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PubMed1999

Orphanin FQ (nociceptin) modulates responses of trigeminal neurons evoked by excitatory amino acids and somatosensory stimuli, and blocks the substance P-induced facilitation of N-methyl-D-aspartate-evoked responses.

The present investigation details the modulation of medullary dorsal horn neuron responses to excitatory amino acids and peripheral cutaneous stimuli by orphanin FQ (nociceptin), an endogenous ligand for the opioid receptor-like, receptor. Effects of orphanin FQ, administered microiontophoretically or given intracerebroventricularly, were tested on the responses of nociceptive-specific, wide dynamic range and low threshold neurons recorded in the superficial and deeper dorsal horn of the medulla (trigeminal nucleus caudalis) in anesthetized (urethane or pentobarbital) male rats. Microiontophoretic application of orphanin FQ reduced the N-methyl-D-aspartate-evoked responses in 86% (71/82) of neurons, and the (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid-evoked responses in 86% (30/35) of neurons. However, orphanin FQ produced a longer lasting inhibitory effect on the N-methyl-D-aspartate-evoked responses relative to the (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid-evoked responses. The inhibitory effect of orphanin FQ was not modality-specific, responses evoked by noxious as well as non-noxious stimuli were reduced in 22/23 neurons. However, the inhibitory effect was more pronounced on noxious stimulus-evoked responses. Naloxone applied at currents that antagonized the inhibitory effects of selective agonists at mu and kappa opioid receptors failed to inhibit the effects of orphanin FQ. Microiontophoretic co-application of substance P with N-methyl-D-aspartate facilitated the N-methyl-D-aspartate-evoked responses in 52% (26/50) of nociceptive neurons. Orphanin FQ blocked or reduced the substance P-induced facilitation by 86+/-24.4% (n = 14). In order to compare electrophysiological data with previous behavioral observations, effects of orphanin FQ administered intracerebroventricularly were tested on the excitatory amino acid-evoked responses. Orphanin FQ reduced the N-methyl-D-aspartate-evoked responses in 85% (11/13) of neurons whereas the (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid-evoked responses were facilitated in 69% (9/13) of neurons. We suggest that orphanin FQ produces a predominantly inhibitory effect on, (i) noxious stimuli evoked responses, (ii) excitatory amino acid receptor-mediated transmission and, (iii) the substance P-induced facilitation of the N-methyl-D-aspartate-evoked responses. We conclude that orphanin FQ primarily produced an antinociceptive action at the level of the dorsal horn of the medulla.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1996

Comparison between allergen-induced and exercise-induced asthma with respect to the late asthmatic response, airway responsiveness, and Creola bodies in sputum.

BACKGROUND: The difference between allergen-induced asthma and exercise-induced asthma with respect to the late asthmatic response and airway responsiveness has not been well elucidated. OBJECTIVE: We compared the incidence of late asthmatic response, the changes in airway responsiveness, the degree of epithelial desquamation, and the activation of eosinophils in the airways after induction of allergen-induced asthma and exercise-induced asthma. METHODS: Allergen-induced asthma or exercise-induced asthma was provoked in asthmatic patients, and sputum was collected before challenge and at the immediate asthmatic response and the late asthmatic response. Clusters of columnar epithelial cells in sputum (Creola bodies) were detected to evaluate respiratory epithelial damage, and the sputum eosinophil cationic protein (ECP) concentration was measured to evaluate eosinophil activation in the airways. Airway responsiveness was measured before and 48 hours after the challenge. RESULTS: The maximal % fall in FEV1 with the late asthmatic response was significantly higher after induction of allergen-induced asthma than after exercise-induced asthma, even though the maximal % fall in FEV1 with the immediate asthmatic response was similar. Airway responsiveness increased significantly at 48 hours after allergen-induced asthma, while it did not change after exercise-induced asthma. The increase in airway responsiveness was not correlated with the maximal % fall in FEV1 with the late asthmatic response, but was correlated with the degree of epithelial damage evaluated by observation of Creola bodies. The sputum ECP concentration and the percentage of sputum eosinophils increased significantly with the late asthmatic response after allergen-induced asthma, but did not change after exercise-induced asthma. CONCLUSIONS: We conclude that less airway inflammation was provoked by exercise-induced asthma resulting in less epithelial damage and no increase of airway responsiveness in contrast to allergen-induced asthma.

