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The importance of the atmospheric deposition of biologically essential trace elements, especially iron, is widely recognized, as are the difficulties of accurately quantifying the rates of trace element wet and dry deposition and their fractional solubility. This paper summarizes some of the recent progress in this field, particularly that driven by the GEOTRACES, and other, international research programmes. The utility and limitations of models used to estimate atmospheric deposition flux, for example, from the surface ocean distribution of tracers such as dissolved aluminium, are discussed and a relatively new technique for quantifying atmospheric deposition using the short-lived radionuclide beryllium-7 is highlighted. It is proposed that this field will advance more rapidly by using a multi-tracer approach, and that aerosol deposition models should be ground-truthed against observed aerosol concentration data. It is also important to improve our understanding of the mechanisms and rates that control the fractional solubility of these tracers. Aerosol provenance and chemistry (humidity, acidity and organic ligand characteristics) play important roles in governing tracer solubility. Many of these factors are likely to be influenced by changes in atmospheric composition in the future. Intercalibration exercises for aerosol chemistry and fractional solubility are an essential component of the GEOTRACES programme.This article is part of the themed issue 'Biological and climatic impacts of ocean trace element chemistry'.
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Deposition of continental mineral aerosols (dust) in the Eastern Tropical North Atlantic Ocean, between the coast of Africa and the Mid-Atlantic Ridge, was estimated using several strategies based on the measurement of aerosols, trace metals dissolved in seawater, particulate material filtered from the water column, particles collected by sediment traps and sediments. Most of the data used in this synthesis involve samples collected during US GEOTRACES expeditions in 2010 and 2011, although some results from the literature are also used. Dust deposition generated by a global model serves as a reference against which the results from each observational strategy are compared. Observation-based dust fluxes disagree with one another by as much as two orders of magnitude, although most of the methods produce results that are consistent with the reference model to within a factor of 5. The large range of estimates indicates that further work is needed to reduce uncertainties associated with each method before it can be applied routinely to map dust deposition to the ocean. Calculated dust deposition using observational strategies thought to have the smallest uncertainties is lower than the reference model by a factor of 2-5, suggesting that the model may overestimate dust deposition in our study area.This article is part of the themed issue 'Biological and climatic impacts of ocean trace element chemistry'.
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BACKGROUND: Two features of alcohol addiction that have been widely studied in animal models are relapse drinking following periods of alcohol abstinence and the escalation of alcohol consumption after chronic continuous or intermittent alcohol exposure. The genetic contribution to these phenotypes has not been systematically investigated. METHODS: HXB/BXH recombinant inbred (RI) rat strains were given access to alcohol sequentially as follows: alcohol (10%) as the only fluid for 1 week; alcohol (10%) and water in a 2-bottle choice paradigm for 7 weeks ("pre-alcohol deprivation effect [ADE] alcohol consumption"); 2 weeks of access to water only (alcohol deprivation); and 2 weeks of reaccess to 10% alcohol and water ("post-ADE alcohol consumption"). The periods of deprivation and reaccess to alcohol were repeated 3 times. The ADE was defined as the amount of alcohol consumed in the first 24 hours after deprivation minus the average daily amount of alcohol consumed in the week prior to deprivation. Heritability of the phenotypes was determined by analysis of variance, and quantitative trait loci (QTLs) were identified. RESULTS: All strains showed increased alcohol consumption, compared to the predeprivation period, in the first 24 hours after each deprivation (ADE). Broad-sense heritability of the ADEs was low (ADE1, 9.1%; ADE2, 26.2%; ADE3, 16.3%). Alcohol consumption levels were relatively stable over weeks 2 to 7. Post-ADE alcohol consumption levels consistently increased in some strains and were decreased or unchanged in others. Heritability of pre- and post-ADE alcohol consumption was high and increased over time (week 2, 38.5%; week 7, 51.1%; week 11, 56.8%; week 15, 63.3%). QTLs for pre- and post-ADE alcohol consumption were similar, but the strength of the QTL association with the phenotype decreased over time. CONCLUSIONS: In the HXB/BXH RI rat strains, genotypic variance does not account for a large proportion of phenotypic variance in the ADE phenotype (low heritability), suggesting a role of environmental factors. In contrast, a large proportion of the variance across the RI strains in pre- and post-ADE alcohol consumption is due to genetically determined variance (high heritability).
