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At least 1,117 records · Page 62Linked to original sources
PubMed1999

Evaluation of antibody parameters as potential correlates of protection or enhancement by experimental vaccines to equine infectious anemia virus.

We previously demonstrated in trials of a variety of experimental vaccines to equine infectious anemia virus (EIAV) a remarkable spectrum of efficacy ranging from sterilizing protection to severe enhancement of virus replication and disease, depending on the immunization strategy used. This range of vaccine efficacy observed in vivo offers a unique opportunity for evaluating potential in vitro immune correlates of protection and enhancement. We describe here a comprehensive analysis and comparison of EIAV envelope-specific antibody responses elicited by attenuated, inactivated whole virus and envelope subunit vaccines to EIAV, and we evaluate the potential of in vitro antibody assays as correlates of protection or enhancement. Thus vaccine-induced serum antibody responses in experimentally immunized ponies at the day of challenge were assayed using a panel of quantitative, qualitative, and functional in vitro assays, including end-point titer of total and isotypic IgG, serum antibody avidity, conformational dependence, and serum neutralization. The results of these studies revealed substantial differences in the EIAV envelope-specific antibody responses elicited by the different vaccines, indicating the importance of envelope glycoprotein antigen presentation in determining the specificity of vaccine immunity. Although no single in vitro parameter provided a statistically significant correlate of protection or enhancement, the use of multiple parameters (titer, avidity index, and conformation ratio) could be used as a reliable correlate of vaccine protection and that the level of vaccine protection was closely associated with the development of mature antibody responses. These studies demonstrate the importance of using multiple antibody assays to evaluate lentiviral vaccine responses and emphasize the need for the development of new in vitro antibody assays that may provide more insight into vaccine protection and enhancement.

Animals↗
PubMed2006

Extracellular matrix and synaptic functions.

Comprehensive analysis of neuromuscular junction formation and recent data on synaptogenesis and long-term potentiation in the central nervous system revealed a number of extracellular matrix (ECM) molecules regulating different aspects of synaptic differentiation and function. The emerging mechanisms comprise interactions of ECM components with their cell surface receptors coupled to tyrosine kinase activities (agrin, integrin ligands, and reelin) and interactions with ion channels and transmitter receptors (Narp, tenascin-R and tenascin-C). These interactions may shape synaptic transmission and plasticity of excitatory synapses either via regulation of Ca2+ entry and postsynaptic expression of transmitter receptors or via control of GABAergic inhibition. The ECM molecules, derived from both neurons and glial cells and secreted into the extracellular space in an activity-dependent manner, may also shape synaptic plasticity through setting diffusion constraints for neurotransmitters, trophic factors and ions.

Agrin↗
PubMed2007

Elucidating the mode-of-action of compounds from metabolite profiling studies.

Metabolite profiling has been carried out for decades and is as such not a new research area. However, the field has attracted increasing attention in the last couple of years, and the term metabolome is now often used to describe the complete pool of metabolites associated with an organism at any given time. Mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy are the best candidates for comprehensive analysis of the metabolome and the application of these technologies is presented in this chapter. In this relation, the importance of efficient metabolite screening for discovery of novel drugs is discussed. Related to metabolite profiling, the principals underlying the application of labeled substrates to quantify in vivo metabolic fluxes are introduced, and the chapter is concluded by discussing the perspectives of metabolite measurements in systems biology.

Anti-Infective Agents↗
PubMed1983

Host resistance to metastasis from mouse mammary carcinomas.

Although undisturbed primary mouse mammary tumors may give rise to overt metastases, these have generally been observed near the terminal stage of progressive tumor growth. Unlike malignant breast disease in women, metastases are seldom the cause of death in mice, and in some strains as few as 2% of mammary tumor hosts may be affected (1). Highly metastatic tumors may, of course, be found, and hosts of the mammary carcinoma WHT all develop metastases (2). Evidence from animal models suggests that host defense reactions against immunogenic tumors may affect the incidence of metastatic spread (3-5). But nonimmunogenic and weakly immunogenic tumors probably represent the majority of mammary carcinomas (2, 6, 7), and this class was once considered outside control by the host. However, natural protective factors are also known which may prevent metastasis independently of specific antitumor immunity (8-10). There are therefore most likely several different biological factors and mechanisms which prevent circulating, viable cancer cells from developing into metastases. But one can not yet generalize whether natural resistance factors or induced resistance factors are the most important, or whether any resistance factors are as important in preventing metastases as is the basic unacceptability of cells in heterotopic locations. This review will not attempt to present a comprehensive analysis of cell-mediated and humoral immunity to mouse mammary tumors because this topic has recently been exhaustively treated in the reviews by Stutman (11) and Blair (12). We will focus primarily on information from in vivo investigations of the role of host resistance in the control of mammary tumor cells progressing through successive levels of metastasis from the primary tumor, through lymphatic or hematogenous dissemination, to colonization of distant organs.

