Auditory temporal integration and the power function model.

The auditory temporal integration function was studied with the objective of improving both its quantitative description and the specification of its principle independent variable, stimulus duration. In Sec. I, temporal integration data from 20 studies were subjected to uniform analyses using standardized definitions of duration and two models of temporal integration. Analyses revealed that these data were best described by a power function model used in conjunction with a definition of duration, termed assigned duration, that de-emphasized the rise/fall portions of the stimuli. There was a strong effect of stimulus frequency and, in general, the slope of the temporal integration function was less than 10 dB per decade of duration; i.e., a power function exponent less than 1.0. In Sec. II, an experimental study was performed to further evaluate the models and definitions. Detection thresholds were measured in 11 normal-hearing human subjects using a total of 24 single-burst and multiple-burst acoustic stimuli of 3.125 kHz. The issues addressed are: the quantitative description of the temporal integration function; the definition of stimulus duration; the similarity of the integration processes for single-burst and multiple-burst stimuli; and the contribution of rise/fall time to the integration process. A power function in conjunction with the assigned duration definition was again most effective in describing the data. Single- and multiple-burst stimuli both seemed to be integrated by the same central mechanism, with data for each type of stimulus being described by a power function exponent of approximately 0.6 at 3.125 kHz. It was concluded that the contribution of the rise/fall portions of the stimuli can be factored out from the rest of the temporal integration process. In Sec. III, the conclusions that emerged from the review of published work and the present experimental work suggested that auditory temporal integration is best described by a power function in conjunction with the assigned duration definition. The exponent for the power function is typically less than 1.0, and varies with frequency and hearing level. Second, a means of empirically assaying the contribution of the rise-fall portions of the stimuli is presented and evaluated. Finally, properties of a central auditory integrator are hypothesized.(ABSTRACT TRUNCATED AT 250 WORDS)

Scintigraphy with In-111-labeled monoclonal antitumor antibodies: kinetics, biodistribution, and tumor detection.

The purpose of this study was to evaluate and compare the kinetics, biodistribution, and tumor-depicting properties of three intact indium-111-labeled murine monoclonal antibodies (MoAb) and to determine if use of In-111-labeled F(ab')2 fragments of one of them had advantages over its intact counterpart for immunoscintigraphy. Ten patients with prostate cancer were studied with an anti-prostatic acid phosphatase MoAb (PAY-276), with a resultant tumor detection rate of 15%. Twenty-eight patients with melanoma were studied with ZME-018, a MoAb that targets the KD-240 melanoma antigen. Forty-three percent of the known lesions were detected. Forty patients with carcinoembryonic antigen (CEA)-producing tumors were studied, 24 with intact ZCE-025, and anti-CEA MoAb, and 16 with its F(ab')2 fragment. With use of intact ZCE-025, 34% of known lesions were detected versus 83% with its F(ab')2 fragment. The distribution of each MoAb appears unique unto itself with regard to kinetics, normal tissue distribution, and response to MoAb mass.

Breast cancer imaging with In-111 human IgM monoclonal antibodies: preliminary studies.

Detection of specific tumor sites was studied with scintigraphy and radiolabeled human IgM monoclonal antibodies (MoAbs). Ten patients with metastatic breast cancer received an infusion of one of three indium-111-labeled anti-breast carcinoma MoAbs. The time of infusion ranged from 30 minutes to 2 hours. Three patients received YBB-190 at total doses of 2, 4.25, or 11 mg, four patients received YBM-209 at total doses of 1 mg (n = 1) or 20 mg (n = 3), and three patients each received 22 mg of YBY-088. Imaging was performed immediately after infusion and at 4, 24, 48, 72, 120, and 144 hours. Many presumed sites of metastatic disease were imaged in three of the four patients who received 20 mg of YBM-209 and in two of the three patients who received YBY-088. Tumor was not detected in any of the patients who received YBB-190, in the patient who received a 1-mg dose of YBM-209, or in the patient who received YBY-088 and in whom a biopsy of tumor tissue failed to demonstrate target antigen. The authors conclude that In-111-labeled human IgM MoAbs can target human breast cancer, but antigen expression and antibody dose determine successful immunoscintigraphy.

