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PubMed2003

Prediction of initial cytogenetic response for subsequent major and complete cytogenetic response to imatinib mesylate therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia.

BACKGROUND: Obtaining a major (Philadelphia chromosome [Ph] of < 35%) or a complete cytogenetic response (Ph of 0%) has been associated with excellent long-term survival. Cytogenetic response may continue to improve with therapy. Because early allogeneic stem cell transplantation (SCT) may be associated with a better outcome, early parameters predicting for subsequent cytogenetic responses would optimize the treatment decision-making. METHODS: The current study was performed to analyze whether early cytogenetic responses may be predictive of later major or complete cytogenetic responses to imatinib mesylate therapy in patients with Ph-positive chronic myelogenous leukemia (CML). RESULTS: Two hundred sixty-one patients with Ph-positive, chronic-phase CML after failure with interferon therapy who were treated with imatinib mesylate therapy were analyzed. A persistence of 100% Ph-positive cells after > or = 6 months of imatinib mesylate therapy was associated with a major cytogenetic response rate of 9-13% and a complete cytogenetic response rate of 0-4%. However, a minor cytogenetic response after 3-12 months of therapy still was associated with high rates of major (68-83%) or complete (35-54%) cytogenetic response rates. CONCLUSIONS: Patients with Ph-positive, chronic-phase CML who have persistent 100% Ph-positive disease after > or = 6 months of imatinib mesylate therapy may be offered allogeneic SCT or considered for alternative investigational therapies.

Benzamides↗
PubMed1990

Type 6 and 19 pneumococcal polysaccharides coupled to erythrocytes elicit pneumococcal cell wall-specific primary IgM responses and capsular polysaccharide-specific secondary IgG responses.

Previous results have shown that the primary murine antibody responses to vaccine preparations of type 6 (S6; Danish type 6A) or type 19 (S19; Danish type 19F) pneumococcal capsular polysaccharides consist entirely of IgM antipneumococcal cell wall carbohydrate (PnC)-specific antibodies. No capsular polysaccharide-specific IgM antibodies were detectable by plaque-forming cell or enzyme-linked immunosorbent assay techniques. In this report, antibodies specific for S6 and S19 capsular polysaccharides were induced in secondary responses to chicken erythrocyte (CRBC) conjugates of S6 and S19. Essentially all detectable IgG produced in the secondary response was capsular polysaccharide specific and included all subclasses of IgG. In contrast, all detectable IgM produced in the primary response to S6-CRBC and S19-CRBC, and the IgM produced in the secondary response to S6-CRBC was not capsular polysaccharide specific since it reacted with PnC. Thus, there is a major change in the specificity of the primary IgM response compared to the secondary IgG response of mice immunized with S6-CRBC or S19-CRBC. Injection of PnC or any PnC-containing polysaccharide prior to immunization with S6-CRBC or S19-CRBC resulted in suppression of the primary IgM response. In contrast, only the capsular polysaccharide used in the immunizing polysaccharide-erythrocyte conjugate suppressed induction of the capsular polysaccharide-specific secondary IgG response. These results suggest that S6 and S19 capsular polysaccharide-specific IgG-producing memory B cells derive from capsular polysaccharide-specific precursors which do not produce detectable antibody after primary immunization.

Animals↗
PubMed1993

The expression of CD45RB on antigen-responsive CD4+ lymphocytes: mouse strain polymorphism and different responses to distinct antigens.