Animals↗
PubMed1992

The microanatomy of canine islets of Langerhans: implications for intra-islet regulation.

In recent years models for the internal ("intra-islet") regulation of hormone secretion have been proposed to explain how different islet cells might regulate each other by means of their respective secretory peptides. Models that emphasize the importance of a directed intra-islet blood flow and sequence of perfusion of islet cells rely on a certain type of islet microanatomy and vascular supply. The experimental studies underlying these models have partly been performed in dogs. To extend the incomplete morphological knowledge of the canine endocrine pancreas both canine islets of Langerhans and extrainsular cells have been analysed in immunostained serial semithin (0.5 microns) sections. In addition to their occurrence within islets of Langerhans, all endocrine cell types are also found at extrainsular sites (about 9% of all endocrine cells) where they are distributed in different quantities among the epithelial lining of exocrine acini or excretory ducts and the connective tissue. There are continuous transitions from single extrainsular cells to small mono- and polycellular cell groups to islets. In a comprehensive analysis of whole islets, including computer-assisted three-dimensional reconstructions, the size, shape and vascularization of the islets as well as their cellular composition and the microtopology of islet cells have been studied. We have found marked intra- and inter-islet heterogeneities of the parameters investigated that are not compatible with concepts of a uniform and directed vascular perfusion of the various islet cell populations. Instead, their paracrine regulation may occur primarily via hormonal secretion into the intercellular spaces or vascular hormonal delivery to adjacent cells.

Animals↗
PubMed1983

Differential recognition of the serologically defined HLA-A2 antigen by allogeneic cytotoxic T cells. II. Definition of three HLA-A2 subtypes by CTLs.

A comprehensive analysis of human alloimmune cytotoxic T lymphocytes (CTLs) specific for the HLA-A2 antigen identified 11% of HLA-A2 positive cells as outliers. In total, 11 unrelated serologically indistinguishable, but distinguishable by cell-mediated lympholysis (CML) HLA-A2 positive outlier cells were identified. The outlier cells could be subdivided in two subgroups according to reactivity patterns obtained with CTLs directed against the HLA-A2 antigen of outlier cells and their inhibitory capacity in specific competitive inhibition experiments. Thus, the serologically defined HLA-A2 specificity can be divided into at least three subtypes using CTLs specific for the HLA-A2 antigen. Moreover, CTLs specific for an HLA-A2 subtype could be induced when responder cells expressed a different HLA-A2 subtype antigen. On the basis of several family studies, we conclude that the subtype HLA-A2 antigens are inherited in a codominant way.

Epitopes↗
PubMed1979

Influence of age and of desmotropic drugs on the step phenomenon observed in rat skin.

Comprehensive analysis of the mechanical properties of rat skin revealed the "step phenomenon". This particular observation was made after constant strain rate (analysis of stress strain curves) as well as after constant load (creep experiments). Relative low extensions or low loads were necessary to provoke the steps. In most cases two, sometimes three steps were observed. The step phenomenon was found mainly in skin strips punched out perpendicularly to the body axis. Probably some bonds in the fibrous network are broken giving way to additional elongation whereafter stronger links take over the stress. Since earlier studies demonstrated a pronounced influence of age and of desmotropic drugs on mechanical properties at ultimate load, e.g., tensile strength, ultimate modulus of elasticity, and ultimate strain, also the step phenomenon was studied under these conditions. In stress-strain experiments most of the steps were found at the ages of 2 and 4 months. Total stress loss and total work loss due to the steps were the highest at the age of 4 months. If, however, these values were calculated as percentage of ultimate values, the highest figures were found in young animals. Elongation gain due to the steps also showed a maximum at time of maturation, e.g., 4 months. Similar findings were achieved in creep experiments at medium load (200 g). After treatment with prednisolone acetate more steps and after treatment with D-penicillamine fewer steps were observed. In stress-strain experiments total stress loss and total work loss due to steps were more than twice as high than controls after prednisolone treatment and only one half after D-penicillamine. If calculated as percentage of ultimate stress or percentage of work input, these changes disappeared because of similar changes at ultimate load. However, elongation gain due to steps, which was not significantly influenced by prednisolone acetate but significantly decreased by D-penicillamine, showed the same changes when calculated as percentage of ultimate strain. Under all conditions the step phenomenon mainly influenced the extension parameters. The data presented here confirm earlier observations that mechanical properties at low loads or low and medium extensions show at least to some extent a different pattern under the influence of maturation and age and after treatment with desmotropic drugs compared to the mechanical parameters at ultimate load.

