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PubMed1990

Inhibition of anti-IgE induced skin response in normals by formoterol, a new beta 2-adrenoceptor agonist, and terbutaline. 1. Dose response relation and duration of effect on the early wheal and flare response.

The intention of the present study was to compare formoterol and terbutaline regarding ability to inhibit immediate wheal and flare responses (WFR) to anti-human IgE with focus on the duration of anti-WFR action. Formoterol is a novel beta 2-adrenergic agonist with a prolonged duration of bronchodilation capacity after inhalation. The drugs injected intradermally 2 min prior to challenge with anti-IgE in volunteers produced a dose-dependent inhibition of the WFR in the range 1pg-100ng (formoterol) and 1ng-1 microgram (terbutaline). Formoterol was 70 times (flare) and 25 times (wheal) more potent (ID40) than terbutaline on a weight basis. The duration of the anti-WFR action for formoterol, injected in a 25 times lower dose than terbutaline, was significantly longer, namely greater than 24 h versus 8 h for terbutaline. The histamine-induced wheal reaction was attenuated by 15% and 25% by terbutaline and formoterol, respectively. The results indicate a higher beta 2-receptor activity for formoterol with respect to inhibition of IgE-dependent mast cell mediator release in addition to an anti-leak effect exerted by both drugs. The prolonged duration of antagonistic effect by formoterol on the WFR to anti-IgE might be due to the lipophilic property of the drug, with an expected higher retention of formoterol at the target tissue compared with the more hydrophilic compound terbutaline.

Adrenergic beta-Agonists↗
PubMed1986

Olfactory bulb responses to odor stimulation: analysis of response pattern and intensity relationships.

Extracellular recordings were made from mitral cells, tufted cells, and presumed glomerular layer and external plexiform layer interneurons of the olfactory bulb of anesthetized rats during odor stimulation. Intensity responses of these cells were studied by presenting a series of six or seven concentrations, spanning a range greater than two log units, in a cyclic artificial sniff paradigm, which produced repeated response measures at each concentration. Experiments focused on obtaining a complete intensity series, including interspersed unstimulated spontaneous activity records, for a single odorant (usually amyl acetate), but concentration responses to other odorants were tested when possible. Odor responses of 46 cells were studied with two approaches. Response form was examined in an attempt to define response classes based on qualitative characteristics of the temporal pattern of response. Assessment of response magnitude was attempted, in order to construct stimulus-response functions for each cell, independent of response form. As previously reported for olfactory bulb cells, the cells in our sample responded to odor stimulation with spike trains of a variety of temporal patterns, consisting of excitatory and inhibitory components that were frequently recognizable in the responses of a cell across a range of concentrations. However, response patterns usually changed significantly with concentration, such that response form across the concentration range could not be predicted from the response at any one concentration. Responses of different cells were sometimes similar to each other in form at one concentration and quite different from each other in the rest of their concentration-response profiles. Classification of response profiles into discrete types, based on consistency of response form throughout the profile, was therefore not feasible. In agreement with other reports, response of a single cell to different odorants sometimes showed similar forms and sometimes showed very different forms across the concentration-response profiles. Since the response form depends on the stimulus intensity as well as the stimulus quality, characterization of response magnitude and of the pattern of response to different odors require testing with a series of stimulus concentrations. Because odor responses consisted of temporally patterned spike trains, whose components changed in complex ways with stimulus intensity, it was not possible to quantify response magnitude by measuring characteristics of particular response components or counting mean frequency.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1975

The failure to show a necessary role for C3 in the in vitro antibody response.

The in vitro antibody response of mouse spleen cells to TNP coupled to both T-dependent and T-independent carriers as well as to sheep erythrocytes has been studied to investigate the possible role of complement activation in the induction of antibody formation. The following has been found. (1) In vitro responses of both IgM and IgG can be obtained to both T-dependent and T-independent antigens in serum-free media, although they are smaller than those found in serum-containing media. This shows that no exogenous source of complement is necessary for in vitro antibody formation by spleen cells. (2) Similarly, normal antibody responses are obtained if the cultures are grown in human serum depleted of C3b-inactivator, which contains high concentrations of C3b. (3) In the presence of antibody to mouse C3 the response to the T-independent antigen is reduced, the IgM responses being more affected than the IgG. However, purified F(ab')2 anti-C3 has no inhibitory effect and it therefore seems likely that it is the formation of intact immune complexes containing Fc rather than the interference with C3 function that is responsible for the inhibition seen. (4) The conventionally purified anti-complementary factor from cobra venom has no effect on the antibody response in serum-free culture or when human or fetal calf sera are used. In no experiment was any potentiation of T-dependent responses observed. However, the presence of quite small concentrations (2%) of cobra veno

Animals↗
PubMed1984

Murine immune responses to Salmonella lipopolysaccharide: oral administration of whole bacteria to C3H/HeJ mice induces secondary anti-LPS responses, especially of the IgA isotype.

