Effects of age, HIV, and HIV-associated clinical factors on neuropsychological functioning and brain regional volume in HIV+ patients on effective treatment.

It is yet unclear if people infected with human immunodeficiency virus (HIV+) on stable, combined antiretroviral therapies (cARTs) decline with age at the same or greater rate than healthy people. In this study, we examined independent and interactive effects of HIV, age, and HIV-related clinical parameters on neuropsychological functioning and brain regional volume in a sizable group of Polish HIV+ men receiving cART. We also estimated the impact of nadir CD4 cell count, CD4 cell count during participation in the study, duration of HIV infection, or duration of cART along with age. Ninety-one HIV+ and 95 control (HIV-) volunteers ages 23-75 completed a battery of neuropsychological tests, and 54 HIV+ and 62 HIV- of these volunteers participated in a brain imaging assessment. Regional brain volume in the cortical and subcortical regions was measured using voxel-based morphometry. We have found that HIV and older age were independently related to lower attention, working memory, nonverbal fluency, and visuomotor dexterity. Older age but not HIV was associated with less volume in several cortical and subcortical brain regions. In the oldest HIV+ participants, age had a moderating effect on the relationship between the duration of cART and visuomotor performance, such as that older age decreased speed of visuomotor performance along with every year on cART. Such results may reflect the efficacy of cART in preventing HIV-associated brain damage. They also highlight the importance of monitoring neuropsychological functioning and brain structure in HIV+ patients. This is particularly important in older patients with long adherence to cART.

An association between viral genes and human oncogenic alterations: the adenovirus E1A induces the Ewing tumor fusion transcript EWS-FLI1.

Malignant transformation of human cells requires the accumulation of multiple genetic alterations, such as the activation of oncogenes and loss of function of tumor suppressor genes or those related to genomic instability. Among the genetic alterations most frequently found in human tumors are chromosomal translocations that may result in the expression of chimeric products with transforming capability or are able to change the expression of oncogenes. We show here that the adenovirus early region 1A (E1A) gene can induce a specific human fusion transcript (EWS-FLI1) that is characteristic of Ewing tumors. This fusion transcript was detected by RT-PCR in normal human fibroblasts and keratinocytes after expression of the adenovirus E1A gene, as well as in human cell lines immortalized by adenoviruses. Cloning and sequencing of the RT-PCR product showed fusion points between EWS and FLI1 cDNA identical to those detected in Ewing tumors. In addition, we detected a chimeric protein by western blot analysis and immunoprecipitation and a t(11,22) by fluorescent in situ hybridization. This association between a single viral gene and a specific human fusion transcript indicates a direct link between viral genes and chromosome translocations, one of the hallmarks of many human tumors.

Oxidative phosphorylation by membrane vesicles from Bacillus alcalophilus.

ADP and Pi-loaded membrane vesicles from t-malate-grown Bacillus alcalophilus synthesized ATP upon energization with ascorbate/N,N,N',N'-tetra-methyl-P-phenylenediamine. ATP synthesis occurred over a range of external pH from 6.0 to 11.0, under conditions in which the total protonmotive force delta-mu-H+ was as low as -30 mV. The phosphate potentials (delta Gp) were calculated to be 11 and 12 kcal/mol at pH 10.5 and 9.0, respectively, whereas the delta-mu-H+ values in vesicles at these two pH values were quite different (-40 +/- 20 mV at pH 10.5 and -125 +/- 20 mV at pH 9.0). ATP synthesis was inhibited by KCN, gramicidin, and by N,N1-dicyclohexylcarbodiimide. Inward translocation of protons, concomitant with ATP synthesis, was demonstrated using direct pH monitoring and fluorescence methods. No dependence upon the presence of Na+ or K+ was found. Thus, ATP synthesis in B. alcalophilus appears to involve a proton-translocating ATPase which functions at low delta-mu-H+.

Adjuvant chemotherapy with and without tamoxifen in the treatment of primary breast cancer: 5-year results from the National Surgical Adjuvant Breast and Bowel Project Trial.

