RESUMO
BACKGROUND: The Shingles Prevention Study (SPS; Department of Veterans Affairs Cooperative Study 403) demonstrated that zoster vaccine was efficacious through 4 years after vaccination. The Short-Term Persistence Substudy (STPS) was initiated after the SPS to further assess the persistence of vaccine efficacy. METHODS: The STPS re-enrolled 7320 vaccine and 6950 placebo recipients from the 38 546-subject SPS population. Methods of surveillance, case determination, and follow-up were analogous to those in the SPS. Vaccine efficacy for herpes zoster (HZ) burden of illness, incidence of postherpetic neuralgia (PHN), and incidence of HZ were assessed for the STPS population, for the combined SPS and STPS populations, and for each year through year 7 after vaccination. RESULTS: In the STPS as compared to the SPS, vaccine efficacy for HZ burden of illness decreased from 61.1% to 50.1%, vaccine efficacy for the incidence of PHN decreased from 66.5% to 60.1%, and vaccine efficacy for the incidence of HZ decreased from 51.3% to 39.6%, although the differences were not statistically significant. Analysis of vaccine efficacy in each year after vaccination for all 3 outcomes showed a decrease in vaccine efficacy after year 1, with a further decline thereafter. Vaccine efficacy was statistically significant for the incidence of HZ and the HZ burden of illness through year 5. CONCLUSIONS: Vaccine efficacy for each study outcome was lower in the STPS than in the SPS. There is evidence of the persistence of vaccine efficacy through year 5 after vaccination but, vaccine efficacy is uncertain beyond that point.
Assuntos
Vacina contra Herpes Zoster/administração & dosagem , Herpes Zoster/prevenção & controle , Idoso , Estudos de Coortes , Efeitos Psicossociais da Doença , Método Duplo-Cego , Monitoramento Epidemiológico , Herpes Zoster/epidemiologia , Herpes Zoster/imunologia , Vacina contra Herpes Zoster/imunologia , Humanos , Incidência , Pessoa de Meia-Idade , Placebos , Estados Unidos/epidemiologia , Vacinação/estatística & dados numéricosRESUMO
BACKGROUND: The incidence and severity of herpes zoster and postherpetic neuralgia increase with age in association with a progressive decline in cell-mediated immunity to varicella-zoster virus (VZV). We tested the hypothesis that vaccination against VZV would decrease the incidence, severity, or both of herpes zoster and postherpetic neuralgia among older adults. METHODS: We enrolled 38,546 adults 60 years of age or older in a randomized, double-blind, placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine ("zoster vaccine"). Herpes zoster was diagnosed according to clinical and laboratory criteria. The pain and discomfort associated with herpes zoster were measured repeatedly for six months. The primary end point was the burden of illness due to herpes zoster, a measure affected by the incidence, severity, and duration of the associated pain and discomfort. The secondary end point was the incidence of postherpetic neuralgia. RESULTS: More than 95 percent of the subjects continued in the study to its completion, with a median of 3.12 years of surveillance for herpes zoster. A total of 957 confirmed cases of herpes zoster (315 among vaccine recipients and 642 among placebo recipients) and 107 cases of postherpetic neuralgia (27 among vaccine recipients and 80 among placebo recipients) were included in the efficacy analysis. The use of the zoster vaccine reduced the burden of illness due to herpes zoster by 61.1 percent (P<0.001), reduced the incidence of postherpetic neuralgia by 66.5 percent (P<0.001), and reduced the incidence of herpes zoster by 51.3 percent (P<0.001). Reactions at the injection site were more frequent among vaccine recipients but were generally mild. CONCLUSIONS: The zoster vaccine markedly reduced morbidity from herpes zoster and postherpetic neuralgia among older adults.
