Proximate versus nonproximate risk factor associated primary deep venous thrombosis: clinical spectrum and outcomes.

OBJECTIVE: Although the treatment for acute deep vein thrombosis (DVT) is uniform, the circumstances under which it develops vary widely and may impact outcomes. This study compared clinical features and outcomes in patients who developed a primary DVT associated with a defined risk to those without any proximate risk factor. METHODS: Consecutive patients with a primary DVT and no past venous thromboembolism history from 2000 to 2002 were abstracted for demographics, risk factors, DVT anatomical characteristics, treatment, and outcomes of death and new pulmonary embolism. Comparison between patients with a proximate risk event within 30 days of DVT (Inpt) and those presenting with DVT with no defined proximate event (Outpt) was done by univariable and multivariable statistics. A validated survey was mailed to all living patients to assess long-term sequela. RESULTS: A total of 293 patients with a mean age of 55 years and 49% men had confirmed DVT by objective means (92% duplex) with a mean follow-up of 25 +/- 21 months. Inpts were more likely to have recent surgery or blunt trauma, bilateral DVT, less use of low molecular weight heparin (LMWH), and new pulmonary emboli (all P <.05). Outpts with DVT were more likely to have a history of malignancy, tibial-popliteal DVT compared with iliofemoral DVT, higher use of LMWH, and coumadin. However, there was no difference in mortality. From the patient survey (21% response), Outpts were more likely than Inpts to develop later varicosities and have daily frustration related to their legs (P < .05), but no difference in edema or ulceration. Considering the entire group, independent factors associated with freedom from PE included ambulation (odds ratio [OR] = 2.3; 95% confidence interval [CI] = 1.1-5.0; P = .04) while bilateral DVT (OR = .26; 95% CI = .09-.76; P = .013) or subcutaneous heparin (OR = 22; 95% CI = .05-.98; P = .047) were associated with greater risk. Independent factors associated with survival included ambulation (OR = 3.0; 95% CI = 1.3-7.2; P = .02), Coumadin use (OR = 2.7; 95% CI = 1.2-6.1; P = .015), and tibiopopliteal DVT (OR = 2.4; 95% = 1.1-5.5; P = .03), while malignancy (OR = 0.1; 95% CI = .05-.24; P < .01) and myocardial infarction (OR = 0.12; 95% CI = .01-.92; P = .04) were associated with lower survival. CONCLUSION: Patients who develop DVT related to a defined proximate risk event (Inpt) generally have more extensive DVT, an increased risk of PE, but less long-term functional morbidity and no difference in long-term mortality compared to those with no proximate risk.

Photostabilization of organic UV-absorbing and anti-oxidant cosmetic components in formulations containing micronized manganese-doped titanium oxide.

Micronized titanium oxide (TiO(2)) and manganese-doped titanium oxide (TiO(2):Mn) particles have been incorporated into a variety of oil-in-water (O/W) and water-in-oil-in-water (W/O/W) emulsions in conjunction with the UV-absorbing organic compounds butyl methoxydibenzoylmethane (BMDM) and octyl methoxycinnamate (OMC) and with the anti-oxidants vitamin E and vitamin C. The retention of the organics under solar exposure has been shown to be significantly enhanced by the addition of TiO(2):Mn to the formulation. In the case of BMDM and OMC, the retention is increased from 20% and 24% to 63% and 83%, respectively, after two hours of solar exposure. In this system, TiO(2) particles are shown to provide only limited protection relative to BMDM and OMC. Vitamin E and vitamin C are actively degraded by the presence of TiO(2) in the emulsion during solar exposure. This effect is reversed with TiO(2):Mn, the use of which can protect >90% of anti-oxidants in both the oil and water phases of the formulation. The absence of reactive oxygen species (ROS) generation and surface scavenging of ROS by TiO(2):Mn is responsible for a significantly reduced ROS load on the organic components and consequent photostabilization of the emulsion.

Modal distribution analysis, synthesis, and perception of a soprano's sung vowels.