In this National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trial, 1,891 women with primary operable breast cancer and positive axillary nodes were randomized between Jan, 1977 and May 1980 to receive L-phenylalanine mustard (L-PAM) and 5-fluorouracil (5-FU) either with or without tamoxifen (TAM)-PFT. This report presents life table probabilities, cumulative odds ratios, and P values for disease-free survival (DFS) and survival at yearly intervals through 5 years of observation (mean time on study, 72 months). When patients were examined overall without regard for any discriminant associated with outcome, ie, age, number of positive nodes, or tumor receptor status, there was a significant prolongation of DFS (P = .002), but not survival through the fifth postoperative year. The benefit was almost entirely restricted to those greater than or equal to 50 years with greater than or equal to 4 positive nodes. In that group there was a 66% greater chance of remaining disease free if PFT was received (P less than .001), and there was also a significant survival benefit (P = .02). The advantage from PFT was found to be associated with tumor estrogen receptor (ER) and progesterone receptor (PR) as well as patient age and nodal status. Overall there was a significant improvement in DFS from PFT in those having tumors with an ER or PR level greater than or equal to 10 femtomole (fmol) (P = .01 and .009, respectively). No significant benefit in DFS or survival has been observed in patients less than or equal to 49 years old related either to nodes or tumor receptor status. Survival continues to be adversely affected by TAM in those patients (less than or equal to 49 years old), particularly when their tumors have a PR of 0 to 9 fmol (P = .007). In patients greater than or equal to 50 years old with four or more positive nodes, a significant DFS benefit persisted through the fifth year of observation in those having tumor ER or PR levels greater than 10 fmol (P less than .001 and .002). The advantage was observed in patients 50 to 59 years old as well as those 60 to 70. Women in the older decade demonstrated some advantage from PFT when their tumor ER or PR was 0 to 9 fmol. The most likely explanation for this finding is analytical error in receptor analyses.(ABSTRACT TRUNCATED AT 400 WORDS)

Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-22.

PURPOSE: The National Surgical Adjuvant Breast and Bowel Project (NSABP) initiated a randomized trial (B-22) to determine if intensifying but maintaining the total dose of cyclophosphamide (Cytoxan, Bristol-Myers Squibb Oncology, Princeton, NJ) in a doxorubicin (Adriamycin, Pharmacia, Kalamazoo, MI)-cyclophosphamide combination (AC), or if intensifying and increasing the total dose of cyclophosphamide improves the outcome of women with primary breast cancer and positive axillary nodes. PATIENTS AND METHODS: Patients (N = 2,305) were randomized to receive either four courses of standard AC therapy (group 1); intensified therapy, in which the same total dose of cyclophosphamide was administered in two courses (group 2); or intensified and increased therapy, in which the total dose of cyclophosphamide was doubled (group 3). The dose and intensity of doxorubicin were similar in all groups. Disease-free survival (DFS) and overall survival were determined using life-table estimates. RESULTS: There was no significant difference in DFS (P = .30) or overall survival (P = .95) among the groups through 5 years. At 5 years, the DFS of women in group 1 was similar to that of women in group 2 (62% v 60%, respectively; P = .43) and to that of women in group 3 (62% v 64%, respectively; P = .59). The 5-year survival of women in group 1 was similar to that of women in group 2 (78% v 77%, respectively; P = .86) and to that of women in group 3 (78% v 77%, respectively; P = .82). Grade 4 toxicity increased in groups 2 and 3. Failure to note a difference in outcome among the groups was unrelated to either differences in amount and intensity of cyclophosphamide or to dose delays and intervals between courses of therapy. CONCLUSION: Intensifying or intensifying and increasing the total dose of cyclophosphamide failed to significantly improve either DFS or overall survival in any group. It was concluded that, outside of a clinical trial, dose-intensification of cyclophosphamide in an AC combination represents inappropriate therapy for women with primary breast cancer.

Preliminary experience in external quality control of RT-PCR PML-RAR alpha detection in promyelocytic leukemia.

