第4期9卷 803-812页

作者： Lingyang Xu Yanghua He Yi Ding George E.Liu Huanmin Zhang Hans H.Cheng robert L.taylor jr. Jiuzhou Song Department of Animal & Avian Sciences University of Maryland Animal Genomics and Improvement Laboratory U.S. Department of Agriculture-Agricultural Research Services Laboratory of Molecular Biology and Bovine Breeding Institute of Animal Science Chinese Academy of Agricultural Sciences United States Department of Agriculture-Agriculture Research Service (ARS) Avian Disease and Oncology Laboratory Animal and Nutritional Sciences Davis College of Agriculture West Virginia University

Background: Marek’s disease(MD) is a highly contagious pathogenic and oncogenic disease primarily affecting chickens. However, the mechanisms of genetic resistance for MD are complex and not fully understood. MD-resistant line 63and MD-susceptible line 72are two highly inbred progenitor lines of White Leghorn. Recombinant Congenic Strains(RCS) were developed from these two lines, which show varied susceptibility to ***: We investigated genetic structure and genomic signatures across the genome, including the line 63and line72, six RCSs, and two reciprocally crossed flocks between the lines 63and 72(F1 63× 72and F1 72× 63) using Affymetrix~? Axiom~? HD 600 K genotyping array. We observed 18 chickens from RCS lines were specifically clustered into resistance sub-groups distributed around line 63. Additionally, homozygosity analysis was employed to explore potential genetic components related to MD resistance, while runs of homozygosity(ROH) are regions of the genome where the identical haplotypes are inherited from each parent. We found several genes including SIK, SOX1, LIG4, SIK1 and TNFSF13B were contained in ROH region identified in resistant group(line 63and RCS), and these genes have been reported that are contribute to immunology and survival. Based on FSTbased population differential analysis, we also identified important genes related to cell death and anti-apoptosis, including AKT1, API5, CDH13, CFDP and USP15,which could be involved in divergent selection during inbreeding ***: Our findings offer valuable insights for understanding the genetic mechanism of resistance to MD and the identified genes could be considered as candidate biomarkers in further evaluation.

关键词： Genetic structure Genomic signature Homozygosity Marek's disease Recombinant Congenic Strains(RCS)

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Designing General Anesthetics That Have a Better Safety Profile

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Pharmacology & Pharmacy 2019年第10期10卷 407-415页

作者： robert B. Raffa Joseph V. Pergolizzi jr. robert taylor jr. Neumentum Inc.，Palo Alto CAUSA College of Pharmacy University of Arizona Tucson AZ USA Temple University School of Pharmacy Philadelphia PA USA NEMA Research Inc. Naples FL USA.

General anesthetics constitute some of the most important and widely-used therapeutic drugs in the pharmacotherapeutic armamentarium. They are routinely used effectively and with adequate precaution-safety throughout the world for a multitude of clinical applications, predominantly as adjunctive agents for surgical procedures. Nevertheless, they have potential adverse effects (such as a drop in blood pressure and the inhibition of steroid production), particularly in vulnerable populations such as the very young and the frail elderly. It would be desirable therefore to have alternative agents that are just as efficacious, but have a better safety profile in a broader spectrum of patients. Toward this end, an anesthetic based on a unique chemical core (viz., an N-arylpyrrole derivative) has been reported in preclinical models to produce anesthetic effects without hemodynamic suppression. This lead could pave the way for new general anesthetics that are safer and easier to use.

关键词： General Anesthetic Intravenous Drug Discovery GABAA Receptor Molecular Modeling

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“Atropisomeric” Drugs: Basic Concept and Example of Application to Drug Development

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Pharmacology & Pharmacy 2020年第1期11卷 1-8页

作者： robert B. Raffa Joseph V. Pergolizzi jr. robert taylor jr. Neumentum Inc. Palo Alto CA USA College of Pharmacy University of Arizona Tucson AZ USA School of Pharmacy Temple University Philadelphia PA USA NEMA Research Inc. Naples FL USA.