Acetylcholine↗
PubMed2005

Dissociating stimulus-stimulus and response-response effects in the Stroop task.

The separate semantic and response competition interactions between colour and word processing in a manual Stroop task were evaluated by comparing three trial types. Identity trials are both semantically compatible and response compatible (e.g., BLUE in the colour blue), different response trials are both semantically incompatible and response incompatible (e.g., BLUE in the colour green, where blue and green have different response keys), and same response trials are semantically incompatible and response compatible (e.g., the word BLUE in the colour red, where blue and red have the same key press response). Ink colours were embedded in two different word types, colour words, and colour associates. The results using colour words replicated the findings of De Houwer (2003) and demonstrated both a semantic effect (a difference between same response trials and identity trials) and response competition (a difference between same response trials and different response trials). In contrast, the results using colour associates provided evidence for only a semantic effect. These findings support interpretations of the colour associate Stroop effect that attribute the effect to semantics, but challenge Klein's (1964) response competition account and Sharma and McKenna's (1998) claim that the effect of colour associates is dependent on verbal responding. The results confirm that the Stroop colour-word task appears to involve at least two mechanisms, a semantic mechanism and a response competition mechanism.

Attention↗
PubMed2003

Measuring response in solid tumors: comparison of RECIST and WHO response criteria.

BACKGROUND: Objective tumor response is a common endpoint in daily practice as well as in clinical trials to evaluate the efficacy of anti-cancer agents. Traditionally, the standard World Health Organization (WHO) criteria has been adopted in these contexts. However, the recent development of new classes of anti-cancer agents and progress in imaging technology have required new methodology to evaluate response to treatment. Recently, the Response Evaluation Criteria in Solid Tumors Group (RECIST) proposed new guidelines using unidimensional measurement. Theoretically, the simple sum of the maximum diameters of individual tumors is more linearly related to cell kill than is the sum of the bidimensional products. To validate these new guidelines, we have compared the standard WHO response criteria with the new RECIST guidelines in the same patient population. METHODS: Data from 79 patients enrolled in eight prospective phase II studies at Samsung Medical Center were retrospectively re-analyzed to determine the concordance between the two response criteria. The two response criteria were applied separately, and the results were compared using the kappa statistic to test concordance for overall response rate. RESULTS: The overall response rate according to the WHO criteria was 31.6%. Using the RECIST criteria, nine patients were reclassified and the overall response rate was 30.4%. There was excellent agreement between the unidimensional and bidimensional criteria in 23 of 25 responses (92%). The kappa statistic for concordance for overall response was 0.91. CONCLUSIONS: We conclude that the new RECIST guidelines are comparable to the old response criteria in evaluating response in solid tumors. Moreover, the new guidelines are just as simple and reproducible in the measurement of response in daily practice as they are in clinical trials.

Antineoplastic Agents↗
PubMed1985

Responses to head tilt in cat central vestibular neurons. II. Frequency dependence of neural response vectors.

The responses of central vestibular neurons in the decerebrate cat subjected to whole-body tilt were examined as a function both of stimulus orientation (with respect to the cat's head) and frequency, with the aim of understanding the neural processing responsible for producing the observed response patterns. Responses to whole-body tilt were recorded from vestibular neurons in and around the lateral vestibular nucleus (LVN). By plugging all six semicircular canals, the otolith contribution was studied in isolation. For each neuron, a response vector was defined as having three components: orientation, gain, and phase. These components were examined using sinusoidal stimulus frequencies of 0.01 to 2 Hz. The orientation component of the neural response vector does not vary as a function of stimulus frequency. Thus response dynamics previously described with a fixed (roll) axis cannot be explained by changes in the angle between the response vector orientation and a fixed stimulus axis. Two major classes of neural responses were observed. One class had a phase lead at low frequencies and gain that showed a modest increase with frequency. It could be described by a model that included a fractional s exponent operator. These response dynamics resemble that of otolith afferents, suggesting that these neurons may be acting as simple relays. The other major response class was characterized by a large gain increase and a phase lag of as much as 180 degrees as frequency increased; such response dynamics have been previously observed in otolith-evoked neck and forelimb reflexes. A more complex model, consisting of a parallel excitatory and high-pass-filtered inhibitory limb, was necessary to describe these responses. The orientation component of the response vector of most of the neurons whose dynamics were best described by the parallel pathway model pointed toward the contralateral side, implying they would be excited by side-up tilt (at low frequencies). Most other neurons had ipsilateral vectors.