Assuntos
Vacina contra Varicela , Herpes Zoster/prevenção & controle , Herpesvirus Humano 3 , Neuralgia/prevenção & controle , Idoso , Vacina contra Varicela/efeitos adversos , Vacina contra Varicela/imunologia , Efeitos Psicossociais da Doença , Método Duplo-Cego , Feminino , Seguimentos , Herpes Zoster/complicações , Herpes Zoster/epidemiologia , Herpesvirus Humano 3/imunologia , Humanos , Memória Imunológica , Incidência , Masculino , Pessoa de Meia-Idade , Neuralgia/virologia , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/imunologia , Ativação ViralRESUMO
OBJECTIVES: To describe the complete history of major opportunistic events experienced by 1883 HIV-infected persons prior to and specifically within 6 months of death, and to determine whether the frequency of specific events varies according to demographic characteristics, risk behaviors or geographic location. DESIGN: Descriptive case series. METHODS: Of 6682 HIV-infected individuals enrolled in studies sponsored by the Community Programs for Clinical Research on AIDS between September 1990 and June 1994, 1883 died during follow-up. A complete history of AIDS-defining events was determined for these patients by combining medical history data obtained at the time of enrollment, new events that occurred during follow-up, and causes of death. RESULTS: The most common opportunistic AIDS-defining events these 1883 patients experienced before death were Pneumocystis carinii pneumonia (PCP; 45%), Mycobacterium avium complex (MAC; 25%), wasting syndrome (25%), bacterial pneumonia (24%), cytomegalovirus (CMV) disease (23%) and candidiasis (esophageal or pulmonary; 22%). In addition, 47% of patients experienced two or three AIDS-defining events before death, and 22% experienced four or more events. In the 6 months prior to death, 22% of patients had PCP, 21% had MAC, and 20% had CMV disease. Significant sex and ethnic differences were found: bacterial pneumonia occurred more often before death in women compared with men; fewer blacks and Latinos than whites experienced Kaposi's sarcoma (KS); and fewer blacks than whites had CMV disease before death. The percentage of patients with KS and CMV also varied by risk behavior. The frequency of 10 opportunistic diseases varied by geographic region after adjustment for demographic characteristics and risk behavior. Of note, many more patients in northeastern USA had tuberculosis and fewer had MAC. CONCLUSION: A large percentage of individuals with HIV infection experienced multiple AIDS-defining opportunistic diseases before death. PCP, MAC, wasting syndrome, bacterial pneumonia, CMV disease, and candidiasis (esophageal or pulmonary) account for a substantial proportion of morbidity associated with HIV infection. More diseases varied by geographic location than by demographic characteristics or risk behavior of patients. Continued research on the etiology and prevention of these diseases and how they relate to one another should be a high priority.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/epidemiologia , Infecções Oportunistas Relacionadas com a AIDS/etnologia , Infecções Oportunistas Relacionadas com a AIDS/mortalidade , Negro ou Afro-Americano , Caquexia/epidemiologia , Candidíase/epidemiologia , Infecções por Citomegalovirus/epidemiologia , Feminino , Hispânico ou Latino , Humanos , Masculino , Infecção por Mycobacterium avium-intracellulare/epidemiologia , Pneumonia Bacteriana/epidemiologia , Pneumonia por Pneumocystis/epidemiologia , Fatores de Risco , Fatores Sexuais , População BrancaRESUMO
Since the early work of RA Fisher, exact methods have been recognized as important tools in data analysis because they provide valid statistical inference even with small sample sizes, or with sparse or skewed data. With the recent advance of computational power and the availability of commercial software packages, exact methods have gained substantial popularity over the past two decades. However, most of these exact methods have been devoted to testing classical null hypotheses of no differences, and until recently little was known about exact methods dealing with non-inferiority or equivalence hypotheses. The presence of nuisance parameters in testing non-inferiority/equivalence hypotheses presents a special challenge for exact methods because of the intense computational requirement. In this paper, we review exact methods available for proving non-inferiority or equivalence of two treatments with a dichotomous endpoint. First, we present the general methodology for conducting exact tests for non-inferiority or equivalence; we then discuss several unconditional and conditional methods available for constructing hypothesis tests and confidence intervals based on three commonly used measures, namely, the difference, relative risk, and odds ratio of two independent proportions or rates. Finally, we illustrate with several examples the application of these exact methods in analysing and planning non-inferiority or equivalence trials.
Assuntos
Pesquisa Biomédica , Interpretação Estatística de Dados , Resultado do Tratamento , Intervalos de Confiança , Humanos , Razão de Chances , Projetos de Pesquisa/estatística & dados numéricos , Risco , Software , Equivalência Terapêutica , Estados UnidosRESUMO
GGOPT is a derivative-free non-linear optimizer for smooth functions with added noise. If the function values arise from observations or from extensive computations, these errors can be considerable. GGOPT uses an adjustable mesh together with linear least squares to find smoothed values of the function, gradient and Hessian at the center of the mesh. These values drive a descent method that estimates optimal parameters. The smoothed values usually result in increased accuracy.