The levels of CD45RB expression by HGG-specific CD4+ cells residing in the Ag-draining lymph nodes of HGG-primed CBA/CaJ mice were analyzed. When sorted populations of CD4+, CD45RBhi, and CD4+, CD45RBlo cells were cultured with HGG and Ag-presenting cells, the majority of the proliferative response was found in the CD45RBlo fraction early after in vivo priming (Day 6), and this pattern remained stable through 12 days postpriming. To determine whether this segregation of responsiveness was consistent in other mouse strains, HGG-primed C57BL/6J mice were similarly analyzed. In contrast to findings with the CBA/CaJ strain, the CD4+, CD45RBhi cell fraction obtained from C57BL/6J mice was the predominant responding population early after in vivo priming (Day 6); however, there was a parallel increase in responsiveness of CD4+, CD45RBhi, and CD4+, CD45RBlo cells by Day 12. Thus, there was not a decrease in CD45RBhi expression with a concommitant increase in CD45RBlo expression in CD4+ cells proliferating to HGG. Despite the heterogeneity in CD45RB expression by the primed CD4+ cells of the two strains, the entire proliferative response to HGG early after priming resided in the fraction bearing high levels of membrane CD44, thus arguing for the existence of CD45RBhi, CD44hi and CD45RBlo, CD44hi cells during the early phase of the response. In both mouse strains the CD4+, CD45RBhi subset of primed lymph node cells produced significant levels of IL-2 in response to HGG and APC, whereas no significant IL-2 or IL-4 production was detectable in HGG-stimulated CD45RBlo cells of either strain. The CD4+, CD45RBhi subset also proliferated more vigorously in response to polyclonal activation than the CD4+ CD45RBlo fraction. To examine whether the patterns of CD45RB expression on HGG-primed cells from C57BL/6J mice were common to other antigens, the response profiles were examined after in vivo priming with a second antigen, KLH. In contrast to studies with HGG as the Ag, the proliferative response to KLH in C57BL/6J mice was evenly divided among the CD45RBhi and CD45RBlo fractions on Day 8 after priming, but shifted markedly to the CD45RBlo fraction by Day 12 after priming. Taken together, these data show that the patterns of CD45RB expression on primed populations of CD4+ cells can exhibit mouse strain polymorphism and can differ depending on the choice of antigen for immunization.

Animals↗
PubMed1997

Lack of T cell response to cardiac myosin and a reduced response to PPD in patients with idiopathic dilated cardiomyopathy.

Idiopathic dilated cardiomyopathy (IDCM) is the main cause of cardiac transplantation in young adults in the 20-40 years age group in the Western world. Recent evidence supports a possible role for autoimmune pathogenesis in IDCM and it has been suggested that T cells could mediate the disease. Cardiac myosin is one of the putative autoantigens recognized by antibodies from patients with IDCM, but T cell responses to cardiac myosin have not previously been assessed. Proliferation to cardiac myosin by peripheral blood mononuclear cells (PBMC) from patients, their relatives and controls was assessed in a lymphoproliferation assay specifically designed to measure low frequency T cell precursor responses. The study group consisted of 23 patients with IDCM and 29 relatives. The control groups consisted of 10 patients with heart failure secondary to ischaemic heart disease (IHD) and 22 healthy laboratory controls. A response to myosin was observed in 16.7% of the subjects studied. However, these responses were all of low precursor frequency and no dose response for antigen-specific proliferation could be observed. More importantly, there was no correlation between myosin-specific T cell responses and IDCM, as only one IDCM patient and four IDCM relatives (three out of the four with left ventricular enlargement (LVE)) were among the 14 subjects whose PBMC exhibited a proliferative response. However, proliferation of PBMC to purified protein derivative of Mycobacterium bovis (PPD) was significantly suppressed in IDCM patients when compared with the laboratory control group (P<0.05). PPD response data suggested that the PPD suppression correlated with disease progression. The results of our present study indicate an absence, or lack, of cardiac myosin-specific peripheral blood T cells in IDCM patients, along with the possibility of underlying impaired cell mediated immunity, reflected in the suppressed responses to PPD. Future studies looking at T cell immune mechanisms in IDCM should concentrate on the analysis of T cells from the heart itself, or look at other potential cardiac antigens from normal and diseased heart tissue.

