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Antiviral Research: Strategies in Antiviral Drug Discovery
Editor: Robert L. LaFemina, Ph. D.
Content Type: Monograph
Format: Electronic
Category: Viruses and Viral Pathogenesis; Clinical Microbiology
e-ISBN : 9781555815493
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This book captures the state of the science with twenty reviews that examine the latest in today's antiviral drug discovery efforts. The introduction of nucleoside analogs and investigations of novel antiviral targets have brought significant new possibilities to the field. These reviews range from in-depth analyses of a specific viral target, to examination of multiple targets in medically important viruses. All chapters include the authors' thoughts regarding future developments in their specific topic, and the book concludes with an Afterword in which several experts consider the general future of antiviral drug discovery.
With its coverage of many different types of viruses including influenza virus, herpesvirus, the SARS coronavirus, orthopox- and flaviviruses, hepatitis C virus, and a wide range of topics in HIV-1, Antiviral Research offers investigators a broad view of the current state of nucleoside analogs and other antiviral strategies. This book is certain to help stimulate new ideas and approaches for virologists, biochemists, pharmaceutical chemists, and other investigators.
Electronic Only, 373 pages, full-color insert, illustrations, index.
Chapter 1 : Antiherpesviral DNA Polymerase Inhibitors
Author: Donald M. Coen
Acyclovir (ACV), whose mechanism is detailed in this chapter, heralded the second generation of antivirals for herpesviruses and set the standard for the development of antiviral drugs. Two limitations of oral acyclovir have been its limited oral bioavailability (~15%) and short half-life. These limitations require administration of large pills as often as every four hour. Valacyclovir and famciclovir overcome these limitations and would have completely displaced the use of acyclovir except for the expiration of the acyclovir patent resulting in the availability of low-cost generic drug. Both valacyclovir and famciclovir can be used for applications of oral acyclovir. In the herpesviruses considered here, there are six gene products with activities at the replication fork. The viral proteins that have thus far served as the best targets for antiherpesvirus drugs are the viral DNA polymerases that are required for viral DNA replication, which are thus targets for inhibition, and viral kinases. All of the nucleoside analogs discussed in this chapter are converted to analogs of deoxynucleoside triphosphates (dNTPs) that inhibit herpesvirus DNA polymerases. The mechanism of acyclovir action begins with the TK encoded by herpes simplex virus (HSV) or varicella-zoster virus (VZV). An important unanswered question is whether new antiherpesvirus drugs can be developed to combat drug-resistant human infections. Although the number of drug-resistant HSV infections is relatively small, the need for new drugs that are active against acyclovir-resistant viruses and that have good pharmacokinetic and toxicity profiles is substantial for the patients involved.
Chapter 2 : Entry Inhibitors of Human Immunodeficiency Virus
Author: Masanori Baba
Highly active antiretroviral therapy (HAART) based on the combination of different classes of inhibitors has dramatically improved the prognosis of human immunodeficiency virus type 1 (HIV-1) infection after its establishment. This chapter focuses on the viral entry processes that play crucial roles in HIV-1 replication and describes inhibitors thereof. It talks about three kinds of inhibitor named as fusion inhibitors, coreceptor inhibitors and viral attachment inhibitors. Maraviroc was approved for use in combination with other antiretroviral medications for the treatment of R5 HIV-1 in adults whose viral loads remain detectable despite existing antiretroviral treatment or who have multidrug-resistant HIV-1. HIV-1 variants resistant to Cyanovirin-N (CV-N) or cross-resistant to additional carbohydrate-binding agents were generated and examined for their biological properties. A study on resistance to CV-N demonstrated that the resistant variants had increased susceptibility to immunoglobulins and sera obtained from HIV-1-infected patients and particularly to V3-loop-directed monoclonal antibodies. The maraviroc-resistant R5 HIV-1 retained full susceptibility to SCH-C and aplaviroc, suggesting that although the CCR5 binding sites for these agents are similar, their impacts on the surface conformation of the receptor are different. The results of the study also suggest that the envelope proteins of maraviroc-resistant viruses are able to recognize and utilize inhibitor-bound CCR5, which involves the ordered accumulation of mutations in the viral envelope, both in the V3 loop and elsewhere within gp120. In addition to the inhibitors described in the chapter, several antibodies have been shown to interact with the molecules essential for HIV-1 entry to the host cells.
Chapter 3 : Human Immunodeficiency Virus Type 1 Non-Nucleoside Reverse Transcriptase Inhibitors
Authors: Dirk Jochmans, Johan Vingerhoets, Eric Arnoult, Luc Geeraert, Jérôme Guillemont
This chapter discusses the non-nucleoside reverse transcriptase inhibitors (NNRTI), which is a valuable component of first-line highly active antiretroviral therapy (HAART) today. Reverse transcriptase (RT) is an essential enzyme in the replication cycle of HIV. Several high-resolution structures representing the different intermediates in the polymerization reaction are available for human immunodeficiency virus type 1 (HIV-1) RT. Rilpivirine is currently in phase IIb clinical trials for treatment of HIV-1 infection in treatment-naïve subjects. With the widespread use of anti-HIV therapy, resistance has grown steadily and is now common among treatment-experienced HIV-infected patients, with NNRTI resistance occurring in 20 to 30% of patients. This has changed with the DUET-1 and DUET-2 trials, two large phase III clinical trials that examined the efficacy of etravirine in treatment-resistant HIV-1-infected patients. K103N and Y181C were the first NNRTI mutations to be identified and to date are among the most prevalent in clinical HIV-1 isolates. They have been observed in patients failing on nevirapine, efavirenz, or delavirdine, and the clinical utility of these drugs is hampered by the presence of a single K103N or Y181C mutation. Recently, predictors of virologic response to etravirine were identified based on pooled data from DUET-1 and DUET-2.
Chapter 4 : Nucleoside Analogue Inhibitors of Human Immunodeficiency Virus Reverse Transcriptase
Authors: Jérôme Deval, Matthias Götte
More than 20 different antiretroviral agents have been approved for human immunodeficiency virus (HIV) treatment. These compounds target distinct stages in the life cycle of this retrovirus that include (i) its entry into the cytoplasm, which marks the beginning of the infection; (ii) the process of reverse transcription, i.e., the conversion of the single-stranded RNA genome into double-stranded DNA; (iii) the integration of proviral, double-stranded DNA into the host chromosome; and (iv) the processing of viral precursor proteins at later stages. These steps are vital for viral replication, and with the exception of the entry process, each of the aforementioned reactions involves viral enzymes, i.e., the reverse transcriptase (RT), the integrase, and the protease, respectively, that can be targeted by antiretroviral drugs. This chapter focuses on nucleoside analogue RT inhibitors (NRTIs) in the context of mechanisms of action and resistance and on the implications for the development of future strategies designed to counteract resistance. All approved NRTIs show a broad spectrum of antiviral activity against HIV-1, HIV- 2, and sometimes even hepatitis B virus (HBV), which points to structurally highly related active sites. A given mutation or mutational cluster can affect susceptibility to different NRTIs to various degrees, which makes it difficult to group the mutations. It will be interesting to investigate how established and novel NRTIs can be most effectively combined with new classes of compounds with the ultimate goal of further reducing the risk of resistance development, while maintaining high standards regarding problems associated with toxicities and dosing.
Chapter 5 : Integrase as a Novel Target for the Inhibition of Human Immunodeficiency Virus Type 1 Infection: Current Status and Future Perspectives
Authors: Linos P. R. Vandekerckhove, Frauke Christ, Zeger Debyser, Andrew Owen, David Back, Arnout Voet, Jonathan Schapiro, Dirk Vogelaers
This chapter describes the unique role of integrase (IN) in the human immunodeficiency virus type 1 (HIV-1) replication cycle and its interaction with different cellular proteins. It addresses the efficacy and toxicity data of the new drugs targeting IN, along with their biochemical, pharmacokinetic, and pharmacodynamic characteristics. It also discusses clinical perspectives and viral resistance against IN inhibitors as well as recently identified new antiviral targets in HIV IN. Since retroviral integration is a multistep process, the different cofactors can theoretically play a role during one of the following steps: (i) catalysis, (ii) nuclear import of the PIC, (iii) target site selection, and (iv) repair of the DNA gaps. The chapter gives an overview of the search for HIV-1 IN inhibitors, and discusses current IN inhibitors in clinical development. The major mechanism of clearance of MK-0518 (raltegravir) in humans is UDP-glucuronyltransferase (UGT) isoform, 1A1-mediated glucuronidation. In a multicenter, double-blind, randomized study (MK-0518 protocol 005), the safety and efficacy of MK-0518 versus placebo, both regimens also using optimized background therapy (OBT), were evaluated. This study was designed to include highly antiretroviral therapy (ART)-experienced patients with a documented genotypic/phenotypic resistance for more than one drug in each of the three classes (NNRTI, NRTI, and PI) with HIV RNA levels of >5,000 copies and CD4 counts of >50 cells/mm3. Resistance to IN inhibitors has been relatively well defined for a new class of antiretroviral agents. IN has only been recently validated in clinical trials as a target for antiretroviral therapy.
Chapter 6 : Human Immunodeficiency Virus Type 1 Tat and Rev as Potential Targets for Drug Development
Authors: Sergei Nekhai, Kuan-Teh Jeang
This chapter discusses the potential of HIV Tat, Rev, and their cellular cofactors as drug targets. Tat interacts with numerous transcriptional regulatory factors and presumably by virtue of its interaction with transcription activation response (TAR) RNA, recruits these factors to the human immunodeficiency virus type 1 (HIV-1) promoter. Thus, HIV-1 transcription directed from the viral long terminal repeat (LTR) is balanced by the actions of kinases and phosphatases, and both can be potential targets for drug development. Tat promotes the elongation of viral transcripts by increasing the occupancy time of CDK9/cyclin T1 on the HIV-1 LTR. Small-molecule inhibitors of Tat-TAR RNA interaction, small-molecule inhibitors of CDKs such as CDK9 or CDK2, and inhibitors that disrupt the interaction of Tat with additional host cell factors such as p300/CREB binding protein-associated factor (PCAF) and/or inhibit cellular activities of the host cell factors could all be viable anti-HIV drug candidates. Both Tat and TAR RNA are essential for activated HIV-1 transcription, and were thus the first candidates to be considered for drug design that targeted HIV-1 transcription. Antiviral development against HIV-1 regulatory proteins Tat and Rev represents a conceptual work in progress. In the arena of inhibiting Tat and Rev cellular cofactors, the concerns over host toxicity have not been fully resolved. Future efforts are needed to address the two major challenges of mechanistic specificity and functional toxicity.
Chapter 7 : Inhibitors of the Human Immunodeficiency Virus Protease
Authors: Jorge L. Martinez-Cajas, Mark A. Wainberg
HIV protease inhibitors (PIs) were first introduced into clinical practice in 1996, and their use has resulted in major clinical benefits for human immunodeficiency virus (HIV) -infected people in terms of better viral suppression, improved immune restoration, reduced morbidity, and longer survival. This chapter focuses on the biochemical and molecular basis of inhibition of HIV-1 aspartic protease (PR), the virological basis of PI resistance, and implications on the therapeutics of HIV infections and proposes the research that is still needed in order to further improve on the benefits that PIs offer for HIV medicine. Drug-resistant viruses have been described for all PIs developed to date. Some strains of HIV recovered from extensively treated patients display cross-resistance to a variety of PIs. Additionally, structural data from a highly resistant PR containing 10 resistance mutations revealed an expansion in the active site, as a result of a separation of the flaps by as much as 10 Å, while this distance is only 4 Å in the case of wild-type PR. The degree of suppression of viral replication is the result of the interaction between exposure of the virus to the drug and the inherent susceptibility of the infecting virus to such drug, all this within the diverse environments of human tissues. The study of efflux transporters and their role in PI penetration into, and distribution within, so-called sanctuary sites may lead to ways of making HIV in these compartments more susceptible to antiretrovirals (ARVs).
Chapter 8 : Hepatitis C Virus Polymerase as a Target for Antiviral Drug Intervention: Non-Nucleoside Inhibitors
Authors: Yaya Liu, Yupeng He, Akhteruzzaman Molla
This chapter focuses on Hepatitis C virus (HCV) polymerase as a drug target for designing non-nucleoside inhibitors, and discusses details related to HCV sequence variation and quasispecies, HCV polymerase structure and mechanism, classes of polymerase inhibitors, inhibitors currently under development, the nature of drug resistance, and the need for combination therapy. Among the non-nucleoside inhibitors, compounds with thiophene carboxylic acid, pyranoindole, dihydropyranone, or phenylalanine scaffolds have been shown to bind to HCV polymerase in the thumb allosteric pocket by X-ray cocrystallization structures. C316Y and G554D appear to be the most important resistance mutations, suggesting overlapping resistance with HCV-796 and likely binding to the HCV polymerase active-site priming nucleotide pocket. Both sequence variations between genotypes and the quasispecies nature of HCV may contribute to drug resistance. Patients may have low levels of preexisting variants in their quasispecies that are resistant to antiviral drugs. These preexisting variants may be selected upon drug treatment and quickly become the dominant species. Many groups have reported on resistant mutants selected with various HCV polymerase inhibitors in vitro using the HCV replicon system. GSK reported several mutants against a benzothiadiazine (Compound 4), including M414T and N411S. Due to the high replication rate of HCV and errorprone nature of HCV polymerase, monotherapy will lead to the selection of preexisting resistance mutations and ultimately to the inability to eradicate HCV.
Chapter 9 : Nucleoside Analog Inhibitors of Hepatitis C Viral Replication
Authors: Steven S. Carroll, Robert L. LaFemina
The discovery of an infectious virus system based on virus from a patient with fulminant hepatitis has created another tool for investigating the viral replication cycle. All of the nucleoside drugs used to treat infections with human immunodeficiency virus (HIV), hepatitis B virus, and herpesviruses can be considered to be 29-deoxynucleoside analogs. Since its nucleotide substrates are ribonucleotides, Hepatitis C virus (HCV) RNA polymerase novel has different substrate specificity regarding substituents at the 29 position of the ribose ring. Thus, it is likely that substituents at the 2' position of the ribose ring of nucleoside analog inhibitors of RNA polymerase that give rise to potent inhibition will be different from those active as inhibitors of DNA polymerase activity. Inhibition of HCV replication at other putative sites of replication such as lymphocytes may also be important to achieve viral clearance. Roche has disclosed the discovery of nucleoside analog inhibitors of HCV replication having modifications at the 4' position. Ribavirin (1-b-d-ribofuranosyl-1,2,4-triazole-3-carboxamide) is a nucleoside analog with a long history of use as a chemotherapy to treat viral infection with a broad spectrum of activity. Liver biopsy showed hepatic pathogenesis typical of HCV infection. Reisolation of virus used to infect new chimps showed that the H77 strain was infectious in subsequent recipient chimps. It is more difficult to address ribavirin resistance in cell culture because ribavirin is not a very effective replication inhibitor of 1b replicons. Since nucleoside analogs must be converted to the triphosphate, they are inherently prodrugs.
Chapter 10 : Antiviral Targets in Orthopoxviruses
Authors: Mark N. Prichard, Earl R. Kern
This chapter summarizes many targets for orthopoxviruses that might be exploited in the discovery of additional agents for potential diseases and indicates the mechanisms of action of a number of compounds. The viral DNA polymerase performs a critical role in viral replication, and its susceptibility to nucleoside analogs has made it the dominant target for the development of antiviral drugs. The synthesis of deoxynucleotides is also catalyzed by the heterodimeric ribonucleotide reductase encoded by F4L and I4L. Ribonucleotide reductase converts ribonucleotides to the corresponding deoxyribonucleotides at the level of the diphosphate and supplies deoxyribonucleoside triphosphates to support DNA replication in the cytoplasm. A number of small molecules are known to broadly target protein kinases, and it is possible that medicinal chemistry efforts could identify selective inhibitors. Immature virions containing genomic DNA undergo complex maturation that leads to the condensation of virus cores and involves proteolytic events, the loss of D13, and the formation of new disulfide linkage catalyzed by the viral redox system. The complex replication cycle of the orthopoxviruses requires the concerted activities of numerous viral proteins. The chapter also summarizes each of the stages of viral replication, notes the viral proteins that perform critical functions, and identifies specific inhibitors that affect these processes.
Chapter 11 : Influenza Virus Antiviral Targets
Authors: Gillian M. Air, Wayne J. Brouillette
Influenza viruses are classified as type A, B, or C based on antigenic reactions of their internal proteins. Type A influenza viruses are further divided into subtypes according to the antigenic properties of their surface antigens, the glycoproteins hemagglutinin (HA) and neuraminidase (NA). The genome of influenza virus consists of eight segments of single-stranded RNA, ranging in size from ~900 to 2,300 nucleotides. Each RNA segment contains the coding information for one or two proteins, but in the negative sense. The RNA segments are coated with the nucleoprotein (NP), and some are associated with the three subunits of the viral RNA-dependent RNA polymerase complex. The chapter discusses targets for antivirals against influenza. The M2 ion channel is the target of the earliest licensed antiviral drugs against influenza, amantadine and rimantadine. NA is the second most abundant glycoprotein on the virus surface. It cleaves sialic acid residues from glycoproteins and some glycolipids, thus acting as a receptordestroying activity. The cyclopentane peramivir was developed by BioCryst, again based on the crystal structure of NA and its interactions with inhibitors. The aim was to find an inhibitor that was readily synthesized and orally available and that did not induce resistance. The chapter talks about development of antiviral drugs targeted to influenza, and targeting host functions. The diversity of influenza viruses and their capacity to change present a particular challenge to the development and use of anti-influenza antivirals.