Assuntos
Biometria , Software , AlgoritmosRESUMO
BACKGROUND: A double-blind, placebo-controlled trial that involved 38,546 subjects > or =60 years old demonstrated efficacy of a high-potency live-attenuated Oka/Merck varicella-zoster virus (VZV) vaccine. The trial included an immunology substudy to determine the relationship of VZV-specific immune responses to vaccination and clinical outcome. METHODS: The immunology substudy enrolled 1395 subjects at 2 sites where blood samples obtained prior to vaccination, at 6 weeks after vaccination, and at 1, 2, and 3 years thereafter were tested for VZV-specific cell-mediated immunity (VZV-CMI) by gamma-interferon ELISPOT and responder cell frequency assays and for VZV antibody by glycoprotein ELISA. RESULTS: VZV-CMI and VZV antibodies were significantly increased in vaccine recipients at 6 weeks after vaccination. The vaccine-induced increases in VZV-CMI persisted during the 3 years of follow-up, although their magnitude decreased over time. The magnitude of these VZV-specific immune responses was greater in subjects 60-69 years old than in subjects > or =70 years old. CONCLUSIONS: The zoster vaccine induced a significant increase in VZV-CMI and VZV antibody. The magnitude and duration of the boost in VZV-CMI in vaccine recipients and the relationship of this boost to age paralleled the clinical effects of the vaccine observed during the efficacy trial. These findings support the hypothesis that boosting VZV-CMI protects older adults against herpes zoster and postherpetic neuralgia.
Assuntos
Vacina contra Herpes Zoster/imunologia , Herpes Zoster/prevenção & controle , Herpesvirus Humano 3/imunologia , Fatores Etários , Idoso , Anticorpos Antivirais/sangue , Método Duplo-Cego , Feminino , Herpes Zoster/imunologia , Herpes Zoster/virologia , Vacina contra Herpes Zoster/sangue , Vacina contra Herpes Zoster/farmacocinética , Vacina contra Herpes Zoster/uso terapêutico , Humanos , Imunidade Celular , Masculino , Vacinas Atenuadas/imunologia , Vacinas Atenuadas/farmacocinética , Vacinas Atenuadas/uso terapêuticoRESUMO
Noninferioritylequivalence designs are often used in vaccine clinical trials. The goal of these designs is to demonstrate that a new vaccine, or new formulation or regimen of an existing vaccine, is similar in terms of effectiveness to the existing vaccine, while offering such advantages as easier manufacturing, easier administration, lower cost, or improved safety profile. These noninferioritylequivalence designs are particularly useful in four common types of immunogenicity trials: vaccine bridging trials, combination vaccine trials, vaccine concomitant use trials, and vaccine consistency lot trials. In this paper, we give an overview of the key statistical issues and recent developments for noninferioritylequivalence vaccine trials. Specifically, we cover the following topics: (i) selection of study endpoints; (ii) formulation of the null and alternative hypotheses; (iii) determination of the noninferioritylequivalence margin; (iv) selection of efficient statistical methods for the statistical analysis of noninferioritylequivalence vaccine trials, with particular emphasis on adjustment for stratification factors and missing pre-or post-vaccination data; and (v) the calculation of sample size and power.