Adolescent↗
PubMed1992

PreS antigen expression and anti-preS response in hepatitis B virus infections: relationship to serum HBV-DNA, intrahepatic HBcAg, liver damage and specific T-cell response.

The diagnostic value of preS antigens and anti-preS antibodies during Hepatitis B virus (HBV) infections have not yet been clearly elucidated. Therefore, the objectives of this study were: 1) to better understand the clinical significance of the expression of both preS1 and preS2 antigens (preS1Ag and preS2Ag) in the serum of chronic HBsAg carriers, and 2) to define the respective role of antibody responses to HBs-, preS2- and preS1-specific determinants in the course of acute hepatitis B (AH-B) infections with different outcomes. Our data showed that the serum preS1Ag/HBsAg ratio correlated well with the level of viral replication (serum HBV-DNA as monitored by PCR assay and liver HBcAg), especially in anti-HBe positive chronic carriers. The complete eradication of virions required a persistent antibody response to conformation-dependent HBs-epitopes, temporally associated with a vigorous T cell response to nucleocapsid antigens. Recovery from hepatitis B can be achieved when there is no early antibody response to preS2- and preS1-proteins, which was found to be transient, concomitant with a flare-up of the liver disease, and preceding anti-HBs production. Information on the patterns of preS antigens and their antibodies remained clouded because of the varying specificities and sensitivities of research methods used in studies to date. We have, therefore, developed original Polyclonal-Monoclonal RadioImmunoAssays (PAb-MAb RIAs) by using monoclonal antibodies (MAbs) having previously well-defined specificities. We could thus detect and quantify simultaneously the three distinct antigenicities of the HBV envelope, HBsAg, preS2Ag and preS1Ag, with the same sensitivity. In this way, the preS1Ag/HBsAg and preS2Ag/HBsAg ratios can be calculated to estimate the serum expression of both preS1Ag and preS2Ag in relation to total HBsAg activity during different stages of chronic HBV infection. For optimal management of the state of HBV replication in chronic viral infection, the detection of HBV-DNA in serum was monitored by the Polymerase Chain Reaction (PCR) assay. We extended our work by investigating the clinical significance of antibody response to preS-specific determinants in patients with AH-B showing different outcomes in both natural course or response to alpha-interferon therapy. In a first attempt, we chose to use the Western Immuno-Blotting Assay (WIBA) to obtain a qualitative assessment of the nature of preS antibody responses. Finally, the cell-mediated immune response to HBV antigens was also studied in several patients with self-limited AH-B leading to a relevant finding which may help to clarify the mechanisms responsible for complete clearance of HBV.

Acute Disease↗
PubMed1991

Sugar response element enhances wound response of potato proteinase inhibitor II promoter in transgenic tobacco.

The promoter region of the potato proteinase inhibitor II (PI-II) gene was studied to identify cis-acting regulatory sequences involved in sugar response using transgenic tobacco plants. The 5' control region covering an 892 nucleotide sequence upstream from the cap site and a 32 nucleotide untranslated region of the PI-II promoter was able to activate a reporter chloramphenicol acetyltransferase (cat) gene by wounding or by incubating in a sugar-free medium. This wound response was further enhanced by sugar. Hexoses, disaccharides, and some trisaccharides were strong inducers whereas pentoses, deoxy sugars, sugar acids, TCA cycle intermediates, amino acids, and other carbohydrates had little effect on the promoter activity. Deletion of the sequence between -892 and -573 abolished the wound response but not the sugar response. An additional 5' deletion to -453 removed the sugar inducibility. Locations of the cis-acting regulatory elements were further elucidated by 3' deletion analysis. Deletion of the downstream region from -520 did not affect the wound or sugar response of the promoter. However, 3' deletion mutant -574 was unable to respond to sugar but did respond weakly to wounding. Further deletion to -624 abolished both responses. Therefore, it can be concluded that a wound response element is located in between -624 and -574 and that the response is further enhanced by a sugar response element located in the sequence between -573 and -520.

