Minocycline treatment for HIV-associated cognitive impairment: results from a randomized trial.

OBJECTIVE: We conducted a study of minocycline to assess its safety, tolerability, and efficacy for the treatment of HIV-associated cognitive impairment. METHODS: HIV-1-infected individuals with progressive neurocognitive decline were enrolled in a double-blind, placebo-controlled study of minocycline. Participants were randomized to receive minocycline 100 mg or matching placebo orally every 12 hours. The primary efficacy measure was change in a neuropsychological test composite z score (NPZ-8) from baseline to week 24. Measures of safety included the frequency of adverse events and changes over time in laboratory tests. After 50% of participants completed the double-blind phase, an interim analysis of futility for the primary outcome measure was performed, and our Data and Safety Monitoring Board recommended early study termination. RESULTS: A total of 107 HIV-1-infected individuals with cognitive impairment were enrolled. The minocycline group did not show improvement in the primary outcome measure (NPZ-8) (mean 24-week change = 0.12) compared to placebo (mean 24-week change = 0.17) (95% confidence interval = [-0.26, 0.39], p = 0.70). There were few severe adverse events or laboratory abnormalities in either treatment group. CONCLUSION: Minocycline was safe and well-tolerated in individuals with HIV-associated cognitive impairment, but cognitive improvement was not observed. Classification of evidence. This interventional study provides Class II evidence for the safety, tolerability, and efficacy of minocycline for the treatment of HIV-associated cognitive impairment.

The neural organization of discourse: an H2 15O-PET study of narrative production in English and American sign language.

In order to identify brain regions that play an essential role in the production of discourse, H2 15O-PET scans were acquired during spontaneous generation of autobiographical narratives in English and in American Sign Language in hearing subjects who were native users of both. We compared languages that differ maximally in their mode of expression yet share the same core linguistic properties in order to differentiate the stages of discourse production: differences between the languages should reflect later, modality-dependent stages of phonological encoding and articulation; congruencies are more likely to reveal the anatomy of earlier modality-independent stages of conceptualization and lexical access. Common activations were detected in a widespread array of regions; left hemisphere language areas classically related to speech were also robustly activated during sign production, but the common neural architecture extended beyond the classical language areas and included extrasylvian regions in both right and left hemispheres. Furthermore, posterior perisylvian and basal temporal regions appear to play an integral role in spontaneous self-generated formulation and production of language, even in the absence of exteroceptive stimuli. Results additionally indicate that anterior and posterior areas may play distinct roles in early and late stages of language production, and suggest a novel model for lateralization of cerebral activity during the generation of discourse: progression from the early stages of lexical access to later stages of articulatory-motor encoding may constitute a progression from bilateral to left-lateralized activation. This pattern is not predicted by the standard Wernicke-Geschwind model, and may become apparent when language is produced in an ecologically valid context.

PET evaluation of bilingual language compensation following early childhood brain damage.

We report a positron emission tomography (PET) study in a 37-year-old, right handed, bilingual (English and American Sign Language) male with left frontal lobe damage, without evidence of language or general intellectual dysfunction. A brain MRI scan demonstrated an atrophic lesion of the left dorsolateral prefrontal, orbital, and opercular cortices extending from the frontal pole to precentral gyrus and including parts of anterior cingulate cortex, due to an probable infantile encephalitis. H(2) (15)O PET scans found evidence of increased right hemisphere activity compared to normal controls during spontaneous generation of narrative in both English and ASL. Neuropsychological data were within normal limits with the exception of visuospatial function. The results suggest the possibility that plasticity, unmasking of neural pathways, and or other adaptations of language function in the right hemisphere may have occurred, and are discussed with regard to the crowding hypothesis.

Flow cytometric detection of HLA-specific antibodies as a predictor of heart allograft rejection.