A high-resolution time-frequency analysis technique, the modal distribution, is applied to sung vowels from a soprano singer. Parameters are estimated for each partial component of notes analyzed with the modal distribution. These estimates are used in an additive synthesis model to generate replicates of the original recording, using a series of time-varying sinusoids. Additionally, a source-filter model is applied to create synthetic signals, where pitch- and vowel-specific filters and driving functions are constructed from the amplitude and frequency estimates obtained. Different driving functions, which sample the range of this singer's rate and excursion variation, are transposed and filtered to create synthetic signals. The perceptual salience of the different rates and excursions is then determined via a paired-comparison listening experiment. It is found that listeners are sensitive to small variations in both average vibrato rate and average vibrato excursion. However, the perceived amount of vibrato excursion varies somewhat depending upon the pitch at which the vibrato is "played" synthetically. Finally, the naturalness and sound quality of these synthetic examples is determined through both paired-comparison and single-note sound quality scaling listening experiments.

Synthesis and Properties of Sub-50-nm Europium Oxide Nanoparticles.

Eu2O3 nanocrystals are synthesized by a colloidal precipitation route in the size range 2-40 nm. The nanocrystals are passivated with a surface layer of trioctyl phosphine oxide (TOPO) in order to eliminate surface recombination effects. When pumped at 254 nm (4f --> 5d transition) the nanocrystals exhibit red luminescence characteristic of 5D0 --> 7Fn Eu3+ transitions within the cubic form of Eu2O3. The efficiency of the luminescence is increased by a factor of five as the particle size drops below 10 nm; it is suggested that confinement of the long lifetime Eu3+ excitation within the nanocrystal is responsible for this effect. Copyright 1999 Academic Press.

Phase I study of the antineovascularization drug CM101.

CM101 is a bacterial polysaccharide that induces neovascular inflammation in malignant tumors. Fifteen patients with refractory malignancies received CM101 i.v. by a 15-min infusion every other day, three times in 1 week, at doses ranging from 1 unit (7.5 microgram)/kg to 5 units/kg. Serum was analyzed for anti-CM101 IgG and IgM weekly. Plasma levels of inflammatory cytokines, including tumor necrosis factor alpha, interleukin 8, interleukin 10, MIP-1alpha, and soluble E-selectin, were analyzed from -15 min to 12 h during each treatment. Dose-limiting toxicities, including grade IV dyspnea and arrhythmia, were encountered at the 5-unit/kg level. Toxicities occurred primarily within the first 12 h after therapy and included mild-to-moderate fever and chills, nausea, cough, headache, facial flushing, dyspnea, myalgias, and acute tumor-related pain. No patient developed detectable antibodies to CM101. All patients experienced marked time- and dose-dependent elevations in all cytokines studied. Three patients experienced tumor shrinkage. The results show that CM101 can be safely administered at doses that produce evidence for severe, and possibly tumor-specific, inflammation. Further study is necessary to better characterize the mechanism of action and determine the optimal dose and schedule of this new agent.

Soluble E-selectin in cancer patients as a marker of the therapeutic efficacy of CM101, a tumor-inhibiting anti-neovascularization agent, evaluated in phase I clinical trail.