Animals↗
PubMed1988

Two types of gastric excitatory responses to stimulation of the vagal trunk in cats: efferent and afferent responses.

Experiments were performed on cats anesthetized with pentobarbital sodium and gallamine triethiodide. Gastric motility was recorded by a balloon method. The excitatory response to electrical stimulation of the vagal trunk was composed of an initial response during the stimulation period and a late response following stimulation. The maximal excitation of the initial response was elicited by a short pulse duration and that of the late response by a long pulse duration. The initial response was inhibited by treatment with hexamethonium or atropine. The late response was hexamethonium-resistant. This hexamethonium-resistant response was inhibited by atropine, hemicholinium and morphine, and enhanced by physostigmine. Treatment with (D-Pro2, D-Trp7,9)-substance P did not affect the hexamethonium-resistant response. Treatment with morphine inhibited the late response without affecting the initial response. From these results, it was suggested that the initial excitatory response was probably due to the activation of the parasympathetic cholinergic fibers. The late response might be due to the activation of the vagal afferent cholinergic fibers, since the pharmacological nature of the late response was similar to that in the cat with supranodose vagotomy (surviving afferent fibers) in our previous reports.

Afferent Pathways↗
PubMed1991

Response patterns and cardiovascular effects during response sequence acquisition by humans.

The effects of temporal delays imposed between successive responses and of vitamin C administration were examined on the acquisition of response sequences and on cardiovascular reactivity during sequence acquisition. Thirteen adult subjects (6 female, 7 male), in good health, gave written consent prior to participating in 12 weekly 45-min sessions. Points, exchanged for money after each session, were presented when subjects completed 15-response sequences on a touch-sensitive three-response keypad. A position counter increased from 0 to 14 as subjects emitted correct responses in the sequence. Four novel 15-response sequences were presented each session. No delays were imposed between successive responses during the acquisition of one sequence; delays were imposed immediately following each response during the acquisition of a second sequence, thereby delaying response feedback; delays were imposed following feedback during acquisition of a third sequence, resulting in the removal of the stimulus correlated with sequence position; and, as a control condition, delays were imposed following feedback, but stimuli correlated with sequence position were reinstated prior to the next response during acquisition of a fourth sequence. Subjects were exposed to one of two delay durations (0.2 and 0.5 or 0.5 and 1.0 s) each session, and delay durations alternated every session. During Weeks 5 to 8, subjects received 3 grams of vitamin C per day, whereas during Weeks 1 to 4 and 9 to 12, subjects received placebo under single-blind conditions. All subjects acquired the sequences, as evidenced by decreasing percentages of incorrect responses across trials. When temporal delays were imposed between successive responses during sequence acquisition, acquisition efficiency was enhanced. Examination of response latencies suggested that the status of preceding responses (i.e., correct or incorrect) rather than the status of the position counter influenced subsequent responding. Cardiovascular effects were inversely related to the length of the temporal delay. Neither cardiovascular reactivity or sequence acquisition were related to vitamin C administration.

Adult↗
PubMed1999

Stage, percentage of basophils at diagnosis, hematologic response within six months, cytogenetic response in the first year: the main prognostic variables affecting outcome in patients with chronic myeloid leukemia in chronic phase treated with interferon-alpha. Results of the CML89 trial of the Spanish Collaborative Group on interferon-alpha2a and CML.