Assuntos
Consumo de Bebidas Alcoólicas/genética , Alcoolismo/genética , Característica Quantitativa Herdável , Ratos Endogâmicos , Consumo de Bebidas Alcoólicas/psicologia , Alcoolismo/psicologia , Animais , Comportamento Aditivo/genética , Comportamento Aditivo/psicologia , Comportamento de Escolha , Genótipo , Masculino , Fenótipo , Locos de Características Quantitativas/genética , Ratos , Especificidade da EspécieRESUMO
Anthrax lethal toxin (LT) is a bipartite protease-containing toxin and a key virulence determinant of Bacillus anthracis. In mice, LT causes the rapid lysis of macrophages isolated from certain inbred strains, but the correlation between murine macrophage sensitivity and mouse strain susceptibility to toxin challenge is poor. In rats, LT induces a rapid death in as little as 37 minutes through unknown mechanisms. We used a recombinant inbred (RI) rat panel of 19 strains generated from LT-sensitive and LT-resistant progenitors to map LT sensitivity in rats to a locus on chromosome 10 that includes the inflammasome NOD-like receptor (NLR) sensor, Nlrp1. This gene is the closest rat homolog of mouse Nlrp1b, which was previously shown to control murine macrophage sensitivity to LT. An absolute correlation between in vitro macrophage sensitivity to LT-induced lysis and animal susceptibility to the toxin was found for the 19 RI strains and 12 additional rat strains. Sequencing Nlrp1 from these strains identified five polymorphic alleles. Polymorphisms within the N-terminal 100 amino acids of the Nlrp1 protein were perfectly correlated with LT sensitivity. These data suggest that toxin-mediated lethality in rats as well as macrophage sensitivity in this animal model are controlled by a single locus on chromosome 10 that is likely to be the inflammasome NLR sensor, Nlrp1.
Assuntos
Antraz/genética , Antraz/mortalidade , Antígenos de Bactérias/metabolismo , Toxinas Bacterianas/metabolismo , Predisposição Genética para Doença , Proteínas do Tecido Nervoso/genética , Sequência de Aminoácidos , Animais , Antraz/imunologia , Células Cultivadas , Mapeamento Cromossômico , Cromossomos de Mamíferos , Modelos Animais de Doenças , Feminino , Fibroblastos/citologia , Macrófagos/imunologia , Macrófagos/microbiologia , Camundongos , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/imunologia , Estrutura Terciária de Proteína , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos Dahl , Ratos Endogâmicos F344 , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Ratos Sprague-DawleyRESUMO
The pelagic brown macroalgae Sargassum spp. have grown for centuries in oligotrophic waters of the North Atlantic Ocean supported by natural nutrient sources, such as excretions from associated fishes and invertebrates, upwelling, and N2 fixation. Using a unique historical baseline, we show that since the 1980s the tissue %N of Sargassum spp. has increased by 35%, while %P has decreased by 44%, resulting in a 111% increase in the N:P ratio (13:1 to 28:1) and increased P limitation. The highest %N and δ15N values occurred in coastal waters influenced by N-rich terrestrial runoff, while lower C:N and C:P ratios occurred in winter and spring during peak river discharges. These findings suggest that increased N availability is supporting blooms of Sargassum and turning a critical nursery habitat into harmful algal blooms with catastrophic impacts on coastal ecosystems, economies, and human health.
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Nitrogênio/análise , Nutrientes , Sargassum/química , Água do Mar/química , Animais , Oceano Atlântico , Biomassa , Ecossistema , Peixes , Proliferação Nociva de Algas , Biologia Marinha , Rios , Sargassum/crescimento & desenvolvimento , Alga MarinhaRESUMO
The localization and intracellular transport of major histocompatibility complex (MHC) class II molecules nd lysosomal hydrolases were studied in I-Cell Disease (ICD) B lymphoblasts, which possess a mannose 6-phosphate (Man-6-P)-independent targeting pathway for lysosomal enzymes. In the trans-Golgi network (TGN), MHC class II-invariant chain complexes colocalized with the lysosomal hydrolase cathepsin D in buds and vesicles that lacked markers of clathrin-coated vesicle-mediated transport. These vesicles fused with the endocytic pathway leading to the formation of "early" MHC class II-rich compartments (MIICs). Similar structures were observed in the TGN of normal beta lymphoblasts although they were less abundant. Metabolic labeling and subcellular fractionation experiments indicated that newly synthesized cathepsin D and MHC class II-invariant chain complexes enter a non-clathrin-coated vesicular structure after their passage through the TGN and segregation from the secretory pathway. These vesicles were also devoid of the cation-dependent mannose 6-phosphate (Man-6-P) receptor, a marker of early and late endosomes. These findings suggest that in ICD B lymphoblasts the majority of MHC class II molecules are transported directly from the TGN to "early" MIICs and that acid hydrolases cam be incorporated into MIICs simultaneously by a Man-6-P-independant process.