A polysaccharide toxin, GBS toxin, is produced by group B Streptococcus (GBS) isolates from neonates who died of "early-onset disease". GBS toxin, named CM101 in the clinic, was hypothesized, on the basis of our previous in vivo studies, to induce inflammation in pulmonary neovasculature in neonates by cross-linking of embryonic receptors still expressed after birth and in tumor neovasculature in adults. Immunohisto chemical in vitro analysis of human biopsies showed that tumor neovasculature is indeed a binding site for CM101. In vivo studies in mice have demonstrated that CM101 induced inflammatory responses in neoplastic tumor neovasculature causing inhibition of tumor growth and tumor cell necrosis. These experimental observations warranted a phase I clinical trial for CM101 as an anti-neovascularization agent in human cancer therapy. Cancer patients received one cycle of therapy consisting of three treatments during 1 week. CM101 was administered over 15 min by i.v. infusion. Dosages of 7.5 micrograms/kg (1 U/kg), n = 3; 15 micrograms/kg (2 U/kg), n = 6; 24.75 micrograms/kg (3.3 U/kg), n = 3; and 37.5 micrograms/kg (5 U/kg), n = 3 were used. Enzyme-linked immunosorbent sandwich assays (ELISA) of the patients sera showed a marked elevation of soluble E-selectin with a peak concentration observed at 8-12 h after each CM101 infusion. The average baseline value for soluble E-selectin prior to the first treatment was 97.3 +/- 23.4 ng/ml (mean +/- SEM, n = 15) and the average peak level at 8 h was 441.6 +/- 62.4 (mean +/- SEM, n = 15; P < 0.001). Subsequent treatments gave average maximum soluble E-selectin levels again at 8 h of 466.9 +/- 87.6 and 412.0 +/- 67.8 ng/ml, for treatments 2 and 3 respectively. Baseline values for treatments 2 and 3 were 192.3 +/- 26.4 and 226.4 +/- 26.1 ng/ml respectively (p < 0.01 versus treatment 1). Out of 15 patients, 5 showed tumor reduction or stabilization and were given additional cycles of therapy. CM101 induced an increase in soluble E-selectin levels, which remained elevated over baseline at the start of the following treatment cycles. The baseline remained elevated for several weeks after the final treatment, i.e., P < 0.01 for levels before treatment 1 compared to those at week 4 after treatment. Elevated soluble E-selectin is considered proof of endothelial engagement in an inflammatory process. Our data support the contention that the inflammatory response observed in these cancer patients is targeting the tumor neovasculature and that measurement of soluble E-selectin levels in patients treated with CM101 can provide important information on the magnitude of CM101-mediated neovascular endothelial activation and tumor cell damage in cancer of endothelial origin, or cancer with a major neo-angiogenic component.

Comparison of electrode discrimination, pitch ranking, and pitch scaling data in postlingually deafened adult cochlear implant subjects.

The goal of this study was to investigate the relationship between variation in electrode site of stimulation and the perceptual dimensions along which such stimuli vary. This information may allow more effective use of electrode place when encoding speech information. To achieve this goal, two procedures which measure pitch in subjects implanted with the Nucleus/Cochlear Corporation multichannel device were performed. Estimates of electrode discriminability that can be obtained from these procedures were compared to a more direct measure of electrode discriminability that was obtained in a previous study [Collins et al., Assoc. Res. Otolaryng. Abstracts, No. 642 (1994)]. In the first task, subjects performed a pitch ranking procedure similar to that used in previous studies [Townshend et al., J. Acoust. Soc. Am. 82, 106-115 (1987); Nelson et al., J. Acoust. Soc. Am. 98, 1987-1999 (1995)]. Estimates of the pitch percept elicited by stimulation of each electrode as well as the discriminability of the electrodes were generated from the data using two different statistical analyses. In the second task, subjects performed a pitch scaling procedure similar to one used in a previous study [Busby et al., J. Acoust. Soc. Am. 95, 2658-2669 (1994)]. Again, two different statistical analyses were performed to generate estimates of the pitch percept corresponding to stimulation of each electrode and to generate estimates of electrode discriminability. In general, the estimates of the relationships between the pitch percepts obtained from the two procedures were not identical. In addition, the estimates of electrode discriminability were not equivalent to the electrode discrimination measures obtained from the same subjects during the previous study. Signal detection theory has been used to model the decision processes required by each of the procedures described above [e.g., Jesteadt and Bilger, J. Acoust. Soc. Am. 55, 1266-1276 (1974)]. However, these models do not predict the differences that were observed between the data sets obtained during this study. An alternate model is proposed which may explain the data obtained from these subjects. This model is based on the assumption that the percept that is elicited by electrical stimulation of an electrode is multidimensional, as opposed to unidimensional in nature. Therefore, the perceived signal is more appropriately modeled using a multidimensional random vector, where each element of the vector represents the perceived value of one of the dimensions of the signal.