Assuntos
Modelos Estatísticos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Vacinas/farmacocinética , Determinação de Ponto Final/métodos , Determinação de Ponto Final/estatística & dados numéricos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Equivalência Terapêutica , Vacinas/efeitos adversos , Vacinas/imunologia , Vacinas/uso terapêuticoAssuntos
Alphapapillomavirus , Displasia do Colo do Útero/prevenção & controle , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus , Neoplasias do Colo do Útero/prevenção & controle , Adolescente , Adulto , Anticorpos Antivirais/sangue , Displasia do Colo do Útero/virologia , Método Duplo-Cego , Feminino , Doenças dos Genitais Femininos/epidemiologia , Humanos , Incidência , Análise de Intenção de Tratamento , Infecções por Papillomavirus/epidemiologia , Vacinas contra Papillomavirus/administração & dosagem , Neoplasias do Colo do Útero/virologiaRESUMO
Exact tests of equivalence and efficacy with a non-zero lower bound based on two independent binomial proportions for comparative trials are proposed. These exact tests are desirable for studies with small sample sizes. They generalize classical methods to include testing of null hypotheses of prespecified differences and can be used to demonstrate a new treatment's efficacy or its equivalence to a standard treatment. The proposed exact tests use unconditional distributions of the test statistics. Variances of test statistics are estimated via a constrained maximum likelihood method (Farrington and Manning). Data from oncology and vaccine clinical trials are used to illustrate the exact tests.
Assuntos
Modelos Estatísticos , Ensaios Clínicos Controlados Aleatórios como Assunto , Criança , Humanos , Incidência , Vírus da Influenza A/imunologia , Vacinas contra Influenza/administração & dosagem , Influenza Humana/epidemiologia , Influenza Humana/prevenção & controle , Neoplasias Renais/epidemiologia , Neoplasias Renais/terapia , Funções Verossimilhança , Tamanho da Amostra , Tumor de Wilms/epidemiologia , Tumor de Wilms/terapiaRESUMO
Confidence intervals are often provided to estimate a treatment difference. When the sample size is small, as is typical in early phases of clinical trials, confidence intervals based on large sample approximations may not be reliable. In this report, we propose test-based methods of constructing exact confidence intervals for the difference in two binomial proportions. These exact confidence intervals are obtained from the unconditional distribution of two binomial responses, and they guarantee the level of coverage. We compare the performance of these confidence intervals to ones based on the observed difference alone. We show that a large improvement can be achieved by using the standardized Z test with a constrained maximum likelihood estimate of the variance.
Assuntos
Biometria , Ensaios Clínicos como Assunto/estatística & dados numéricos , Intervalos de Confiança , Humanos , Funções Verossimilhança , Modelos Estatísticos , Tamanho da Amostra , Vacinas/isolamento & purificação , Vacinas/uso terapêuticoRESUMO
The extraction of serotonin from the blood during transorgan passage through the heart was studied using Langendorff-perfused rabbit hearts. Outflow dilution curves of 131I- or 125I-labeled albumin, [14C]sucrose, and [3H]serotonin injected simultaneously into the inflow were fitted with an axially distributed blood-tissue exchange model to examine the extraction process. The model fits of the albumin and sucrose outflow dilution curves were used to define flow heterogeneity, intravascular dispersion, capillary permeability, and the volume of the interstitial space, which reduced the degrees of freedom in fitting the model to the serotonin curves. Serotonin extractions, measured against albumin, during single transcapillary passage, ranged from 24 to 64%. The ratio of the capillary permeability-surface area products for serotonin and sucrose, based on the maximum instantaneous extraction, was 1.37 +/- 0.2 (n = 18), very close to the predicted value of 1.39, the ratio of free diffusion coefficients calculated from the molecular weights. This result shows that the observed uptake of serotonin can be accounted for solely on the basis of diffusion between endothelial cells into the interstitial space. Thus it appears that the permeability of the luminal surface of the endothelial cell is negligible in comparison to diffusion through the clefts between endothelial cells. In 18 sets of dilution curves, with and without receptor and transport blockers or competitors (ketanserin, desipramine, imipramine, serotonin), the extractions and estimates of the capillary permeability-surface area product were not reduced, nor were the volumes of distribution. The apparent absence of transporters and receptors in rabbit myocardial capillary endothelium contrasts with their known abundance in the pulmonary vasculature.
Assuntos
Capilares/metabolismo , Endotélio Vascular/metabolismo , Miocárdio/metabolismo , Serotonina/farmacocinética , Animais , Transporte Biológico , Técnicas In Vitro , Radioisótopos do Iodo , Modelos Cardiovasculares , Coelhos , Técnica de Diluição de Radioisótopos , Albumina Sérica/farmacocinética , Sacarose/farmacocinética , TrítioRESUMO
A mathematical function has been developed for approximating unimodal functions, particularly those which are non-Gaussian, skewed, and incomplete. It is useful as an alternative to cubic splines in smoothing noisy experimental data. Particular applications are to indicator-dilution curves and probability density functions of varied form. In its Fortran implementation, SMOEX, it is computationally inexpensive compared to standard cubic spline smoothing routines and requires less storage to preserve the smoothed function for retrieval or interpolation.