Aging↗
PubMed1989

Age-related effect induced by oxidative stress on the cerebral glutathione system.

In the forebrain from male Wistar rats aged 5, 15 and 25 months, age-related putative alterations in the glutathione system (reduced and oxidized glutathione; redox index) were chronically induced by the administration in drinking water of free radical generators (hydrogen peroxide, ferrous chloride) or of inhibitors of endogenous free radical defenses (diethyl-dithio-carbamate, an inhibitor of superoxide dismutase activity). In hydrogen peroxide administered rats, both reduced glutathione and the cerebral glutathione redox index markedly declined as a function of aging, whereas oxidized glutathione consistently increased. In contrast, chronic iron intake failed to modify the reduced glutathione in forebrain from the rats of the different ages tested, whereas the oxidized glutathione was increased in the older brains. The chronic intake of diethyl-dithio-carbamate enhanced the concentrations of reduced glutathione in the forebrains from the rats of the different ages tested, the oxidized glutathione being unchanged. In 15-month-old rats submitted to chronic oxidative stress, ergot alkaloids (and particularly dihydroergocriptine) interfered with cerebral glutathione system, while papaverine was always ineffective. The comprehensive analysis of the data indicates that: (a) both the type of oxidative stress and the age of the animals modulate the cerebral responsiveness to the putative modifiers in the level of tissue free radicals; (b) aging magnifies the cerebral alterations induced by oxidative stress; the (c) cerebral glutathione system may be modified by metabolic rather than by circulatory interferences; (d) a balance between the various cerebral antioxidant defenses is present, the perturbation of an antioxidant system resulting in the compensatory modified activity of component(s) of another system.

Administration, Oral↗
PubMed1995

Pharmacokinetics of human-mouse chimeric anti-GD2 mAb ch14.18 in a phase I trial in neuroblastoma patients.

A comprehensive analysis of the pharmacokinetics of human-mouse chimeric anti-ganglioside GD2 antibody mAb ch14.18 was performed during a phase I clinical trial of ten children with neuroblastoma and one adult with osteosarcoma. The patients received a total of 20 courses of ch14.18 at dose levels from 10 mg/m2 to 200 mg/m2. The plasma clearance of ch14.18 was biphasic. Following the first course of treatment t1/2,alpha was 3.4 +/- 3.1 h and t1/2,beta 66.6 +/- 27.4 h in 9/10 children. The t1/2,beta values were significantly less than those of 181 +/- 73 h previously reported in adult melanoma patients (P < or = 0.001), and 147.5 h in the adult osteosarcoma patient in our trial. The latter suggests different pharmacokinetics of mAb ch14.18 in children and adults. After a second course of treatment, administered to 5/10 children, t1/2,beta decreased significantly from 72.9 +/- 19.8 h to 31.7 +/- 18.4 h (P = 0.015). We therefore conclude that the elimination kinetics of mAbs ch14.18 in children and adults are different, and furthermore that repeated administration of mAb ch14.18 to children with neuroblastoma leads to accelerated antibody clearance.

Adult↗
PubMed1995

Pharmacokinetics of anti-ganglioside GD2 mAb 14G2a in a phase I trial in pediatric cancer patients.

A phase I trial of a murine anti-ganglioside (GD2) monoclonal antibody (mAb) 14G2a was conducted in 14 neuroblastoma patients and 1 osteosarcoma patient to assess its safety, toxicity and pharmacokinetics in pediatric patients. The pharmacokinetics of mAb 14G2a were biphasic with a t alpha 1/2 of 2.8 +/- 2.8 h and a t beta 1/2 of 18.3 +/- 11.8 h. In general, t beta 1/2 was dose-dependent with a level of significance of P = 0.036, and it reached a plateau at doses of 250 mg/m2 or more. Overall the peak serum levels were dose-dependent at P < 0.001. However, they demonstrated an abrupt increase between doses of 100 mg/m2 and 250 mg/m2. The latter two suggest a saturable mechanism for mAb elimination. In addition, peak serum concentrations were observed earlier at higher mAb doses, which indicates the achievement of a steady state. The t beta 1/2 of mAb 14G2a in children appears to be shorter than in adults. Furthermore, 2 patients demonstrated a considerable decrease in t beta 1/2 following retreatment with 14G2a. This was paralleled by high human anti-(mouse Ig) antibody levels. This study represents the first comprehensive analysis of murine mAb pharmacokinetics in children and will be useful in the future design of mAb therapy.