Because our past studies have shown that oral administration of thymic-dependent antigens induces higher IgA responses in lipopolysaccharide (LPS) nonresponsive C3H/HeJ mice than in syngeneic, LPS-responsive C3H/HeN animals, it was of interest to compare anti-LPS responses in these mouse strains after oral administration of particulate antigens containing LPS. C3H/HeJ and C3H/HeN mice were given smooth Salmonella typhimurium LT-2 or rough S. minnesota Rb (R345) or Re (R595) organisms by gastric intubation for 3 consecutive days/wk for 2 wk and were boosted by the i.v. route with either the same bacterial immunogen or with purified homologous LPS. Four days later, splenic anti-LPS plaque-forming cell (PFC) responses were assessed with a panel of indicator sheep erythrocytes (SRBC) coated with LPS derived from either smooth (S-LPS-SRBC) or rough (Rb-LPS-SRBC or Re-LPS-SRBC) Salmonella. In separate studies, both serum and salivary antibodies of the IgM, IgG, and IgA isotypes were determined by ELISA, with whole Salmonella cells used as the coating antigen. Oral immunization with LT-2 resulted in good IgM, IgG1 and IgA splenic anti-LPS PFC responses in C3H/HeJ mice, with the major isotype being IgA. Mice boosted i.v. with purified LPS gave five- to sixfold higher anti-S-LPS PFC responses than did mice given whole bacteria by the i.v. route. Low anti-Rb-LPS and anti-Re-LPS PFC responses were seen in both mouse strains. Enhanced immune responses in orally primed C3H/HeJ mice was not due to LPS-induced polyclonal responses, because splenic cultures from these mice gave poor mitogenic responses to LPS. A similar pattern of response was obtained when C3H/HeJ or C3H/HeN mice were given RB (R345) or Re (R595) bacteria orally and boosted i.v. with purified homologous LPS or whole cells. C3H/HeJ mice again showed higher immune responses in all isotypes than did C3H/HeN animals. Mice given Rb (R345) immunogen gave maximum responses to Rb-LPS, lower responses to Re-LPS, and no responses to S-LPS, whereas C3H/HeJ mice immunized with Re (R595) immunogen gave maximum PFC responses to Re-LPS and lower responses to Rb-LPS. Serum and salivary antibody titers closely paralleled the splenic PFC responses, and IgA antibodies were the predominant isotype observed, with higher IgA responses occurring in orally immunized C3H/HeJ mice than in C3H/HeN animals. These results clearly indicate that C3H/HeJ mice given whole Salmonella by gastric intubation elicit higher PFC and antibody responses to the three major LPS regions than do identically treated LPS-responsive C3H/HeN mice.

Administration, Oral↗
PubMed2004

Smoking and immunomodulators do not influence the response or duration of response to infliximab in Crohn's disease.

OBJECTIVE: Clinical predictors for infliximab response are still unknown. Identifying predictors of response to infliximab in Crohn's disease may improve our selection of patients. METHODS: Two hundred patients with luminal (61%) or fistulous (39%) Crohn's disease and at least 6 months of follow-up following a total of 416 infliximab infusions were evaluated. Clinical response and duration of response were the primary endpoints. RESULTS: Patients with fistulous disease had a higher response rate (83% versus 70%, P = 0.044) and a significantly longer duration of response compared with patients with luminal disease (17.4 versus 10.1 wks, P = 0.017). For luminal disease, nonsmokers and smokers had similar response rates (74% versus 64%, P = 0.5) and similar durations of response (9.4 wks versus 8.4 wks P = 0.6) while patients taking concurrent immunomodulators had similar response rates compared with those not taking immunomodulators (74% versus 71%, P = 0.9) and similar durations of response (10.4 wks versus 10.6 wks, P = 0.9). For fistulous disease, response rates (89% versus 83% P = 0.9) and duration of response (16.9 wks versus 10.1 wks, P = 0.10) were similar between nonsmokers and smokers and concurrent immunomodulators had no effect on response (89% versus 86%, P = 0.9) or duration of response (19.8 wks versus 15.4 wks, P = 0.46). Multivariable analysis confirmed that neither smoking, corticosteroids, immunomodulator therapy, gender, age, age of disease onset, disease duration, nor luminal disease location significantly influenced response or duration of response. CONCLUSIONS: Patients with fistulous disease had a higher response rate and a significantly longer duration of response compared with patients with luminal disease. However, among patients with luminal or fistulous disease, neither smoking nor immunomodulators had any effect on response or duration of response.

Adjuvants, Immunologic↗
PubMed2004

Artifactual responses when recording auditory steady-state responses.

