Long-term follow-up of didanosine administered orally twice daily to patients with advanced human immunodeficiency virus infection and hematologic intolerance of zidovudine.

This phase 1 trial was conducted to evaluate the safety and tolerance of didanosine (ddI) in subjects with AIDS or AIDS-related complex (ARC) who previously had demonstrated hematologic intolerance of zidovudine. Thirty subjects, 21 with AIDS and nine with ARC, were enrolled. Initially, didanosine was administered orally twice daily for a total daily dose of either 750 mg or 1,500 mg. Subsequently, the dosage for those receiving 1,500 mg/d was reduced to a maximum of 750 mg/d (375 mg twice daily) when data from this and other phase 1 studies showed that the dosage of 1,500 mg/d (750 mg twice daily) was associated with an unacceptable risk of developing neuropathy. The subjects were studied for 46 weeks (mean time; range, 7-122 weeks). The dose-limiting toxic effect observed was peripheral neuropathy, which occurred in eight patients. Other significant toxic effects included pancreatitis in three patients and xerostomia in eleven. In general, didanosine was well tolerated from a hematologic standpoint by the majority of patients during prolonged administration.

Diverse and contrasting effects of habitat fragmentation.

Different components of an ecosystem can respond in very different ways to habitat fragmentation. An archipelago of patches, representing different levels of fragmentation, was arrayed within a successional field and studied over a period of 6 years. Ecosystem processes (soil mineralization and plant succession) did not vary with the degree of subdivision, nor did most measures of plant and animal community diversity. However, fragmentation affected vertebrate population dynamics and distributional patterns as well as the population persistence of clonal plant species. The results highlight the dangers of relying on broad community measures in lieu of detailed population analyses in studies of fragmented habitats.

Phase I study of 2'-3'-dideoxyinosine administered orally twice daily to patients with AIDS or AIDS-related complex and hematologic intolerance to zidovudine.

PURPOSE: To evaluate the safety and hematologic tolerance of 2'-3'-dideoxyinosine (didanosine, ddI) in subjects with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex and prior hematologic intolerance to zidovudine. PATIENTS AND METHODS: A Phase I trial with two dose groups at a single-center, university-affiliated hospital ambulatory care center. Of 30 subjects enrolled, 21 had AIDS and nine had AIDS-related complex. All had CD4 lymphocyte counts less than 0.2 x 10(9)/L at entry. Didanosine was administered orally twice daily at a total daily dose of 750 mg or 1,500 mg for 12 weeks. Subjects who completed the 12-week study continued to receive ddI at the lower dose. All subjects were monitored for toxicity. Virologic and immunologic response markers were also measured. RESULTS: For the group as a whole, there was no significant decrease in mean hemoglobin level or leukocyte or platelet counts. The dose-limiting toxicity was peripheral neuropathy. Other significant toxicities included pancreatitis and hypocalcemia. Uric acid elevations were common but were without clinical consequence. A sustained decrease in serum p24 antigen of at least 50% was noted in 42% of subjects who were p24 antigen-positive at entry. The mean CD4 lymphocyte count showed an initial increase that was not sustained over the 12-week study. All subjects remained anergic to skin testing. CONCLUSIONS: Didanosine is well tolerated hematologically in some patients with prior significant hematologic intolerance to zidovudine. The toxicity profile for ddI differs from that of zidovudine and includes peripheral neuropathy and pancreatitis. Changes in CD4 lymphocyte number and HIV p24 antigen levels in some patients suggest antiviral activity of ddI in this population.

The safety and pharmacokinetics of recombinant soluble CD4 (rCD4) in subjects with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. A phase 1 study.

STUDY OBJECTIVE: To evaluate the safety and pharmacokinetics of recombinant, soluble human CD4 (rCD4) in subjects with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. The protein rCD4 binds to envelope protein, gp120, of the human immunodeficiency virus (HIV) and blocks HIV infection of CD4 lymphocytes in vitro. DESIGN: Phase 1 trial with dose escalation. SETTING: Two university-affiliated hospital clinics. SUBJECTS: Of 42 subjects enrolled, 29 had AIDS and 13 had AIDS-related complex. INTERVENTIONS: The rCD4 was administered by rapid intravenous infusion on day 1, followed by a 3-day washout, then once a day for 10 days, followed by a 7-day washout, and then three times a week for 8 weeks. Doses of 1, 10, 30, 100, and 300 micrograms/kg body weight per day of rCD4 were administered intravenously to 6 subjects at each dose level. Twelve additional patients received 300 micrograms/kg.d of rCD4: 6 by intramuscular and 6 by subcutaneous injection. All subjects were monitored for toxicity. Immunologic and virologic variables were also monitored. MEASUREMENTS AND MAIN RESULTS: Administration of rCD4 was not associated with important toxicity as determined by clinical monitoring or by serum chemistry, hematologic, or immunologic variables. No subjects required dose reduction or discontinuation of therapy due to rCD4-related toxicity. No consistent or sustained changes in CD4 lymphocyte populations or HIV antigen levels were observed. The volume of distribution of rCD4 was small, and clearance remained constant over the dose range studied. The bioavailability of intramuscular injection and subcutaneous injection was 51% and 45%, respectively. CONCLUSIONS: At the dose levels used in this study, rCD4 appears safe and well tolerated. Serum concentrations of rCD4 were achieved that were comparable to concentrations shown to have antiviral activity in vitro. Further studies are indicated to determine whether rCD4 or related molecules will be useful in treating HIV infection.