Assuntos
Linfócitos B/metabolismo , Compartimento Celular , Células-Tronco Hematopoéticas/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Mucolipidoses/metabolismo , Antígenos de Diferenciação de Linfócitos B/metabolismo , Linfócitos B/imunologia , Linfócitos B/ultraestrutura , Transporte Biológico , Catepsina D/isolamento & purificação , Catepsina D/metabolismo , Linhagem Celular , Clatrina/metabolismo , Vesículas Revestidas/metabolismo , Endocitose , Glicoproteínas/metabolismo , Complexo de Golgi/metabolismo , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/ultraestrutura , Antígenos de Histocompatibilidade Classe II/isolamento & purificação , Humanos , Membranas Intracelulares/química , Lisossomos/metabolismo , Mucolipidoses/imunologia , Pepsinogênios/metabolismoRESUMO
Intrathecal (IT) delivery of nicotinic agonists evokes dose dependent nocifensive behavior and cardiovascular responses. Previous studies suggested that these effects may be attenuated by the loss of substance P positive (sP(+)) primary afferents. To further characterize these cell systems, we examined the effect of selectively destroying neurokinin 1 receptor bearing (NK1-r(+)) dorsal horn neurons on IT nicotinic agonist evoked responses. In the dorsal spinal cord, confocal immunohistochemical microscopy revealed that nAChR subunits (alpha3, alpha4, alpha5, beta2 and beta4), NeuN B (neuronal marker) and NK1-r were all co-expressed in the superficial dorsal horn; however alpha3, alpha5, beta2 and beta4 exhibited the highest degree of colocalization with NK1-r expressing neurons. After intrathecal substance P-saporin (sP-SAP), NK1-r(+) cell bodies and dendrites in the superficial dorsal horn were largely abolished. The greatest loss in co-expression of nAChR subunits with NK1-r was observed with alpha3, alpha5, beta2 and beta4 subunits. Following intrathecal sP-SAP, the nocifensive responses to all nicotinic agonists were reduced; however, in contrast, while cardiovascular responses evoked by IT nicotine were unaltered, IT cytisine and epibatidine exhibited enhanced tachycardia and pressor responses. These results indicate subunit-specific relationships between the NK1-r and nicotinic receptor systems. The loss of nocifensive activity after destruction of the NK1-r bearing cells in spite of the persistence of nicotinic subunits on other cells, emphasizes the importance of the superficial marginal neuron in mediating these nicotinic effects. Further, the exaggerated cardiovascular responses to cytisine following loss of NK1-r bearing cells suggest the presence of a nicotinic receptor-mediated stimulation of inhibitory circuits at the spinal level.
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Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Neurônios/fisiologia , Agonistas Nicotínicos/farmacologia , Nociceptores/efeitos dos fármacos , Receptores da Neurocinina-1/fisiologia , Medula Espinal/fisiologia , Alcaloides/farmacologia , Animais , Azocinas/farmacologia , Comportamento Animal/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Morte Celular/efeitos dos fármacos , Imuno-Histoquímica , Ligantes , Masculino , Neurônios/efeitos dos fármacos , Células do Corno Posterior/efeitos dos fármacos , Células do Corno Posterior/metabolismo , Piridinas/farmacologia , Quinolizinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Colinérgicos/efeitos dos fármacos , Receptores da Neurocinina-1/efeitos dos fármacos , Proteínas Inativadoras de Ribossomos Tipo 1/toxicidade , Saporinas , Transdução de Sinais/efeitos dos fármacos , Medula Espinal/citologia , Medula Espinal/efeitos dos fármacos , Substância P/análogos & derivados , Substância P/toxicidadeRESUMO
Antimicrobial agents continue to account for a significant portion of institutional pharmaceutical expenditures. Pharmacoeconomic analysis is a valuable tool in assessing antibacterial agents for their place in institutional formularies. This article reviews various types of pharmacoeconomic analyses, their respective limitations, and their roles in the antibacterial formulary decision-making process. We also discuss the current state of the antibacterial pharmacoeconomic literature, including the economic impact of antimicrobial resistance.