OBJECTIVE: The goal of this study was to investigate, in hearing-impaired participants who could not hear the stimuli, the possibility of artifactual auditory steady-state responses (ASSRs) when stimuli are presented at high intensities. DESIGN: ASSRs to single (60 dB HL) and multiple (20 to 50 dB HL; 500 to 4000 Hz) bone-conduction stimuli as well as single 114 to 120 dB HL air-conduction stimuli, were obtained using the Rotman MASTER system, using analog-to-digital (A/D) conversion rates of 500, 1000, and 1250 Hz. Responses (p < 0.05) were considered artifactual when their numbers exceeded that expected by chance. In some conditions, we also obtained ASSRs to "alternated" stimuli (stimuli inverted and ASSRs to the two polarities averaged). A total of 17 subjects were tested. RESULTS: Bone conduction results: 500 Hz A/D rate: Large-amplitude (43 to 1558 nV) artifactual ASSRs were seen at 40 and 50 dB HL for the 500 Hz carrier frequency. Smaller responses (28 to 53 nV) were also recorded at 20 dB HL for the 500 Hz carrier frequency. Artifactual ASSRs (17 to 62 nV) were seen at 40 dB HL and above for the 1000 Hz carrier frequency and at 50 dB HL for the 2000 Hz carrier frequency. Alternating the stimulus polarity decreased the amplitude and occurrence of these artifactual responses but did not eliminate responses for the 500 Hz carrier frequency at 40 dB HL and above. No artifactual responses were recorded for 4000 Hz stimuli for any condition. 1000 Hz A/D rate: Artifactual ASSRs (15 to 523 nV) were seen at 50 dB HL and above for the 500 Hz carrier frequency and 40 dB HL and above for the 1000 Hz carrier frequency. Artifactual responses were also obtained at 50 dB HL for a 2000 Hz carrier frequency but not at lower levels. Artifactual responses were not seen for the 4000 Hz carrier frequency. Alternating the stimulus polarity removed the responses for the 1000 and 2000 Hz carrier frequencies but did not change the results for the 500 Hz carrier frequency. 1250 Hz A/D rate: Artifactual ASSRs (16 to 220 nV) were seen at 50 dB HL and above for the 500 Hz carrier frequency and 60 dB HL and above for the 1000 Hz carrier frequency. Alternating the stimulus polarity removed the responses for the 1000 Hz carrier frequency but did not change the results for the 500 Hz carrier frequency. There were no artifactual responses at 2000 and 4000 Hz. Air conduction results: 500 Hz A/D rate: Artifactual ASSRs (49 to 153 nV) were seen for 114 to 120 dB HL stimuli for 500 and 1000 Hz carrier frequencies. Alternating the stimulus polarity removed these responses. There were no artifactual responses at 2000 and 4000 Hz. 1000 and 1250 Hz A/D rates: Artifactual ASSRs (19 to 55 nV) were seen for a 120 dB HL stimulus for a 1000 Hz carrier. Alternating the stimulus polarity removed these responses. CONCLUSIONS: High-intensity air- or bone-conduction stimuli can produce spurious ASSRs, especially for 500 and 1000 Hz carrier frequencies. High-amplitude stimulus artifact can result in energy that is aliased to exactly the modulation frequency. Choice of signal conditioning (electroencephalogram filter slope and low-pass cutoff) and processing (A/D rate) can avoid spurious responses due to aliasing. However, artifactual responses due to other causes may still occur for bone-conduction stimuli 50 dB HL and higher (and possibly for high-level air conduction). Because the phases of these spurious responses do not invert with inversion of stimulus, the possibility of nonauditory physiologic responses cannot be ruled out. The clinical implications of these results are that artifactual responses may occur for any patient for bone-conduction stimuli at levels greater than 40 dB HL and for high-intensity air-conduction stimuli used to assess patients with profound hearing loss.

Acoustic Stimulation↗
PubMed2005

Response rates and response bias for 50 surveys of pediatricians.

RESEARCH OBJECTIVE: To track response rates across time for surveys of pediatricians, to explore whether response bias is present for these surveys, and to examine whether response bias increases with lower response rates. DATA SOURCE/STUDY SETTING: A total of 63,473 cases were gathered from 50 different surveys of pediatricians conducted by the American Academy of Pediatrics (AAP) since 1994. Thirty-one surveys targeted active U.S. members of the AAP, six targeted pediatric residents, and the remaining 13 targeted AAP-member and nonmember pediatric subspecialists. Information for the full target samples, including nonrespondents, was collected using administrative databases of the AAP and the American Board of Pediatrics. STUDY DESIGN: To assess bias for each survey, age, gender, location, and AAP membership type were compared for respondents and the full target sample. Correlational analyses were conducted to examine whether surveys with lower response rates had increasing levels of response bias. PRINCIPAL FINDINGS: Response rates to the 50 surveys examined declined significantly across survey years (1994-2002). Response rates ranged from 52 to 81 percent with an average of 68 percent. Comparisons between respondents and the full target samples showed the respondent group to be younger, to have more females, and to have less specialty-fellow members. Response bias was not apparent for pediatricians' geographical location. The average response bias, however, was fairly small for all factors: age (0.45 years younger), gender (1.4 percentage points more females), and membership type (1.1 percentage points fewer specialty-fellow members). Gender response bias was found to be inversely associated with survey response rates (r=-0.38). Even for the surveys with the lowest response rates, amount of response bias never exceeded 5 percentage points for gender, 3 years for age, or 3 percent for membership type. CONCLUSIONS: While response biases favoring women, young physicians, and nonspecialty-fellow members were found across the 52-81 percent response rates examined in this study, the amount of bias was minimal for these factors that could be tested. At least for surveys of pediatricians, more attention should be devoted by investigators to assessments of response bias rather than relying on response rates as a proxy of response bias.