To standardize the results obtained in PML/RAR alpha RT-PCR detection by laboratories of hospitals involved in the Spanish Program for Treatment of Hematological Malignancies (PETHEMA) LPA-96, designed for the treatment of acute promyelocytic leukemia (APL), cDNA samples obtained by reverse transcription of RNA from bone marrow samples of patients with APL were sent to participating laboratories. During the first year of this external quality assessment trial nine samples were tested by a maximum of 12 laboratories. The control gene was satisfactorily amplified in 90% of the samples (62 of 69 samples), supporting the adequacy of the cDNA to be used as control sample. There was an 83% concordance between laboratories for PML/RAR alpha detection with similar results for the type of PML/RR alpha rearrangements. However, 17% disagreement still remained, attributable to low sensitivity or inadequacy of methods followed. The results stressed the need for implementation of an external quality assessment scheme to ensure the standardization of the results.

Change in neuropsychological performance in asymptomatic HIV infection: 1-year follow-up.

OBJECTIVE: To examine the stability of cognitive function in patients with asymptomatic HIV infection. DESIGN: Previous longitudinal studies of cognitive function have focused on patients who progress in terms of disease stage. The present study avoided this potential confounding factor by including only subjects who remained in the asymptomatic stage of infection over the follow-up period. METHOD: Subjects were administered an extensive neuropsychological test battery at baseline and 1 year follow-up. Overall performance was characterized as normal or abnormal based on the performance of a well-matched HIV-negative control group. RESULTS: A significantly higher proportion of HIV-positive subjects became abnormal at the follow-up examination. Comparison of the seropositive subjects who remained normal with those who became abnormal revealed no differences at baseline on age, education, depression or CD4 levels. Subjects who became abnormal had worse performance at baseline on measures of information processing, verbal learning and memory, and reaction time. CONCLUSIONS: These data indicate that cognitive function may decline in some patients who continue to be in the asymptomatic stage of infection. Patients with a pattern of cognitive abnormalities at baseline, which includes information processing and reaction time deficits, may be at increased risk for declines in function during early stages of infection.

Neuropsychological performance in symptomatic and asymptomatic HIV infection.

OBJECTIVE: To examine cognitive function in patients at various stages of HIV infection, and to determine the nature and severity associated with stage of illness. DESIGN: Subjects were administered an extensive battery of neuropsychological tests. SUBJECTS: Two hundred and thirty-three HIV-1-infected homosexual/bisexual men and 77 HIV-negative control subjects who had been screened for previous neurological illness. All subjects were volunteers in a longitudinal study of neurobehavioral complications of HIV infection. RESULTS: Patients with symptomatic infection differed from controls on a large number of measures, and asymptomatic patients had a more circumscribed pattern of deficit. On a summary measure of cognitive impairment, there was a twofold increase in the prevalence of impairment in asymptomatic patients relative to controls, and a fourfold increase in symptomatic patients. Memory and dexterity problems appear to be early features of neurobehavioral dysfunction, and frontal lobe deficits were found in patients with symptomatic infection. CONCLUSION: These data indicate that there is a steady increase in the prevalence of neurobehavioral abnormalities associated with stage of infection. The pattern of abnormality also varies with disease stage.

Effects of cocaine on sensory inhibition in rats: preliminary data.

The purpose of this study was to determine the effect of cocaine on inhibitory sensory processing mechanisms in the brain. To accomplish this aim, recording electrodes were surgically placed into the vertex region of 12 rats. After recovery from surgery, rats were injected once daily for 5 days with either cocaine (20 mg/kg, IP) or saline. Immediately and 23 hr after each injection, the rats were tested for sensory gating mechanisms. They were presented with a series of two clicking sounds, a conditioning and testing click, delivered 0.5 sec apart, and the amplitude of the N40 responses to each of these clicks was recorded. The ratios of the amplitude of the N40 response to the testing click over that of the conditioning click (T/C ratio) were calculated for each animal for each testing period. The T/C ratios of the control (Saline-injected) animals were less than one, indicating that the conditioning stimulus was able to activate inhibitory neural pathways, producing a decrease in the response to the testing stimulus. The T/C ratios of the cocaine-treated animals were significantly greater than those of controls when the tests were conducted either immediately after injection or 23 hr later. These observations suggest that cocaine can impair mechanisms involved in the gating of responses to auditory stimuli. The higher T/C ratio found at 23 hr after cocaine injection suggests that an impairment in the gating mechanism may be produced by an arousal response that is associated with the environment in which the animals had been injected with cocaine.