BACKGROUND AND OBJECTIVE: Interferon-a (IFN) is increasingly being used as the drug of choice in chronic myeloid leukemia patients. The main objectives of the study were to study the influence of the classic prognostic variables and response to IFN, and to assess the influence of this response on the course of the disease and survival. DESIGN AND METHODS: Single arm, prospective, multicenter study, without a control group. Only Ph1-positive CML patients were included. The treatment scheme was biphasic: the patients first received standard chemotherapy and thereafter IFN-a2a was used as monotherapy, with a target dose of 9 MU/d/s.c. RESULTS: Twenty-one centers in Spain enrolled 132 patients (72 men, 60 women). The median dose of IFN given was 5.8 MU/d, and the median treatment duration was 431 days (range: 18-2,597). Seventy-two percent of patients obtained a hematologic response in the first six months of IFN treatment. Genetic response was obtained in 47% of the patients, and the response was major or complete in 27% and 19%, respectively. The median time to obtain this response was 7, 9, and 18 months for minimal, partial and complete genetic response, respectively. Multivariant analysis showed that only a higher percentage of basophils at diagnosis was associated with a worse hematologic response at six months (p=0.001) (OR: 1.23) and with a worse cytogenetic response in the first year of IFN therapy (p=0.018) (OR: 1.4). Over an observation period of 8 years, 35.6% of the patients died, and 85 (64.4%) remained alive. With a median follow-up of 42 months (3.7-98), the 6-year projected probabilities of survival and transformation-free survival were 0.61+/-0.07 vs. 0.54+/-0.07, respectively. Patients with Kantarjian's stage 3 disease or in a high-risk Sokal group had lower probabilities of survival, but these systems did not adequately discriminate in our series. Obtaining a complete hematologic response in the first six months of IFN therapy was favorable in terms of overall survival (p=0.05; HR=0.33). Cox's analysis demonstrated that obtaining a cytogenetic response in the first year was independently associated with better overall survival (p=0.04; HR=0.19) and better transformation-free survival (p=0.0035; HR=0.11). INTERPRETATION AND CONCLUSIONS: Nearly half of the patients obtained some degree of Philadelphia suppression, which was major in 27%, and complete in 19%. A higher percentage of basophils at diagnosis was the only variable associated with a lower probability of cytogenetic response. Obtaining a cytogenetic response during the first year of IFN treatment was a favorable and independent variable in terms of survival and transformation-free survival. Obtaining a major cytogenetic response during this period decreased the risk of transformation twenty times. Our results suggest that the effect of IFN on survival is independent of the classic prognostic variables.

Adolescent↗
PubMed1988

Differential expression of pseudoconditioning and sensitization by siphon responses in Aplysia: novel response selection after training.

Nonassociative training with a noxious unconditioned stimulus (US) applied to the head or tail of freely moving Aplysia caused a qualitative change in siphon responses to midbody test stimulation, so that the midbody test responses came to resemble the unconditioned siphon response (UR) to the US when tested 1 d after exposure to the US. Such a nonassociative, US-induced transformation of test responses into responses resembling the UR has traditionally been termed "pseudoconditioning." Short-term pseudoconditioning was compared to sensitization and to habituation in a reduced preparation that used a photocell to distinguish "head-type" siphon responses from qualitatively different "tail-type" responses. Transformation of test responses (pseudoconditioning) was observed only when the type of preexisting alpha response to the midbody test stimulus was different from the UR. Sensitization, defined as a US-induced enhancement of the alpha response to the test stimulus, was observed when the initial alpha response and the UR were of the same type. General sensory facilitation was excluded as a critical mechanism for pseudoconditioning by the observation that the same midbody test response could be transformed to either a head-type or tail-type response, depending on the site of the US, and by the observation that simply increasing the intensity of the midbody test stimulus in the absence of a head or tail US did not produce similar response transformations. These studies demonstrate pseudoconditioning in a preparation amenable to analysis at the level of identified neurons, and draw attention to a distinctive and widespread form of behavioral modifiability that has been neglected by investigators of learning.

Animals↗
PubMed1985

An innate host response to the neoplastic cell: syngeneic rat tumor cells can elicit a rapid de novo lymphoid procoagulant response.