Electrode discrimination and speech recognition in postlingually deafened adult cochlear implant subjects.

This study investigated the relationship between electrode discrimination and speech recognition in 11 postlingually deafened adult cochlear implant subjects who were implanted with the Nucleus/Cochlear Corporation multichannel device. The discriminability of each electrode included in a subject's clinical map was measured using adaptive and fixed-level discrimination tasks. Considerable variability in electrode discriminability was observed across subjects. Two subjects could discriminate all electrodes, and discrimination performance by the remaining nine subjects varied from near perfect to very poor. In these nine subjects, the results obtained from the discrimination tasks were used to create a map that contained only discriminable electrodes, and subjects' performance on speech recognition tasks using this experimental map was measured. Four different speech recognition tests were administered: a nine-choice closed-set medial vowel recognition task, a 14-choice closed-set medial consonant recognition task, the NU6 Monosyllabic Words Test [T. W. Tillman and T. Carhart, Tech. Rep. No. SAM-TR-66-55, USAF School of Aerospace Medicine, Brooks Air Force Base, Texas (1966)] scored for both words and phonemes correct, and the Central Institute for the Deaf (CID) Everyday Sentences test [H. Davis and S. R. Silverman, Hearing and Deafness (Holt, Rinehart, and Winston, New York, 1978)]. Seven of the nine subjects tested with the experimental map showed significant improvement on at least one speech recognition measure, even though the experimental map contained fewer electrodes than the original map. Three subjects' scores improved significantly on the CID Everyday Sentences test, three subjects' scores improved significantly on the NU6 Monosyllabic Words test, and five subjects' scores improved significantly on the NU6 Monosyllabic Words test scored for phonemes correct. None of the subjects' scores improved significantly on either the vowel or consonant tests. No significant correlation was observed between electrode discrimination ability and speech recognition scores or between electrode discrimination ability and improvement in speech recognition scores when programmed with the experimental map. The results of this study suggest that electrode discrimination tasks may be used to improve speech recognition of some cochlear implant subjects, and that each electrode site does not necessarily provide perceptually distinct information.

Temporal pattern discrimination and speech recognition under electrical stimulation.

Discrimination of temporal patterns has been suggested as a relevant process in speech recognition by subjects with normal hearing [Sorkin, J. Acoust. Soc. Am. 87, 1695-1701 (1990)]. This paper investigates whether performance of Nucleus multichannel cochlear implant subjects on a temporal pattern discrimination task is an efficient and valid psychophysical measure of speech recognition ability. Stimuli consisted of temporal sequences defined by twelve 35-ms tones and eleven randomly generated temporal gaps separating the tones. A fixed-level same/different paradigm was used to measure the discriminability of these sequences as a function of their average correlation across a block of trials. On each trial, the "standard" sequence was generated randomly by drawing gap durations from a Gaussian distribution. The gaps of the comparison sequence were generated in a similar fashion with a specified average correlation with the gaps of the first sequence. Performance of implanted and normal hearing subjects decreased monotonically with increasing average sequence correlation. However, performance across implanted subjects ranged from that observed for acoustically stimulated subjects with audiometrically normal hearing to levels near chance. Comparing these data with measures of speech recognition in the same subjects, we have found that performance on standard speech recognition tests correlates with ability to discriminate among such random temporal patterns.

The spectral shaping of neural discharges by refractory effects.

It has previously been shown that post-stimulus time (PST) histograms have autoregressive properties, which implies that the neural firings have spectral components that are determined by these properties. The expected power spectral density of neural discharges is derived when the process is firing at a constant rate (similar to tonal stimulation at CF with no phase locking). Although the unconditional intensity of the process is not time varying, the spectrum exhibits prominent spectral peaks. The effect of histogram bin size, stimulus intensity, and refractory effects are examined with respect to spectral shape and it is shown that stimulus intensity determines the magnitude of spectral peaks while refractory duration determines the peak locations. The effectiveness of predicting the spectrum is demonstrated with eight-nerve data and point process simulations.