Many therapeutic drugs are racemates;i.e. they are chiral molecules consisting of “left”- and “right-handed” enantiomers (stereoisomers that are mirror images of each other, and are non-superimposable). In some cases, both enantiomers of the drug contribute to some extent (or equally) to the therapeutic effect;in other cases they contribute not at all. The same is true for the adverse effects of racemate drugs: the adverse effects of a racemate drug can be greater-than, less-than, or equal to one or the other enantiomer. An unusual situation arises when a drug consists of “atropisomers”, stereoisomers arising because of hindered rotation about a single chemical bond. We summarize the concept of atropisomerism, and give examples.

关键词： Atropisomer Chirality Pharmacotherapy Drug Development NaV1.7 Inhibitor

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The Role of Medical Literature, Clinical Trials and Experimental Research in Drug Product-Injury Litigation: A Primer with Two Examples

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Pharmacology & Pharmacy 2018年第6期9卷 208-227页

作者： Jan M. Kitzen Joseph V. Pergolizzi jr. robert taylor jr. robert B. Raffa Kitzen Pharmaceutical Consulting Collegeville USA Temple University School of Medicine Philadelphia USA NEMA Research Inc. Naples USA University of Arizona College of Pharmacy Tucson USA Temple University School of Pharmacy PhiladelphiaUSA

When any type of product has been ordered to be removed from the marketplace by a governmental regulatory body, that action is a powerful indicator that the product has been determined to be unsafe for further use, thereby branding the product as defective and opening up the possibility of product liability litigation. When the product is a drug or medical device, it is especially serious since the possibility of personal injury (acute and/or chronic) or death may occur. Needless to say, in these situations, product injury litigation will almost surely follow. We review the definition and requisite claims needed to establish drug product liability, and the role that the medical literature, clinical trial data, and even experimental research data can play in product (drug)-injury litigation. We show how each of these resources played a significant role in two well-known cases: Fen-Phen and thimerosal. The ultimate goal of such knowledge is to make better informed decisions about drug safety.

关键词： Drug Safety Product Quality Injury Litigation Fen-Phen Thimerosal

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Crisaborole and Apremilast: PDE4 Inhibitors with Similar Mechanism of Action, Different Indications for Management of Inflammatory Skin Conditions

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Pharmacology & Pharmacy 2018年第9期9卷 357-381页

作者： Jan M. Kitzen Joseph V. Pergolizzi jr. robert taylor jr. robert B. Raffa Kitzen Pharmaceutical Consulting Collegeville PA USA Temple University School of Medicine Philadelphia PA USA NEMA Research Inc. Naples FL USA Neumentum Inc. Palo Alto CA USA University of Arizona College of Pharmacy Tucson AZ USA Temple University School of Pharmacy Philadelphia PA USA

Two selective phosphodiesterase-4 (PDE4) inhibitors—viz., crisaborole (Eucrisa®, Pfizer) and apremilast (Otezla®, Celgene)—have recently received approval by the United States Food and Drug Administration for the treatment of related but different dermatologic skin conditions (viz., atopic dermatitis and plaque psoriasis, respectively). The purpose of this review is to summarize the underlying biochemistry and pathophysiology associated with these dermatologic conditions, review the chemistry, pharmacology and safety of each of these products, and present preclinical and clinical evidence that may help explain why these two PDE4 inhibitors offer new treatment options for these skin conditions.