Assuntos
Técnicas de Diluição do Indicador , Computação Matemática , Animais , Interpretação Estatística de Dados , CãesRESUMO
Nonlinear least squares optimization is used most often in fitting a complex model to a set of data. An ordinary nonlinear least squares optimizer assumes a constant variance for all the data points. This paper presents SENSOP, a weighted nonlinear least squares optimizer, which is designed for fitting a model to a set of data where the variance may or may not be constant. It uses a variant of the Levenberg-Marquardt method to calculate the direction and the length of the step change in the parameter vector. The method for estimating appropriate weighting functions applies generally to 1-dimensional signals and can be used for higher dimensional signals. Sets of multiple tracer outflow dilution curves present special problems because the data encompass three to four orders of magnitude; a fractional power function provides appropriate weighting giving success in parameter estimation despite the wide range.
Assuntos
Análise dos Mínimos Quadrados , Modelos Cardiovasculares , Modelos Estatísticos , Dinâmica não Linear , Capilares/metabolismo , Intervalos de Confiança , Interpretação Estatística de Dados , Difusão , Permeabilidade , Sensibilidade e Especificidade , Albumina Sérica/metabolismo , SoftwareRESUMO
Analysis of data on tissue depositions obtained by positron tomographic or NMR imaging, or of multiple tracer outflow dilution curves, requires fitting data with models composed of aggregates of capillary-tissue units. These units account for heterogeneities of flows and multisolute exchanges between longitudinally distributed regions across capillary and cell barriers within an organ. Because the analytic solutions to the partial differential equations require convolution integration, solutions are obtained relatively efficiently by a fast numerical method. Our approach centers on the use of a sliding fluid element algorithm for capillary convection, with the time step set equal to the length step divided by the fluid velocity. Radial fluxes by permeation between plasma, interstitial fluid, and cells and axial diffusion exchanges within each time step are calculated analytically. The method enforces mass conservation unless there is regional consumption. Solution for a 2-barrier, 3-region model, accurate to within 0.5%, are 100 to 1000 times faster than the corresponding, purely analytic solution, and over 10,000 times for a 4-region model. Applications include multiple indicator dilution studies of kinetics of transcapillary exchange and positron emission tomographic studies of the mechanisms of substrate transport into cells of organs in vivo.
Assuntos
Algoritmos , Capilares/metabolismo , Modelos Cardiovasculares , Transporte Biológico , Difusão , Troca Iônica , PermeabilidadeRESUMO
The escape of solutes from the blood during passage along capillaries in heart and skeletal muscle occurs via diffusion through clefts between endothelial cells and, for some solutes, via adsorption to or transport across the luminal plasmalemma of the endothelial cell. To quantitate the rates of permeation via these two routes of transport across capillary wall, we have developed a linear model for transendothelial transport and illustrated its suitability for the design and analysis of multiple simultaneous indicator dilution curves from an organ. Data should be obtained for at least three solutes: 1) an intravascular reference, albumin; 2) a solute transported by endothelial cells; and 3) another reference solute, of the same molecular size as solute 2, which neither binds nor traverses cell membranes. The capillary-tissue convection-permeation model is spatially distributed and accounts for axial variation in concentrations, transport through and around endothelial cells, accumulation and consumption within them, exchange with the interstitium and parenchymal cells, and heterogeneity of regional flows. The upslope of the dilution curves is highly sensitive to unidirectional rate of loss at the luminal endothelial surface. There is less sensitivity to transport across the antiluminal surface, except when endothelial retention is low. The model is useful for receptor kinetics using tracers during steady-state conditions and allows distinction between equilibrium binding and reaction rate limitations. Uptake rates at the luminal surface are readily estimated by fitting the model to the experimental dilution curves. For adenosine and fatty acids, endothelial transport accounts for 30-99% of the transcapillary extraction.