Adult↗
PubMed2006

Dynamics of response-conflict monitoring and individual differences in response control and behavioral control: an electrophysiological investigation using a stop-signal task.

OBJECTIVES: The aim of the present study was to investigate the functional significance of error (related) negativity Ne/ERN and individual differences in human action monitoring. A response-conflict model of Ne/ERN should be tested applying a stop-signal paradigm. After a few modifications of Ne/ERN response-conflict theory (Yeung N, Botvinick MM, Cohen JD. The neural basis of error detection: conflict monitoring and the error-related negativity. Psychological Review 2004:111(4);931-959), strength and time course of response conflict could be modeled as a function of stop-signal delay. METHOD: In Experiment 1, 35 participants performed a visual two-choice response-time task but tried to withhold the response if an auditory stop signal was presented. Probability of stopping errors was held at 50% using variable delays between visual and auditory stimuli. Experiment 2 (n=10) employed both auditory go and stop signals and confirmed that Ne/ERN effects are due to conflict induced by the auditory stop signal, and not the mere presence or absence of an additional stimulus. RESULTS: As predicted, amplitudes of both the stimulus-locked and response-locked Ne/ERN were largest for non-stopped responses, followed by successfully stopped and go responses. However, independently of response type Ne/ERN also increased with increasing stop-signal delay. Since longer delay invokes stronger response conflict, results specifically support the notion of Ne/ERN reflecting response-conflict monitoring. Furthermore, individual differences related to measures of response control and behavioral control were observed. Both low response control estimated from stop-task performance and high psychometric impulsivity were accompanied by smaller Ne/ERN amplitude on stop trials, suggesting reduced response-conflict monitoring. CONCLUSIONS: The present study supported the response-conflict view of Ne/ERN. Furthermore, the observed relationship between impulsivity and Ne/ERN amplitude suggested that individuals with low behavioral control were characterized by lower activity in anterior cingulate cortex, the neural generator of Ne/ERN, in situations of strong response conflict. SIGNIFICANCE: The present study, for the first time, employed a stop-signal paradigm to verify predictions regarding the temporal dynamics of response-conflict processing as derived from response-conflict theory of ERN.

Adult↗
PubMed2006

Japanese IGT subjects with high insulin response are far more frequently associated with the metabolic syndrome than those with low insulin response.

Impaired glucose tolerance (IGT) represents a prediabetic state positioned somewhere between normal glucose tolerance and diabetes, which is also assumed to make individuals in this state highly susceptible to atherosclerotic disease. IGT also accounts for a highly heterogeneous population, with the condition varying from individual to individual. In this study, we stratified subjects with IGT by their insulin response and compare the pathology of IGT when it is associated with high or low insulin response to gain insight into the diverse pathology of IGT. Of the male corporate employees who underwent 75 g OGTT at the corporation's healthcare center, 150 individuals diagnosed with IGT (isolated IGT, combined IGT and IFG) comprised our study subjects. The study subjects were stratified into four quartiles by percentile AUC for insulin, and those in the 25th or less percentile were defined as the low insulin response group (n = 37), vs those in the 76th or greater percentile defined as the high insulin response group (n = 38), and these groups were compared. There was no significant difference observed between the two groups in regard to post-OGTT glucose response and area under the glucose curve. However, the high insulin response group was associated with higher BMI, subcutanesous fat area, uric acid levels, HOMA-beta cell values, and delta insulin/delta glucose (30 min) than the low insulin response group. The number of risk factors for the metabolic syndrome detected (as defined by the ATPIII diagnostic criteria) per subject was 2.84 +/- 0.17 and 2.08 +/- 0.20, respectively, in the high insulin response group and in the low insulin response group, with the number significantly (p < 0.05) higher in the high insulin response group. Furthermore, the incidence of the metabolic syndrome as defined by the ATPIII diagnostic criteria was 63.2% (24/38) in the high insulin response group vs 32.4% (12/27) in the low insulin response group, with the incidence significantly (p < 0.01) higher in the high insulin response group. Likewise, the incidence of the metabolic syndrome as defined by the Japanese diagnostic criteria was found to be significantly (p < 0.05) higher in the high insulin response group at 50% (19/38) compared to 27.0% (10/37) in the low insulin response group. Our study findings suggest that IGT subjects with high insulin response and those with low insulin response vary greatly in regard to the number of atherosclerotic risk factors complicated and the frequency with which they are associated with the metabolic syndrome. It is also shown in middle-aged Japanese males that of the two forms of IGT, IGT with high insulin response is more closely linked to the pathogenesis of atherosclerotic cardiovascular disease.