BACKGROUND: Historically, panel reactive antibody (PRA) analysis to detect HLA antibodies has been performed using cell-based complement-dependent cytotoxicity (CDC) techniques. Recently, a flow cytometric procedure (FlowPRA) was introduced as an alternative approach to detect HLA antibodies. The flow methodology, using a solid phase matrix to which soluble HLA class I or class II antigens are attached is significantly more sensitive than CDC assays. However, the clinical relevance of antibodies detected exclusively by FlowPRAhas not been established. In this study of cardiac allograft recipients, FlowPRA was performed on pretransplant sera with no detectable PRA activity as assessed by CDC assays. FlowPRA antibody activity was then correlated with clinical outcome. METHODS: PRA analysis by anti-human globulin enhanced (AHG) CDC and FlowPRA was performed on sera corresponding to final cross-match specimens from 219 cardiac allograft recipients. In addition, sera collected 3-6 months posttransplant from 91 patients were evaluated. The presence or absence of antibodies was correlated with episodes of rejection and patient survival. A rejection episode was considered to have occurred based on treatment with antirejection medication and/or histology. RESULTS: By CDC, 12 patients (5.5%) had pretransplant PRA >10%. In contrast, 72 patients (32.9%) had pretransplant anti-HLA antibodies detectable by FlowPRA (34 patients with only class I antibodies; 7 patients with only class II antibodies; 31 patients with both class I and class II antibodies). A highly significant association (P<0.001) was observed between pretransplant HLA antibodies detected by FlowPRA and episodes of rejection that occurred during the first posttransplant year. Fifteen patients died within the first year posttransplant. Of nine retrospective flow cytometric cross-matches that were performed, two were in recipients who had no pretransplant antibodies detectable by FlowPRA. Both of these cross-matches were negative. In contrast, five of seven cross-matches were positive among recipients who had FlowPRA detectable pretransplant antibodies. Posttransplant serum specimens from 91 patients were also assessed for antibodies by FlowPRA. Among this group, 58 patients had FlowPRA antibodies and there was a trend (although not statistically significant) for a biopsy documented episode of rejection to have occurred among patients with these antibodies. CONCLUSIONS: Collectively, our data suggest that pre- and posttransplant HLA antibodies detectable by FlowPRA and not AHG-CDC identify cardiac allograft recipients at risk for rejection. Furthermore, a positive donor reactive flow cytometric cross-match is significantly associated with graft loss. Thus, we believe that detection and identification of HLA-specific antibodies can be used to stratify patients into high and low risk categories. An important observation of this study is that in the majority of donor:recipient pairs, pretransplant HLA antibodies were not directed against donor antigens. We speculate that these non-donor-directed antibodies are surrogate markers that correspond to previous T cell activation. Thus, the rejection episodes that occur in these patients are in response to donor-derived MHC peptides that share cryptic determinants with the HLA antigens that initially sensitized the patient.

N-benzyladriamycin-14-valerate (AD 198)-resistant cells exhibit highly selective cross-resistance to other anthracyclines that circumvent multidrug resistance.

N-Benzyladriamycin-14-valerate (AD 198)-resistant murine J774.2 macrophage-like cells (A300) exhibited a novel mechanism of resistance in which P-glycoprotein was overexpressed without decreased AD 198 accumulation. Cross-resistance to Adriamycin (ADR), N-benzyladriamycin, and Adriamycin-14-valerate was due, at least in part, to reduced accumulation, suggesting that circumvention of P-glycoprotein-mediated transport was associated with extreme lipophilicity conferred by both substitutions. Thus, unlike multidrug resistance mediated by either P-glycoprotein, the multidrug resistance-associated protein (MRP), or decreased topoisomerase II activity, cross-resistance in A300 cells was highly structure-specific. In order to further characterize the specificity of AD 198 resistance, the cytotoxicity, accumulation, and intracellular localization of a series of 3'-morpholinyl, 3'-deamino and halogenated ADR congeners that have been reported to circumvent MDR was determined in AD 198-resistant J774.2 and P388 AD 198-resistant cells. Cross-resistance correlating with increased AD 198 resistance was observed for 2'-bromo-4'-epi-hydroxy-daunomycin (13-fold), morpholinyl doxorubicin (24-fold), and 4'-iodo-4'-deoxydoxorubicin (2.8-fold), but was attributable to decreased accumulation. Cross-resistance to 3'-hydroxy-14-O-palmitoyl-doxorubicin (6-fold) was not due to reduced accumulation. No cross-resistance was observed for the highly cytotoxic metabolite of WP474, 3'-hydroxyldoxorubicin (hydroxyrubicin; WP159), nor for the much less cytotoxic 3'-O-benzylated congeners, including 3'-O-benzyl-doxorubicin-14-valerate. These findings indicate that AD 198 resistance confers cross-resistance to compounds that, like AD 198, localize in the cytoplasm but are metabolized to highly cytotoxic, nuclear-localizing compounds.