Assuntos
Sangue/metabolismo , Capilares/metabolismo , Endotélio Vascular/metabolismo , Animais , Transporte Biológico , Capilares/citologia , Permeabilidade Capilar , Difusão , Endotélio Vascular/citologia , Humanos , Modelos CardiovascularesRESUMO
Multiple indicator-dilution experiments were done to compare the transcapillary exchange of tracer amounts of L-[14C]ascorbate and D-[3H]glucose (against an intravascular reference 131I-albumin) in Ringer-perfused (5 mM glucose) isolated rabbit hearts. The indicator-dilution curves for the two were virtually superimposed over the first 40-80 s. Estimates of the capillary permeability-surface area products, PSc, were the same, 2.3 +/- 0.7 (SD) ml X g-1 X min-1 (n = 18), in accord with the coincidence of their instantaneous extractions. The similarity of glucose and ascorbate permeabilities is explained by the similarity in molecular weights and passive diffusivity, their lipophobic nature, and the paucity of carrier-mediated endothelial transport for either molecule. The data were analyzed via a model composed of aggregates of spatially distributed capillary-tissue units (capillary blood, interstitium, myocytes) accounting for the heterogeneity of regional flows. The interstitial volumes in this preparation are enlarged, 0.30 +/- 0.04 ml/g. There is substantial entry into myocardial cells, the cell permeability-surface area products being approximately 2-3 ml X g-1 X min-1 for ascorbate and glucose. The estimated volumes of interstitial and intracellular space, 0.30 and 0.47 ml X g-1 X min-1, reflect interstitial edema and are very close to measured values, giving reassurance concerning the methods of modeling analysis.
Assuntos
Ácido Ascórbico/metabolismo , Glucose/metabolismo , Miocárdio/metabolismo , Animais , Transporte Biológico , Permeabilidade Capilar , Técnicas de Diluição do Indicador , Modelos Cardiovasculares , Coelhos , Técnica de Diluição de RadioisótoposRESUMO
Capillary-tissue exchange of inert hydrophilic solutes in the heart occurs through aqueous channels, the clefts between endothelial cells (ECs). For adenosine (and other vasoactive agents and substrates), there is also transport across the plasmalemma of the ECs. The multiple-indicator dilution technique comparing tracer adenosine flux with that of 9-beta-D-arabinofuranosylhypoxanthine (an analog that is not transported by the nucleoside carrier) can be used to estimate the conductance of the facilitated transport mechanism, which is equivalent to a permeability-surface area product. Analysis by using a model of exchanges among capillary, EC, interstitium, and myocardial cells suggests that the abluminal surface of the ECs is also highly permeable to adenosine. The inference is that ECs may be an important component of a system for adenosine exchange and regulation in the heart.
Assuntos
Capilares/metabolismo , Adenosina/metabolismo , Animais , Arabinonucleosídeos/metabolismo , Transporte Biológico , Capilares/fisiologia , Vasos Coronários/metabolismo , Vasos Coronários/fisiologia , Endotélio/metabolismo , Endotélio/fisiologia , Cobaias , Modelos Cardiovasculares , Albumina Sérica/metabolismoRESUMO
The deposition of microspheres in small tissue regions is not strictly flow dependent. In comparison with the soluble flow marker 2-iododesmethylimipramine (IDMI), deposition of 16.5-microns microspheres was mildly but systematically biased into high flow regions of rabbit hearts (Bassingthwaighte JB, Malone MA, Moffett T-C, King RB, Little SE, Link JM, Krohn KA. Am J Physiol 1987;253 (Heart Circ Physiol 22):H184-H193). To examine the possibility of bias in larger hearts, a similar study was undertaken in sheep. 141Ce- and 103Ru-labeled 16.5-microns microspheres in one syringe and 125I- and 131I-DMI in another syringe were injected simultaneously into the left atrium of five open-chest sheep while obtaining reference blood samples from the femoral artery. In six other sheep, one microsphere type and one IDMI were used. Hearts were removed 1 minute after injection, cut into approximately 254 pieces averaging 217 mg, and regional deposition densities calculated for each tracer from the isotopic counts. Correlations in the five animals between the two differently labeled IDMIs and between the two microspheres were both greater than or equal to 0.98. In all 11 sheep, scatter plots of microsphere deposition densities versus IDMI densities showed that differences between microspheres and IDMI had substantially more scatter (0.84 less than r less than 0.98) but were not random. Microsphere depositions tended to be lower than IDMI depositions in low flow regions and higher in high flow regions, in accord with the expected bias that at a bifurcation a microsphere is most likely to enter the branch with higher flow. There was less bias ascribable to endomyocardial/epicardial maldistribution. Thus, while microsphere depositions appear to err systematically with respect to flow when the regions of interest are small enough that the diameters of their arterioles are only a few times those of the microspheres, microspheres are, in sheep as in rabbits, adequate for estimating regional flows.