Atherosclerosis↗
PubMed1995

[Auditory steady-state response to sinusoidally amplitude-modulated tones. Second report: investigation of response in the sleeping state].

The auditory steady state response (SSR) elicited by a sinusoidally amplitude-modulated (SAM) tone may be an important technique in objective audiometry, which provides frequency-specific information. This response is affected the state of arousal of the subject. An effect of sleep on the amplitude of this response has been observed by a number of previous investigators. Since young children must usually be sedated to carry out evoked potential testing, the effects of sleep on this response are a crucial factor limiting clinical applicability. The basic characteristics of SSR elicited by a 500 Hz SAM tone were studied in 21 adults with normal hearing during sleep. The responses while sleeping were compared with the responses in the awake state. The responses to 2048 stimuli were averaged with the analysis time set at 102.4 ms, and responses were judged by passing the waveforms through a 20-100 Hz digital filter. The same technique was performed in 25 infants (2 months-2 years 9 months) evaluated as having normal hearing. The results obtained are summarized as follows: The amplitude of the response while sleeping was approximately half the amplitude in the awake state. Responses with a modulation frequency of 70Hz, however, showed a persistent decrease in 71.0%, suggesting a trend different from that seen at a modulation frequency of less than 70Hz. The effect of modulation frequency on response amplitude was almost the same for the sleeping state and the awake state. Even during sleep, the response amplitude was maximal at modulation frequencies of 20, 30 and 40Hz, and there was no significant difference between the values at 20Hz -40Hz. The latency of the response was measured by the Diamond method, and the results showed that latency is significantly prolonged while sleeping (p < 0.01). The response threshold at the 500Hz SAM tone (modulation rate 40Hz, modulation depth 90%) was 8.5dBnHL when awake and 13.9dBnHL during sleep. The rise in threshold as a result of sleep was no more than about 5dB. In infants, the response amplitude at a modulation frequency of 20Hz was maximal, and amplitude at the 40Hz was significantly smaller (p < 0.01). Latency measured by the Diamond method in infants was 12.8ms. Thus, a difference from the response in adults was confirmed. Comparisons were made between the responses of infants under 1 year of age and infants over 1 year of age to confirm changes in response according to age.

Adolescent↗
PubMed2003

Response to intravenous immunoglobulin predicts splenectomy response in children with immune thrombocytopenic purpura.

OBJECTIVE: Response to intravenous immunoglobulin (IVIG) has been shown to predict response to splenectomy in adults with immune thrombocytopenic purpura (ITP). However, reports in children have been inconsistent. We sought to determine whether response to IVIG is predictive of response to splenectomy in children. METHODS: Thirty-two assessable children were identified by a retrospective chart review. Response was graded according to previously published criteria as follows: "excellent" (platelets >150 000 within 1 week), "good" (platelets between 50 000 and 150 000), and "poor" (platelets <50 000). "Response" refers to both splenectomy and IVIG, and response to splenectomy was counted only when it was durable. RESULTS: Twenty-one of 23 patients who had a good or excellent response to IVIG also had an excellent response to splenectomy. Six of 9 patients who had a poor response to IVIG also had a poor response to splenectomy. Response to IVIG was a sensitive predictor of response to splenectomy in 88% of patients. Response to IVIG had a specificity of 75%, a positive predictive value of 91%, and a negative predictive value of 67%. Response to prednisone and length of time to splenectomy were not correlated with splenectomy response. CONCLUSIONS: These results suggest that response to IVIG is predictive of response to splenectomy in children with chronic ITP. This correlation may be of value in deciding whether a splenectomy should be performed in children with chronic ITP.

Adolescent↗
PubMed1987

Automatic postural responses in the cat: responses of distal hindlimb muscles to paired vertical perturbations of stance.