Agrobacterium tumefaciens↗
PubMed1985

A parametric description of amphetamine's effect on response rate: changes in reinforcement efficacy and response topography.

A mathematical model was used to describe the effects of amphetamine on the rate of a reinforced response in the rat. The model provides measures of reinforcement efficacy and response topography for behavior maintained by variable-interval reinforcement schedules. In this study the measured behavior was a lever press, the reinforcer was water, and the variable-interval schedules provided five different rates of reinforcement, ranging from about 20 to 660/h. In each session the rats were exposed to each of the five schedules, and as reinforcement rate increased, the rate of lever pressing increased in a negatively accelerated manner that was closely approximated by the equation for a rectangular hyperbola. Amphetamine changed response rate and the parameters of the best-fitting hyperbolas. The 0.25-1.0-mg/kg doses increased response rate, and the parameter changes supported the interpretation that the increases were due primarily to an increase in reinforcement efficacy. The 2.0- and 3.0-mg/kg doses decreased response rates maintained by low reinforcement rates and increased response rates maintained by high reinforcement rates, and the parameter changes supported the interpretation that at higher doses amphetamine produced counteracting changes in reinforcement efficacy and response topography: reinforcement efficacy decreased, whereas response topography changed so as to increase response rates.

Animals↗
PubMed1984

Ultrasound elicits tonic responses and diminishes the phasic responses to adequate stimuli in thread-hair mechanoreceptors of Acheta domesticus.

Single mechanoreceptor cells in filiform hair sensilla on the cercus of Acheta domesticus were stimulated adequately by steplike deflections in their plane of least restraint and inadequately by ultrasound. Ultrasound was fed either into the cercus or into the thread-hair as substrate-borne sound of 110-120 kHz. The receptor responds to deflections of the thread-hair (adequate stimuli) with phasic receptor potentials which can be picked up transepithelially . These responses can be either depolarizing (excitatory responses) or hyperpolarizing (inhibitory responses). Ultrasound applied simultaneously or shortly preceding the adequate stimulus reduces both kinds of responses in a graded way. The receptor can respond to ultrasound alone. At small intensities the responses are predominantly inhibitory; with increasing intensity they may become excitatory. In both cases the responses to ultrasound are tonic and do not reach the peak responses to saturating adequate stimuli. The "off-effect", which follows adequate stimuli and leads to inhibitory responses after excitatory stimuli and vice versa, typically does not occur or is excitatory at the end of sonication. The observed effects of sonication are totally reversible. The correlation between transepithelial voltage, spike frequencies and spike amplitudes in the unsonicated and sonicated sensilla allows the responses to be attributed to sonication to the same conductance, which is also modulated by adequate stimuli. A model is discussed, according to which ultrasound exerts its effects by facilitating dissipative relaxation in the dendritic membrane, which is assumed to be involved in stimulus-energy transfer.

Animals↗
PubMed1995

Mechanisms of coronary hyperconstriction in response to serotonin induced by X-irradiation in miniature pigs: increased constrictive response of medial smooth muscle.

Experimental and clinical studies suggest that X-irradiation to the coronary artery may enhance vasoconstrictive response. This study aimed to clarify the effect of X-irradiation on the vasomotor response of porcine coronary artery. X-ray (15 Gy) was selectively irradiated to the left anterior descending coronary artery (LAD) in 14 Göttingen miniature pigs. The coronary vasomotor responses to serotonin at the irradiated site (LAD) and the control site (the left circumflex artery; LCX) were assessed by quantitative arteriography before and 1 h and 1, 2, and 4 weeks after X-irradiation. At 2 weeks, endothelium-dependent vasodilation in response to substance P was also evaluated arteriographically in vivo. At 2 weeks, isometric tension studies were performed to evaluate the constrictive responses of medial muscle strips and endothelium-dependent relaxation. Coronary vasoconstriction in response to serotonin was enhanced 1 week after, and further augmentation was noted 2 and 4 weeks after X-irradiation. Endothelium-dependent vasodilation in response to substance P in vivo was preserved 2 weeks after X-irradiation. Coronary arteriography showed no organic stenosis at the irradiated site. In vitro studies demonstrated that medial muscle strips of the irradiated site showed hypercontraction in response to serotonin and that endothelium-dependent relaxation in response to serotonin and substance P was preserved at the irradiated site. A histological study revealed no appreciable changes of the endothelial cells or intimal thickening.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Response-dependent versus response-independent presentation of cocaine: differences in the lethal effects of the drug.