An efficient method for detecting connectivity in neural ensembles.

Modern technology is allowing researchers to collect data from neural ensembles with a large number of units, and the analysis of interaction between these units can be very time consuming. Estimation of pairwise connectivity is the most common method of determining the neural 'network' but usually necessitates the production of numerous histograms for each pair considered. We present a method which will indicate which pairs in a network represent potential connections and thereby simplify the postexperimental analysis. The technique uses cross-interval information to create an n x n matrix which represents all possible connections in an n neuron ensemble and can be calculated recursively on-line. The performance of this technique is analyzed with respect to data size and strength of the connections. It is compared to 2 similar techniques that are also presented here, one in which perfect knowledge of the timing of the excitation is known, and one in which the timing can be bounded.

Temporal integration and multiple looks.

The decrease in detection and discrimination thresholds with increases in signal duration has often been taken to indicate that a process of relatively long-term temporal integration occurs in hearing. Two experiments are reported that suggest that no such process occurs. The first experiment is similar to the two-pulse experiment reported by Zwislocki [J. Zwislocki, J. Acoust. Soc. Am. 32, 1046-1059 (1960)] in which the threshold in quiet for a pair of brief pulses is measured as a function of the temporal separation between them. Our data indicate that power integration occurs only for separations less than approximately 5 ms. For separations larger than 5-10 ms, thresholds do not change with separation and the pulses appear to be processed independently. In the second experiment, brief 1-kHz tone pulses separated by 100 ms are presented during gaps in a wideband noise. The threshold for a pair of pulses is lower than that for either pulse presented alone, indicating that some type of "integration" occurs. However, the threshold for the pulse pair is not affected by changes in the level of the noise during the interval between the pulses. These data are inconsistent with the classical view of temporal integration that involves long-term integration. They are consistent with the notion that the input is sampled at a fairly high rate and that these samples or "looks" are stored in memory and can be accessed and processed selectively. This multiple-look model can account for the data from the present experiment and also can account for the data on temporal integration for tones and noise.(ABSTRACT TRUNCATED AT 250 WORDS)

Discrimination of modulation depth of sinusoidal amplitude modulation (SAM) noise.

The detection of sinusoidal amplitude modulation (SAM) provides a lower bound on the degree to which temporal information in the envelope of complex waveforms is encoded by the auditory system. The extent to which changes in the amount of modulation are discriminable provides additional information on the ability of the auditory system to utilize envelope fluctuations. Results from an experiment on the discrimination of modulation depth of broadband noise are presented. Discrimination thresholds, expressed as differences in modulation power, increase monotonically with the modulation depth of the standard, but do not obey Weber's law. The effects of carrier level and of modulation frequency are consistent with those observed in modulation detection: Changes in carrier level have little effect on modulation discrimination; changes in modulation frequency also have little effect except for standards near the modulation detection threshold. The discrimination of modulation depth is consistent with the leaky-integrator model of modulation detection for standards below--10 dB (20 log ms); for standards greater than--10 dB, the leaky integrator predicts better performance than that observed behaviorally.

Mode of suppression of pituitary and gonadal function after acute or prolonged administration of a luteinizing hormone-releasing hormone antagonist in normal men.