Chapter 12 : Developments in the Search for Small-Molecule Inhibitors for Treatment of Severe Acute Respiratory Syndrome Coronavirus
Authors: Dale L. Barnard, Yohichi Kumaki
Severe acute respiratory syndrome (SARS) is the first new infectious disease of this century, caused by a novel human coronavirus (SARS-CoV), and the disease is associated with severe pulmonary pathological features leading to high mortality. This chapter talks about different kinds of inhibitors such as small-molecule inhibitors, peptide, and papain-like proteinase inhibitors. SARS-CoV is a positive-sense single-stranded (ss) RNA virus. The 30-kb genome is predicted to encode at least 10 open reading frames (ORF), some of which encode proteins involved in virus entry into cells. Receptor-virus interaction can be inhibited using two approaches. First, develop inhibitors that block the cellular receptor with which the virus attachment protein interacts. Second, block the domain in the virus attachment protein that binds to the cellular receptor. Researchers have determined the crystal structures of human coronavirus 3CLpro and suggested that the rhinovirus 3CLpro inhibitor AG7088 could serve as a starting point for an anti-SARS drug based on the theoretical homology model of SARS-CoV 3CLpro. Researchers have showed that the RNAi targeting of the coronavirus RdRp using synthesized short hairpin expression plasmids significantly reduced the expression of target protein in 293 cells and HeLa cells and blocked plaque formation of SARS-CoV in Vero E6 cells. Development of inhibitors of the innate immune response might also be worthwhile, with the caveat that humans, like animals, are reservoirs of mixed infections, latent, chronic, and acute, and that down-regulating an immune response to ameliorate a SARS infection may exacerbate a coexisting infection from another infectious agent.
Chapter 13 : Antiviral Treatment of Flaviviruses
Author: Justin G. Julander
This chapter discusses the key question of unavailability approved antiviral treatments for flavivirus pathogens which cause significant morbidity and mortality, examines the progress made in the development of therapies, identifies key targets of therapy, and reviews the challenges to overcome in the development of antiflaviviral disease treatments. It deals only with members of the Flavivirus genus, which include viruses of human concern, such as dengue virus (DV), yellow fever virus (YFV), West Nile virus (WNV), Japanese encephalitis virus (JEV), Murray Valley encephalitis virus (MVEV), Saint Louis encephalitis virus (SLEV), and tick-borne encephalitis virus (TBEV), all of which cause morbidity and mortality. A few flaviviruses, primarily DV and YFV, cause hemorrhagic manifestations in severe infection. The chapter investigates targets for the treatment of flaviviruses, including viral and host elements that may be effectively targeted for treatment. Important progress in the treatment of flavivirus infections has been made recently, bringing ever closer to fruition the important goal of developing a broad-spectrum agent that is effective after disease manifestation. New animal models of flaviviral disease would be important in developing a better understanding of basic virology and antiviral treatment. Epidemiological methods to detect and predict the severity and location of outbreaks would be beneficial in control of DV diseases, giving better chances to efficacy of antiflaviviral agents. Alerting physicians or veterinarians of emerging flaviviral outbreaks would also help improve the diagnosis and treatment of human or animal infections.
Chapter 14 : Clinical Aspects of Hepatitis C Virus Infection
Authors: David Durantel, Fabien Zoulim
Recently, the most significant progress in knowledge of hepatitis C virus (HCV) biology and interaction with host cells has concerned the role of lipids for genome replication, assembly and egress, and entry into cells. The major hepatic consequence of HCV infection is the progression to cirrhosis and its complications, such as ascites, hepatic insufficiency, and hepatocellular carcinoma (HCC). With the identification in 1989 of HCV as the infectious agent responsible for non-A/non-B hepatitis and the development of specific detection tests, it has become possible to monitor the efficacy of interferon (IFN)-α treatment. With the increased survival associated with the use of highly active antiretroviral therapy (HAART), morbidity and mortality from HCV-induced liver disease have started to increase significantly. Microarray results from liver biopsy tissue taken before therapy in a cohort of patients given pegIFN and ribavirin were recently reported. In this study, patients who were subsequently identified as non-responders had high baseline expression of IFN-stimulated genes (ISGs), whereas responders to therapy more closely resembled healthy controls. Kempf et al. illustrated the need for good knowledge of drug metabolism to improve the efficacy of a drug in vivo. In this study it was shown that a pharmacokinetic enhancement of telaprevir and boceprevir could be achieved by codosing with ritonavir, a potent inhibitor of the cytochrome P450 3A, which is involved in the metabolism of both drugs.
Chapter 15 : Microbicides: Molecular Strategies for Prevention of Sexually Transmitted Viral Disease
Author: Raina N. Fichorova
This chapter provides an overview on molecular strategies for prevention of sexually transmitted viral disease. The chapter focuses on the perceived need, basic research challenges, and scientific grounds for confidence in the development of anti-human immunodeficiency virus (HIV) type 1 (HIV-1) microbicides with emphasis on viral/pathogen synergies and mucosal factors of susceptibility. Synergistic mechanisms underlying the phenomenon of "amplified transmission" are discussed in the chapter. Mathematical modeling predicts that even a partial protection would substantially relieve the burden of the HIV pandemic. Nevertheless, because of the viral diversity and the complexity and redundancy of the viral mucosal penetration routes, it is unlikely that a single microbicide or multiple microbicides inhibiting acquisition via a single target would prove to be fully efficient. The major mechanisms of action targeted by microbicides, so far, are degrading or neutralizing the virus before it reaches its target cells, blocking the viral entry and intercellular passage, as well as attacking the intra-cellular steps of the viral cycle, mainly the reverse transcription and viral integration processes. The mechanism of action of the antiretroviral drugs nucleoside and non-nucleoside RT inhibitors (NRTIs and NNRTIs) is discussed in detail. The development of prevention strategies and tools to encompass the global diversity of HIV-1, to be holistically compatible with the wide range of age and multicultural and socioeconomic backgrounds, is a colossal international undertaking that has mobilized scientists, advocates, philanthropists, and policy makers around the world.
Chapter 16 : Phenotypic Susceptibility Assays for Human Immunodeficiency Virus Type 1
Authors: Neil T. Parkin, Eoin Coakley, Christos J. Petropoulos
Phenotypic susceptibility assays are used in the laboratory to measure the susceptibility of a virus to an antiviral agent. They are used for some viruses, such as human immunodeficiency virus type 1 (HIV-1), in clinical settings to help construct the drug regimen most active against an individual patient's virus. This chapter summarizes the technology behind commonly used antiviral drug susceptibility assays for HIV-1 and the interpretation of results generated by them. Currently there are two approved anti-HIV drugs that target virus entry: the fusion inhibitor enfuvirtide (ENF) and the CCR5 coreceptor antagonist maraviroc. The chapter describes phenotypic assays for determining HIV-1 coreceptor tropism. Assays that determine HIV-1 viral tropism in a patient are needed to allow the clinician to make an informed decision as to whether a CCR5 co-receptor antagonist is an appropriate drug choice for a given patient. Two standardized MT-2 assay approaches have been described. In the first, viral stocks from stimulated patient lymphocytes co-cultured with lymphocytes from an HIV-negative donor are generated. The second method utilizes direct cocultivation of patient lymphocytes with MT-2 cells, followed by microscopic examination. Currently approved, interferon/ribavirin-based treatment of hepatitis C virus (HCV) infection is incompletely effective and is associated with significant toxicity and tolerability issues. Approaches to measure HCV drug susceptibility can be broadly classified into four categories: (i) intact virus assays, (ii) replicon-based recombinant virus assays (RVAs), (iii) cell-based (nonreplicon) assays, and (iv) enzymatic assays. Phenotypic assays are useful during preclinical development, clinical development, and potentially in clinical practice.
Chapter 17 : Metabolism of Antiviral Nucleosides and Nucleotides
Authors: Adrian S. Ray, Michael J. M. Hitchcock
Nucleoside and nucleotide analogs have served as the cornerstones of antiviral therapy against human immunodeficiency virus (HIV), herpesviruses (including herpes simplex virus type 1 [HSV-1], HSV-2, varicella-zoster virus, and cytomegalovirus), and the hepatitis B and C viruses (HBV and HCV, respectively). Rather than providing a comprehensive discussion of the metabolism of individual agents, this chapter gives a general overview of enzymes involved in the metabolism of nucleoside and nucleotide analogs. It also highlights a few examples illustrating the unique pharmacology of the molecules. Competing with anabolism, various modes of catabolism and egress can serve to limit the maximal and temporal levels of the active species in target cells. Antiviral nucleoside and nucleotide analogs represent a large structural diversity with analogs mimicking virtually all the natural ribose and 2'-deoxyribose nucleosides and nucleotides. The importance of the 3' hydroxyl in the interaction of nucleosides with nucleoside transporters may differentiate the distribution of 3'-deoxynucleoside analogs and 3'-hydroxyl-containing nucleoside analogs. Anion and cation transporters with more general substrate specificity have also been identified to interact with nucleosides and nucleotides. In addition to anabolic drug interactions, highly catabolized nucleosides can have their levels altered due to interference with their degradation pathways. Drug interactions due to changes in elimination have also been observed to occur between nucleoside and nucleotide analogs and concomitant agents not related to nucleosides. Successful prodrug strategies promise to more effectively target infected tissues while decreasing exposure to sites of toxicity, offering the potential to increase efficacy while decreasing unwanted side effects.
Chapter 18 : Targeting the Interferon Response for Antiviral Therapy
Author: Michael D. Robek
This chapter provides a general introduction and overview of the interferon (IFN) pathway. Separate sections of this chapter address the different types of IFN, activation of IFN-α/β expression, IFN-mediated signal transduction, antiviral mechanisms, and viral resistance to the IFN-α/β response. The IFNs are classified into three types (I, II, and III) based on receptor usage, sequence homology, and chromosome location of their genes. The chapter primarily focuses on the type I IFNs, as these cytokines are most closely associated with antiviral activity and therapeutic use. Like RNA, cytosolic DNA also induces the production of IFN-β. Therefore, in addition to RNA viruses, a mechanism also exists to detect the genomes from DNA viruses in the cytoplasm of infected cells. The Toll-like receptors (TLRs) are critical for recognizing different molecular patterns that are unique to viral or bacterial pathogens. As with the cytoplasmic sensors, specificity for pathogen-derived nucleic acids by the TLRs is at least in part provided at the level of nucleic acid modifications. IFN-α/β is important for certain aspects of the adaptive immune response and serves as one example of a bridge between innate and adaptive immunity. In addition to antiviral and immunomodulatory functions, IFN-α/β can also negatively influence cellular proliferation. Future research into improved IFN-based antiviral therapies might focus on improving the antiviral properties of these cytokines while decreasing the unwanted side effects. This goal might be accomplished in a number of distinct ways.
Chapter 19 : Toll-Like Receptors: Novel Molecular Targets for Antiviral Immunotherapy
Authors: Raymund R. Razonable, Albert Eid, Martin Henault
This chapter reviews the role of toll-like receptors (TLRs) in innate antiviral responses and in coordinating the antiviral adaptive immune system, and discusses the potential for TLRs as novel molecular targets for antiviral immunomodulatory therapy. A mutation in the Toll gene in Drosophila that results in defective protein was associated with reduced survival after fungal infection. The chapter discusses TLR recognition of pathogen-associated molecular patterns, TLR signaling pathway, biological outcomes of TLR activation, and TLRs and the pathogenesis of selected viral pathogens. The potential role for TLR-7 and TLR-8 in HSV pathogenesis is highlighted by ongoing research efforts to control herpes simplex virus (HSV) infections with the use of small-molecule TLR-7 and TLR-8 agonists. Many viruses, however, have evolved to develop strategies that block the effector mechanisms induced through TLR signaling pathways. Coronavirus, a contagious viral pathogen that causes the highly fatal severe acute respiratory syndrome (SARS), has an attenuated ability to induce type I interferons (IFNs), which are essential for the efficient control of the infection, because it has developed a TLR evasion mechanism characterized by failure of IRF-3 activation. The chapter describes TLRs as targets for immunomodulation and antiviral therapies. The successful clinical development of imiquimod, the prototype TLR immune response-modifying drug, provides a solid example of the promise and remarkable potential that TLR modulators have in bringing novel antiviral therapeutic strategies in the clinical setting.
Chapter 20 : New Herpes Simplex Virus Replication Targets
Author: Sandra K. Weller
The human alphaherpesviruses include human herpes simplex viruses types 1 and 2 (HSV-1 and HSV-2) and varicella-zoster virus (VZV). HSV-1 and HSV-2 are responsible for primary and recurrent herpetic lesions of the mouth and genital tract, as well as more serious and potentially life-threatening infections of the eye and central nervous system. This chapter discusses alternative targets for antiherpesviral therapy. The roles of various viral glycoproteins in the attachment and penetration steps at the outset of the infection cycle are only now being identified; however, as with human immunodeficiency virus (HIV), the processes of attachment, receptor recognition, and penetration are likely be excellent targets for the development of antiviral therapy. Several reports have described a class of agents that inhibit the adsorption of the virus to host cells. Viral genes are classified as immediate early, early, or late and are transcribed from both strands of the viral genome by cellular RNA Pol II. The authors have proposed that recombination-dependent DNA replication plays an important role in viral DNA replication. Procapsids formed in the nucleus are competent to undergo encapsidation of the viral genome accompanied by a major conformational change in its structure from a sphere to a more angular shape.
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Our ever-increasing understanding of viral replication, not only in terms of the functions of viral proteins, but also those of cellular ones, has allowed the development of antiviral agents that have proved a real success in the treatment of diseases caused by herpes viruses, human immunodeficiency virus and influenza virus, and it probably will not be long before hepatitis C virus can be added to the list. This book describes the efforts that are being made to identify and validate antiviral targets and evaluate their efficacy in animal models and in the clinic. The critical issue of drug resistance is discussed, as is the possibility of using microbicides to prevent infection. The book contains a wealth of information and I can recommend it to all students, research scientists and clinicians interested in human viral disease and its management. The book's hefty price tag, however, is likely to limit its purchase to institutions.
Society for General Microbiology: Microbiology Today
Reviewer: Christopher Ring, Middlesex University
Review Date: Feb 2009
Doody Enterprises
After fifty years of work on antiviral agents we still have far fewer than are needed. This volume describes antiviral drug discovery from a target-based approach.
This book reviews the biochemical mechanisms of current antiviral agents and examines the approach taken to discover new antiviral agents. It also provides details on the techniques used to discover and test these new compounds.
It is designed to bring together research on antiviral agents in a single place and compare the methods used to discover new therapeutic antiviral agents. The compilation of this information in one book will aid other scientist in developing new antiviral agents.
This will appeal to scientists working on new compounds that act to interrupt the viral pathogenesis pathways. It also might be of interest to those involved in the study of cell processes. It is written by accomplished scientists who work in this area of antiviral drug discovery and would be of interest to more advanced scientists.
The book begins with a review of the first successful antiviral agent used as effective therapy against herpes simplex virus. This sets the stage for the rest of the book. It is clear that the current antiviral agents have had a tremendous impact on the clinical outcome of several well-known viral infections such as human immunodeficiency virus and herpesvirus infection. However, viruses are very fluid and have begun to develop resistance to the current agents, thus new drugs are needed to continue to control these devastating diseases. The discovery of new antiviral agents begins with an understanding of the cellular pathway required for viral replication. New agents can then be designed to block the viral replication without damaging uninfected cells. The remaining chapters describe this discovery process and the potential for new antiviral agents. They also describe the methods used in this endeavor.
This book details information on viral pathways in the cell and the mechanism of antiviral action and would be very useful to scientists working on antiviral agents. Most of the chapters address drugs that target HIV and herpesviruses, and there is no data on antiviral agents used to treat hepatitis B, a major viral pathogen.
Reviewer: Rebecca Horvat, PhD, D(ABMM) (University of Kansas Medical Center)
Date Reviewed: May 2009
©Doody's Review Service
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Antiviral Research — Recommend this title to your library