The active components of the quadrupedal diagonal stance response to rapid removal of the support from beneath a single limb were studied in cats to further define the mechanisms that trigger and generate the response. We recorded EMG activity from lateral gastrocnemius and tibialis anterior muscles in awake, behaving cats while they stood on an hydraulic posture platform. By dropping the support from beneath a single limb, we evoked the diagonal stance response, with its characteristic changes in vertical force and EMG patterns. As the animal responded to this drop, a second perturbation of posture was then presented at intervals of 10 to 100 ms following the first. The second perturbation, which consisted of dropping the support from beneath the two limbs that were loaded as a result of the initial limb drop, made the first response biomechanically inappropriate. The EMG responses observed in both muscles during paired perturbations were triggered by the somatosensory events related to the perturbations. Muscle responses that were appropriate for the first perturbation always occurred with amplitudes and latencies similar to control trials. This was true even when the second perturbation occurred 10-20 ms after the first, that is, when this perturbation either preceded or was coincident with the response to the initial limb drop. The EMG responses that were normally associated with the second perturbation were delayed and/or reduced in amplitude when the time interval between perturbations was short. As the inter-perturbation interval was lengthened beyond 60-100 ms, however, EMG responses to the second perturbation were unaffected by the occurrence of the first perturbation. When the hindlimb containing the recording electrodes was dropped as part of the second perturbation, a myotatic latency response was observed in tibialis anterior. The amplitude of this response to the second perturbation was greater than controls when this displacement was presented during the period between initiation of the first perturbation and execution of the response to it. When the second displacement was presented after execution of the first response began, the amplitude of the myotatic response was reduced below control levels. While the results do not preclude the possibility that these "automatic" postural responses are segmental or suprasegmental reflexes, they support the hypothesis that the active component of the response to drop of the support beneath a single limb is centrally programmed and that the appropriate response can be triggered very rapidly by the somatosensory information signalling the perturbation.

Animals↗
PubMed1999

Tumor Treatment Response Based on Visual and Quantitative Changes in Global Tumor Glycolysis Using PET-FDG Imaging. The Visual Response Score and the Change in Total Lesion Glycolysis.

"Functional" tumor treatment response parameters have been developed to measure treatment induced biochemical changes in the entire tumor mass, using positron emission tomography (PET) and [F-18] fludeoxyglucose (FDG). These new parameters are intended to measure global changes in tumor glycolysis. The response parameters are determined by comparing the pre- and posttreatment PET-FDG images either visually from the change in image appearance in the region of the tumor, or quantitatively based on features of the calibrated digital PET image. The visually assessed parameters are expressed as a visual response score (VRS), or visual response index (VRI), as the estimated percent response of the tumor. Visual Response Score (VRS) is recorded on a 5 point response scale (0-4): 0: no response or progression; 1: 1-33%; 2: >33%-66%; 3: >66%-99%; and 4: >99%, estimated response, respectively. The quantitative changes are expressed as total lesion glycolysis TLG or as the change in TLG during treatment, also called deltaTLG or Larson-Ginsberg Index (LGI), expressed as percent response. The volume of the lesion is determined from the PET-FDG images by an adaptive thresholding technique. This response index is computed as, deltaTLG (LGI) = {[(SUV(ave))(1) * (Vol)(1) - (SUV(ave))(2) * (Vol)(2)]/[(SUV(ave))(1) * (Vol)(1)]} * 100. Where "1" and "2" denote the pre- and posttreatment PET-FDG, scans respectively. Pre- and posttreatment PET-FDG scans were performed on a group of 41 locally advanced lung (2), rectal (17), esophageal (16) and gastric (6) cancers. These patients were treated before surgery with neoadjuvant chemo-radiation. Four experienced PET readers determined individual VRS and VRI blinded to each other as well as to the clinical history. Consensus VRS was obtained based on a discussion. The interobserver variability captured by intraclass correlation coefficient was 89.7%. In addition, reader reliability was assessed for the categorized VRS using Kendall's coefficient of concordance for ordinal data and was found to be equal to 85% This provided assurance that these response parameters were highly reproducible. The correlation of deltaTLG with % change in SUV(ave) and % change in SUV(max), as widely used parameters of response, were 0.73 and 0.78 (P <.0001) respectively. The corresponding correlation of VRI were 0.63 and 0.64 (P <.0001) respectively. Both deltaTLG and VRI showed greater mean changes than SUV maximum or average (59.7% and 76% vs. 46.9% and 46.8%). We conclude that VRS and deltaTLG are substantially correlated with other response parameters and are highly reproducible. As global measures of metabolic response, VRS, VRI and deltaTLG (LGI) should provide complementary information to more commonly used PET response parameters like the metabolic rate of FDG (MRFDG), or the standardized uptake value (SUV), that are calculated as normalized per gram of tumor. These findings set the stage for validation studies of the VRS and deltaTLG as objective measures of clinical treatment response, through comparison to the appropriate gold standards of posttreatment histopathology, recurrence free survival, and disease specific survival in well characterized populations of patients with locally advanced cancers.

Journal Article↗
PubMed2000

Responsiveness of the core set, response criteria, and utilities in early rheumatoid arthritis.