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Antibacterianos/economia , Infecção Hospitalar/tratamento farmacológico , Farmacoeconomia , Formulários de Hospitais como Assunto , Serviço de Farmácia Hospitalar/economia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Análise Custo-Benefício , Infecção Hospitalar/economia , Infecção Hospitalar/microbiologia , Custos de Medicamentos , Farmacorresistência Bacteriana Múltipla , Humanos , Índice de Gravidade de DoençaRESUMO
We have demonstrated previously that there is a marked decrease in the level of labeled fucose incorporated into an amino acid fucoside, i.e., fucosyl-N-acetylglucosaminylasparagine (FL4c) in SV40-transformed human embryonic lung cells (SV40-WI-38) as compared to WI-38 cells (Morton, P.A., Klinger, M. M., and Steiner, S. Cancer Res., 42: 3022-3027, 1982). In the current study, we have observed that the reduction in labeled fucose incorporated into FL4c in the SV40-WI-38 cells is paralleled by reduced chemical quantity of that component. [3H]-Fucose pulse/chase and long-term fucose labeling/chase studies, in some instances in the presence of tunicamycin, have revealed that FL4c is a relatively stable end produce of N-linked-type glycoprotein metabolism. The relative metabolic stability argues against breakdown of FL4c as the basis for the markedly reduced level in the SV40-WI-38 cells. However, the transformed cells manifested an almost 3-fold higher level of alpha-L-fucosidase activity when p-nitrophenyl-alpha-fucoside was used as substrate. These results raise the possibility that the parent glycoprotein of FL4c might be more rapidly catabolized in the SV40-WI-38 cells than in the WI-38 cells. Whatever the biochemical basis for the decrease in level of FL4c in transformed human cells, it would seem to underlie a difference between normal and transformed cells in membrane glycoprotein catabolism.
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Asparagina/análogos & derivados , Transformação Celular Neoplásica , Fucose/análogos & derivados , Vírus 40 dos Símios/genética , Asparagina/biossíntese , Asparagina/metabolismo , Linhagem Celular , Fucose/biossíntese , Fucose/metabolismo , Humanos , Cinética , Pulmão/embriologia , Trítio , alfa-L-Fucosidase/análiseRESUMO
The incorporation of radioisotopically labeled fucose into a prominent fucosylated component, i.e., fucose-labeled amino acid fucoside 4c (FL4c), of human embryonic lung cells is markedly decreased in cell lines derived from human tumors. In the current study, we have extended the above observations by examining more closely related normal and transformed human cells, e.g., Wi38 cells and SV40-transformed Wi38 cells. We have found that the level of radioisotopically labeled fucose incorporated into FL4c of the SV40-transformed human embryonic lung cells is dramatically reduced as compared to their normal counterpart cells. Additionally, we have chemically characterized FL4c. FL4c was purified from monkey tissues using a combination of gel filtration chromatography, ion-exchange chromatography, and preparative thin-layer chromatography. Analysis of this material was accomplished by amino acid analyzer and by gas-liquid chromatography; fucose, glucosamine, and aspartic acid in molar ratios of approximately 1.0:1.0:1.0 were observed. Furthermore, alpha-L-fucosidase treatment of [3H]fucose-labeled FL4c revealed that the fucose was alpha-linked and in a terminal position. Similar treatment of [3H]glucosamine-labeled FL4c yielded a component that cochromatographed with N-acetylglucosaminylasparagine. The combined results of the structural studies are consistent with the structure of FL4c being alpha-fucosyl-N-acetylglucosaminylasparagine.