Radioimmunodetection of cancer with the use of indium-111-labeled monoclonal antibodies.

We have infused 13 111In-labeled murine IgG monoclonal antibodies (MAb) into 73 patients who had been diagnosed as having 7 types of cancers, and 3 111In-labeled human MAb into 8 patients with breast cancer. To each patient, 1.5-5 mCi attached to a maximum of 1 mg MAb had been given in a total MAb dose of 0.5-500 mg. The most encouraging overall results have been obtained with anti-human T-cell MAb T101 (33 of 33 tumor sites imaged in 5 patients), antimelanoma MAb P96.5 (47 of 88 sites imaged in 21 patients), anti-prostate MAb PSA399 (14 of 21 sites imaged in 4 patients), and anti-colon MAb ZCE025 (16 of 26 sites imaged in 12 patients). Poor imaging results were related to lower doses, reactivity with circulating cells, and limited antigen expression in various tumor sites. The problems involved in radioimmunodetection included low extraction of MAb from the serum by the tumor that resulted in poor tumor uptake of the radiopharmaceutical, and high background activity in the liver, heart, spleen, and gastrointestinal tract that made imaging difficult in those areas. Heterogeneous antigen production leaves some tumor deposits without targets, and the immunogenicity of the MAb limits use of these agents repetitively in humans. Nevertheless, these early results are encouraging for their potential diagnostic and therapeutic applications.

Continuous infusion of T101 monoclonal antibody in chronic lymphocytic leukemia and cutaneous T-cell lymphoma.

We report results of 24-h continuous infusions of murine monoclonal antibody T101 in six patients with chronic lymphocytic leukemia (CLL), and 10 with cutaneous T-cell lymphoma (CTCL), at doses of 10, 50, 100, or 500 mg. Similar side-effects were seen in CLL and CTCL, including direct toxic effects of therapy, such as fever, sweats, and chilling, and a 30% frequency of allergic manifestations. In vivo binding of T101 to target cells in blood, skin, lymph nodes, tumor masses, and bone marrow was demonstrated. Antigenic modulation occurred rapidly in all cases, and persisted throughout the infusion period. Peak serum T101 levels for equivalent doses were somewhat higher, and persisted longer in CTCL, perhaps because of differences in the number of circulating target cells. Antimouse antibodies were demonstrated in 5 of 10 CTCL vs. 0 of 6 CLL patients. In all five cases, there was a substantial component of T101 specificity in the antimouse response. Brief objective clinical responses were observed in 4 of 10 CTCL and 2 of 6 CLL patients. Acute anti-tumor effects of T101 were substantially more dramatic in CTCL than CLL, but appeared limited by antigenic modulation and the emergence of antimouse antibodies. In view of the in vivo binding and modulation, more durable anti-tumor effects may be achievable with cytotoxic immunoconjugates of this monoclonal antibody.

Toxicities and side effects associated with intravenous infusions of murine monoclonal antibodies.

Toxicity was assessed during and following 186 infusions of various murine monoclonal antibodies (MoAbs) in 82 patients afflicted with 10 different malignancies. Doses ranged from 0.5 to 500 mg per infusion and were administered over 0.25-24 h. Reactions of varying degrees were noted in 27 patients (33%) during or following 57 (31%) infusions. For antibodies that reacted with circulating cells, toxicity was seen in 20/82 of the first infusions compared with 0/55 for patients receiving antibodies that did not react with circulating cells. A 25% decrease in white blood cells (WBC) was associated with side effects in 40/66 courses whereas only 9/81 courses were associated with any sort of toxicity when the WBC decreased by less than 25%. Fevers, rigors, chills, and diaphoresis were observed in 21-23% of patients, but only in association with removal of circulating cells that bound the antibody. Presumed hypersensitivity reactions, including urticaria, pruritus, bronchospasm, and anaphylaxis occurred in 15 patients (18%). The two episodes of bronchospasm and single episode of anaphylaxis occurred in patients treated more than once, at least 2 weeks after a previous treatment. There was no clear relationship between dose or rate of infusion and toxicity for these antibodies. We conclude that murine MoAbs can be given with an acceptable frequency of serious allergic reactions and that the biologic effects of specific antibody-antigen reactions may be a more significant source of toxicity for such antibodies.

