Sensitivity of the Procleix HIV-1/HCV assay for detection of human immunodeficiency virus type 1 and hepatitis C virus RNA in a high-risk population.

The Procleix HIV-1/HCV Assay is a high-throughput nucleic acid test for the simultaneous detection of human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) RNA during blood donor screening. This study evaluated the clinical sensitivity of the Procleix assay and assessed the assay's ability to identify HIV-1- and HCV-infected individuals undetected by standard serologic tests. Plasma samples were obtained prospectively from 539 individuals at high risk for HIV-1 and HCV infection at seven clinics affiliated with Johns Hopkins University. Samples were tested in the Procleix HIV-1/HCV Assay and, if reactive, were then tested in the Procleix HIV-1 and HCV discriminatory assays to differentiate the source of viral RNA positivity. Of these 539 subjects, 287 (53.2%) tested reactive in the Procleix HIV-1/HCV Assay. In discriminatory assay testing, 12 of 287 subjects (4.2%) were reactive for HIV-1 RNA only, 260 (90.6%) were reactive for HCV RNA only, and 11 (3.8%) were coinfected with HIV-1 and HCV. The clinical sensitivity for samples tested neat was 100% for HIV-1 and 99.3% for HCV. Three subjects with Procleix HCV reactive/seronegative results seroconverted upon follow-up and were confirmed as Procleix HCV yield cases. The Procleix HIV-1/HCV Assay is a highly sensitive test that detects ongoing and early HIV-1 and HCV infection in a significant number of subjects at high risk for these diseases. Confirmation of Procleix yield cases upon follow-up demonstrated the ability of the Procleix HIV-1/HCV Assay to detect the presence of HIV-1 and HCV in blood earlier than standard serologic tests.

Effects of hyperbaric oxygenation therapy on cerebral metabolism and intracranial pressure in severely brain injured patients.

OBJECT: Hyperbaric oxygenation (HBO) therapy has been shown to reduce mortality by 50% in a prospective randomized trial of severely brain injured patients conducted at the authors' institution. The purpose of the present study was to determine the effects of HBO on cerebral blood flow (CBF), cerebral metabolism, and intracranial pressure (ICP), and to determine the optimal HBO treatment paradigm. METHODS: Oxygen (100% O2, 1.5 atm absolute) was delivered to 37 patients in a hyperbaric chamber for 60 minutes every 24 hours (maximum of seven treatments/patient). Cerebral blood flow, arteriovenous oxygen difference (AVDO2), cerebral metabolic rate of oxygen (CMRO2), ventricular cerebrospinal fluid (CSF) lactate, and ICP values were obtained 1 hour before and 1 hour and 6 hours after a session in an HBO chamber. Patients were assigned to one of three categories according to whether they had reduced, normal, or raised CBF before HBO. In patients in whom CBF levels were reduced before HBO sessions, both CBF and CMRO2 levels were raised 1 hour and 6 hours after HBO (p < 0.05). In patients in whom CBF levels were normal before HBO sessions, both CBF and CMRO2 levels were increased at 1 hour (p < 0.05), but were decreased by 6 hours after HBO. Cerebral blood flow was reduced 1 hour and 6 hours after HBO (p < 0.05), but CMRO2 was unchanged in patients who had exhibited a raised CBF before an HBO session. In all patients AVDO2 remained constant both before and after HBO. Levels of CSF lactate were consistently decreased 1 hour and 6 hours after HBO, regardless of the patient's CBF category before undergoing HBO (p < 0.05). Intracranial pressure values higher than 15 mm Hg before HBO were decreased 1 hour and 6 hours after HBO (p < 0.05). The effects of each HBO treatment did not last until the next session in the hyperbaric chamber. CONCLUSIONS: The increased CMRO2 and decreased CSF lactate levels after treatment indicate that HBO may improve aerobic metabolism in severely brain injured patients. This is the first study to demonstrate a prolonged effect of HBO treatment on CBF and cerebral metabolism. On the basis of their data the authors assert that shorter, more frequent exposure to HBO may optimize treatment.