To analyze unique molecular differences between normal and neoplastic cells, we have examined host responses to tumor cells. The present study provides the first evidence for an innate rapid recognitive response of the lymphoid system to some syngeneic tumors. The lymphoid procoagulant (PCA) response, a T cell-instructed monocyte response that activates proteases of the coagulation cascade culminating in thrombin formation, is considered a component of classic delayed-type hypersensitivity responses. We have demonstrated that three syngeneic rat mammary carcinomas elicit this cellular response in vitro in lymphoid cells of the unimmunized rat. The response was rapid, reaching maximum within 6 hr. Analysis was compounded by the constitutive PCA activity of some tumors; however, the PCA product produced in the response to tumor challenge in vitro was newly biosynthesized and was of lymphoid cell origin, differing from the PCA of tumor cells. The lymphoid PCA response was prothrombinase-like and did not require vitamin K for biosynthesis, nor were other gamma-carboxylation-dependent extrinsic pathway proteases other than prothrombin required for thrombin generation. Both in vivo and in vitro derived mammary carcinoma cells elicited the response, whereas a fibrosarcoma and nontransformed syngeneic cells did not. Tumor shed substances, which were devoid of PCA and sedimentable only in part at 100,000 X G, induced this cellular response. The same stimuli shed from tumor cells did not directly elicit a PCA response from elicited peritoneal macrophages; however, in the presence of T lymphocytes a PCA response of these macrophages was produced. This study provides novel information to indicate that a T-enriched lymphocyte-dependent monocyte-macrophage response to some tumors, before effective in vivo immunization, may participate in initial local protease generation and fibrin deposition, both thought to play a significant role in the local pathobiology of tumors.

Adenocarcinoma↗
PubMed1986

High-pass digital filtration of the 40 Hz response and its relationship to the spectral content of the middle latency and 40 Hz responses.

This study analyzed the effects of high-pass filtration on the 40 Hz response using zero and standard phase shift digital filtration. Filtration effects were compared to the spectral content of the middle latency response (MLR) and 40 Hz response. The spectral composition of the MLR was found to contain major response energy at 10 and 40 Hz. The major energy of the 40 Hz response was at 40 Hz with minor peaks every 40 Hz above the fundamental frequency. The elimination of the 10 Hz response energy in the 40 Hz response was due to cancellation caused by phase differences which occurred in the production of a steady state potential. The reduction was confirmed by the minor amplitude effects created by zero-phase-shift high-phase filtration (cutoff frequency 30 Hz with 36 dB/oct slopes) on the 40 Hz response as compared to the MLR. The only beneficial effect of high-pass filtration was the elimination of the mild undulation of the unfiltered waveform. The major effect of phase-shift high-pass filtration on the 40 Hz response was the displacement of the high frequency ABR from the peak to the descending slope and finally to the trough of the MLR. Shifting of the ABR from the peak of the MLR resulted in amplitude loss which may affect response identification at threshold. The authors recommend minimal high-pass filtration (i.e., less than 12 dB/oct slope and a cutoff frequency less than or equal to 15 Hz) when recording the 40 Hz response. The spectral analysis of the evoked response may be able to predict the optimal rate for eliciting a steady state response in divergent subject populations.

Adult↗
PubMed1984

Brainstem evoked responses to paired-click stimuli: the use of digital response subtraction.

Brainstem evoked responses were obtained to 60-dB nHL clicks and click pairs presented at 27/s. Paired-click intervals ranged from 9.8 to 0.5 ms. 6 normal-hearing young adults served as subjects. Derived responses were obtained by digital response subtraction of single-click from paired-click responses. Wave V was observed to unsubtracted click 2 of the click pair at paired-click intervals down to 4 ms. Wave V of the derived (subtracted) click 2 response was observed for paired-click intervals down to 1 ms. To assess additivity, the click 1 response of the click pair was compared to the single-click response, and the unsubtracted click 2 response was compared to the derived click 2 response. At longer paired-click intervals, wave V latency was greater for click 1 of the click pair than for the single-click response. This latency difference decreases at shorter paired-click intervals and is attributed to adaptation of click 1 by click 2 of the previous pair. Wave V amplitudes for single-click and paired-click click 1 responses were not significantly different at any paired-click interval. The latency and amplitude for unsubtracted click 2 and derived click 2 responses were not significantly different at any paired-click interval. It is concluded that the responses to click 1 and click 2 of the paired clicks are additive, at least at very brief paired-click intervals.