LHRH antagonists compete with endogenous LHRH for binding to receptors on pituitary gonadotrophs and thereby inhibit gonadotropin secretion and, consequently, gonadal function. We studied the pituitary and gonadal suppression following single doses and short term administration (1-3 weeks) of a recently developed LHRH antagonist in normal men. First, the antagonist Nal-Glu ([Ac-D2Nal1, D4ClPhe2,D3Pal3,Arg5,DGlu6(AA),DAla10]LHRH ), was given as a single sc injection to five normal men at three dose levels of 1, 5, and 20 mg (study I). Serum FSH, immunoreactive LH (IR-LH), bioactive LH (bio-LH), testosterone, and estradiol were measured before and at frequent intervals for 48 h after Nal-Glu administration. Mean serum FSH decreased (P less than 0.001) by 28.9 +/- 5.4% (+/- SE), 38.2 +/- 7.9%, and 44.5 +/- 3.6% after the 1-, 5-, and 20-mg doses, respectively. Mean serum IR-LH decreased (P less than 0.001) by 39.0 +/- 13.8%, 53.2 +/- 10.0%, and 53.1 +/- 14.4% after the three doses. Serum bio-LH levels and the ratio of bio-LH/IR-LH decreased (P less than 0.001) after the 20-mg dose by 87.8% and 78.5%, respectively. Serum testosterone levels decreased (P less than 0.001) more than 78.5% after all Nal-Glu doses. The duration of testosterone suppression, but not the nadir reached, was dose dependent (P = 0.012). Serum estradiol levels also decreased (P less than 0.001), but the rate of decrease was slower than that of serum testosterone. The apparent plasma disappearance half-life of Nal-Glu after administration of 5 mg was 12.8 +/- 2.7 h. The Nal-Glu antagonist also was given daily as a single sc injection of 5 mg to eight normal men for 21 days (study II) or twice daily to five men for 7 days (study III). In study II, serum FSH, IR-LH, bio-LH, testosterone, estradiol, and 17-hydroxy-progesterone were measured daily, immediately before the next injection, and on days 1, 7, and 21 in frequent blood samples drawn for 24 h. The mean serum testosterone level in study II decreased (P less than 0.001) from 17.6 +/- 2.2 to 4.1 +/- 1.0 nmol/L on day 1, increased (P less than 0.05) between days 2 and 8, and then progressively decreased to below 2 nmol/L from day 18 until 24 h after the end of the study. Serum FSH, IR-LH, and bio-LH levels paralleled those of testosterone.(ABSTRACT TRUNCATED AT 400 WORDS)

Maintenance of the ratio of bioactive to immunoreactive follicle-stimulating hormone in normal men during chronic luteinizing hormone-releasing hormone agonist administration.

Chronic administration of LHRH agonist analogs to humans reduces gonadal function through pituitary desensitization. Serum immunoreactive gonadotropin levels are modestly reduced, whereas serum bioactive LH levels are drastically suppressed. The effects on bioactive FSH levels, however, are not known. In this study, serum bioactive FSH was measured using an in vitro granulosa cell aromatase bioassay in four normal men given a LHRH agonist, [D-Trp6,Pro9-NEt]LHRH (LHRHA; 500 micrograms/day for 16 weeks), by sc infusion and testosterone enanthate (TE; 100 mg, im every 2 weeks) and in five men given 500 micrograms/day LHRHA by daily sc injection for 20 weeks and TE (100 mg every 2 weeks) from weeks 10 through 20. During the first study, serum immunoreactive FSH levels (IR-FSH) decreased by 56.5 +/- 4.8% (+/- SEM), and serum bioactive FSH (Bio-FSH) level decreased by 57.6 +/- 6.4%. The ratio of Bio-FSH to IR-FSH did not change. During the second study, both serum IR-FSH and Bio-FSH levels followed a triphasic pattern, decreasing slightly but not significantly immediately after initiation of LHRHA administration, progressively increasing to a peak (P less than 0.5 vs, baseline) at week 10, and then, after addition of TE to this regimen, decreasing slightly again. The Bio-FSH to IR-FSH ratio, as in the first study, did not change. When serum obtained at week 10 during the second study, just before initiation of TE, was chromatographed on a Sephadex G-100 column, IR-LH eluted in two distinct peaks, while IR-FSH eluted as a single peak. These results demonstrate that in normal men chronic LHRHA administration alone for up to 10 weeks or LHRHA plus TE for up to 16 weeks does not alter the qualitative characteristics of secreted FSH, since there was no dissociation between serum IR- and Bio-FSH levels.