The drug self-administration paradigm is routinely used to assess the abuse liability of psychoactive compounds. Investigations of the behavioral effects of drug use, however, often involve the response-independent (experiment-delivered) administration of the compound. It is frequently assumed that response-independent presentation of a compound has the same effects as response dependent deliveries. The present study examined directly the effects of response-dependent (self-administered) versus response-independent (experimenter-delivered) administration of cocaine on food intake and lethality. Littermate triads were exposed to either cocaine (0.33 mg/infusion) or saline using a yoked-box procedure. One member of the triad self-administered the drug under a fixed-ratio 2 schedule. The other two rats received response-independent infusions of either cocaine or saline. Groups of triads were exposed to two different cocaine access conditions. Daily sessions were terminated after 6 h for one group and after the delivery of 80 infusions for the other. The mean number of infusions delivered each session was 47 (+/- 12) and 70 (+/- 11), respectively, for the 6-h and 80-infusion condition. Under the 80-infusion condition, response-independent infusions of cocaine resulted in a significantly higher rate of mortality compared to littermates self-administering identical amounts of the drug. A fewer number of deaths occurred under 6-h condition; however, only rats exposed to response-independent infusions died under both access conditions. These data indicate that the presence or absence of response dependency can profoundly alter the lethal effects of cocaine.

Animals↗
PubMed1991

The repertoire diversity and magnitude of antibody responses to bacterial antigens in aged mice: I. Age-associated changes in antibody responses differ according to the mouse strain.

Aging influences the host immune responses in various ways. In aging mice we have studied the antibody responses to two unrelated bacterial antigens. Streptococcus pneumoniae R36a vaccine (Pn) and TNP coupled to Brucella abortus (TNP-BA). Aged animals (20-24 months old) of the C57BL/6 strain had markedly reduced numbers of IgM antibody plaque-forming cells (PFC) to Pn as compared to young/adult mice (2-3 months old). In contrast, the anti-Pn IgM PFC responses of aged BALB/c mice were consistently higher than they were in the young/adult mice. The increased anti-Pn responses were not due to a nonspecific immunostimulation, because the responses of aged BALB/c mice to TNP-BA were lower as compared to the adults. However, the aged BALB/c mice responded relatively poorly to Pn challenge, and their IgG responses (as determined by ELISA plaque assay) demonstrated a very high individual variability. The clonotypic diversity of anti-Pn response in young BALB/c and C57BL/6 is limited, such that the majority of PFC produce antibody that express all idiotopes (Id) of the T15 immunoglobulin encoded in the VH-S107/Vk22 genes. In contrast, the PFC from aged mice are diverse, expressing incomplete T15 Id or none at all, suggesting that the antibodies are encoded by altered T15 genes and by different, non-T15 genes. Our data demonstrate that the age-related changes in the magnitude of antibody response to certain antigens are influenced by the host genetic make-up, and that the changes in magnitude and diversity of antibody response may be unrelated to each other.

Aging↗
PubMed1992

Resistance of beta 2-adrenoceptor-mediated responses of lung strips to desensitization by long-term agonist exposure--comparison with atrial beta 1-adrenoceptor-mediated responses.