Acoustic Stimulation↗
PubMed1991

Response to novelty predicts the locomotor and nucleus accumbens dopamine response to cocaine.

The relationship between a rat's locomotor response to a novel environment and its behavioral and dopaminergic responses to cocaine was examined. Subjects were divided into two groups based on their locomotor response to a novel environment. Subjects who had a novelty response above the median were classified as high responders (HR), while those with a novelty response below the median were classified as low responders (LR). Following administration of cocaine-HCl (0, 2.5, 5.0, 10.0, or 15.0 mg/kg), HR rats showed a greater locomotor response than LR rats. Moreover, there was a significant correlation between a subject's locomotor response to the novel environment and the locomotor response to either 10.0 (r = 0.65) or 15.0 (r = 0.92) mg/kg cocaine. In a separate experiment, the extracellular concentration of dopamine in the nucleus accumbens (NACC) was monitored using microdialysis procedures. Following cocaine administration (15.0 mg/kg) HR rats showed a larger NACC dopamine response and greater locomotor activity than LR rats. In addition, there was a threefold greater locomotor activity to dopamine ratio in HR rats than in LR rats. A correlation between a subject's locomotor response to a novel environment and the dopaminergic response to cocaine was also evident. These results suggest that differences in the locomotor response to cocaine can, to some degree, be predicted by a rat's locomotor response to a novel environment, and that variations in dopamine-dependent mechanisms of the NACC may underlie these individual differences.

Animals↗
PubMed1993

Control of IgE responses. III. IL-6 and IFN-alpha are isotype-specific regulators of peak BPO-specific IgE antibody-forming cell responses in mice.

The ability of cytokines (IL-4, IL-5, IL-6, IFN-alpha, IFN-gamma, TNF-alpha, GmCSF) to regulate peak benzylpenicilloyl (BPO)-specific IgE antibody-forming cell (AFC) responses was investigated. These responses were induced in BALB/c mice by ip injection of BPO-keyhole limpet hemocyanin (BPO-KLH; 10 micrograms) in aluminum hydroxide gel on Days 0, 21, and 42. On Day 44, or on Days 43, 44, and 45, mice were injected sc with varying doses of cytokine or anti-cytokine antibody. On Day 46, the numbers of BPO-specific AFC (IgM, IgG1, IgE and IgA) in spleen were determined ex vivo in enzyme-linked immunosorbent spot assay. Among the cytokines tested, only IL-6 suppressed BPO-specific IgE AFC responses in an isotype-specific fashion (60-90%). However, treatment of mice with anti-IL-6 also suppressed these responses, suggesting that IL-6 can either suppress or increase peak antigen specific IgE responses, depending upon its concentration. Among the cytokines tested, only IFN-alpha increased BPO-specific IgE AFC responses in an isotype-specific fashion. Since treatment with anti-IFN-alpha suppressed these responses, it appears that IFN-alpha is required to maintain peak antigen-specific IgE AFC responses. IL-4 or IFN-gamma nonspecifically suppressed responses of all isotypes. Treatment with anti-IL-4 also suppressed IgE responses, suggesting that this cytokine is required to maintain peak antigen specific IgE responses. Treatment with anti-IFN-gamma increased IgE responses, indicating that IFN-gamma suppresses peak antigen-specific IgE responses.

Animals↗
PubMed1983

Developmental changes in taste responses from glossopharyngeal nerve in sheep and comparisons with chorda tympani responses.