As an unemployed person living in Australia, but working from a NZ bank account for the time being. I find myself living in a world that I thought died out years ago alongside Chatter rings.
Yeah, I didn't get the point of them either, Fan of early Mike Myers films.
And no I am not talking about a world without Internet, how do you think I am writing this if that were the case?
And no I am not writing it as text messages on phone with no SIM and flying them out on a Pigeon. Because I know that's what you were thinking.
No I am talking about a world of cash, living back home I would be lucky if I had more than $20 in my pocket, everything was done electronically since there were no fees, and I wasn't a drug dealer so I wasn't being paid in cash.
I may have been a drug baron, but I wasn't a drug dealer.
Since over here, it costs me like $4 a withdrawal, I am living in a world of cash and it is strange and foreign to me, for starters I had to relearn how to use an ATM.
According to the internet I need to be female between 20-35, and not look at the machine at any point.
Once I had successfully retrieved my money from the machine I went to put it in my wallet. However having lived in a cash-free society my wallet doesn't really have receptacles for notes anymore.
Yeah you can get your 50 in there smart guy, show me how you get it out.
When I spent my first note on something, the situation became even more dire. It is exasperated by the fact in Australia they seem to be going for some sort of world record for the world's largest coin.
I can barely move it across our coffee table, how am I meant to transport it?
The best part is it isn't even there most valuable coin, it's the third most valuable coin. So I got worried, if this was only their third most valuable coin, how much bigger do they get, what sort of belt am I going to have to get to keep my pants up carrying all these coins?
Even one with metal reinforcing would be no match for these behemoths.
But it turns out I didn't need to worry the Australian's have built their coins in some sort of pyramid formation with apex, at the 50 cent piece, then they descend in size.
I think they realised they got too big with the 50 and had to make some sort of logical pattern.
Their $2 coin is the same size as their 5 cent piece?! To be fair it is fatter but still. And why do they still have a 5 cent piece? Seriously as an unemployed person I want to know because if there are things in Australia I can buy for 5 cents I want to know what they are.
To be fair there was a time I could probably put a deposit on a house in NZ for Australian 5 cents. But not anymore go NZD!
There is an upside to this tiny $2 coin though, a couple of weeks ago I went out with $100 in my pocket and after buying a few beers and dinner I only had like $30 in notes in my pocket. I thought to myself I knew this country was expensive but $70? I then put my hand in my other pocket and pulled out a handful of coins expecting them to add to maybe $4.50 (obviously with no 50 cent pieces, I can't even get one of them in my hand). Turns out I had about $20 in $2 dollar coins just in my pocket, so I can imagine cleaning out one's couch or backseat of a car could mean you can pay off the power bill.
Being an unemployed person affords one a lot of spare time, and I think I finished the internet ( I won't spoil it for you, but let's just say Rick Astley plays a very important part), so I needed to find some new activities.
One of the reasons Melbourne seemed like a good destination to move to, was the fact it had a Zoo. I figured going midweek would mean we would have the Zoo to ourselves save for some old people, mothers & homeless people seeking shelter in the butterfly enclosure.
I am going to need more butterflies if I am going to hide overnight.
But turns out I picked the day every school in Victoria decided to do a field trip to the Zoo.There were so many school kids there that when we had lunch, we thought we had accidentally taken a wrong turn and were eating at a school canteen.
Each of the cliques wore a different school uniform.
While I am talking about the lunch you would have thought that people at the Zoo would be able to recognise animals.
Because whatever animal they killed to make these nuggets, it sure as hell wasn't a chicken.
Some of the parental behavior at the Zoo, also left a lot to be desired, more then one parent stood idly by while their small child screamed at small animals (and I mean directly at them). I wasn't expecting them to yell or tell the child off, but maybe just explain to them its quite scary when something larger then you makes a lot of noise for no reason.
My personal favourite parent though, was the lady who decided to dangle her small baby into a deadly animal's cage, and didn't seem to blink an eyelid as the animal within paws reach eyed up the child with great interest. Admittedly this deadly creature was a wombat but still have you seen the claws on those things.
Artists Rendition of aforementioned event.
While I spent over 6 hours at the Zoo, I was able to walk everywhere, whereas the animals are confined to a much smaller area, so I did wonder what they spend the day doing? The Gorillas seemed to be plotting something evil?
"First I will steal that ladies bag, then I will try and take over the World, Muhahaha"
Other animals seemed upset they weren't given the same tools, despite lacking opposable thumbs..
I also watched with interest as the Zookeepers cleaned the Elephant cage with great care removing the dung and the uneaten cabbages from the last feeding. They took forever to do this while the Elephants waited impatiently at the gate.
"Come on, Come on, no time to wait for the door to fully open."
My girlfriend said she would be annoyed if a restaurant took that long to let her in, just to do the final dusting, I pointed out she should be grateful the restaurant let her back in if she had shat all over the place last time she was there. But after all that cleaning, I then observed as the Elephants came in and stood on the new cabbages before eating them, I wondered if the Elephants were that bothered, or if perhaps dirt is to Elephants, what salt is to Humans.
And poop water is Elephant salad dressing.
##Disclaimer: While some of the captions and photos imply the Zoo is not taking care of the animals properly, they are intended for humour purposes only. The Zoo is doing a great job and I highly recommend a visit.
So you might have noticed that since my last entry the Earth has made a full rotation around the sun, and then some, and the question on many (estimations range wildly from 1-100000) people's lips is "Why?"
Due to the large size of Mick Jagger's lips, there are lots of things on them, so it is a safe assumption "Why hasn't there been an Underthinkingit blog in over a year?" is one of them.
Well truth be told it was a culmination of many things, actually two things, it was a culmination of two things.
So because I love all of you so much I remedied the situation by becoming unemployed, and then moving to Australia.
Thanks to great mobile competition, everyone is connected in Australia.
The other benefit of moving to Australia is, there is room for new material. So it is with great pleasure we announce the return of Underthinking it.
If you missed the official announcement I apologise, the tickets sold out on the VISA presales.
So where to begin, well I have been here for a two weeks now, and I have made a few observations about how my life will be very different. Today I want to look at Beer Sales.
They call Australia the lucky country because of all their mineral wealth, and their ability to win Winter Olympics medals on the back of not falling down. But the thing is they need the wealth to afford to pay for booze, in fact the speed skater probably didn't fall down because he couldn't afford enough beer. I have picked up two errors in their sales of beer.
1/. The imported beer costs the same as the local beer.
The Supermarket, not this place they just wanted to send me to college in America.
...to purchase some beer, I surveyed my options. Just to give some context to this story I am in Melbourne, which is in Victoria, given this I figured that VB would be a cheap option, it was 14.99 for a 6 pack, so I continued to survey. I found Peroni (an Italian beer) was 13.50 a 6 pack, I am not sure what they don't understand about pricing, but surely transport would be a factor, and last time I checked Italy is further from Melbourne then Melbourne is. But just to be sure I ran some tests.
So either Italy are in possession of some sort of teleporter, that the rest of us aren't, or VB is using some seriously expensive transport.
"Maybe we should send more then one can at a time, and stop buying the delivery guy lunch, and stop flying from Melbourne to Melbourne"
The more astute readers will have noticed I was comparing 6 packs and would have said of course its expensive, you need should buy in bulk. The problem is in Australia the next multiple of beer after 6 is buttloads.
It's an official unit, don't ask how it's measured.
They have skipped the 12 and went straight to the 24, which would be okay, except I live in a smallish apartment with 4 other people and we don't have storage space for 24 beers. Well I mean we could but then we would have to not eat.
"Eatings Cheating am I right?"
And if I am heading off to a party I don't want to take 24 beers, nor do I wish to take 6. If I take 24 I have to lug a huge carton around on the public transport, then when the party moves to town, realise I am leaving 11-15 beers behind and well that is just too high a flat tax.
When I get close to 12 beers I start to feel like this guy looks.
If I take 6 beers, then I am going to have to take tiny sips to make those 6 beers last out the evening, because everyone else has brought 6 packs and no one has enough to share.
"Did you actually take a drink? or did you spit some of the last sip back into the bottle?"
I didn't realise until I left the shores of NZ but the 12 pack is literally the optimum purchasing amount of beer for a wide variety of situations, so for you lucky folk back in NZ cherish it.
Want to keep Underthinking? Try one these.


