RESUMO
We discuss new effects related to relativistic aberration, which is the apparent distortion of objects moving at relativistic speeds relative to an idealized camera. Our analysis assumes that the camera lens is capable of stigmatic imaging of objects at rest with respect to the camera, and that each point on the shutter surface is transparent for one instant, but different points are not necessarily transparent synchronously. We pay special attention to the placement of the shutter. First, we find that a wide aperture requires the shutter to be placed in the detector plane to enable stigmatic images. Second, a Lorentz-transformation window [Proc. SPIE9193, 91931K (2014)PSISDG0277-786X10.1117/12.2061415] can correct for relativistic distortion. We illustrate our results, which are significant for future spaceships, with raytracing simulations.
RESUMO
BACKGROUND: Heart failure is associated with reversal to a fetal gene expression pattern of contractile and metabolic genes. Substantial recovery of ventricular function with assist devices is rare. Our goal was to evaluate the effects of assist devices on fetal gene expression and hypoxia inducible factor-1 alpha (HIF-1 alpha), a transcriptional factor in hypoxic signaling. METHODS: Human heart tissue was obtained from the left ventricular apex at the time of assist device implantation and again from the left ventricular free wall during cardiac transplantation. Non-failing tissue was obtained from unused hearts from human donors. Gene expression was measured with the Affymetrix 133 plus 2 Array. HIF-1 alpha was measured by Western blotting with commercially available antibodies. RESULTS: Heart failure was associated with a decrease in alpha-myosin heavy chain and sarcoplasmic reticulum-Ca(2+) adenosine triphosphatase messenger RNA expression along with an increase in skeletal tropomyosin. This pattern persisted after assist device therapy. Heart failure was also associated with abnormalities in regulatory metabolic genes including glucose transporter 1 (GLUT1). These patterns also persisted after assist device therapy despite a reduction in atrial natriuretic peptide expression and normalization of HIF-1 alpha. CONCLUSIONS: Failure of assist devices to produce sustained recovery of myocardial contractile function may be due in part to persistent fetal transcriptional patterns of contractile and metabolic genes.
Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Perfilação da Expressão Gênica , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/terapia , Coração Auxiliar , Contração Miocárdica/genética , Adulto , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Regulação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Insuficiência Cardíaca/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Tropomiosina/genética , Tropomiosina/metabolismoRESUMO
Cycloxygenase (COX) pathways have long been targeted for the treatment of inflammatory pain, initially through the use of NSAIDs. With the demonstration of two major COX isoforms, COX-1 and COX-2, involved in the production of prostanoids, but with different distribution and regulation, selective COX-2 inhibitors have been developed. This review covers factors influencing COX enzyme activity, the role of their products in the development and maintenance of pain and discusses recent safety concerns of COX-2 inhibitors.
Assuntos
Ciclo-Oxigenase 1/metabolismo , Inibidores de Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/fisiologia , Dor/enzimologia , Transdução de Sinais , Sítios de Ligação , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/normas , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Humanos , Modelos Biológicos , Estrutura Molecular , Nociceptores/fisiologia , Dor/tratamento farmacológico , Dor/etiologia , Isoformas de Proteínas , Estrutura Terciária de ProteínaRESUMO
Although heart transplantation remains the gold standard for patients who remain in advanced heart failure despite optimal medical therapy, limited donor supplies allows for just >2000 transplant each year in the United States. Recent enthusiasm has developed for the role of mechanical circulatory support for this ever-growing population of sick patients. Although much attention has been directed toward ventricular assist devices, less information is available regarding the role of the total artificial heart. Indeed, efforts in this latter technology have allowed the relatively recent deployment of a variety of complete circulatory assist devices. The purpose of this article is to review the historical development, current use, and future role of total artificial hearts.
Assuntos
Insuficiência Cardíaca/cirurgia , Coração Artificial , Disfunção Ventricular Esquerda/cirurgia , Efeitos Psicossociais da Doença , Fontes de Energia Elétrica , Insuficiência Cardíaca/economia , Coração Artificial/economia , Coração Artificial/história , Coração Auxiliar , História do Século XX , Humanos , Desenho de Prótese , Falha de Prótese , Resultado do Tratamento , Estados Unidos , Disfunção Ventricular Esquerda/economiaRESUMO
OBJECTIVE: To describe the Western and South Australian response to the Boxing Day tsunami disaster in Aceh, Indonesia. METHOD: Reports from three of the responders. RESULTS: Comment has been made on organising a response, the first team to Banda Aceh, the second team to Banda Aceh, and lessons learned. CONCLUSIONS: These experiences have identified areas in which we could be better prepared for the next international disaster response.
Assuntos
Desastres , Serviços Médicos de Emergência/organização & administração , Socorro em Desastres/organização & administração , Atitude do Pessoal de Saúde , Planejamento em Desastres/métodos , Humanos , Indonésia , Cooperação Internacional , Austrália do Sul , Austrália OcidentalRESUMO
A recombinant vaccinia virus, expressing the NS3-to-NS5 region of the N clone of hepatitis C virus (HCV), was generated and utilized both in a gel-based assay and in an enzyme-linked immunosorbent assay (ELISA) to evaluate the pyrrolidine-5,5-trans-lactams, a series of inhibitors of the HCV NS3/4A protease. The absolute levels of processed, mature HCV nonstructural proteins in this system were found to decrease in the presence of the trans-lactams. Monitoring of this reduction enabled end points and 50% inhibitory concentrations to be calculated in order to rank the active compounds according to potency. These compounds had no effect on the transcription or translation of the NS3-5 polyprotein at concentrations shown to inhibit NS3/4A protease, and they were shown to be specific inhibitors of this protease. The ELISA, originally developed using the vaccinia virus expression system, was modified to utilize Huh-7 cells containing an HCV replicon. Results with this assay correlated well with those obtained with the recombinant vaccinia virus assays. These results demonstrate the utility of these assays for the characterization of NS3/4A protease inhibitors. In addition, inhibitors of other viral targets, such as polymerase and helicase, can be evaluated in the context of the replicon ELISA.
Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Lactamas/farmacologia , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Linhagem Celular , Chlorocebus aethiops , Ensaio de Imunoadsorção Enzimática , Hepacivirus/enzimologia , Humanos , Lactamas/química , Testes de Sensibilidade Microbiana/métodos , Replicon , Vaccinia virus/enzimologia , Vaccinia virus/genética , Células Vero , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismoRESUMO
The pathogenic form of the cyclooxygenase (COX) enzyme, COX-2, is also constitutively present in the spinal cord and has been implicated in chronic pain states in rat and man. A number of COX-2 inhibitors, including celecoxib and rofecoxib, are already used in man for the treatment of inflammatory pain. Preclinically, the dual-acting COX-2 inhibitor, GW406381X [2-(4-ethoxyphenyl)-3-[4-(methylsulfonyl)phenyl]-pyrazolo[1,5-b]pyridazine, where X denotes the free base], is as effective as rofecoxib and celecoxib in the rat established Freund's Complete Adjuvant model with an ED(50) of 1.5 mg/kg p.o. compared with 1.0 mg/kg p.o. for rofecoxib and 6.6 mg/kg p.o. for celecoxib. However, in contrast to celecoxib (5 mg/kg p.o. b.i.d.) and rofecoxib (5 mg/kg p.o. b.i.d.), which were without significant effect, GW406381X (5 mg/kg p.o. b.i.d.) fully reversed mechanical allodynia in the chronic constriction injury model and reversed thermal hyperalgesia in the mouse partial ligation model, both models of neuropathic pain. GW406381X, was also effective in a rat model of capsaicin-induced central sensitization, when given intrathecally (ED(50) = 0.07 mug) and after chronic but not acute oral dosing. Celecoxib and rofecoxib had no effect in this model. Several hypotheses have been proposed to try to explain these differences in efficacy, including central nervous system penetration, enzyme kinetics, and potency. The novel finding of effectiveness of GW406381X in these models of neuropathic pain/central sensitization, in addition to activity in inflammatory pain models and together with its central efficacy, suggests dual activity of GW406381X compared with celecoxib and rofecoxib, which may translate into greater efficacy in a broader spectrum of pain states in the clinic.
Assuntos
Inibidores de Ciclo-Oxigenase/uso terapêutico , Hidrocarbonetos Aromáticos/uso terapêutico , Nitrogênio/uso terapêutico , Dor/tratamento farmacológico , Animais , Encéfalo/metabolismo , Células COS , Capsaicina , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Hidrocarbonetos Aromáticos/farmacocinética , Hiperalgesia/tratamento farmacológico , Masculino , Camundongos , Nitrogênio/farmacocinética , Pirazóis , Piridazinas , RatosRESUMO
The term "promiscuous" inhibitors has been coined for compounds whose inhibition mechanism involves the interaction of aggregates of many compound molecules with the target protein, rather than the binding of individual molecules. This paper demonstrates that promiscuous inhibitors can be differentiated from classical 1:1 inhibitors by the judicious use of detergents, making it possible to configure assays that significantly reduce this undesirable mechanism of inhibition without compromising assay performance.
Assuntos
Detergentes/química , Inibidores Enzimáticos/química , Inibidores de beta-Lactamases , Acetofenonas/química , Ampicilina/química , Benzopiranos/química , Ácidos Borônicos/química , Catálise , Vermelho Congo/química , Enterobacter cloacae/química , Indóis/química , Tiofenos/química , beta-Lactamases/químicaRESUMO
[reaction: see text] In this, the first of two letters, we outline the use of the pyrrolidine-5,5-trans-lactam template to design small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. The hitherto unreported reaction of the acyl iminium ion precursor 4 with dialkyl-substituted silyl ketene acetals (e.g., 8b) is described. Compound 12b, with a spirocyclobutyl P1 substituent and a cyclopropylacyl substituent on the lactam nitrogen, has a k(obs)/I of 400 M(-)(1) s(-)(1) and demonstrates activity in a replicon cell-based surrogate HCV assay.
Assuntos
Hepacivirus/enzimologia , Lactamas/síntese química , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Pirrolidinas/síntese química , Serina Endopeptidases/metabolismo , Proteínas não Estruturais Virais/antagonistas & inibidores , Linhagem Celular , Desenho de Fármacos , Estabilidade de Medicamentos , Hepacivirus/efeitos dos fármacos , Humanos , Lactamas/química , Estrutura Molecular , Inibidores de Proteases/química , Pirrolidinas/química , Proteínas não Estruturais Virais/metabolismoRESUMO
Using a pyrrolidine-5,5-trans-lactam template, we have designed small, neutral, mechanism-based inhibitors of hepatitis C NS3/4A protease. Compound 11a, with an alpha-ethyl P1 substituent and a Boc-valine substituent at the pyrrolidine nitrogen, has an IC(50)=30 microM.