OBJECTIVE: Validation of responsiveness and discriminative power of the World Health Organisation/International League of Associations for Rheumatology (WHO/ILAR) core set, the American College of Rheumatology (ACR), and European League for Rheumatology (EULAR) criteria for improvement/response, and other single and combined measures (indices) in a trial in patients with early rheumatoid arthritis (RA). METHODS: Ranking of measures by response (standardised response means and effect sizes) and between-group discrimination (unpaired t test and chi(2) values) at two time points in the COBRA study. This study included 155 patients with early RA randomly allocated to two treatment groups with distinct levels of expected response: combined treatment, high response; sulfasalazine treatment, moderate response. RESULTS: At week 16, standardised response means of core set measures ranged between 0.8 and 3.5 for combined treatment and between 0.4 and 1.2 for sulfasalazine treatment (95% confidence interval +/-0.25). Performance of patient oriented measures (for example, pain, global assessment) was best when the questions were focused on the disease. The most responsive single measure was the patient's assessment of change in disease activity, at 3.5. Patient utility, a generic health status measure, was moderately (rating scale) to poorly (standard gamble) responsive. Response means of most indices (combined measures) exceeded 2.0, the simple count of core set measures improved by 20% was most responsive at 4.1. Discrimination performance yielded similar but not identical results: best discrimination between treatment groups was achieved by the EULAR response and ACR improvement criteria (at 20% and other percentage levels), the pooled index, and the disease activity score (DAS), but also by the Health Assessment Questionnaire (HAQ) and grip strength. CONCLUSIONS: Responsiveness and discrimination between levels of response are not identical concepts, and need separate study. The WHO/ILAR core set comprises responsive measures that discriminate well between different levels of response in early RA. However, the performance of patient oriented measures is highly dependent on their format. The excellent performance of indices such as the ACR improvement and EULAR response criteria confirms that they are the preferred primary end point in RA clinical trials.

Adult↗
PubMed1993

Cochlear nerve fiber responses to amplitude-modulated stimuli: variations with spontaneous rate and other response characteristics.

1. Single-fiber responses to sinusoidally amplitude-modulated (AM) tones were recorded from the cochlear nerves of anesthetized guinea pigs. Stimuli were presented at the fiber's characteristic frequency (CF) and covered the intensity range between the fiber's minimum rate threshold and 90-100 dB SPL in 5- or 6-dB steps. The amount of modulation in each fiber's response and the average rate of the responses were quantified. The observed response modulation was compared with the modulation to be expected on the assumption that the instantaneous discharge rates varied with intensity in the same way that the average rates did (i.e., as predicted from each fiber's average-rate vs. level function). 2. The difference between the observed and expected response modulation varied widely across fibers. In most fibers' the responses to a limited range of stimulus intensities (typically between 20 and 30 dB above the fiber's rate threshold) were modulated far more than expected on the basis of their average rates, with responses to stimuli either above or below this range differing progressively less from expectation. Little or no response modulation was observed above approximately 70 dB SPL in these fibers. Other fibers exhibited response modulation that exceeded the expected modulation by smaller amounts, but maintained this modulation to much higher sound pressure levels. 3. The discrepancy between the observed and expected responses to AM stimuli also varied with the frequency of modulation (fm) within individual fibers. The discrepancies were least pronounced at low fms (e.g., 10 Hz) but became progressively larger as fm was increased to between 50 and 320 Hz (subject to the inter-fiber variations described in 2, above). 4. The AM response characteristics varied systematically with the fiber's spontaneous rate and other response characteristics (e.g., rate threshold, CF rate vs. level function type, and rapid adaptation characteristics). In particular, the most sensitive, high spontaneous rate fibers had responses that adapted rapidly after the onset of a stimulus, and showed the greatest enhancement of AM-related information at low-to-moderate stimulus intensities. However, these fibers appeared incapable of encoding AM-related information at high intensities, since their response rates "saturated" and their AM response enhancements diminished around 30 dB above threshold. In contrast, the less sensitive (i.e., higher threshold), lower spontaneous rate fibers showed less evidence of rapid adaptation near the onsets of their response, and lesser enhancements of the modulated responses predicted from their average-rate versus level functions.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2005

Activation of conflicting responses in Parkinson's disease: evidence for degrading and facilitating effects on response time.

Response selection often occurs in a context of competition among conflicting responses. According to recent models, the basal ganglia may play an integral role in resolving this competition by focusing the selection and inhibition of responses. We hypothesized that basal ganglia dysfunction produced by Parkinson's disease (PD) disrupts selection among conflicting responses. Using a version of the Eriksen flanker task, we tested the specific prediction that individuals with PD would experience greater response interference when distractors in the visual field activate a response that conflicts with the target response. In addition, we investigated whether greater response interference induced by these distractors could actually reduce normal response time costs in PD when the task required production of the response opposite the target. Compared to 16 healthy controls (HC), 16 individuals with PD showed an exacerbated slowing when target and distracting stimuli corresponded to conflicting responses. No group differences occurred when targets and distractors corresponded to the same response. Furthermore, the slowing induced by the distractors was reduced in both groups, but more so in PD, when execution of a response opposite the target response (i.e. incompatible response) was required. Moreover, among individuals with PD, the magnitude of the interference produced by the distractors was related to clinical ratings of bradykinesia. These findings are consistent with the hypothesis that basal ganglia dysfunction due to Parkinson's disease disrupts processes that resolve response conflict.