Assuntos
Fucose/análise , Glicopeptídeos/análise , Pulmão/análise , Aminoácidos/análise , Animais , Carboidratos/análise , Transformação Celular Viral , Chlorocebus aethiops , Feminino , Células HeLa/análise , Humanos , Rim/análise , Fígado/análise , Pulmão/embriologia , Gravidez , Vírus 40 dos Símios/genéticaRESUMO
The anaerobic reaction of bovine hemoglobin with divinyl sulfone results in a non-cross-linked intramolecularly-modified new derivative. This chemically-modified hemoglobin is homogeneous with respect to its molecular mass (64 kDa) and electrophoretic properties. The absence of any 32 kDa band from its SDS-PAGE pattern proves the lack of intramolecular cross-linkage, while a single-peak high-performance gel-permeation chromatogram demonstrates the absence of intermolecular cross-linkage. The oxygen binding properties determined at 37 degrees C, 0.15 M Cl- and pH 7.4 display a P50 of 52 mmHg and a Hill coefficient n of 1.9. Under the same experimental conditions the oxygen affinity is not sensitive to chloride anions, suggesting that the covelant modification is in the beta-cleft. The maximum number of Bohr protons released is 0.8/tetramer, which is half that of normal bovine hemoglobin. The retention time in circulation, measured in rats, is similar to that of native bovine hemoglobin. Using a high molar ratio of divinyl sulfone to modified hemoglobin, it is feasible to effect anaerobic intermolecular cross-linkage. The polymerized material, isolated from a 24 h reaction, is a mixture of modified intermolecularly-crosslinked hemoglobins with a molecular mass range from 130 to approx. 500 kDa. The oxygen-transport characteristics of the polymerized material are similar to those of the modified non-cross-linked derivative, whereas its retention time in rats is increased three-fold with respect to native bovine hemoglobin.
Assuntos
Hemoglobinas/química , Sulfonas/química , Regulação Alostérica , Anaerobiose , Animais , Bovinos , Hemoglobinas/metabolismo , Hemoglobinas/farmacocinética , Masculino , Taxa de Depuração Metabólica , Oxigênio/metabolismo , Ratos , Sulfonas/metabolismo , Sulfonas/farmacocinéticaRESUMO
UNLABELLED: A quantitative genetic approach, which involves correlation of transcriptional networks with the phenotype in a recombinant inbred (RI) population and in selectively bred lines of rats, and determination of coinciding quantitative trait loci for gene expression and the trait of interest, has been applied in the present study. In this analysis, a novel approach was used that combined DNA-Seq data, data from brain exon array analysis of HXB/BXH RI rat strains and six pairs of rat lines selectively bred for high and low alcohol preference, and RNA-Seq data (including rat brain transcriptome reconstruction) to quantify transcript expression levels, generate co-expression modules and identify biological functions that contribute to the predisposition of consuming varying amounts of alcohol. A gene co-expression module was identified in the RI rat strains that contained both annotated and unannotated transcripts expressed in the brain, and was associated with alcohol consumption in the RI panel. This module was found to be enriched with differentially expressed genes from the selected lines of rats. The candidate genes within the module and differentially expressed genes between high and low drinking selected lines were associated with glia (microglia and astrocytes) and could be categorized as being related to immune function, energy metabolism and calcium homeostasis, as well as glial-neuronal communication. The results of the present study show that there are multiple combinations of genetic factors that can produce the same phenotypic outcome. Although no single gene accounts for predisposition to a particular level of alcohol consumption in every animal model, coordinated differential expression of subsets of genes in the identified pathways produce similar phenotypic outcomes. DATABASE: The datasets supporting the results of the present study are available at http://phenogen.ucdenver.edu.