Assuntos
Circulação Coronária , Desipramina/análogos & derivados , Animais , Microesferas , Modelos Cardiovasculares , Miocárdio/metabolismo , Ovinos , Distribuição TecidualRESUMO
We used the multiple-indicator-dilution technique to observe the capillary transport of adenosine in isolated Krebs-Henseleit-perfused guinea pig hearts. Tracer concentrations of radiolabeled albumin, sucrose, and adenosine were injected into the coronary inflow; outflow samples were collected for 10-25 s and analyzed by high-performance liquid chromatography (HPLC) and by gamma- and beta-counting. The albumin data define the intravascular transport characteristics; the sucrose data define permeation through interendothelial clefts and dilution in interstitial fluid (ISF). Parameters calculated from adenosine data include permeability-surface area products for endothelial cell uptake at the luminal and abluminal membranes and intraendothelial metabolism. We found that in situ endothelial cells avidly take up and metabolize adenosine. Tracer adenosine in the capillary lumen is twice as likely to enter an endothelial cell as it is to permeate the clefts. There was no adenosine in the arterial perfusate. Under control conditions, the steady-state venous adenosine concentration was 3.6 +/- 0.8 nM, which from the flow and the parameters estimated from the tracer data gave a calculated ISF concentration of 6.8 +/- 1.5 nM. During dipyridamole infusion (10 microM) at constant pressure, the cell permeabilities went essentially to zero, whereas the venous adenosine concentration increased to 44.0 +/- 12.6 nM, giving an estimated ISF concentration of 191 +/- 53 nM. With constant flow perfusion, venous concentration during dipyridamole infusion was 30.9 +/- 6.3 nM, and estimated ISF concentration was 88 +/- 20 mM. We conclude that in this preparation, at rest, the ISF adenosine concentration is about twice the venous concentration and the ISF adenosine concentration increases with dipyridamole administration.
Assuntos
Adenosina/farmacocinética , Espaço Extracelular/análise , Miocárdio/metabolismo , Adenosina/análise , Animais , Transporte Biológico , Capilares/metabolismo , Circulação Coronária , Dipiridamol/farmacologia , Endotélio Vascular/metabolismo , Feminino , Cobaias , Hemodinâmica , Técnicas In Vitro , MasculinoRESUMO
BACKGROUND: Pain at the injection site is one of the most commonly-reported local reactions associated with administration of a vaccine, but it has not been quantified by a validated instrument for pain measurement. We conducted a randomised, double-blind clinical trial to evaluate the measurement characteristics of two commonly-used pain questionnaires, the McGill Present Pain Intensity (PPI) and the Brief Pain Inventory (BPI) Current Pain Question, in the assessment of intramuscular injection-site pain associated with vaccine administration. The PPI measures pain on a scale of 0 (no pain) to 5 (excruciating pain) and the BPI measures pain on a scale of 0 (no pain) to 10 (pain as bad as you can imagine). METHODS: Two hundred healthy adults were randomised to one of the five regimens: tetanus and diphtheria toxoids adsorbed (Td), aluminum hydroxide adjuvant (alum), physiological saline, or one of the two licensed hepatitis A vaccines, VAQTA, or HAVRIX. Pain assessment was made at eight time-points over a 2-day period after injection. RESULTS: The differences in the time-averaged pain (+/- standard deviation) on the PPI were statistically significant between Td (0.58+/-0.59) and either saline (0.14+/-0.23) (p < 0.005) or alum (0.22+/-0.35) (p < 0.01). Reported time-averaged pain were significantly lower for VAQTA than HAVRIX (p = 0.028). Similar differences were observed for the BPI. CONCLUSIONS: Both instruments have sufficient discriminative validity to distinguish between different levels of injection-site pain in adults.