Aged↗
PubMed1983

Nocifensive responses to cutaneous thermal stimuli in the cat: stimulus-response profiles, latencies, and afferent activity.

Rapid-onset thermal pulses (38 degrees C X s-1) ranging from 43 to 60 degrees C (adapting temperature, 38 degrees C) were applied by contact thermodes to the shaved outer thighs of 29 partially restrained cats while they were eating (coincident stimuli) or between eating periods (noncoincident stimuli). The stimulus-associated probability and latency of three putative nocifensor responses were determined: interruption of eating or of exploration for food, hindlimb movement, and vocalization. These behavioral responses terminated the stimulus. An analysis of response trends and latencies supports the interpretation that these are unlearned escape responses to noxious stimuli. Response threshold was defined as the lowest temperature at which the average response probabilities at the test temperature and at 38 degrees C were outside one another's 95% confidence limits. Average threshold varies with the type of response and the behavior at the time of stimulation. Noncoincident stimuli elicit both interrupt and movement responses at 47 degrees C and vocalization at 53 degrees C. Coincident stimuli also elicit interrupt responses at 47 degrees C but are associated with an increased hindlimb movement threshold (51 degrees C) and vocalization threshold (55 degrees C). The lowest threshold determined for an individual cat was 43 degrees C. Response probability increases as a nonmonotonic function of stimulus intensity. Maximum sensitivity to increases in temperature occurs at stimulus intensities between 50 and 55 degrees C. Above 55 degrees C, some cats show an attenuation of response sensitivity. Special tests failed to reveal any evidence that receptor sensitization or suppression affected the stimulus-response profiles. The average response latency for all behaviors of all cats is 2.3 +/- 0.12 (SE)s from the onset of the stimulus pulse plateau. Most responses occurred within 2.5 s. No significant relationship was found between response latency and type of response or stimulus intensity. The composition and time of onset of heat-evoked afferent activity in the lateral femoral cutaneous nerve was investigated in six cats by colliding antidromic A-delta- and C-fiber volleys with the orthodromic discharge evoked by the thermodes used in the behavioral studies. There was no evidence that noxious thermal pulses evoked activity in A-delta-afferents, but C-fibers could be shown to become active at approximately 46 degrees C, at or before the onset of the thermal pulse plateau.(ABSTRACT TRUNCATED AT 400 WORDS)

Afferent Pathways↗
PubMed1977

Luteinizing hormone responses to luteinizing hormone releasing hormone, and growth hormone and cortisol responses to insulin induced hypoglycaemia in functional secondary amenorrhoea.

Luteinizing hormone (LH) responses to luteinizing hormone releasing hormone (LHRH), and growth hormone (GH) and cortisol responses to insulin induced hypoglycaemia were studied in 56 women classified into 4 distinct groups of functional secondary amenorrhoea. The groups were: I, self-induced weight reduction (20 patients); II, post pill amenorrhoea (14 patients); III, anorexia nervosa (10 patients); and IV, idiopathic secondary amenorrhoea (12 patients). Only patients with no overlapping anamnestic factors were included. Group I patients had the most heavily impaired LHRH-LH responses, and the GH response to hypoglycaemia was smaller than in other groups. Cortisol responses were normal. Group II patients showed blunted LH responses and normal GH and cortisol responses. Group III patients showed normal or exaggerated LH responses in the recovery phase of anorexia nervosa, while those two patients who were in the static phase of the illness had impaired responses. GH responses varied greatly. Group IV patients had normal basal levels of LH and normal LH, GH and cortisol responses. The restoration of LH response is not solely correlated to body mass, since patients recovering from anorexia nervosa showed greater LHRH-LH responses with nutritional rehabilitation at 76% of ideal body weight than patients with self-induced weight reduction at 87% of ideal body weight. In idiopathic amenorrhoea the hypothalamic pituitary axis seems to be practically intact. The function of hypothalamic-pituitary axis may be impaired selectively in functional amenorrhoea. Corticotrophin releasing hormone function remains intact, and GH-response may be impaired or normal independently of the LH-response to LHRH. In self-induced weight reduction both functions were impaired. These tests are easily carried out with out-patients, and they give more information about the functional state of hypothalamic-pituitary axis than basal analyses of hypothalamic-pituitary axis than basal analyses of gonadotrophins and oestrogens. However, a single pathologic reading in the LH response is not specific enough to indicate to which group of amenorrhoea the patients belong, but these tests together elucidate the severity of lesion in hypothalamic pituitary axis.

Adolescent↗