Light deprivation soon after frontal brain trauma accelerates recovery from attentional deficits and promotes functional normalization of basal ganglia.

BACKGROUND: Light deprivation significantly accelerates recovery from attention deficits (neglect) after cortical ablation in rats. We hypothesized that light deprivation would improve recovery after traumatic contusive brain injury (TBI) and do so by enhancing dopaminergic function in the ipsilateral basal ganglia. METHODS: Adult rats received left frontal contusion injury and were placed into darkness or standard light/dark cycling for 48 hours. Neurologic evaluation included attentional and sensorimotor tasks. Amphetamine-induced production of the immediate early gene protein product Fos was quantified to determine neuronal dopaminergic response in caudate-putamen (striatum). RESULTS: Unilateral frontal TBI produced severe contralateral deficits in all tasks. Postoperative light deprivation resulted in improved recovery from attentional but not sensorimotor deficits. Five days after injury, ipsilateral striatal Fos expression was reduced by 51% in TBI rats experiencing normal light cycling (p < 0.006). In contrast, postoperative light deprivation normalized striatal Fos expression. By 6 weeks, all TBI rats demonstrated nearly full recovery and striatal Fos expression was symmetrical between the two striata. CONCLUSION: Postoperative light deprivation may improve recovery from TBI-induced attention deficits by normalizing basal ganglia function.

Light deprivation accelerates recovery from frontal cortical neglect: relation to locomotion and striatal Fos expression.

Rats given unilateral medial agranular (AGm) cortex ablations show neglect for contralateral multimodal stimuli, symptoms that are reversed by 48 hr of light deprivation. To address processes that contribute to this restorative effect, both the rats' locomotion and basal ganglia c-fos expression were studied. AGm-lesioned rats showed less activity in continuous darkness than in normal (12 hr light/12 hr dark) cycles, and the reduced locomotion correlated with the extent of their subsequent behavioral recovery. The AGm ablation reduced the numbers of amphetamine-stimulated Fos-immunoreactive nuclei in the ipsilateral dorsolateral striatum, where the AGm innervation is normally densest. Light deprivation also reduced Fos in this striatal region and attenuated the lesion-induced hemispheric Fos asymmetry. A restored balance of activity between the 2 hemispheres, especially the basal ganglia, appears central to the action of light deprivation.

Reduced eticlopride-induced Fos expression in caudate-putamen and globus pallidus after unilateral frontal cortex injury: relation to neglect.

Unilateral ablation of medial agranular cortex in rats results in neglect of contralateral stimuli and reductions in amphetamine-induced expression of the immediate early gene, c-fos, in both caudate-putamen and globus pallidus. Both unilateral neglect and the reductions in dopamine agonist induction of subcortical Fos immunoreactivity dissipate over a matter of weeks. Dopamine agonism induces Fos predominantly in striatonigral cells and in globus pallidus via striatopallidal disinhibition, whereas Fos is induced in striatopallidal cells by administration of antagonists of the D2 dopamine receptor subfamily. To examine more directly effects of cortical injury on striatopallidal function, induction of striatal Fos by the D2 antagonist eticlopride (0.1 mg/kg, s.c.) was examined in rats with medial agranular cortex ablation. In the same animals, eticlopride-induced Fos in globus pallidus was also examined. Five days after unilateral cortex injury, in rats showing neglect, the numbers of Fos immunoreactive nuclei induced by eticlopride were reduced by 50% in caudate-putamen and 25% in globus pallidus of the ipsilateral hemisphere. These lesion effects were restricted to dorsolateral caudate-putamen and dorsal pallidum. Three or more weeks after cortical injury, in rats recovered from neglect, eticlopride-induced Fos was normalized in caudate-putamen, but still decreased by 20% in globus pallidus. Along with previous findings, these results suggest that behavioral recovery from neglect produced by cortical injury may be at least partially mediated by normalizations of function of both striatopallidal and striatonigral neurons. In addition, the present findings suggest that normalization of function of pallidal cells activated by eticlopride is not necessary for behavioral recovery from frontal cortex ablation. Lingering reductions in excitatory cortico-subthalamo-pallidal input may be responsible for the longer-lasting dysfunctions of these pallidal cells.