Treatment of infantile spasms with high-dose ACTH: efficacy and plasma levels of ACTH and cortisol.

Fifteen children with infantile spasms and a hypsarrhythmic EEG defined by EEG-videotelemetry monitoring received a regimen of high-dose (150 IU/m2/d) ACTH for their seizures. We carried out an endocrinologic evaluation before and after initiation of the ACTH and conducted a time course study of plasma ACTH and cortisol levels after ACTH dosing. Spasms were controlled and the EEG normalized in 14 of the 15 children. Prior to starting ACTH therapy all the patients had normal prolactin, insulin, cortisol, and ACTH levels in plasma and normal thyroid function. Although the pattern of rise of ACTH levels in plasma after ACTH dosing was similar in all the children, there was great individual variation in the absolute concentrations. However, both the pattern of rise and absolute level of cortisol in plasma after ACTH was highly predictable in all patients. Plasma cortisol rose rapidly within 1 hour of ACTH administration and continued a slower rise for 12 to 24 hours after the ACTH dose. High-dose ACTH therapy seems quite effective in infantile spasms, perhaps because of a sustained high level of plasma cortisol. This sustained plateau of cortisol may be more effective in controlling infantile spasms than the pulse effect expected with oral steroids or lower doses of ACTH.

Treatment of epileptic falling spells with ethosuximide.

We used ethosuximide as an adjunctive anticonvulsant drug in 19 children with multiple seizure types in whom the primary and most troubling seizure was falling to the ground. All patients were having multiple, daily falls, intractable to phenobarbital, valproic acid, and clonazepam. Seizures were characterized and quantitated by video-electroencephalographic telemetry. Twelve children became completely free of epileptic falls on ethosuximide. Four children showed a 50-75% decrease in the number of falls while 3 showed no change in frequency of falls. All children had an abnormal electroencephalogram (EEG) prior to starting ethosuximide with generalized bursts of spike and wave in a frequency range of 1-4 cycles per second (cps). The only EEG abnormality common to those patients who became free of epileptic falls with ethosuximide treatment was a generalized, synchronous 4 cps discharge. Our experience suggests that ethosuximide may be a valuable adjunctive treatment for epileptic falling spells that occur in the context of multiple seizure types.

Exacerbation of seizures in children by carbamazepine.

We studied 15 children with complex partial seizures in whom one or more seizure type was exacerbated during treatment with carbamazepine. The most common seizure type that was exacerbated was generalized atypical absence (11 patients). Four patients had more frequent and severe generalized convulsive seizures. Monitoring with video-electroencephalographic telemetry suggested that the electroencephalogram can be used to predict the risk of seizure exacerbation with carbamazepine. A bilaterally synchronous spike-and-wave discharge of 2.5 to 3 cycles per second is predictive of increased atypical absence seizures with carbamazepine, whereas generalized bursts of spikes and slow waves of 1 to 2 cycles per second suggest a risk of increased generalized convulsive seizures. Carbamazepine should be used with caution in children with a mixed seizure disorder, particularly those with a generalized bilaterally synchronous discharge of 2.5 to 3 cycles per second on the electroencephalogram. The drug should be considered a possible precipitating factor in any child with an increased frequency of generalized convulsive or generalized absence seizures concomitant with administration of this anticonvulsant agent.