Placebo-controlled trial to evaluate zidovudine in treatment of human immunodeficiency virus infection in asymptomatic patients with hemophilia. NHF-ACTG 036 Study Group.

One hundred ninety-three asymptomatic patients with hereditary coagulation disorders and human immunodeficiency virus (HIV) infection were studied in a controlled trial of zidovudine (ZDV) versus a placebo (with an average of 9.7 months on study). Pretreatment characteristics were well balanced between the placebo and drug-treated groups, including CD4 distributions, types of clotting disorders, transaminase abnormalities, and use of various hemostatic agents. At the time of analysis, 161 patients either were still receiving treatment or had previously reached an endpoint of disease progression while receiving treatment. Twenty-five patients withdrew voluntarily. The toxic effects noted included granulocytopenia and anemia, especially in older patients, and subjective symptoms of asthenia, malaise, and nausea, consistent with the known consequences of treatment with 300 mg ZDV five times daily. There was a trend toward more diagnoses of acquired immunodeficiency syndrome (AIDS), advanced or early AIDS-related complex (ARC), single ARC symptoms, or death in placebo recipients as compared with those receiving ZDV (22 v 13). Because older patients with hemophilia have more rapid disease progression, the same efficacy analysis was performed in the 89 patients aged more than 30 years who were receiving treatment. In this subgroup, there was a similar trend (11 v 6). With regard to the most advanced problems of the infection among the older patients, there were five patients who were newly diagnosed with AIDS or died in the placebo group versus none in the ZDV group (P = .02) among the older patients. The pretreatment distribution of CD4 counts for the placebo and ZDV groups were similar, but patients aged more than 30 years had significantly (P less than .049) fewer CD4 cells than patients aged less than 30 years. A beneficial ZDV effect is also supported by a trend toward higher CD4 counts (a 48-cell increase in the ZDV group at 24 weeks as compared with a four-cell increase in the placebo group) and a significant (P = .03) difference in weight gain in the ZDV patients aged more than 30 years (8 pounds) as compared with the older placebo patients (aged more than 30 years) (2 pounds) at week 24. The findings in the asymptomatic hemophilic patients aged more than 30 years support a useful effect of ZDV, which is similar to observations in the larger study of its use in asymptomatic, nonhemophilic patients.     

Chronic recording of the vestibulo-ocular reflex in the restrained rat using a permanently implanted scleral search coil

A technique is described which allows accurate long-term monitoring of eye movements in the rat using permanently implanted scleral search coils. Search coils permanently sutured around the sclera yield vestibulo-ocular reflex (VOR) gain and phase values which are comparable to those reported previously in the literature using acutely implanted coils or electrooculographic electrodes. Considerations related to strain, sex and surgical procedures which permit measurement of responses in the chronically restrained rat are described. VOR gain and phase show a time course to their recovery following the implant surgery, with asymptotic performance typically attained approximately 10 days post-surgically. This technique, with the ability to monitor eye movements over weeks to months, appears ideal for development of rodent models of reflex adaptation which require observation of reflex behavior over extended periods of time. Development of a chronic procedure for monitoring eye movement in rodents is especially important given their initial response to restraint (extensive struggling). Finally, adaptation of this technique to smaller species (e.g., mouse) appears technically feasible which should permit the application of transgenic and knockout techniques to the determination of various vestibular reflex functions requiring long-term monitoring.     

Directional sensitivity of anterior, posterior, and horizontal canal vestibulo-ocular neurons in the cat

Neurons subserving the vestibulo-ocular reflex transform the directionality and timing of input from semicircular canals into commands that are appropriate to rotate the eyes in a compensatory fashion. In order to assess the degree to which this transformation is evident in vestibular nucleus neurons of alert cats, we recorded the extracellular discharge properties of 138 second-order vestibular neurons in the superior and medial vestibular nucleus, including 64 neurons identified as second-order vestibulo-ocular neurons by antidromic responses to oculomotor nucleus stimulation and short-latency orthodromic responses to labyrinth stimulation (1.3 ms or less). Neuronal response gains and phases were recorded during 0.5-Hz sinusoidal oscillations about many different horizontal axes and during vertical axis rotations to define neuronal response directionality more precisely than in past studies. Neurons with spatial responses similar to anterior semicircular canal afferents were found to have more diverse maximal activation direction vectors than neurons with responses resembling those of posterior or horizontal canal afferents. The mean angle from neuron response vector to the axis of the nearest canal or canal pair was 19 degrees for anterior canal second-order neurons (n=28) and 20 degrees for anterior canal second-order vestibulo-ocular neurons (n=18), compared with 11 degrees for posterior canal second-order neurons (n=43) and 11 degrees for posterior canal second-order vestibulo-ocular neurons (n=25). Only two second-order vestibulo-ocular neurons (3%) showed a marked dependence of response phase on rotation direction, which is indicative of convergent inputs that differ in both dynamics and directionality. This suggests that spatiotemporal convergence is uncommon in the three-neuron vestibulo-ocular reflex arc of the cat. Neuron vectors included many that were closely aligned with canal axes and several that were better aligned with oblique or superior rectus extraocular muscle excitation axis vectors. Only single examples of second-order vestibulo-ocular neuron vectors were approximately aligned with the pitch and roll coordinate axes. We conclude that second-order vestibulo-ocular neurons do not exclusively represent either the semicircular canal sensory coordinate frame or the extraocular muscle excitation motor coordinate frame, and instead are mostly distributed on a continuum between the input and output coordinate frames, with anterior canal neurons having the widest distribution of directionality.     

Anterior canal neurons in cat vestibular nuclei have large phase leads during low frequency vertical axis pitch

Vestibulo-ocular and second-order neurons in medial and superior vestibular nuclei of alert cats were identified by antidromic and orthodromic electrical stimulation, and their responses to whole body rotations were recorded in the dark. Neurons that had spatial sensitivity most closely aligned with the anterior canal (anterior canal neurons) were compared with neurons that had spatial sensitivity most closely aligned with the posterior canal (posterior canal neurons). Responses were recorded during low frequency earth-horizontal axis pitch rotations in the normal upright posture, and during earth-vertical axis pitch with the head and body lying on the left side. During upright pitch, response phases of anterior canal neurons slightly lagged those of posterior canal neurons or primary vestibular afferents, as previously reported. During on-side pitch, anterior canal neurons showed far greater phase leads with respect to head velocity than posterior canal neurons, primary vestibular afferents, or previously reported vestibulo-ocular reflex eye movements. These results provide challenges for vestibulo-ocular reflex models to incorporate central mechanisms for phase leads among the inputs to anterior canal neurons and to explain how the anterior canal neuron signals reported here combine with other signals to produce observed vestibulo-ocular reflex behavior.