Assuntos
Consumo de Bebidas Alcoólicas/genética , Encéfalo/metabolismo , Redes Reguladoras de Genes , Animais , Bases de Dados de Ácidos Nucleicos , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Masculino , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos , Ratos Wistar , Recombinação Genética , TranscriptomaRESUMO
Evidence exists implying multiple blood pressure quantitative trait loci (QTL) on rat chromosome 2. To examine this possibility, four congenic strains and nine substrains were developed with varying size chromosome segments introgressed from the spontaneously hypertensive rat (SHR/lj) and normotensive Wistar-Kyoto rat (WKY/lj) onto the reciprocal genetic background. Cardiovascular phenotyping was conducted with telemetry over extended periods during standard salt (0.7%) and high-salt (8%) diets. Our results are consistent with at least three independent pressor QTL: transfer of SHR/lj alleles to WKY/lj reveals pressor QTL within D2Rat21-D2Rat27 and D2Mgh10-D2Rat62, whereas transfer of WKY/lj D2Rat161-D2Mit8 to SHR/lj reveals a depressor locus. Our results also suggest a depressor QTL in SHR/lj located within D2Rat161-D2Mgh10. Introgressed WKY/lj segments also reveal a heart rate QTL within D2Rat40-D2Rat50 which abolished salt-induced bradycardia, dependent upon adjoining SHR/lj alleles. This study confirms the presence of multiple blood pressure QTL on chromosome 2. Taken together with our other studies, we conclude that rat chromosome 2 is rich in alleles for cardiovascular and behavioral traits and for coordinated coupling between behavior and cardiovascular responses.
Assuntos
Pressão Sanguínea/genética , Cromossomos/genética , Frequência Cardíaca/genética , Locos de Características Quantitativas , Animais , Animais Congênicos , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Mapeamento Cromossômico , Feminino , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Cloreto de Sódio na Dieta/administração & dosagemRESUMO
Spontaneously hypertensive rats (SHR) exhibit enhanced pressor, heart rate, and nociceptive responses to spinal nicotinic agonists. This accompanies a paradoxical decrease in spinal nicotinic receptor number in SHR compared with normotensive rats. The congenic strain, SHR-Lx, with an introgressed chromosome 8 segment from the normotensive Brown-Norway-Lx strain (BN-Lx) exhibits reduced blood pressure. This segment contains a gene cluster for three nicotinic receptor subunits expressed in the nervous system. We examined the implication of this gene cluster in the enhanced responsiveness of the SHR. Pressor and nociceptive responses to spinal cytisine, a nicotinic agonist, were diminished in SHR-Lx. Moreover, with repeated administration, these responses desensitized faster in SHR-Lx and progenitor BN-Lx than in progenitor SHR/Ola. This implicates the gene cluster in both cardiovascular and nociceptive responses to spinal nicotinic agonists. Since diminished responsiveness to agonist stimulation is greater than the basal blood pressure differences between the strains and the introgressed rat chromosome maps to a quantitative trait locus in human hypertension, polymorphisms in the three nicotinic receptor genes become candidates for altered central control of blood pressure.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/genética , Cromossomos/genética , Hipertensão/genética , Família Multigênica/genética , Receptores Nicotínicos/genética , Alcaloides/administração & dosagem , Alcaloides/metabolismo , Animais , Animais Congênicos , Azocinas , Esquema de Medicação , Tolerância a Medicamentos/fisiologia , Feminino , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/genética , Injeções Espinhais , Masculino , Agonistas Nicotínicos/administração & dosagem , Agonistas Nicotínicos/metabolismo , Quinolizinas , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos SHR , Nervos Espinhais/química , Nervos Espinhais/efeitos dos fármacos , Cauda/irrigação sanguíneaRESUMO
Sensorimotor gating, measured by prepulse inhibition (PPI) of the startle reflex, is reduced in schizophrenia patients and in rats treated with dopamine agonists. Strain and substrain differences in the sensitivity to the PPI-disruptive effects of dopamine agonists may provide insight into the genetic basis for human population differences in sensorimotor gating. We have reported greater sensitivity to the PPI-disruptive effects of the D1/D2 agonist apomorphine in Harlan Sprague-Dawley (SDH) vs Wistar (WH) rats. In the present study, we assessed the inheritance pattern of this phenotypic difference. Sensitivity to the PPI-disruptive effects of apomorphine was compared across parental SDH and WH strains, offspring (F1) of an SDH x WH cross, and subsequent offspring (N2) of an SDH x F1 cross. Apomorphine sensitivity followed a gradient of SDH>N2>F1>WH. Parental SDH and WH strains exhibited comparable sensitivity to the PPI-disruptive effects of phencyclidine. The nature of this gradient of APO sensitivity suggests relatively simple additive effects of multiple genes on the phenotype of PPI sensitivity.