Unilateral frontal cortex ablation producing neglect causes time-dependent changes in striatal glutamate receptors.

This study's goal is to identify adaptations involving striatal glutamate (GLU) or dopamine (DA) receptors that may contribute to recovery of function following cortical injury. Unilateral aspiration of the medial agranular region of frontal cortex (AGm) in rats produces neglect of contralateral stimuli. Pharmacological and immunocytochemical studies suggest that glutamatergic and dopaminergic processes within striatum may contribute to spontaneous recovery from this neglect. This study examined by autoradiography radioligand binding to striatal GLU and DA receptor subfamilies in AGm-ablated rats surviving 5 days (unrecovered) or 3 or more weeks (recovered) postsurgery. Density of radioligand binding was quantified in striatal subregions by computerized image analysis. Compared to striatal binding densities in the intact hemisphere, [3H]kainate binding and [3H]GLU binding to NMDA receptors were decreased in the lesioned hemisphere of unrecovered AGm-ablated rats, but normalized (for kainate) or increased (for NMDA) in the lesioned hemisphere of recovered rats. Ablation of AGm did not affect [3H]AMPA binding or the binding of [3H]SCH23390, [3H]spiperone, or [3H]mazindol to dopaminergic D1 or D2 receptor subfamilies, or to DA uptake sites, respectively. The results suggest that a small percentage of NMDA and kainate receptors are located on corticostriatal axon terminals, and that over time an upregulation of striatal NMDA and/or kainate receptors may offset the loss of cortical glutamatergic input caused by cortical injury. These time-dependent alterations in GLU receptors may contribute to the recovery of function and normalizations of immediate early gene expression seen weeks after AGm ablation. Upregulation of striatal dopamine receptors was not evident, and thus is unlikely to mediate recovery from neglect produced by cortical injury.

Frontal cortex ablation reversibly decreases striatal zif/268 and junB expression: temporal correspondence with sensory neglect and its spontaneous recovery.

This study's goal is to identify subcortical adaptations that may contribute to recovery of function following cortical injury. After unilateral aspiration of the medial agranular region of frontal cortex (AGm), rats demonstrate neglect of contralateral stimuli and recover within 3-4 weeks. Previous studies indicate that compensatory neural alterations involving dopamine (DA) occur following this cortical injury and that recovery from neglect produced by frontal injury is accompanied by normalization of glucose utilization within subcortical structures including the basal ganglia. The current study examined Zif and JunB, IEG protein products constitutively expressed in striatum, rendering it possible to investigate the effects of unilateral AGm ablation on striatal function during unstimulated as well as amphetamine-stimulated conditions. Five days after surgery, when contralateral neglect was still evident, the numbers of Zif-like or Jun-like immunoreactive (IR) nuclei in the ipsilateral striata of AGm-ablated rats were reduced. These lesion effects were similar for both constitutive and amphetamine-stimulated IEG expression and were restricted to the dorsolateral caudate-putamen, where excitatory input from AGm is most dense. In contrast, 3 or more weeks after AGm ablation, in rats demonstrating recovery, normal striatal Zif- and JunB-like immunoreactivity occurred. Thus, striatal zif/268 and junB expression is reduced 5 days after AGm injury in rats demonstrating neglect and normalized 3 or more weeks later in recovered rats. These findings indicate that adaptations involving the striatal medium spiny neuron, a site of convergence of cortical glutamatergic and nigral dopaminergic afferents, may contribute to behavioral recovery following neocortical injury.