In vitro desensitization of beta 2-adrenoceptor-mediated relaxation of guinea-pig isolated parenchymal strips was examined. Concentration-response curves for isoprenaline were obtained and after long-term incubation with isoprenaline, followed by washout, a second curve was obtained. Correction for time-dependent loss of sensitivity was made from time-matched controls. After incubation with 10(-5) M isoprenaline for 0.5, 1, 2, 4 and 8 h, loss of responsiveness of carbachol-contracted lung strips was observed after 4h as a reduced post-incubation maximum response. When the concentration was reduced to 10(-6) M, a 4 h incubation with 1 h washout no longer induced a shift of the post-incubation curve in carbachol-contracted lung strips. In contrast, lung strips with intrinsic tone displayed reduced responsiveness to isoprenaline after 4 h incubation with 10(-6) M isoprenaline. Incubation of the tissue for 4 h with lanthanum (1.4 x 10(-6) M), a relaxant not operating through beta 2-adrenoceptors or their effector coupling, had the same effect upon isoprenaline concentration-response curves as incubation with isoprenaline. This was irrespective of whether intrinsic tone (10(-6) M isoprenaline) or carbachol-contracted (10(-5) M isoprenaline) lung strips were used. It was concluded that the loss of beta 2-adrenoceptor responsiveness after incubation with 10(-6) M isoprenaline was due to the prolonged maximal relaxation of the tissue for 4 h rather than desensitization of the beta 2-adrenoceptor. Indeed, after correction for maximal relaxation and for time, no significant change in beta 2-adrenoceptor sensitivity of the lung occurred after incubation with 10(-6) M isoprenaline for 4 h. This contrasts with significant rightwards shifts of the concentration-response curves for the beta 1-adrenoceptor-mediated increases in rate and tension of guinea-pig right and left atria after identical incubation conditions. Thus whereas beta 1-adrenoceptor-mediated responses displayed desensitization after long-term in vitro agonist exposure, the beta 2-adrenoceptor-mediated responses were resistant.

Adrenergic beta-Agonists↗
PubMed1985

The primary immune response in bronchial asthma. I. A kinetic study of Helix pomatia hemocyanin-specific IgE, IgG, IgA, and IgM antibody responses in patients with asthma and in matched controls.

Eleven asthmatic patients with allergy and 10 age- and sex-matched controls were immunized subcutaneously with 1 mg of the primary test immunogen Helix pomatia hemocyanin (HPH). The HPH-specific IgE, IgG, IgA, and IgM antibody response was measured by ELISA. After immunization, not only the IgE but also the IgG antibody response of the patients exceeded that of the controls (p less than 0.01). IgA antibody response also tended to be higher in the asthmatic group (NS). Except for an earlier rise after immunization in the asthmatic group (p less than 0.05), IgM peak responses did not differ significantly between the two groups. There was a high correlation (r = 0.9) between the magnitude of the IgE and the IgG antibody responses. IgM antibody response did not correlate with the response in any of the other antibody classes measured. The total serum immunoglobulin concentration was determined before immunization. Only the IgE level was significantly higher in the asthmatic group (p less than 0.01). No correlation was found between serum immunoglobulin concentrations and the magnitude of the HPH-specific antibody response in the same class. We conclude that the increased humoral responsiveness of asthmatic patients with allergy is not restricted to the IgE class nor to a limited number of commonly encountered antigens (allergens).

Adult↗
PubMed1988

Cutaneous allergic response in atopic dogs: relationship of cellular and histamine responses.