Assuntos
Apomorfina/farmacologia , Endogamia , Desempenho Psicomotor/efeitos dos fármacos , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/genética , Animais , Animais Recém-Nascidos , Feminino , Masculino , Gravidez , Desempenho Psicomotor/fisiologia , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Especificidade da EspécieRESUMO
PURPOSE: To study the role of costimulatory signaling through the CD28-B7 interaction in experimental autoimmune anterior uveitis (EAAU). METHODS: Naive Lewis rats were immunized with insoluble melanin-associated antigen (MAA) derived from bovine iris and ciliary body. CTLA4-Fc, a recombinant protein comprised of the extracellular domain of human CTLA4 bound to mouse IgG2a Fc, was used to block the CD28-B7 interaction. A mutant version (CTLA4-Fc-mutant) was used as a control. The effect of CTLA4-Fc on the in vivo induction of disease with MAA was studied. Subsequently, the mechanism by which CTLA4-Fc blocked the interaction of CD28 and B7 was investigated in vivo, using the adoptive transfer of T cells derived from CTLA4-Fc-treated rats, and in vitro, using the proliferative response and cytokine production of MAA-T cells in the presence of CTLA4-Fc. RESULTS: CTLA4-Fc markedly reduced the incidence and severity of EAAU in Lewis rats after sensitization with MAA. The adoptive transfer of sensitized T cells from CTLA4-Fc-treated donors did not induce EAAU in naive recipients. CTLA4-Fc inhibited the expansion of antigen-specific MAA-T cells and the production of TNF-alpha. CONCLUSIONS: The costimulatory signal delivered through CD28-B7 is required for the induction and pathogenesis of EAAU. In the absence of this signal, antigen-specific expansion of MAA reactive T cells as well as production of TNF-alpha is inhibited. Abrogation of this costimulatory signal may be an important therapeutic option for EAAU.
Assuntos
Doenças Autoimunes/imunologia , Antígeno B7-1/imunologia , Imunoconjugados , Ativação Linfocitária , Uveíte Anterior/imunologia , Abatacepte , Transferência Adotiva , Animais , Antígenos CD , Antígenos de Diferenciação/imunologia , Autoantígenos/imunologia , Doenças Autoimunes/patologia , Doenças Autoimunes/prevenção & controle , Antígenos CD28/imunologia , Antígeno CTLA-4 , Linhagem Celular , Ensaio de Imunoadsorção Enzimática , Incidência , Ativação Linfocitária/imunologia , Masculino , Melaninas/imunologia , Modelos Animais , Ratos , Ratos Endogâmicos Lew , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/biossíntese , Uveíte Anterior/patologia , Uveíte Anterior/prevenção & controleRESUMO
One hundred and eighty-eight patients with evolving acute myocardial infarction were treated with intravenous streptokinase. Serial 12-lead electrocardiograms were recorded for 3 hours after treatment and inspected for rapid repolarization changes of the ST segment and T wave. Abrupt electrocardiographic repolarization changes were observed in 106 patients (56%) and were strongly predictive for an open infarct-related coronary artery at a mean of 6 days after treatment (predictive value = 0.92, sensitivity = 0.67). Abrupt electrocardiographic changes were not observed in 82 patients (44%). This absence was not a good predictor of an occluded infarct-related coronary artery (predictive value = 0.4). There was no relation between the presence or absence of abrupt electrocardiographic changes and global or regional left ventricular function after streptokinase treatment. Abrupt repolarization changes after thrombolytic treatment indicate a high probability of an open infarct-related artery. When abrupt repolarization changes do not occur, the patency of the infarct-related coronary artery cannot be predicted with accuracy. Serial electrocardiographic recordings do not provide sufficient information about coronary patency to eliminate the need for coronary arteriography.