关键词： Crisaborole Apremilast Phosphodiesterase PDE4 Inflammation Cytokines Interleukins cAMP

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Vitamin D and Number of Falls in a Long-Term Care Facility

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Pharmacology & Pharmacy 2012年第4期3卷 453-457页

作者： robert B. Raffa Frank Breve robert taylor jr. Joseph V. Pergolizzi jr. Mid Atlantic PharmaTech Consultants LLC Ventnor City NJ USA Temple University School of Pharmacy Philadelphia PA USA NEMA Research Inc. Naples FL USA Temple University School of Medicine Temple University Philadelphia PA USA The Johns Hopkins University School of Medicine Baltimore MD and Georgetown University School of Medicine Washington DC USA

Falls represent a significant contribution to the morbidity and mortality of the elderly population. Because vitamin D is important in bone physiology, the use of vitamin D to restore deficient bone and ameliorate the effects of bone fractures due to falls has become a common practice in recent years. Following introduction of widespread use, reports began to emerge that vitamin D not only aided in repair of fall-induced bone fractures, but that it also reduced the occurrence of falls. Vitamin D now has become a routine intervention as a fall-prevention measure. Early analyses found evidence of prevention efficacy (reduced falls), but recent analyses are more equivocal. We retrospectively examined the records of 350 patients in a long-term care facility in which vitamin D administration and the number of falls were recorded as part of a comprehensive database of care. We found a dramatic rise in vitamin D use over the period covered (2006 – 2011) and a corresponding dramatic decrease in the number of falls. However, the number of falls continued to decline after 2008, despite a plateau in number of patients on vitamin D, particularly females. It appears that other factors contribute to the overall decline.

关键词： Falls Bone Fracture Vitamin D Long-Term Care Facility

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Treating Insomnia in Older Adult Patients: Limiting Benzodiazepine Use

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Pharmacology & Pharmacy 2019年第3期10卷 116-129页

作者： Joseph V. Pergolizzi jr. robert taylor jr. Jo Ann LeQuang Errol Gould robert B. Raffa NEMA Research Inc. Naples FL USA Neumentum Palo Alto CA USA LeQ Medical Angleton TX USA Pernix Therapeutics Morristown NJ USA University of Arizona College of Pharmacy Tucson AZ USA Temple University School of Pharmacy Philadelphia PA USA

As aging comes, an increased prevalence of medical maladies and chronic pain independently or interactively disrupt sleep, which in turn can exacerbate either one. Furthermore, anxiety about pain can further negatively impact sleep. Fortunately, good quality sleep can improve pain management. Because benzodiazepine receptor agonists (including the “Z” drugs) can reduce anxiety and improve sleep, they seem a convenient choice. However, their use in this population, particularly for more than short-term (guidelines range from 2 to 6 weeks max), is not recommended because of increased likelihood of falls, further disruption of sleep, dependence, and problems with discontinuation (withdrawal). Besides, this population is often likely to take concomitant medication for pain or other central nervous system depressants leading to potentially serious and even life-threatening interactions involving synergistic amplification of respiratory depression (opioids being a particularly dangerous interaction). Therefore, insomnia in older adults should ideally be treated with a non-benzodiazepine receptor agonist;if indicated, they may be used, but should be closely monitored and tapered to avoid long-term adverse problems (direct or from withdrawal). Older adult patients with insomnia may be more optimally treated with sleep aids that do not interact with the GABAA receptor.

关键词： Pain Insomnia Older Adults Benzodiazepines “Z”-Drugs GABAA Receptor

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E-Cigarette Survey among Student Pharmacists Reveals Troubling Results

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Pharmacology & Pharmacy 2020年第6期11卷 127-136页

作者： Jamie L. McConaha Phillip Lunney Jan M. Kitzen Joseph V. Pergolizzi jr. robert taylor jr. robert B. Raffa Duquesne University School of Pharmacy Pittsburgh PA USA Lachman Consultants Westbury NY USA Kitzen Pharmaceutical Consulting Collegeville PA USA NEMA Research Naples FL USA University of Arizona College of Pharmacy Tucson AZ USA Neumentum Inc. Palo Alto CA USA Temple University School of Pharmacy Philadelphia PA USA