Adolescent↗
PubMed1987

Laterobasal membranes from intestinal epithelial cells: isolation free of intracellular membrane contaminants.

A simplified method for isolating highly purified laterobasal membranes (LBM) from enterocytes is based on treatment of membranes with 8 mM CaCl2 concentration in order to aggregate intracellular membrane contaminants. The resultant LBM showed an average 15-fold enrichment and constituted 8% of the original K-stimulated phosphatase in the initial crude homogenate. It showed typical LBM migration on counter-current distribution (CCD) and was essentially free of contamination with endoplasmic reticulum and Golgi membranes. This method is highly efficient and yields sufficient purified LBM to allow comprehensive analysis of enterocyte membrane events.

Animals↗
PubMed1995

Conserved nonplanar heme distortions in cytochromes c.

A nonplanar distortion of the heme of c-type cytochromes is conserved in the proteins isolated from diverse species based upon a comprehensive analysis of available high-resolution X-ray crystal structures. This distortion is induced through the cysteine thioether linkages between the porphyrin pyrrole groups and the polypeptide and results in an asymmetric pyrrole distortion. This asymmetry in the heme distortion is also conserved. For other heme proteins which lack these covalent bonds, nearly planar porphyrins are observed. Resonance Raman evidence indicates that nonplanar distortion of porphyrins containing metals, like iron, with large core sizes (> or = 2.00 A) is energetically unfavorable and can occur only in the presence of significant environmental perturbations. Further, energy minimization and dynamics calculations on the ferric form of yeast iso-1-cytochrome c, starting from the crystallographic coordinates and using a molecular mechanics force field which accurately reproduces nonplanar distortions in metalloporphyrins, suggest that this distortion is indeed maintained by the protein tertiary structure. It is proposed that this protein-linked heme distortion modulates electron transfer function through modification of redox potentials of the porphyrin ring and the protein binding properties of c-type cytochromes.

Cytochrome c Group↗
PubMed1995

Differential effects of clonidine, haloperidol, diazepam and tryptophan depletion on focused attention and attentional search.

As the catecholamines have long been implicated in attentional processes, the present investigation compared the effects of the mixed alpha 1/alpha 2 adrenoceptor agonist clonidine (CLO), the benzodiazepine diazepam (DZP), the D1/D2 antagonist haloperidol (HAL) and a low-tryptophan drink (Lo-TRP) on performance of tests of selective attention with distractors in four groups of young, healthy volunteers. Using a placebo-controlled, cross-over design, selective and dissociable effects on performance were found with each pharmacological manipulation. Specifically, CLO acted to broaden the focus of attention, HAL generally slowed reaction times during attentional search, and DZP and Lo-TRP produced differential effects on stimulus-response compatibility during attentional search. Furthermore, these results underline the usefulness of employing a single test with several neurochemical manipulations, allowing for a comprehensive analysis of the neurochemical basis of attention.

Adult↗
PubMed1989

Evolution of the immunoglobulin heavy chain variable region (Igh-V) locus in the genus Mus.

The evolution of the mouse immunoglobulin heavy chain variable region (Igh-V) locus was investigated by the comprehensive analysis of variable region (Vh) gene family content and restriction fragment polymorphism in the genus Mus. The examination of natural Mus domesticus populations suggests an important role for recombination in the generation of the considerable restriction fragment polymorphism found at the Igh-V locus. Although the sizes of individual Vh gene families vary widely both within and between different Mus species, evolutionary trends of Vh gene family copy number are revealed by the analysis of homologues of mouse Vh gene families in Rattus and Peromyscus. Processes of duplication, deletion, and sequence divergence all contribute to the evolution of Vh gene copy number. Certain Vh gene families have expanded or contracted differently in the various muroid lineages examined. Collectively, these findings suggest that the evolution of individual Vh family size is not driven by strong selective pressure but is relatively neutral, and that gene flow, rather than selection, serves to maintain the high level of restriction fragment polymorphism seen in M. domesticus.