Assuntos
Vasos Coronários , Eletrocardiografia , Coração/fisiopatologia , Infarto do Miocárdio/tratamento farmacológico , Estreptoquinase/uso terapêutico , Grau de Desobstrução Vascular/efeitos dos fármacos , Idoso , Angiografia Coronária , Circulação Coronária/efeitos dos fármacos , Estudos de Avaliação como Assunto , Ventrículos do Coração/fisiopatologia , Humanos , Processamento de Imagem Assistida por Computador , Injeções Intravenosas , Valor Preditivo dos Testes , Estreptoquinase/administração & dosagem , Estreptoquinase/farmacologia , Volume Sistólico/efeitos dos fármacos , Fatores de TempoRESUMO
Dextranomer is a hydrophilic dextran polymer advocated as a 'cleansing agent' for various types of exudating wounds or ulcers, including stasis (venous) ulcers and decubitus ulcers. It appears to exert its effect by a capillary action which absorbs wound exudate, as well as wound debris and micro-organisms, into the dextranomer beads or into the spaces between the beads, thus removing such products from the wound surface. Dextranomer is an aid to wound or ulcer management, and does not directly affect tissue repair in such ulcers, but as with other 'cleansing' agents or techniques, removal of debris (and possibly micro-organisms) from the wound could be expected to promote natural healing. Reports of its effectiveness in open studies, often in patients with seemingly resistant lesions, have been encouraging. Similarly, in comparative trials results have usually favoured dextranomer, but a clear indication of the relative efficacy and benefits as compared with other treatments used for exudating lesions has not yet emerged. Further well designed comparative studies are needed to provide such information.
Assuntos
Dextranos/farmacologia , Animais , Queimaduras/tratamento farmacológico , Cromatografia , Dextranos/efeitos adversos , Dextranos/uso terapêutico , Dextranos/toxicidade , Exsudatos e Transudatos/metabolismo , Humanos , Úlcera da Perna/tratamento farmacológico , Úlcera por Pressão/tratamento farmacológico , Cicatrização/efeitos dos fármacosRESUMO
Co-administration of synthetic chemically modified oligonucleotides with irinotecan, a selective topoisomerase I inhibitor, provided a significant enhancement in the antitumor activity of irinotecan. The enhancement of antitumor activity of irinotecan with co-administration of chemically modified oligonucleotides was observed in several tumor models--pancreatic cancer (Panc-1), colon cancer (HCT-116) and melanoma (A375). Inhibition of tumor growth in all three models required the co-administration of irinotecan and chemically modified oligonucleotides, but was independent of the nucleotide sequence of the oligonucleotides. The potentiation of antitumor activity was dependent on the dose of irinotecan and chemically modified oligonucleotides administered. The enhancement of antitumor activity of irinotecan was also observed by co-administration of a phosphorothioate oligonucleotide, however, to a lesser extent than did chemically modified oligonucleotides, suggesting that metabolic stability of the oligonucleotide contributes to the enhancement of antitumor activity seen with irinotecan. The co-administration of dextran sulfate sodium with irinotecan showed insignificant potentiation of antitumor activity of irinotecan, suggesting that the enhancement of antitumor activity of irinotecan observed was not a result of polyanionic characteristic of oligonucleotides. Co-administration of irinotecan and chemically modified oligonucleotides did not result in increased toxicity in the tumor models studied. Potentiation of antitumor activity of irinotecan observed with co-administration of oligonucleotides suggests that the oligonucleotides affect the pharmacokinetics and/or metabolism of irinotecan. The use of chemically modified oligonucleotides together with irinotecan may increase the therapeutic index of irinotecan in cancer patients and continued development of such agents should be considered.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Neoplasias/tratamento farmacológico , Proteínas Nucleares , Oligonucleotídeos Antissenso/uso terapêutico , Proteínas Proto-Oncogênicas/genética , Inibidores da Topoisomerase I , Animais , Proteínas Quinases Dependentes de AMP Cíclico/genética , Relação Dose-Resposta a Droga , Esquema de Medicação , Sinergismo Farmacológico , Feminino , Humanos , Irinotecano , Camundongos , Camundongos Nus , Transplante de Neoplasias , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-mdm2 , Resultado do TratamentoRESUMO
The various limitations to computerized axial tomographic (CT) interpretation are due in part to the 8-13 mm standard tissue plane thickness and in part to the absence of alternative planes of view, such as coronal or sagittal images. This paper describes a method for gathering multiple overlapped 8 mm transverse sections, subjecting these data to a deconvolution process, and then displaying thin (1 mm) transverse as well as reconstructed coronal and sagittal CT images. Verification of the deconvolution technique with phantom experiments is described. Application of the phantom results to human post mortem CT scan data illustrates this method's faithful reconstruction of coronal and sagittal tissue densities when correlated with actual specimen photographs of a sectioned brain. A special CT procedure, limited basal overlap scanning, is proposed for use on current first generation CT scanners without hardware modification.