We studied the cutaneous response to intradermal antigen using clinical, histologic, and physiologic criteria in ragweed-sensitized dogs. The clinical response was measured early (the wheal at 20 minutes) and late (induration at 6 hours). We assessed cutaneous responsiveness to histamine before and 6 hours after injection (intradermally) of ragweed (n = 5, antigen group) and diluent (n = 4, 10% glycerin in 0.9% NaCl, sham group); we measured the wheal in response to histamine (1.0 ng to 0.1 mg, intradermally), constructed a dose-response curve, and interpolated the provocative dose (milligrams) of histamine required to create a wheal 10 mm larger than the response to saline control. Skin biopsy specimens were obtained before and after injection of either ragweed or diluent. Consistent with the human late-phase response, neutrophils and eosinophils were present in the dermis at 1 hour, maximal at 6 hours, and decreased at 24 hours. Mononuclear cells increased significantly at 6 hours and were the predominant cells present at 24 hours after antigen. The late clinical response correlated only with influx of eosinophils (rs = 0.85; p less than 0.005). Histamine responsiveness increased markedly after antigen (p less than 0.0001), did not change after glycerin diluent (sham), and was correlated with the intensity of neutrophil influx at 6 hours (rs = 0.69; p less than 0.05), and to a much greater degree with mononuclear cell influx at 6 hours (rs = 0.85; p less than 0.005).

Animals↗
PubMed2006

Virus and virus-like particle-based immunogens for Alzheimer's disease induce antibody responses against amyloid-beta without concomitant T cell responses.

A vaccine targeting the amyloid-beta (Abeta) peptide is a promising potential immunotherapy for Alzheimer's disease patients. However, experience from a recent clinical trial of a candidate Abeta vaccine has suggested that it is important to develop techniques to induce high titer antibodies against Abeta associated with vaccine efficacy while reducing the T cell responses against Abeta that were potentially responsible for serious side effects. We have previously demonstrated that immunization with self- and foreign antigens arrayed in a repetitive fashion on the surface of virus-like particles (VLPs) induces high titer antibody responses at low doses and in the absence of potentially inflammatory adjuvants. In this study, we examined the antibody and T cell responses upon immunization with human papillomavirus VLP- and Qbeta bacteriophage-based Abeta vaccines. Immunization with Abeta conjugated to VLPs or Qbeta elicited anti-Abeta antibody responses at low doses and without the use of adjuvants. The flexibility of these virus-based display systems allowed us to link and induce antibodies against short Abeta-derived peptides from the amino- and carboxyl-termini of the peptide. Immunization of mice with Abeta peptide in combination with Freund's adjuvant elicited predominantly IgG2c antibodies and strong T cell proliferative responses against Abeta. In contrast, VLP-conjugated Abeta peptides elicited more balanced isotype responses, dominated by IgG1. Both VLP and Qbeta-based Abeta vaccines induced weak or negligible T cell responses against Abeta. T cell responses were largely directed against linked viral epitopes. Taken together, virus-based vaccines that allow the presentation of Abeta in a repetitive dense array are new and potentially more effective vaccine candidates for Alzheimer's disease.

Allolevivirus↗
PubMed1999

Multiple single units and population responses during inhibitory gating of hippocampal auditory response in freely-moving rats.

Paired clicks were presented to awake, freely-moving rats to examine neuronal activity associated with inhibitory gating of responses to repeated auditory stimuli. The rats had bundles of eight microwires implanted into each of four different brain areas: CA3 region of the hippocampus, medial septal nucleus, brainstem reticular nucleus, and the auditory cortex. Single-unit recordings from each wire were made while the local auditory-evoked potential was also recorded. The response to a conditioning stimulus was compared to the response to a test stimulus delivered 500 ms later: the ratio of the test response to the conditioning response provided a measure of inhibitory gating. Auditory-evoked potentials were recorded at all sites. Overall, brainstem reticular nucleus neurons showed the greatest gating of local auditory-evoked potentials, while the auditory cortex showed the least. However, except for the auditory cortex, both gating and non-gating of the evoked response were recorded at various times in all brain regions. Gating of the hippocampal response was significantly correlated with gating in the medial septal nucleus and brainstem reticular nucleus, but not the auditory cortex. Single-unit neuron firing in response to the clicks was most pronounced in the brainstem reticular nucleus and the medial septal nucleus, while relatively few neurons responded in the CA3 region of the hippocampus and the auditory cortex. Taken together, these data support the hypothesis that inhibitory gating of the auditory-evoked response originates in the non-lemniscal pathway and not in cortical areas of the rat brain.