Animals↗
PubMed1996

Energetics of lactation in harp seals (Phoca groenlandica) from the Gulf of St. Lawrence, Canada.

This study reports the findings of an integrated, comprehensive analysis of lactation energetics in harp seals conducted using longitudinal measurements of mass, body composition and milk composition from mother-pup pairs in conjunction with water flux measurements in pups. The nursing period of harp seals is a short, intense and relatively efficient period of energy transfer from mothers to pups. The average daily milk intake for pups was 3.65 +/- 0.24 kg which is equivalent to 79.5 MJ of energy. Eighty-one per cent of the energy received in the milk was metabolisable and 66% of the energy was stored by the pups as body tissue. The field metabolic rate of pups was 3.9 +/- 0.4 time basal metabolic rate. The pups were growing at a rate of 2.2 kg per day during the nursing period. The distribution of this mass gain varied in terms of tissue composition, depending on the age of the pups, but over the whole nursing period approximately half of the tissue was stored as fat. Harp seal mothers lost an average of 3.1 kg per day during lactation which was composed of 37% water, 50% fat, 11% protein and 2% ash. Mothers spent half of their time during the lactation period actively diving and only one-third of their time on the surface of the ice. Milk compositional changes followed the normal phocid pattern with increasing fat content and decreasing water content as lactation progressed. The mean mass transfer efficiency was 73%. However, this value cannot be used without qualification because female harp seals in this study fed to varying degrees, consuming an estimated 0-4.8 kg of fish per day. Feeding does not appear to be required in order to achieve the energy requirements for lactation, given the energy stores possessed by females, and some females do fast through the entire period so feeding may be considered opportunistic in nature.

Animals↗
PubMed1992

Effect of 5-HT1A receptor agonists in two models of anxiety after dorsal raphe injection.

The purpose of the present study was two-fold. Firstly, to present a more comprehensive analysis of the disinhibitory effects of 5-HT1A receptor agonists after discrete dorsal raphe (DRN) injections (Higgins et al. 1988). Secondly, the effects of the 5-HT1B receptor agonist CGS12066B and the 5-HT1B/1C agonist mCPP were examined following injection into this nucleus. The increases in social interaction (SI) induced by intra-raphe injections of 8-OH DPAT (0.02-1 micrograms), buspirone (0.04-0.2 microgram), ipsapirone (0.2 microgram) and gepirone (0.2-1 micrograms) under a high light unfamiliar paradigm (HLU) were typically due to increased bout frequency, duration and a higher incidence of sniff, follow, allogroom behaviour. These increases were qualitatively similar to those seen in control animals tested under low light/familiar (LLF) conditions, thus supporting the belief that the drug-induced increases in SI reflected decreases in anxiety. Furthermore, at doses effective under the HLU condition, 8-OH DPAT, buspirone and gepirone failed to modify SI under conditions of minimal suppression (LLF paradigm). At doses which significantly increased punished responding in a water-lick conflict test 8-OH DPAT, ipsapirone and gepirone tended to also increase unpunished rates of drinking. However, in drug untreated rats, prior habituation to the test apparatus also increased unpunished drinking, suggesting some neophobia-induced suppression. At a comparatively high dose, the 5-HT1B agonist CGS12066B (2.5 micrograms), but not the putative 5-HT1B/1C agonist mCPP (0.5-12.5 micrograms), increased SI under the HLU condition.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

Radiation doses in Europe after the Chernobyl accident.

In the course of the reactor accident at Chernobyl in 1986, large amounts of radioactive materials were released and spread over all of Europe and the rest of the world. A comprehensive analysis of the resulting radiation doses is still in progress through the United Nations Scientific Committee on the Effects of Atomic Radiations. This review lists the most significant nuclides involved and the most significant pathways of exposure. Preliminary estimates of radiation doses made by various organisations are presented. Particular emphasis is given to the collective effective dose equivalent which is important for the assessment of the possible future incidence of leukemia and cancer from the accident. This quantity amounted to about 200,000 mansievert for Europe outside of the Soviet Union, and about twice as much for the European part of the Soviet Union, for the first 50 years after the accident. The uncertainty in these estimates should be less than a factor of three up or down. According to the hypothesis of a linear dose-effect relationship this dose could be calculated to result in 6000 extra cases of cancer and hereditary disease, 4000 of which would be fatal, during 100 years in Europe outside the Soviet Union.

Accidents↗