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HomeU.S. AgricultureMichiganMichigan Local
Michigan Fruit: Pickin' Progress
By Joanie Stiers -
Ag Education
Family Farms
Apples, blueberries, cherries – this varied list of fruits has one thing in common. They're known as super foods, packed with disease-fighting antioxidants, vitamins and other health benefits.
Michigan cherry growers like Don Gregory, who operates Cherry Bay Orchards in Suttons Bay with his brother Bob, son-in-law and nephew, are trying to get the small red fruit added to the superfood list. Historically, tart cherries have been popular in desserts, but research shows that cherries contain antioxidants that help reduce pain from arthritis, gout and headaches, making them beneficial for much more than just pie.
"We're trying to reinvent our tart cherries as a hot new superfruit," says Phil Korson, president of the Cherry Marketing Institute. "It's been an exciting time for us."
Sales of dried cherries and cherry juice concentrate have accelerated as consumers learn more about the science that supports cherries and their new superfruit status.
Michigan's lake-effect climate places it among the nation's major fruit-growing states. The state ranks No. 1 in the production of tart cherries, producing 75 percent of the U.S. supply, according to the National Agricultural Statistics Service. The state ranks fourth in sweet cherries.
About 540 cherry farms operate in Michigan as of 2013. The state's fruit industry remains deeply rooted in experience with its family-owned farms, like High Acres Fruit Farm in Hartford.
"I think it's an exciting time to be in fruit and vegetable production," says Trever Meachum, who operates High Acres Fruit Farm with his father and two brothers. "I think people are more in tune with being healthy and conscious eaters."
See Also: Michigan's Farm to School Connection
The families of Cherry Bay Orchards can relate. They added a drying and juice-making operation to their farm in the last 10 years.
"That's the fastest-growing part of our market today, and it's all related to the health benefits of tart cherries," Gregory says.
Montmorency cherries dominate the tart cherry industry in Michigan and throughout the country. Today, the U.S. is the largest producer of this superfruit in the world, Korson says.
Michigan's Apple Growers
Favorite apple varieties include Honeycrisp, Jonagold, Gala and Fuji, according to the Michigan Apple Committee.
Additionally, Michigan's large bumper crop and commitment to distributing Michigan apples to 26 states and 18 countries left apple shippers busier than ever.
In fact, the Michigan apple industry set new shipment records two weeks in a row in October 2013, shipping 411,973 boxes of apples the week of Oct. 5, and 414,702 boxes of apples the week of Oct. 12.
"Michigan's agriculture and apple industry are very significant to Michigan's economy," says Mike Rothwell, president and general manager at BelleHarvest Sales, Inc. "At BelleHarvest, one of the largest fresh apple marketers in the eastern U.S., we market a product that we are really excited about. We have a tremendous impact on a lot of people's lives, whether it's the people we employ, the growers we serve, or the customers we provide for. As far as economic activity, we are approaching close to a billion dollars based on the Michigan apple industry alone."
Michigan — the nation's third-largest producer of apples — produces on average more than 800 million pounds of apples per year. Sixty percent of those apples are processed for foods such as applesauce, pie filling, apple cider and apple juice. Likewise, Michigan slices more apples than any other state for use in pies and fresh-cut slices.
See Also: Michigan is Dedicated to Safeguarding Your Food
"If you look at production and utilization figures, processing is at least half of that. Processing is still a big sector of the apple industry," says Eric MacLeod, processor for Cherry Growers, Inc. "Right here in Michigan we are growing a lot of apples compared to two years ago. We feel partial that processing is a big contribution to the state's apple industry and the economy. We have a growing apple industry, and production in the future certainly has the ability to be greater than what it has been over the last few years with new plantings and new planting systems. Moving forward, apples and processing will take on a great role in contributing to our economy."
Joanie Stiers
Michigan Agriculture 2019
More in Michigan Local
Why You Should Choose Michigan Cherries
Homegrown superfruit packs a punch beyond the pie shell.
RecoveryPark Farms is Planting Seeds of Change
Hoophouses for Health Helps Farmers with Infrastructure Needs
Why Aquaponic Growing Methods are Important for Year-Round Produce
Michigan Department of Agriculture & Rural Development
Lansing, Michigan 48909
www.michigan.gov/mdard