The rise in “vaping”-associated deaths in the United States raises serious concerns. A justification for some level of risk is that e-cigarettes might provide a “reverse-gateway” from smoking traditional cigarettes to a less-harmful alternative. But are users actually smokers? We developed an electronic on-line survey to gather data regarding e-cigarette usage in a target study population of pharmacy students. The survey was created using Google Forms to collect the responses anonymously. We surveyed medical-savvy healthcare students about their e-cigarette use, and whether or not their healthcare providers were aware of their e-cigarette use. Although nearly one-fourth of a convenience sampling of 134 pharmacy-student respondents (23.9%) reported using e-cigarettes, only 2.0% reported prior regular cigarette use, 28% used cartridges containing nicotine and only 11.2% had tried and wanted to quit. The majority (64.1%) reported that their healthcare providers did not ask about such use, and respondents did not volunteer this information. The results of this pilot survey reveal a significant e-cigarette use among health-aware pharmacy students, and they do not support the notion that the respondents do so to quit smoking. The observation that most of the students’ healthcare providers did not inquire about their e-cigarette use, coupled with the finding that users did not volunteer their vaping behavior, suggests that the information should be included when getting a medical history. Further research is needed to determine what behavioral factors may play a role in this type of decision-making among student healthcare professionals.

关键词： E-Cigarettes Nicotine Smoking Cessation Survey Vaping

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Hormone Replacement Therapy for Restoring the HPG Axis in Pain Patients Treated with Long-Term Opioid Analgesics

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Pharmacology & Pharmacy 2018年第11期9卷 473-480页

作者： Srinivas Nalamachu Joseph V. Pergolizzi jr. robert taylor jr. Jo Ann Le Quang Joseph V. Pergolizzi III robert B. Raffa International Clinical Research Institute and Pain Management Institute Overland Park KS USA NEMA Research Inc. Naples FL USA LeQ Medical Angleton TX USA College of Pharmacy University of Arizona Tucson AZ USA School of Pharmacy Temple University Philadelphia PA USA

Opioids are a treatment option for a variety of chronic pain conditions. But long-term opioid use can be associated with side effects, including hypogonadism. Opioid-induced hypogonadism (OIhG) is associated with the alteration of the hypothalamic-pituitary-gonadal axis (HPG). In males, hypogonadism can result in erectile dysfunction, reduced libido, fatigue, worsening mood, and increased risk of osteoporosis;in females, it can result in changes in the menstrual cycle and reduced libido, among other effects. A current treatment option for these patients is hormone replacement therapy. In this report, we discuss the problem of opioid-induced hypogonadism, and the therapeutic approach and the potential complications of treating pain patients using hormone replacement therapy.

关键词： Opioid Therapy Chronic Pain HPG Axis Hormone Replacement Therapy

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THE GATE SQUALL LINE OF 9-10 AUGUST 1974

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Advances in Atmospheric Sciences 1987年第1期4卷 85-92页

作者：韦统健,robert A. Houze jr. Department of Atmospheric Sciences Nanjing University Nanjing Department of Atmospheric Sciences University of Washington Seattle WA 98195 U.S.A.

A tropical squall line that passed over the ship array of the Global Atmospheric Research Programme's Atlantic Tropical Experiment (GATE) on 9-10 August 1974 is analyzed. This squall line was similar to squall systems that passed over the GATE ship array on four other days. It began as a purely convective cloud line, then developed an associated stratiform cloud and precipitation area. The stratiform rain built up to a maximum amount over a period of 8 h, then gradually diminished over a 6 h period. This stratiform rain is estimated to have accounted for 32% of the squall system's total precipitation. As in other GATE squall lines, the upper-level cloud shield from which the stratiform rain fell, was advected slowly forward of the line during the system's lifetime, the leading line of convective clouds consisted of transient smaller-scale convective elements, which lent the line an irregular shape and pulsatory movement, and the stratiform portion of the system was characterized by the development of a

关键词： line THE GATE SQUALL LINE OF 9-10 AUGUST 1974 GMT LINE

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