Amphetamine-induced Fos expression in globus pallidus is altered by frontal cortex injury.

Functional recovery from cortical injury may result from subcortical compensatory processes. This study examined basal gangliar expression of the immediate early gene c-fos after unilateral medial agranular cortex (AGm) ablation. In the ipsilateral dorsal globus pallidus of rats demonstrating neglect of contralateral stimuli (sacrificed 5 days postinjury), the numbers of amphetamine-induced Fos-positive nuclei were reduced 37% compared to intact hemisphere values. These reductions were no longer apparent in recovered AGm-ablated rats (sacrificed 21 + days postinjury). These findings mirror in timing and direction the changes in Fos seen in dorsolateral striatum after AGm ablation.

D1-class dopamine receptor involvement in the behavioral recovery from prefrontal cortical injury.

Following unilateral aspiration of the left medial agranular cortex (AGm) region of prefrontal cortex, rats demonstrate contralateral neglect, characterized by a failure to orient to visual, tactile and auditory stimuli presented on the contralateral body side. While dopamine (DA) has been implicated in cortical neglect and its recovery, this study specifically examined D1-class DA receptors for their involvement in spontaneous recovery from neglect caused by AGm ablation. In the first experiment, left AGm-ablated rats demonstrated severe neglect of contralateral stimuli of each modality which spontaneously recovered over a period of several weeks. Recovered rats were given 7.0 micrograms/kg (s.c.) of the D1-selective antagonist SCH 23390. SCH 23390 reinstated severe neglect of contralateral stimuli, yet had no effect on orientation to ipsilateral stimuli. The same dose had no effect on the orientation behavior of controls. In a second experiment, D1 receptor characteristics were quantified via binding of [3H]SCH 23390 to tissue homogenates of the caudate-putamen of recovered AGm-ablated rats. Numbers and affinities of striatal D1 receptors of rats with unilateral AGm ablations did not differ between hemispheres or from values obtained from lesioned controls. Considered together, these findings indicate that recovery from neglect produced by cortical injury is associated with an increased dependence on D1-class receptor-mediated events, and that this increased dependence is unlikely to be mediated through changes in D1-class receptor numbers or affinities within caudate-putamen.

Time-dependent changes in dopamine agonist-induced striatal Fos immunoreactivity are related to sensory neglect and its recovery after unilateral prefrontal cortex injury.

This study examined interactions between the corticostriatal glutamatergic system and the nigrostriatal dopaminergic system via immunocytochemical examination of dopamine (DA) agonist induction of the striatal immediate early gene product Fos following cortical injury. After unilateral aspiration of the medial agranular cortex (AGm) region of prefrontal cortex, rats were tested for orientation to visual, tactile, and auditory stimuli. Fos immunoreactivity induced by d-amphetamine (5 mg/kg) or apomorphine (5 mg/kg) was quantified in dorsolateral and ventrolateral regions of caudate-putamen (CPu) in rats still demonstrating sensory neglect (5 days postsurgery) and in rats recovered from sensory neglect produced by AGm ablation (29+ days postsurgery). The pattern of immunoreactivity of rats still demonstrating neglect differed from that of unlesioned rats or recovered AGm-ablated rats. In rats demonstrating sensory neglect, d-amphetamine or apomorphine induction of Fos in the ipsilateral CPu was reduced by about 40% compared to the contralateral CPu or to comparable readings in unlesioned controls. These asymmetries were restricted to dorsolateral CPu, the region receiving the densest input from AGm. In contrast, recovered AGm-ablated rats had DA agonist-induced striatal Fos immunoreactivity that was symmetrical between the two hemispheres and comparable to control values. These findings indicate that adaptations involving the striatal medium spiny neuron, a site of convergence of cortical glutamatergic and nigral dopaminergic afferents, may contribute to recovery from behavioral deficits resulting from neocortical injury.