redpajama_set_name: RedPajamaCommonCrawl


How do you add fields to the main table instead of cstm table?
I would be happy to answer your question for you. You could in theory add the vardef fields to the regular modules directory instead of ./custom/modules. However, it isn't advised to make customizations outside of the ./custom/ directory. The main reason being that if you were to upgrade, any changes not in the ./custom directory will be wiped out.
You can add custom fields in the /custom directory that add the columns to the main table. The question is, why?


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LMT Group Opens International Customer Center
LMT Group opens international customer center.
On September 10, 2015, the LMT Group celebrated the opening of Fette Compacting's machine construction division's newly established customer center in Schwarzenbek. Following almost a year of construction, the very latest testing and acceptance rooms for tablet presses have been unveiled, in addition to new office space, covering approximately 4000 square meters.
Between 2010 and 2014, the LMT Group invested about 100 million euros in the overall development of the company group. Almost 40 million euros of this went to the infrastructure at Schwarzenbek. The company management is pushing its comprehensive renewal strategy forwards with the opening of the customer center for Fette Compacting, a world leader in tableting technology.
"At a cost of around 13 million euros, our new building is not only the biggest single investment in the history of the LMT Group, but above all it gives expression to the company strategy, supported by the family of partners, of investing earnestly in innovation, efficiency and customer relations," said Olaf J. Müller, spokesman for the management of the LMT Group, and general manager of Fette Compacting. "It therefore clearly commits Schwarzenbek as a technological site."
The foundation for this is provided by the sustained and successful development of the LMT Group's business over the years. This is further evidenced by the number of employees at the site: since 2010, the number of staff at Schwarzenbek has kept growing – investment has created new jobs. Altogether about 1000 employees now work at the site, making the group the largest employer in the Duchy of Lauenburg administrative region.
"The new customer center at Fette Compacting and our LMT Group Academy in Schwarzenbek together form a competence center for all aspects of tablet production, one that is unique in the world," said Müller. "On top of long-term investment in our infrastructure, our focus is on the continuous further development and education of our employees."
Partner Regine Bengel underlines the significance of the new construction, saying "Sustainability governs our thoughts and our actions. Through the investment in Fette Compacting's new customer center, we are giving long-term reinforcement to the Schwarzenbek site and its innovative capability within Fette Compacting's global competence network."
In this new construction, Fette Compacting is making available the most modern testing and acceptance rooms for tablet presses in the world. In these rooms, customers from the pharmaceutical, food, and chemical industries are able to participate in every step in the process of Factory Acceptance Tests (FAT). By testing all machine functions, and by performing pressing trials under production-like conditions, Fette Compacting makes sure that the equipment will perform its processes securely and efficiently at the customer's site.
In another, directly adjacent part of the building, additional space for the technical departments will be created starting in 2016.
For related articles, news, and equipment reviews, visit our Equipment Zones
Click here for a List of Equipment Manufacturers