Gonadotropins and testosterone escape from suppression during prolonged luteinizing hormone-releasing hormone antagonist administration in normal men.

The ability of prolonged administration of a LHRH antagonist, [Ac-delta 3Pro1,4F-D-Phe2,D-Trp3,6]LHRH (4F-antagonist), to suppress serum gonadotropin and testosterone levels was studied in normal men. The 4F-antagonist was given either as a continuous 13.3 micrograms/kg X h sc infusion for 72 h or as intermittent sc injections of 100 micrograms/kg every 6 h for 7 days. Serum FSH, LH, and testosterone levels decreased in the period immediately following initiation of 4F-antagonist administration. However, an escape toward baseline levels for each of these hormones occurred during prolonged antagonist administration. When men receiving the continuous infusion were challenged with iv bolus doses of 50 micrograms LHRH, the response of LH after the first 12 h of 4F-antagonist administration was similar to that before its administration. This gonadotropin and testosterone escape suggests that, at the doses used, the inhibitory action of the antagonist on gonadotropin secretion is progressively lost. The initial decrease in androgen levels could serve to augment endogenous LHRH release, which, in turn, overcomes the pituitary effects of the antagonist, or to augment endogenous LH secretion directly. These results demonstrate that the pituitary can escape from the suppressive effects of prolonged LHRH antagonist administration and partially restore serum gonadotropin and testosterone levels to normal in man.

Suppression of pituitary-gonadal function by a potent new luteinizing hormone-releasing hormone antagonist in normal men.

LHRH antagonists compete with endogenous LHRH for binding to receptors on pituitary gonadotrophs and thereby inhibit gonadal function by suppressing gonadotropin secretion. We studied the effects of a recently developed LHRH antagonist on the pituitary-gonadal axis in man. The antagonist Detirelix [( N-Ac-D-Nal(2)1, D-pCl-Phe2,D-Trp3, D-hArg(Et2)6, D-Ala10]LHRH) was given as a single sc injection to nine normal men at three dose levels (5, 10, and 20 mg) at intervals of at least 7 days. Serum FSH, LH, and testosterone levels were measured before treatment, at frequent intervals for 48 h, and 72, 96, and 168 h after administration of the antagonist. Mean serum FSH levels decreased (P less than 0.001) from 6.9 +/- 0.5 (+/- SEM) mIU/mL to nadirs of 4.4 +/- 1.1, 3.6 +/- 0.9, and 4.1 +/- 0.9 after the 5-, 10-, and 20-mg doses, respectively. Serum LH levels decreased (P less than 0.001) from 6.2 +/- 0.3 mIU/mL to nadirs of 3.3 +/- 0.4, 2.8 +/- 0.3, and 2.7 +/- 0.3 after all three doses. Serum testosterone levels decreased (P less than 0.001) in a dose-dependent fashion from 5.1 +/- 0.2 ng/mL to nadirs of 1.3 +/- 0.3, 0.9 +/- 0.3, and 0.6 +/- 0.1 after the same doses. After the initial testosterone decrease, however, escape occurred 12-28 h after the lower doses. The area under the response curve, describing hormone concentrations as a function of time during the study, diminished by 23 +/- 2%, 36 +/- 4%, and 36 +/- 3% for FSH, by 14 +/- 6%, 30% +/- 6%, and 34 +/- 5% for LH, and by 41 +/- 5%, 58 +/- 6%, and 68 +/- 4% for testosterone with the same doses, respectively. The apparent plasma disappearance half-life of Detirelix by RIA was at least 41 h after all three doses. Detirelix elicited only a minor local reaction; no systemic side-effects were observed within the dose range used. These results indicate that this LHRH antagonist is a safe, highly potent inhibitor of the human pituitary-gonadal axis with an exceptionally long duration of action.

Single subcutaneous doses of a luteinizing hormone-releasing hormone antagonist suppress serum gonadotropin and testosterone levels in normal men.