To learn whether there are developmental changes in salt and acid taste responses from the posterior tongue, we recorded from the glossopharyngeal nerve, which innervates taste buds in circumvallate papillae, in sheep fetuses, lambs and adults. Multifiber responses to NH4Cl, KCl, NaCl, LiCl, citric and hydrochloric acids were expressed as ratios, relative to responses for two standard chemicals, NH4Cl and KCl. Response ratios for NaCl and LiCl, relative to either standard, increased during development, but the magnitude of the change was small. KCl elicited very large magnitude responses, relative to NH4Cl, in the youngest fetuses, and then decreased by 50% in stimulating effectiveness. Relative responses to both acids also decreased developmentally. The general shapes of KCl response-concentration functions did not change throughout development; however, in the youngest fetuses, the NH4Cl responses-concentration function was not similar to that in older animals. These developmental changes are different than those for responses from anterior tongue taste buds recorded from the chorda tympani nerve. Anterior tongue responses to NaCl and LiCl change most substantially and those to KCl change very little; acid responses do not change. The developmental differences for anterior versus posterior tongue responses suggest that membrane composition and maturational changes of taste buds in the two locations are not the same. Response-concentration functions from both tongue areas support the proposition that specific membrane components interacting with various salts are added during development.

Aging↗
PubMed1984

Genetic regulation of the immune response to hepatitis B surface antigen (HBsAg). IV. Distinct H-2-linked Ir genes control antibody responses to different HBsAg determinants on the same molecule and map to the I-A and I-C subregions.

We have previously demonstrated that the murine humoral immune responses to the group-specific a and subtype-specific d/y determinants of hepatitis B surface antigen (HBsAg) are controlled by H-2-linked immune response (Ir) genes. High responder (H-2d,q), intermediate responder (H-2a greater than b greater than k) and nonresponder (H-2f,s) haplotypes have been identified (8, 9). The kinetics and specificity of in vivo antibody production after HBsAg immunization in congeneic, H-2-recombinant strains was analyzed to further define relevant Ir genes and their influence on the immune response to distinct antigenic determinants. These studies indicate that the humoral anti-HBs response is regulated by at least two Ir genes, one in the I-A subregion (Ir-HBs-1) and one in the I-C subregion (Ir-HBs-2) of the murine H-2 complex. Ir-HBs-1 regulates the primary responses to all HBsAg determinants, whereas the influence of Ir-HBs-2 is determinant specific, affecting the responses to the d or y determinants. The anti-a response is regulated exclusively by Ir-HBs-1. Strains possessing only the Ir-HBs-2 gene [B10.S(9R) and B10.HTT] produce no anti-a response and a subtype-specific antibody response is detected only after secondary or tertiary immunization. In contrast, the influence of Ir-HBs-2 in the presence of Ir-HBs-1 is detected upon primary immunization and is additive rather than exclusive. There is also suggestive evidence that the presence of the Ek molecule, at least in the context of I-Ak, may have a suppressive influence on the anti-HBs response. Additionally, HBsAg-specific, T cell proliferative responses were H-2 restricted and the kinetics and specificity of T cell proliferative responses paralleled in vivo antibody production. These data indicate that, although the I-A subregion exerts a dominant influence, distinct Ir-HBs genes, mapping in separate I subregions, control immune responses to alternate HBsAg determinants on the same protein molecule.

Animals↗
PubMed1988

Effects of non-sedative anxiolytic drugs on responses to GABA and on diazepam-induced enhancement of these responses on mouse neurones in cell culture.