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In the presence of State Water Resources Minister Shri Devineni Uma Maheshwara Rao, the Water Resources Minister joined the TDP at the office of the District Water Resources Minister Narasimha Rao, the Vice-President of the K. Kododar Mandal and about 50 activists from various parties.
All the people who come together for the development of the state are enthusiastically inviting the Chief Minister, Mr. Chandrababu, who is continuing to carry out the difficult state of the country, needs to be with us. Those who joined the party were businessman Pazhara Nangaleleswarar Rao, Vinay Kumar, Raja, Venkateswara Rao, Yingugula Narendra, Ravi Babu, Jawwadi Sambasivava Rao, Tholleti Kondarreddi, Vaidur Narendra, Bhora Chandrasekhar and Small Ramesh Yadav. He said the members of the government, Chief Minister Nara Chandrababu Naidu and the MLAs and MLAs of the locality, had seen the developments in the development of the Umamaheswara Rao.


text:
Woman arrested for lying about attempted kidnapping | Crime
Woman arrested for lying about attempted kidnapping
Wednesday, September 19th, 2012, 5:26am
Topics: Crime, News
LILBURN, Ga. -- A Lilburn woman was arrested Monday for making up a story about an attempted kidnapping and telling it to police.
Pamela Ann Strong is being held in the Gwinnett County Jail. She has been charged with false report of a crime, according to jail records.
Strong broke down in sobs when she appeared before a Gwinnett County Magistrate Judge Tuesday morning.
Lilburn Police spokesman Capt. Ben Haynes said Strong told investigators she saw a man attempt to kidnap a child from Park Avenue Thrift on Aug. 30.
Investigators interviewed Strong for a second time on Sept. 14, when she admitted that she made up the story, Haynes said.
Strong told police that she made up the story because she was upset that the child's parents were not supervising him while he looked at toys in the thrift store, according to Haynes.
Josh Evans said Strong approached him in the store and told him a man tried to lure his 3-year-old son Erik away with money.
"The child was real close to me, about 10 feet behind, but I had my back turned," Evans told 11Alive News after learning of Strong's arrest. "I couldn't see what was going on. He should have been with me."
Evans said he's not angry at Strong, but is shocked by what she did.
"She wasted police time, she frightened a lot of people in the community and I'm just concerned that she foolishly did all that," he said.
Strong identified a man on store surveillance video, and police circulated the photo to the Atlanta news media.
"I'd like to say sorry to the guy that was on the video because he's caught a bad rap from it and he had nothing to do with it," Evans said.
Police were never able to identify the man.
"This is a serious offense. The department spent several man hours trying to locate this suspect," Capt. Haynes said in a statement. "The department takes these types of reports extremely serious, and when this was initially reported, other investigations were dropped to focus on this one. To later find out this was a fabricated story is extremely disappointing."


Transference, the new VR game from SpectreVision, which comes out next spring, is gathering some impressive acknowledgements. It's been nominated for Best VR Game for the Game Critics Awards, and was voted the Best Rift Game of the recent E3 convention. Congratulations!
:: Here's an interview with Daniel Noah about the mind-bending game that is Transference, and one person's actual experience playing the game.
:: Shooting is still taking place on Dirk Gently and a few more behind the scenes photos have been added.
:: Here is a snippet from an earlier issue of Rogue Magazine where Max Landis and Samuel Barnett talk about the audition with Elijah.
Max: One of my favorite memories of you is during the audition process, when you came to LA and you and Elijah had that struggle. Do you remember that?
Sam: Oh my God, yeah! I didn't know Elijah at all at that point. He was throwing himself about and at one point I pushed him and he fell really hard backwards into the door and I thought, "Oh my God. I've broken Elijah Wood." I didn't know that's what he does, that he throws himself around and never gets hurt, like a bouncing ball! I had no idea. I thought I pushed him too hard and hurt him. But he has freakish upper body strength.
Max: He's quite charming and easy to work with, watching you guys was just very inspiring for me.
:: And it looks like Dirk Gently, in some form will be at San Diego ComicCon on July 21st and 22nd! Just waiting on an official, bona fide, legitimate announcement.
While Elijah and the crew are still tucked away in Vancouver shooting, there are a couple of new announcements. First, Nicolas Cage is slated to star in a new thriller called Mandy and will be produced by SpectreVision. Oscar nominee and SpectreVision client, Johann Johannsson will command the score. XYZ Films, the same folks who brought us the wonderful I Don't Feel At Home in this World Anymore, will split the production duties. Click to read more about the premise and filming.
:: And secondly, SpectreVision's first collaboration with Ubisoft was announced during the Electronic Entertainment Expo also known as E3. Billed as, Transference, the new psychological thriller VR game is said to be quite mind-altering that will linger long after the experience. Check out the video on what's being said about it here and get a sneak peak in the trailer.


text:
Bring back the Yorkshire dialect - 'A reet gradely idea'
A DAUGHTER wants to revive interest in Yorkshire dialect through her late father's work.
Golcar man William Beaumont wrote poetry and prose in the Yorkshire dialect.
His 57-year-old daughter, Katharine, wants a new generation to appreciate his writing.
She said: "I would like my father's work to be promoted because the Yorkshire dialect is important to this area."
William, who died in 1976 aged 58, was a regular contributor to the Examiner and was best known for his series Yar Joe Willie and Throng as Thropp's Wife.
Katharine said: "He talked to people all the time and he wrote about local life. He was an intelligent man, but he never lost contact with the common man."
William also wrote books of poetry, such as Ben Briggs and Other Rhymes, which was published in 1972.
Katharine said: "He didn't believe in making money from his creative activities so the books were sold at cost price."
Katharine, who lives in Golcar, thinks his work is of interest to modern readers.
She said: "I think most of the dialect is easily understandable, it's not obscure. I think people in Yorkshire are beginning to re-discover their past.
"There was a strong pull towards multi-culturalism in the 1960s and 70s which drew us away from what Yorkshire is all about.
"It's very important to remember why Yorkshire, with its textile industry, was the backbone of England."
William was born in Milnsbridge in 1917. He had his first poem printed in the Examiner in 1937.
After serving in the Middle East during the Second World War he settled in Golcar and worked as a teacher for Huddersfield Education Authority.
William and his wife Barbara had three daughters.
Katharine promised her mother before she died last year that she would promote her father's writing.
She said: "My mother had Alzheimer's but, before it got really bad, she used to take my hand and say 'promise me you will do something for your father's work'. I promised my mum I would do my very best.
"My mum was the linchpin. She encouraged him to get an education and become a teacher and a writer. She was a wonderful woman."
Some of William's work, including the book Tales of Moortop, is available in libraries in Kirklees.
Milnsbridge


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So here we are again, presenting our year-end Q&A issue. It seems like just yesterday that we started publishing Camp Business (we're actually in our sixth year).
Yeah. I know. The "seems like yesterday" line is a bit of a cliché, but danged if it isn't too true! It's scary true.
I'll never forget sitting at in a Chevy's Mexican Restaurant in Aurora, Colo., with a newborn son sitting in a car seat on top of the table, blissfully asleep, while I took the "seems like yesterday" cliché into the future.
"You know," I said to my wife as we waited for our waiter. "Next thing you know he'll be asking for the keys to the car."
"Don't say that," my wife retorted. "We'll be (a pause while she does the math in her head, drumming the years on her fingers on the table)… 44!"
Oh, the horror! Our lives flashed before our eyes, and we quickly ordered a bucket of Pacifico.
Now we're about halfway there. Well, more than halfway, as that once tiny infant is now almost nine years of rumbling, stumbling boy.
I suppose there's nothing you can do about time. I also suppose you could fight it every inch of the way, but with every inch you gain, you lose two. So I figure, you might as well enjoy it while you got it, and not fret it so much. And, oh, if I could only take my own seemingly simple advice!
I don't want to trivialize anything any of us do, but we might as well have a good time doing. Doesn't mean it'll be easy, or not challenging at all. But, in fact, we ought to relish challenges. Why do we play sports and games anyway? Is it because it's easy to win? I don't think so.
So we're inviting you to join us next year at our interactive, hands-on training event, LIVE!, Sept. 19-20, at Deer Creek Resort & Conference Center, just 20 miles or so southeast of Columbus, Ohio. Building on this past year's excellent event (see Camp Business, November, page 22 for a full recap), we're putting together one heckuva training opportunity.
We're putting the final touches on two days of relevant, helpful and fun presentations, plus other events and activities, to ensure an event that reaps lasting benefits for your camp. We'll keep you regularly updated here and on the Web site at www.northstarpubs.com/LIVEmain.html.
But why tell you about it now? Space is limited, and we're already getting close to capacity, so make sure you get in before it fills up. You know that time has a funny way of getting by too quickly.
Please let me know if you have any questions or suggestions regarding LIVE!, and the magazine in general.


text:
Q: Kafka/Confluent: ProducerConfig change default max.request.size using docker images I'm using kafka/confluent (3.2.0) to retrive change on a Mongodb instances we have.
The source process is managed by Debezium source connector who uses Source Connect  Api and is deployed on our systems using Mesos (DC/OS) expanding the Confluent Connect docker image.
Kafka itself is deployed on the same DC/OS using the framework version.
Since we've some message bigger than default size I've changed these kafka installation parameters:
•   replica.fetch.max.bytes
•   message.max.bytes
both to 4MB.
Then I start the Connector Docker image using this
docker run -d --rm --net=bridge --name=kafka-connect-mongodb -e CONNECT_BOOTSTRAP_SERVERS=${KAFKA_BOOTSTRAP_SERVERS} -e CONNECT_REST_PORT=${CONNECT_REST_PORT}  -e CONNECT_GROUP_ID="mongo-to-kafka-source-connector" -e CONNECT_CONFIG_STORAGE_TOPIC="${CONFIG.TOPIC}"  -e CONNECT_OFFSET_STORAGE_TOPIC="${OFFSETS.TOPIC}"   -e CONNECT_STATUS_STORAGE_TOPIC="${STATUS.TOPIC}"   -e CONNECT_KEY_CONVERTER="io.confluent.connect.avro.AvroConverter"   -e CONNECT_VALUE_CONVERTER="io.confluent.connect.avro.AvroConverter"   -e CONNECT_KEY_CONVERTER_SCHEMA_REGISTRY_URL="${SCHEMA_REGISTRY_LISTENERS}"   -e CONNECT_VALUE_CONVERTER_SCHEMA_REGISTRY_URL="${SCHEMA_REGISTRY_LISTENERS}"   -e CONNECT_INTERNAL_KEY_CONVERTER="org.apache.kafka.connect.json.JsonConverter"   -e CONNECT_INTERNAL_VALUE_CONVERTER="org.apache.kafka.connect.json.JsonConverter"   -e CONNECT_REST_ADVERTISED_HOST_NAME="${CONNECTOR_HOME}"   -e CONNECT_LOG4J_ROOT_LOGLEVEL=INFO  -e CONNECT_MAX_REQUEST_SIZE=4194304 -e KAFKA_MAX_REQUEST_SIZE=4194304  mongodb-source-connector:1.1