Comments on "Effects of Noise on Speech Production: Acoustic and Perceptual Analyses" [J. Acoust. Soc. Am. 84, 917-928 (1988)].

The effect of background noise on speech production is an important issue, both from the practical standpoint of developing speech recognition algorithms and from the theoretical standpoint of understanding how speech is tuned to the environment in which it is spoken. Summers et al. [J. Acoust. Soc. Am. 84, 917-928 (1988]) address this issue by experimentally manipulating the level of noise delivered through headphones to two talkers and making several kinds of acoustic measurements on the resulting speech. They indicate that they have replicated effects on amplitude, duration, and pitch and have found effects on spectral tilt and first-formant frequency (F1). The authors regard these acoustic changes as effects in themselves rather than as consequences of a change in vocal effort, and thus treat equally the change in spectral tilt and the change in F1. In fact, the change in spectral tilt is a well-documented and understood consequence of the change in the glottal waveform, which is known to occur with increased effort. The situation with F1 is less clear and is made difficult by measurement problems. The bias in linear predictive coding (LPC) techniques related to two of the other changes-fundamental frequency and spectral tilt-is discussed.

Cerebral palsy in a macaque monkey.

Magnetic resonance imaging was used to document brain lesions symptomatic of cerebral palsy in the macaque monkey exhibiting poor motor control and periodic episodes of ocular nystagmus and convulsive twitching. Neuroanatomic deficits most likely resulted from hemorrhage or ischemic infarction at or near the time of birth. Extreme maternal dependency and retarded behavioral development were documented at 3 and 12 months of age. Both social and motor behavior improved significantly when observed at 30 months of age after therapy.

Vocal behavior of captive Sichuan golden monkeys (Rhinopithecus r. roxellana).

Vocal behavior of four pairs of adult Sichuan golden monkeys was studied at the San Diego, Seattle, Los Angeles, and San Francisco zoos between November 1984 and October 1986. Four call types made up 86% (1,357/ 1,578) of vocalizations that occurred during 45 h of tape-recording. All four major vocalization types were made by both sexes. There was, however, significant sexual asymmetry in their production: 82% to 99% of each type was produced by one sex or the other. Frequently, duets developed when an individual male or female responded to the vocalizations of its cagemate. Males vocalized more than did females in each of the four pairs, and males responded vocally to female calls more than twice as frequently.

Salvage procedures for complications of total ankle arthroplasty.

Total ankle arthroplasty (TAA) has been a satisfactory procedure with a low failure rate only when applied to the rheumatoid patient. For the active, posttraumatic patient, ankle joint fusion is superior and avoids the attendant high failure rate. In general, salvage of failed TAA is best solved by ankle fusion. Only in one of five cases (a compliant patient with a clear-cut correctable technical error) was a good result achieved with a revision arthroplasty. To maintain limb length, the authors transplanted iliac crest autogenic bone to fill a large defect. When tightly packed with bone, the joint is slightly distracted and compression enhances fusion. For septic loosening, osteotomy of the malleoli and fusion without grafting is recommended. Persistent pain unassociated with loosening an infection may be treated by removal of impingement of bone overgrowth. Soft tissue release to improve motion is rarely successful. Marginal skin slough was a problem in 8.5% of 71 cases. To facilitate healing, debridement of nonfunctional exposed tendons may be advisable.

Behavioral technology for reducing occupational exposures to styrene.

We conducted a test of the usefulness of behavioral methods to control occupational health problems by reducing workers' exposures to toxic chemicals. Four plastics workers were trained in nine behaviors selected for potential to reduce their exposures to styrene, a common chemical with multiple toxic effects. Behavioral measures indicated that the workers quickly came to emit most of the behaviors. Measures of air samples indicated that large decreases in exposures to styrene accompanied the changes in behaviors for the three workers who had been selected because they most needed relief from their exposures and because they had opportunities to control their exposures by the ways they behaved.

Preservation of vocal tract length in speech. A negative finding.

A primary determinant of vowel quality is vocal tract shape; one aspect of which is vocal tract length. It has been suggested [Perkell, Physiology of Speech Production (MIT, Cambridge, 1969); Riordan, J. Acoust. Soc. Am. 62, 998-1002 (1977)] that vocal tract length is controlled directly, and that one mechanism for its regulation is a coordination between labial and laryngeal gestures. Riordan (1977) observed compensatory changes in the vertical position of the larynx when the characteristic lip protrusion of a rounded vowel was impeded. Although subjects in this study accurately produced the vowels /i/, /a/, /u/, and /delta/ with different amounts of lip protrusion, no compensatory larynx height adjustments were observed.

Safe and unsafe behavior and its modification.

After discussing some of the limitations of existing behavioral safety research, the authors propose a new approach to the problem. The approach is based on systematically controlling the psychological environment by precisely defining and rewarding safe behabiors and extinguishing unsafe behaviors. This approach to changing behavior is broadly designated the experimental analysis of behavior, and comprises two separate components, applied behavior analysis and applied behavior management. Application of the principles to the problem of increasing the frequency of safe behaviors and decreasing the frequency of unsafe behaviors is illustrated with two examples, one real, one hypothetical. A conclusion is drawn that researchers pursuing behavioral approaches to accident reduction should utilize the methods and technology of applied behavior analysis and management.