Radioimmunodetection of melanoma utilizing In-111 96.5 monoclonal antibody: a preliminary report.

The murine 96.5 monoclonal antimelanoma antibody (MoAb) was labeled with In-111, and 1-20 mg were administered to 21 patients who had proved or suspected melanoma metastases. One patient was studied twice. In four patients, unlabeled 96.5 MoAb was administered prior to the radiopharmaceutical. All of the patients tolerated the procedure without toxicity regardless of the mass of MoAb administered. The scans were interpreted by two observers, one with full knowledge, the other with no knowledge of the cases. Increasing the MoAb mass or preinfusing unlabeled MoAb prior to the administration of In-111 MoAb resulted in a prolongation of the serum half time, and appeared to improve tumor detection. Lesions were best seen at 72 hours after infusion or later. In all patients who had metastatic disease, at least one tumor site was apparent. Fifty-six per cent of known lesions 1.5 cm or greater in size were detected by the physician who had knowledge of the cases when data from all doses were considered. There were eight lesions detected that were not suspected in the workup of the patient. When these are included, the detection rate rises to 61%. Forty-nine per cent were detected by the other physician. Subtraction techniques were not employed. Lesions were often better seen with single photon emission computed tomography than with planar imaging techniques. The 96.5 In-111 MoAb appears to have utility for the detection of metastatic melanoma. Further clinical evaluation of 96.5 In-111 MoAb is warranted.

Benzyladenine reversal of abscisic Acid inhibition of growth and RNA synthesis in germinating bean axes.

The effect of benzyladenine on growth, ATP pool size and specific radioactivity, and the rate and amount of RNA synthesis in aseptically cultured axes of Phaseolus vulgaris during the first 24 hours of germination were measured in experiments where the duration of benzyladenine application and its concentration were varied. Maximum promotion of growth (25%) occurs at 10(-5)m benzyladenine. Maximum promotion of RNA synthesis (44%) occurs at 10(-5)m benzyladenine. Benzyladenine has little effect on the size or specific radioactivity of the ATP pool. Benzyladenine can completely counteract abscisic acid inhibition of growth and RNA synthesis, and these reversals are measurable in 2 hours. GA(1) and GA(3) do not promote growth or counteract abscisic acid inhibition of growth in germinating bean axes in these experiments.

Effects of abscisic Acid on growth, RNA metabolism, and respiration in germinating bean axes.

The effect of abscisic acid on growth, respiration, the ATP pool, and rate and amount of RNA synthesis in aseptically cultured axes of Phaseolus vulgaris during the first 24 hours of germination has been measured in experiments where the duration of abscisic acid application and its concentration have been varied. At concentrations from 10(-7) to 10(-4)m, abscisic acid inhibits synthesis of RNA with maximal inhibition (80%) at 10(-5)m. RNA synthesis is inhibited by abscisic acid at all times examined (12, 18, and 24 hours), but the extent of inhibition is maximal at 18 hours. In 18-hour axes RNA synthesis is inhibited 42%, ATP pool size is reduced 3%, and O(2) consumption is decreased by 6% after 75 minutes of abscisic acid treatment. Inhibition of RNA synthesis is complete by 2 hours of treatment with abscisic acid, and recovery to near control levels occurs by the 3rd hour after removal from abscisic acid.