I changed the default max.request.size producer value passing both KAFKA_MAX_REQUEST_SIZE and CONNECT_MAX_REQUEST_SIZE and the log was properly changed to 4MB.
The issue arises when I start the extraction from Mongodb.
To do so i run this POST
curl -X POST \
http://hostname:8083/connectors \
  -d '{
  "name": "source_connector",
  "config": {
    "tasks.max":"1",
    "connector.class": "io.debezium.connector.mongodb.MongoDbConnector",
    "mongodb.hosts": "mongodbhost:27017",
    "mongodb.name": "replica",
    "collection.whitelist": "db[.]table",
    "max.request.size": "4194304"
  }
}'

but then the log says
[2017-10-09 12:22:56,036] INFO ProducerConfig values:
    acks = all
    batch.size = 16384
    block.on.buffer.full = false
    bootstrap.servers = [PLAINTEXT://172.17.0.3:9093]
    buffer.memory = 33554432
    client.id =
    compression.type = none
    connections.max.idle.ms = 540000
    interceptor.classes = null
    key.serializer = class org.apache.kafka.common.serialization.ByteArraySerializer
    linger.ms = 0
    max.block.ms = 9223372036854775807
    max.in.flight.requests.per.connection = 1
    max.request.size = 1048576
    metadata.fetch.timeout.ms = 60000
    metadata.max.age.ms = 300000
    metric.reporters = []
    metrics.num.samples = 2
    metrics.sample.window.ms = 30000
    partitioner.class = class org.apache.kafka.clients.producer.internals.DefaultPartitioner
    receive.buffer.bytes = 32768
    reconnect.backoff.ms = 50
    request.timeout.ms = 2147483647
    retries = 2147483647
    retry.backoff.ms = 100
    sasl.jaas.config = null
    sasl.kerberos.kinit.cmd = /usr/bin/kinit
    sasl.kerberos.min.time.before.relogin = 60000
    sasl.kerberos.service.name = null
    sasl.kerberos.ticket.renew.jitter = 0.05
    sasl.kerberos.ticket.renew.window.factor = 0.8
    sasl.mechanism = GSSAPI
    security.protocol = PLAINTEXT
    send.buffer.bytes = 131072
    ssl.cipher.suites = null
    ssl.enabled.protocols = [TLSv1.2, TLSv1.1, TLSv1]
    ssl.endpoint.identification.algorithm = null
    ssl.key.password = null
    ssl.keymanager.algorithm = SunX509
    ssl.keystore.location = null
    ssl.keystore.password = null
    ssl.keystore.type = JKS
    ssl.protocol = TLS
    ssl.provider = null
    ssl.secure.random.implementation = null
    ssl.trustmanager.algorithm = PKIX
    ssl.truststore.location = null
    ssl.truststore.password = null
    ssl.truststore.type = JKS
    timeout.ms = 30000
    value.serializer = class org.apache.kafka.common.serialization.ByteArraySerializer

So when i start the source process, the default value for max.request.size is used.
Here the full log.
I don't undestand what i miss.

A: the IRC chat helped me:
i had to specify both
KAFKA_PRODUCER_MAX_REQUEST_SIZE
and
CONNECT_PRODUCER_MAX_REQUEST_SIZE
while starting the docker image.

redpajama_set_name: RedPajamaStackExchange


text:
How to Ease the Trauma of Employee Layoffs
10 Trends in Employee Recognition
10 Tips for Business Leaders Hiring a Business Coach
Changing How You Communicate as a Mentor to Get Desired…
Tips for Mentors: Choosing Words that Could, Should, Might Make…
Human Resources Kit For Dummies, 3rd Edition
By Max Messmer
Layoffs differ from firings in a variety of ways, but one critical aspect comes to mind: The people being let go haven't necessarily done anything to warrant losing their jobs. Layoffs occur for a number of reasons, which can include
Seasonal shifts in the demand for the company's products or services
An unexpected business downturn that requires the company to make drastic cost reductions
A plant or company closure
An initiative that restructures work practices, leaving fewer jobs
A merger or acquisition that produces redundancy in certain positions
Whatever the reason for a layoff, the pressure on the HR function is the same. You need to help your company navigate this difficult turn of events with as few long-term repercussions as possible.
How to ease the burden on laid off employees
It is in your company's long-term best interests to do whatever is reasonably possible and fiscally responsible to ease both the financial and psychological pain that layoffs invariably create. You may want to consider offering severance packages (you may have a written policy or practice obligating you to do so). Most employers offering severance benefits require a release of legal claims from the employee in exchange for the separation benefits.
You can take additional steps — for example, help in résumé writing, financial planning, networking, and so on — that won't cost you much money but will, nonetheless, help employees get back on their feet again.
How to offer outplacement services for laid off employees
Outplacement firms are companies that specialize in helping dismissed employees (usually middle managers and above) move through the transition and find new employment. In a typical outplacement program, managers who've been let go get an opportunity to attend seminars or one-on-one sessions in such areas as career counseling, professional goal setting, and job-hunting basics (preparing effective résumés, networking, interviewing, and so on).
Outplacement, which is paid for by the former employer, can get expensive, particularly if your company is dealing with large numbers of dismissed managers. But it's one of the best ways to help those managers who've been with your company a long time and need the support.
In major companies that conduct large-scale layoffs, outplacement services tend to be the rule, not the exception. Also, outplacement firms offer varying levels of services. It may be beneficial to offer at least a basic set of services to displaced employees versus none at all.
How to address the concern of remaining employees
Layoffs are traumatic not only for the people who are laid off but also for those who remain. Apart from the sympathy they may feel for colleagues, remaining workers must generally take on increased workloads. Regrouping after layoffs as quickly and effectively as possible and giving your new, smaller staff a renewed sense of purpose and opportunity is key to your future.
If, at some point, your company finds it necessary to conduct layoffs, keep the following pointers in mind:
Honest, open communication is critical. What you don't say to employees can be as disconcerting and worrisome as what you do say. It's important for managers to have team meetings very soon after layoffs have occurred, not to explain what's taken place, set goals, clarify roles, and, most of all, genuinely listen to concerns.
Treat employees as professionals. Explain why the layoffs were necessary, why current staff members were chosen to stay on, and what you're expecting from them in the future. Make employees aware that their contributions are now more essential to the company's continued success than ever before.
Focus on the future. You'll need to clearly explain why downsizing was an unavoidable move for your company. But instead of focusing too much on what employees have lost in terms of colleagues, focus on what they're gaining in terms of a stronger, more stable company.
Consult a staffing firm. Just as staffing services can help your displaced employees find new work, they also can help you bring in skilled supplemental workers to maintain continuity and prevent burnout on the part of remaining full-time staff.