The ability of single doses of a LHRH antagonist [Ac-delta 3Pro1, 4F-D-Phe2, D-Trp3,6]LHRH (4F-antagonist) to suppress serum gonadotropin and testosterone levels was studied in six normal men. The 4F-antagonist was given sc at four doses: 40, 80, 160, and 320 micrograms/kg body weight. Serum immunoreactive LH, FSH, and testosterone and bioactive LH were measured at intervals for the subsequent 18 h. Serum LH decreased rapidly by (mean +/- SE) 39.7 +/- 2.7%, 41.6 +/- 5.4%, 45.5 +/- 4.7%, and 45.3 +/- 5.4% after each of the four doses. The mean number of LH pulses and their amplitude decreased after each dose and remained suppressed for at least 6 h. After each of the four doses, mean serum FSH levels decreased by 20.0 +/- 4.1%, 33.8 +/- 6.8%, 25.8 +/- 3.6%, and 33.3 +/- 5.7%, and mean serum testosterone levels decreased by 47.7 +/- 7.3%, 55.6 +/- 10.5%, 58.2 +/- 10.8%, and 76.0 +/- 6.0%. Serum testosterone remained low for at least 18 h after the two higher doses. LH bioactivity and the ratio of bioactive LH to immunoreactive LH decreased in all subjects, especially after higher doses of the 4F-antagonist. No side effects or adverse reactions occurred after 4F-antagonist administration, and toxicology studies were negative. These results demonstrate that a single sc injection of this potent LHRH antagonist inhibits the pituitary-gonadal axis in normal men.

Heterogeneity of sperm density profiles following 16-week therapy with continuous infusion of high-dose LHRH analog plus testosterone.

LHRH agonist analogs have been investigated as potential male contraceptives. It has been shown that the LHRH agonistic analog [D-Trp6,Pro9-NEt] LHRH (LHRHA) given to men in single doses up to 500 micrograms daily for up to 20 weeks with the coadministration of testosterone enanthate produces reversible oligozoospermia. Individual responses to the treatment, however, were variable. In this study, we gave the same analog to eight normal male volunteers as a continuous infusion of 500 micrograms daily for 16 weeks. Testosterone enanthate, 100 mg, was given by injection every second week. Six of the subjects became oligozoospermic but the other two retained sperm counts that were greater than 20 million/ml, although their treatment continued for 20 weeks. The reasons for this variability of response are not clear. Serum immunoreactive LH values increased during the infusion period whereas testosterone declined. FSH values fell during treatment in all subjects except the two non-responders. The acute pituitary response to LHRHA during the treatment or shortly thereafter (48 h) was completely abolished, and bioactive LH values were suppressed totally. FSH, LH, testosterone and sperm counts returned to normal in all subjects following discontinuation of LHRHA infusion. Continuous infusion of 500 micrograms of LHRHA daily for 16 weeks with 100 mg of testosterone enanthate every 2 weeks induced desensitization of the pituitary, loss of LH bioactivity, and decreases of FSH and testosterone. This mode of administration, however, did not improve sperm density results obtained earlier by single daily injections of the analog. Heterogeneity of sperm density profiles still persists for reasons that are not yet clear.

Temporal interactions between pure tones and amplitude-modulated noise.

An auditory interaction between the temporal fine structure of a low-frequency tone and the envelope of a high-frequency waveform was observed at very large frequency separations. Thresholds for detection of sinusoidal amplitude modulation of a high-frequency, narrow-band noise were measured as a function of the relative phase between the modulator and a pure tone with the same frequency as the modulator. These "phase functions" were determined at various intensities of the noise and tone for three different modulation frequencies. In general, the phase functions show that low-frequency stimulation has a cyclic effect on the sensitivity to amplitude modulation; over a limited range of relative phases, the modulation threshold is lower than that measured without low-frequency stimulation whereas over a broader range of relative phases, the modulation threshold is much higher. The difference between minimum and maximum modulation thresholds was observed to be as great as 23 dB. Despite this substantial degree of temporal interaction, little, if any, masking by the low-frequency tone of the high-frequency noise was observed.