1. Intracellular microelectrode recording techniques were performed on mouse spinal cord and cerebral hemisphere neurones grown in primary dissociated cell culture. The effects of several anxiolytics applied by local pressure ejection on responses to gamma-aminobutyric acid (GABA) evoked by iontophoresis were investigated. Responses to GABA were depolarizing since intracellular chloride ion concentration was increased by injection from potassium chloride (3M)-filled recording micropipettes and neurones were held at large negative membrane potentials (-70 to -90 mV). The agents studied were six 'non-sedative anxiolytics', CL 218,872 (3-methyl-6-(3-trifluoromethyl-phenyl)1,2,4-triazolo(4,3-b) pyridazine), PK 8165 (2-phenyl-4-(2-(4-piperidinyl)ethyl)-quinoline), PK 9084 (2-phenyl-4-(2-(3-piperidinyl)ethyl)-quinoline), CGS 9896 (2-(4-chlorophenyl)-2,5-dihydropyrazolo(4,3-c)quinoline-3(3H)-one) , ZK 91296 (ethyl 5-benzyloxy-4-methoxymethyl-beta-carboline-3-beta-carboxylate), buspirone (8-4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl-8-azaspiro[4.5]decane- 7,9- dione), and two sedative anxiolytics, diazepam and zopiclone [( 6-(5-chloro-2-pyridyl)-6,7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazin- 5- yl]4-methyl-1-piperazinecarboxylate). 2. Direct effects on responses to GABA were studied for all drugs applied in varying concentrations. For the drugs which significantly altered responses to GABA, the effects of the benzodiazepine receptor antagonists Ro 15-1788 (ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,5a)-(1,4)benzodi azepine - 3-carboxylate) and CGS 8216 (2-phenylpyrazolo(4,3-c)-quinolin-3(5H)-one) were evaluated. For the drugs devoid of significant direct effect on responses to GABA, the influence on diazepam-induced enhancement of responses to GABA was evaluated. 3. Diazepam, zopiclone and CL 218,872 concentration-dependently and reversibly enhanced responses to GABA. Maximal enhancement was 82% for diazepam (500 nM), 64% for zopiclone (10 microM) and 20% for CL 218,872 (10 microM). PK 8165 effects varied with concentration, enhancing responses to GABA (up to 18%) at nM concentrations and reducing responses to GABA (up to 90%) at microM concentrations. CGS 9896, ZK 9126, PK 9084 and buspirone, in concentrations ranging from 1 nM to 10 microM, lacked significant direct effects on responses to GABA. 4. The enhancing effects of diazepam, zopiclone, CL 218,872 and PK 8165 were antagonized by Ro 15-1788. However, the reducing effect on responses to GABA of PK 8165 at microM concentrations was not antagonized by CGS 8216. CGS 9896 and ZK 91296 concentration-dependently blocked the diazepam-induced enhancement of responses to GABA. However, PK 9084 and buspirone did not antagonize the diazepam-induced enhancement of responses to GABA. 5. These results indicate that diazepam and zopiclone may be full agonists, CL 218,872 and PK 8165 are partial agonists, and CGS 9896 and ZK 91296 are pure antagonists at benzodiazepine receptors. On the other hand, PK 9084 and buspirone do not interact with benzodiazepine receptors.

Animals↗
PubMed1998

A prospective randomized comparison between fixed rate response programming and automatic rate response optimization in activity-triggered DDDR pacemakers. Thera Pacemaker Study Group.

Activity rate response programming depends on the physician's experience and on the limited knowledge of patient's daily activities. The present investigation compares a new continuous automatic adjustment of the activity rate response called rate response optimization (OPT) with fixed activity rate response programming (FIXED). At hospital discharge 37 patients with Thera DR pacemakers (Medtronic) were randomized either to FIXED (n = 20; 65 +/- 12 years, male n = 12) or to OPT (n = 17; 65 +/- 12 years, male n = 13). After 1 month's follow-up occurrence of complaints related to rate-responsive pacing and the percentage of pacing were assessed. Other activity sensor parameters were programmed according to clinical judgement and similarly distributed in the two groups. Activity rate response was 7.1 +/- 1.4 (FIXED) and 7.2 +/- 1.7 (OPT), activity threshold was medium in 9 (FIXED) and 8 (OPT), and medium/low in 11 (FIXED) and 9 (OPT) patients, respectively. No patient with FIXED had any complaints with respect to activity-triggered rate response. One patient with OPT reported palpitations due to rapid changes in the pacing rate leading to reprogramming of the pacemaker. Atrium and ventricle were paced in 56 +/- 31% (FIXED) and in 58 +/- 35% (OPT; not significant) and the atrium only in 4 +/- 10% (FIXED) and 0% (OPT; not significant), respectively. In the 17 patients programmed to OPT the pacemaker increased activity rate response in 5 and decreased activity rate response in 3 patients. In conclusion, as only 1 (3%) patient had complaints related to the activity rate response and fixed rate response programming according to clinical judgement already resulting in symptom-free DDDR pacing, no differences could be detected between the fixed rate response programming and rate response optimization.

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