Animals↗
PubMed1998

Hostility and adrenergic receptor responsiveness: evidence of reduced beta-receptor responsiveness in high hostile men.

We examined the relation of Cook and Medley Hostility (Ho) scores to alpha- and beta-adrenergic receptor responsiveness to pharmacological agonists in 22 normotensive and 14 hypertensives (aged 18-34) white males, matched for age and body mass. alpha-Adrenergic receptor responsiveness was measured by the phenylephrine dose required to increase mean blood pressure by 25 mmHg (PD25). beta-Adrenergic responsiveness was measured by the isoproterenol dose needed to increase heart rate by 25 bpm (CD25), and to lower systemic vascular resistance by 40% (VD40). Relative to men with low Ho scores (< or = 21), men with high Ho scores (> or = 21) showed significantly reduced vascular beta 2-adrenergic receptor responsiveness (VD40). Moreover, the decreased vascular responsiveness was more pronounced in borderline hypertensive men with high Ho scores. Ho scores were also marginally significant in predicting cardiac beta 1- and beta 2-adrenergic receptor responsiveness, such that men with high Ho scores showed decreased responsiveness as indexed by a larger CD25. Vascular alpha 1-adrenergic responsiveness was not associated with hostility. These observations suggest that hostility, alone or in conjunction with BP status, is associated with reduced cardiovascular beta-adrenergic receptor responsiveness.

Adolescent↗
PubMed1996

Effect of thermal injury on the expression of transcription factors that regulate acute phase response genes: the response of C/EBP alpha, C/EBP beta, and C/EBP delta to thermal injury.

BACKGROUND: Eukaryotic organisms possess natural defense mechanisms that protect against stress stimuli. One such mechanism is the activation of families of stress response genes (e.g., the acute phase response). Transcription of many of these genes is regulated by the leucine zipper or bZIP proteins (CCAAT binding/enhancer binding proteins [C/EBPs]). The aim of this study was to show that the C/EBP transcription factor genes respond to thermal injury. METHODS: Age- and weight-matched male Buffalo, Sprague-Dawley, and Fischer 344 12- to 16-week-old rats (275 to 325 gm) received a 40% total body surface area scald burn. Total RNA was isolated from livers at 0, 2, 5, 12, 24, and 48 hours. Northern blot hybridization was performed with 32P-labeled C/EBP alpha, C/EBP beta, and C/EBP delta cDNAs. Relative amounts of each mRNA were determined by densitometric analyses. For Western analyses liver nuclear and cytoplasmic protein extracts were prepared from burned and control rats. Nuclear protein extracts were resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, blotted onto a PVDF membrane, and detected by using an enhanced chemiluminescence detection kit. RESULTS: Expression of C/EBP genes is regulated in response to 40% total body surface area scald burn. A simultaneous decrease in C/EBP alpha and an increase in C/EBP beta and C/EBP delta mRNA levels occur in response to thermal injury. Western analyses detect changes in C/EBP alpha and C/EBP beta pool levels that suggest a differential regulation of these genes in response to thermal injury. CONCLUSIONS: The responses of C/EBP alpha, C/EBP beta, and C/EBP delta are similar in Buffalo, Sprague-Dawley, and Fischer rats. The induced level, however, of C/EBP beta mRNA was highest in the Sprague-Dawley strain and lowest in the Buffalo strain and correlates well with the mortality of these strains. Because C/EBP beta is associated with the transactivation of stress response genes, this may explain the intensity of the response in the susceptible strains. This agrees with our hypothesis that the higher degree of sensitivity of the Sprague-Dawley rat to stress relative to the Buffalo strain may be due to inherently higher levels of factors such as C/EBP whose functions are associated with activation of stress response genes.

Acute-Phase Reaction↗