Light deprivation produces accelerated behavioral recovery of function from neglect produced by unilateral medial agranular prefrontal cortex lesions in rats.

Environmental manipulations involving 48 h of light deprivation have been found to produce sparing of function from neglect produced by unilateral destruction of the medial agranular prefrontal cortex (AGm) in rats. The present study is an extension of these findings and examined whether light deprivation would produce recovery in subjects with demonstrated severe neglect produced by unilateral AGm destruction. The orientation behavior of the subjects, 25 left and 16 right AGm operates, was tested at 4 h post injection and if severe neglect was demonstrated, the subjects were placed into one of three environmental conditions: (1) 48 h of total light deprivation, (2) 48 h of continuous light, or (3) 48 h of a 12:12 light/dark cycle. The left vs. right hemisphere comparisons indicated that the left hemisphere operates were significantly more responsive by 4 h postsurgery than the right hemisphere operates, and only five of the right hemisphere operates demonstrated severe neglect. Therefore, the effects of environment on behavioral recovery of function were only examined in left AGm operates with severe neglect. The results indicated that 48 h of light deprivation could produce dramatic behavioral recovery in left AGm operates with demonstrated severe neglect, and that these effects were not produced by disruption of the light/dark cycle.

Spiroperidol reinstates asymmetries in neglect in rats recovered from left or right dorsomedial prefrontal cortex lesions.

The role of dopaminergic mechanisms in spontaneous behavioral recovery from cortical neglect was examined in rats that received lesions of either the left or the right dorsomedial prefrontal cortex (PCm, also referred to as AGm). Neglect was assessed by rating the degree of head orientation to visual, auditory, or tactile stimuli. Following behavioral recovery, separate groups received 0.03, 0.05, 0.07, or 0.10 mg/kg spiroperidol or the vehicle. In accordance with the lateralization of neglect typically seen postsurgery, spiroperidol dose-dependently reinstated contralesional neglect in left PCm operates and ipsilesional neglect in right PCm operates. Neglect was reinstated by spiroperidol in right PCm operates at lower doses than in left PCm operates. Also, only right PCm operates demonstrated asymmetrical bilateral dose-dependent neglect. Spiroperidol did not produce neglect in unilaterally brain-damaged control subjects. The results indicate that dopaminergic mechanisms may underlie spontaneous recovery from cortical neglect and that these mechanisms are asymmetrical in left and right PCm operates.

Hemispheric asymmetry in neglect produced by unilateral lesions of dorsomedial prefrontal cortex in rats.

Unilateral lesions of the medial precentral prefrontal cortex produce severe polymodal neglect which reaches a stable level of recovery over 3 to 4 weeks. Previous research has indicated that neglect is produced by unilateral destruction of this region in either hemisphere, but that the nature of the neglect produced is dependent on the hemisphere damaged. The present study is a further examination of behavioral laterality produced by this unilateral destruction. The results indicated that destruction of medial precentral cortex in the left hemisphere (n = 12) produced severe contralateral multimodal neglect of visual, somatosensory, and auditory stimuli. Identical destruction in the right hemisphere (n = 18) also produced severe neglect, but unlike the left hemisphere operates which always demonstrated contralateral neglect, there were two distinct populations of right hemisphere operates. These subjects demonstrated either ipsilateral neglect or a "switching" response pattern characterized by the initial demonstration of contralateral or ipsilateral neglect and then, during the course of recovery, severe neglect on the opposite body side. Histological analysis indicated that the left and right hemisphere lesions were equivalent, as were the lesions in the two behavioral subcategories of right hemisphere operates. Operated controls (n = 12) did not demonstrate long-standing neglect or this switching pattern. The behavioral laterality observed following unilateral destruction of medial precentral prefrontal cortex is discussed in relationship to the anatomical and neurochemical asymmetries which have been demonstrated in this cortical region.