text:
Lithurgical Ministry
Cathedral Calendar
2020-2021 9:30 Mass Anthem Repertoire
Cathedral St Louis
Wedding Worship Recordings
Cathedral Star Newsletter
Childen's Formation
First Penance
Daily Lunch Program
Haiti News
Parish Twinning Project
St Therese Construction
Congolese Family
Archdiocesan History Center
Audio Tour
The Cathedral sponsors a variety of both choral and instrumental concerts. Past choral performances have included the Louisville Orchestra, the Rose Ensemble, the Chattanooga Boys Choir, Liber unUsualis, the Mainz Cathedral Domchor, and the Westminster Choir. The series also includes the Kelty Endowed Organ Recitals which have brought a wonderfully eclectic representation of national and international organists to the Greater Louisville Community.
Dr. Philip Brisson, Director of Music, (502) 582-2971 Ext. 5220
or pbrisson@cathedraloftheassumption.org.
Click here for the 2020-2021 Music at the Cathedral Brochure
2020-2021 Cathedral Concert Series
All concerts are subject to cancellation due to the COVID-19 Virus.
Please check the Cathedral website
to confirm that the concert will take place.
Friday, October 23, 2020 at 7:00 PM
Fr. Pedro Sanchez: Kelty Organ Recital
Organist, Monastery of El Escorial
Reverend Pedro Alberto Sánchez, OSA Bio
Reverend Pedro Alberto Sánchez, OSA
Reverend Pedro Alberto Sánchez OSA was born in Salamanca, Spain. His earliest music training was as a member of the famous boys' choir at the Real Monasterio de San Lorenzo de El Escorial, and he studied in the music conservatory of Madrid "Arturo Soria", where he graduated with the degree of Organ Professor. He then moved to Rome to attend the well-known Conservatorio Santa Cecilia, specialising in organ and composition under the tutelage of such masters as Ottorino Baldassarri, Jiri Lecjian and Federico del Sordo; he was also a member of the Schola at Saint Peter's Basilica. He later continued his studies at the Pontificio Instituto de Música Sacra in Rome where he specialised in Gregorian chant and improvisation. Father Sánchez received a Master's Degree in Organ Pedagogy from the Real Conservatorio Superior de Musica in Madrid, where his mentor was Dr D. Miguel Bernal Ripol. He has performed organ concerts in Spain, Mexico, Poland, Switzerland, Italy, Panama, Belgium and the United States of America. Father Sánchez is a priest of the Augustinian order, having pursued his religious studies at the Estudios Eclesiásticos por la Universidad Pontificia de Salamanca and Pontifical University of Saint Thomas Aquinas in Rome (Canon Law). He holds the positions of Music Director and Organist at the Real Monasterio del Escorial and Director of the Semana Internacional de Organo de Madrid.
Friday, December 18 at 7:30 PM
Advent Lessons and Carols
The Cathedral Choir and Cathedral Singers join together to mix traditional and contemporary music styles with Advent readings in order to prepare for the joyful season of Christmas.
Dr. Philip Brisson, Director and Organist
Friday, January 22 at 7:30 PM
Louisville Three Choirs Festival Concert
at St. Martin of Tours RC Church
Shawn Dawson, Emily Meixner and Philip Brisson
The choirs of Calvary Episcopal Church, St. Martin of Tours RC Church, and the Catholic Cathedral of the Assumption join together to celebrate the new year with joyful music.
Friday, April 3 at 7:30 PM
Lenten Service:
Dupré/Claudel Stations of the Cross
Dr. Philip Brisson – Organ
Dr. William P. Bradford II – Reader
Friday, April 16, 2021 at 7:30 PM
Levente Kuzma: Kelty Organ Recital
Professor of Organ, University of Szeged
Levente Kuzma Bio
Levente Kuzma
Levente Kuzma was born in Gothenburg, Sweden. He started taking piano lessons at early age with his father, who also played organ, Robert Kuzma. He holds a Bachelor's Degree in Music Education, as well as two Master's Degrees in Organ Performance and Organ Pedagogy from University of Szeged. Levente is also holder of the "Method and Art of Zoltán Kodály" certification. Mr. Kuzma has participated in masterclasses with Jacques van Oortmerssen and Joris Verden at the Göteborg International Organ Academy (GIOA).
He won prizes in numerous organ competitions, including Organi Storici del Basso Friuli in Muzzana del Turgnano in 2009, International Organ Competition Vicenza in 2010, and The Alexander Goedicke International Organ Competition in Moscow in 2011. He earned 1st place in the "Timorgelfest" International Organ Competition Timisoara (Romania) in 2009.
Mr. Kuzma appeared as a featured artist at notable venues including St. Andrew Holborn Church in London, the Great Hall of the Tchaikovsky Conservatory in Moscow, Oliwa Cathedral in Gdansk, Liebfrauenmünster in Ingolstadt, Turku Cathedral in Finland, the Béla Bartók National Concert Hall in Budapest and the St. Mungo's Cathedral in Glasgow.
He has performed with the Hungarian National Orhestra, the Szeged Symphony Orchestra, and the Filarmonica Banatul Timisoara. His repertoire reaches from the Rennaissance to the 21st century, including world premiere performances of hungarian composers. In 2013 he made his US debut at Saint Andrew Catholic Church in Newtown, PA.
In November 2019, Mr. Kuzma launched the sixth edition of the Terra Sancta Organ Festival in the Holy Land with solo recitals in Israel and Palestine at the St. Peter's Church (Tel-Aviv-Jaffo), Basilica of the Annunciation (Nazareth), St. Saviour Monestary (Jerusalem) and St. Catherine Church/Nativity (Bethlehem/Palestine).
Levente Kuzma currently the professor of organ at the University of Szeged Béla Bartók Faculty of Arts, serves as music director at the Piarist Church in Szeged and also serves as principal of "Lieto" School of Music and Arts. Since September 2018, Mr. Kuzma is the Artistic Director of the Cathedral Concert Series at the Cathedral of Our Lady in Szeged.
His debut solo album, Masterworks, was released in 2017 on the Waltman's Artists (UK)
Saturday, May 15, 2021 at 7 PM
Philip Brisson: Kelty Organ Recital
Organist, Cathedral of the Assumption
Philip Brisson Bio
Dr. Philip Brisson is Director of Music and Organist at the Catholic Cathedral of the Assumption in downtown Louisville, the third oldest Catholic Cathedral in the country. In addition to leading the Cathedral's worship program, he also manages the Cathedral's Concert Series, which includes the Kelty Endowed Organ Recitals which have further recognized the Cathedral for not only musical excellence in liturgy but also for outstanding concerts in the Louisville community. Philip has led the Cathedral Choir on international concert tours to England, Ireland, Germany, and Austria. Recently, the choir traveled to Washington DC for performances in the Arlington area and at the National Shrine. Locally, the Cathedral Choirs have performed with the Louisville Orchestra, have been featured on television, and have appeared annually for concerts in collaboration with Louisville's Christ Church Episcopal Cathedral and Calvary Episcopal Church under the title "Louisville's Three Choirs Festival." Recent solo performing experiences have included being "Organist in Residence" at Christ Church Cathedral in Oxford, England; appearing on the L'Organo Recital Series at the Piccolo Spoleto Festival in Charleston, SC; and concertizing in Hasselt, Belgium and Rome, Italy.
Dr. Brisson was instrumental in the founding of the Louisville Master Chorale, a premier chorale ensemble which performs the great chorale literature with orchestra in local churches throughout the Louisville area, where he was Organist and Associate Director for its first five years. Prior to his work with the LMC, he was Chorus Master for the Kentucky Opera and prepared choruses for performances which included Puccini's Turandot and Madame Butterfly, Verdi's La Traviata, Il Trovatore and Otello, Poulenc's Dialogues of the Carmelites, Saint-Saëns' Samson et Dalila, Sullivan's Pirates of Penzance, Massenet's Werther, Floyd's Of Mice and Men, Humperdinck's Hansel and Gretel, Leoncavallo's I Pagliacci, Mascagni's Cavalleria Rusticana, Tchaikovsky's Iolanta, and Donizetti's L'elisir d'Amore.
As an organ soloist, he has given recitals in all 50 states. He has appeared with the Lexington Philharmonic, the Oratorio Society of Queens, and with the Louisville Orchestra as guest soloist performing the Saint-Saëns Organ Symphony with Raymond Leppard conducting. In the summer of 2011, Philip was also a featured performer for the Region V AGO Convention in Lexington, KY and the NPM National Convention in Louisville, KY.
As a teacher, Dr. Brisson served on the faculty of Bellarmine University where he taught organ performance and a Church Music Internship at the Cathedral. Until taking over the Kentucky Opera Chorus, he oversaw the choral program at Indiana University Southeast, where he conducted the Concert Choir, the Community Chorus, and taught choral conducting. He has also presented workshops to the American Guild of Organists and to the National Association of Pastoral Musicians at both the regional and national level.
Originally from New York City, Philip received his BM in Organ Performance from the Aaron Copland School of Music at Queens College, CUNY. While at Queens, he studied organ and conducting with Paul Maynard, the former director of the New York Pro Musica. After being accepted into graduate organ performance programs at Juilliard, Indiana, and Michigan, Philip decided to attend Westminster Choir College in Princeton, New Jersey, where he earned a Masters in Sacred Music. While at Westminster, he studied organ with Robert Carwithen and choral conducting with Allen Crowell. He was also fortunate to regularly sing under Joseph Flummerfelt in the Westminster Symphonic Choir which performed Stravinsky's Symphony of Psalms with the Los Angeles Philharmonic, conducted by Esa-Pekka Salonen and Hindemith's Requiem with the Philadelphia Orchestra, conducted by Wolfgang Sawallisch. In 2005, Philip earned a Doctorate in Organ Performance from the Eastman School of Music in Rochester, New York, where he studied organ with David Higgs and received a choral conducting minor while studying conducting with William Weinert.
Philip Brisson is active in the American Guild of Organists, has served on the Louisville Chapter's Executive Committee and has held both the Sub-Dean and Dean positions for the Guild. He is also the National Association of Pastoral Musicians Organist Liaison for the Louisville Archdiocese, has served as Membership Chairman of the Roman Catholic Conference of Cathedral Musicians, and is a member of The Honorable Order of Kentucky Colonels. Dr. Brisson also founded the concert artist cooperative EastWestOrganists.com, which represents several prominent young American organists in the United States. Philip, his wife, and their eight-year-old daughter reside in Old Louisville, the nation's largest Victorian Historic District.
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Cathedral of the Assumption | 433 S. Fifth Street Louisville, KY 40202 | (502) 582-2971
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In the industrial athletic training setting, one of the more common injuries or conditions that I come across is carpal tunnel syndrome. This can certainly be a challenge to treat. One stretch that can be added to your arsenal in treating this, and other upper extremity injuries for that matter, is a stretch of the brachial plexus.
One little success story to share with you (results not guaranteed) involved a woman with chronic CTS. Her symptoms had been at a relatively dull roar for a while until she started experiencing increased numbness and tingling that were not going away. The symptoms were probably present for a couple of weeks and when I finally showed her this stretch. Her symptoms were gone within a day and she continues to implement this stretch in her normal stretching routine.
Again – taking in the total context – this may be a stretch that you can implement as part of your treatment regime. This stretch is also certainly not just limited to CTS sufferers. This can be used with general upper extremity tightness and more. As always, exercise care when instructing your patients of this stretch and be mindful of any situations that may cause this stretch to be not used in the first place or discontinued.
A couple final thoughts. As you can see from the picture, a small swiss ball was used. I like using the ball because it gives the patient a little flexibility in how they position the hand in order to get the best stretch. The ball provides a little more alterationability (if that's a word) than using the wall as an anchor. A patient can simply use a ball from around the house to replicate this stretch at home. If they don't have a ball, try a plastic mixing bowl and placing this against the wall. This will give a similar effect.
Make sure to keep the shoulder at "shoulder level" or lower so as not to aggravate the shoulder or any additional conditions.
Finally, you'll notice in the picture that I am turing away from the wall. This again is a tweak to the stretch that will allow you to feel this stretch a little bit more. Turn away as much or as little as you wish in order to customize this stretch to personal preference.
Quite honestly this was not a "standard stretch" that I always gave to CTS patients (although one may argue it should have been). The point is – I tried this out one day thinking that it may benefit the patient and sure enough it did. This stretch and others for that matter won't benefit you gathering dust in the bottom of your "toolbox". Give it a try – you might be pleased with the results.