Cognitive impairment and cerebral structure by MRI in bipolar disorder.

The distinction between bipolar disorder and schizophrenia customarily follows examination of the clinical symptomatology and course of illness. The presence of cognitive impairment has been held to be uncommon in bipolar disorder and more likely in schizophrenia. This study explored neuropsychological function in 30 ambulatory outpatients with a DSM-III-R diagnosis of bipolar affective disorder (all of whom had been psychotic during manic episodes), comparing their performance with that of controls. These bipolar patients proved to have significant levels of diffusely represented cognitive impairment when compared with controls. Further, the degree of impairment was significantly correlated with reduction in midsagittal areas of brain structures measured on magnetic resonance imaging scans. The implications of these findings in relation to bipolar disorder are discussed.

Leukoaraiosis in asymptomatic adult offspring of individuals with Alzheimer's disease.

The presence of white matter changes on magnetic resonance imaging (MRI), which has been referred to by Hachinski (1987) as leukoaraiosis, is frequently noted in elderly individuals in conditions ranging from health to frank dementia. This study involved the use of MRI to document cerebral structure if 41 healthy 50-60-year-old individuals, 28 of whom were offspring of Alzheimer's disease victims. On visual inspection of spin-echo images, 13 of the 28 offspring showed white matter lesions whereas all of the controls were free of leukoaraiosis. This statistically significant difference suggests that the presence of leukoaraiosis might be of importance in understanding changes in the white matter among populations at increased risk for Alzheimer's disease.

Third-ventricle enlargement and neuropsychological deficit in schizophrenia.

Cerebral ventricular enlargement is present in a substantial subgroup of schizophrenic patients. Most, but not all studies examining neuropsychological performance and ventricular size in schizophrenics show more severe cognitive impairment in those patients with greatest ventricular enlargement. Inconsistencies in this literature have been attributed to different neuroimaging techniques, variation in patient characteristics across studies, and the variety of neuropsychological batteries used. In the present study, schizophrenic patients (n = 49 men, n = 23 women) and normal controls (n = 13 men, n = 18 women) underwent magnetic resonance (MR) imaging of the brain and extensive neuropsychological testing including measures of frontal and temporal lobe function. A complete coronal set of MR images was used to calculate volumetric estimates of lateral and third cerebral ventricles. Highly significant associations were found between cognitive deficits and third-ventricle volume, with measures of frontal functioning, attention, and concentration showing the most robust correlations. In contrast, neuropsychological performance was not highly associated with lateral ventricular size. These findings further support the pathophysiological relevance of ventricular enlargement in schizophrenia. More specifically, third, but not lateral, ventricular enlargement was associated with greater cognitive disturbance in this sample. Results are consistent with pathological involvement of periventricular diencephalic structures resulting in dysfunctional frontal and limbic processing in a subgroup of patients.

Phenylethylaminergic mechanisms in attention-deficit disorder.

Urinary excretion (24-hr) of beta-phenylethylamine (PEA), phenylacetic acid (PAA), phenylalanine (Phe), and p-tyrosine (Tyr), and plasma levels of PAA, Phe, and Tyr were examined in 18 normal children and 26 children diagnosed as having attention-deficit hyperactivity disorder (ADHD). The results indicated that urinary excretion (expressed per g of creatinine) of free and total PEA was significantly lower in the ADHD patients, and plasma levels of Phe and Tyr were also decreased in the ADHD subjects compared with the normal controls.

Failed suicide attempt by emission gas poisoning.

After prolonged exposure to emission gases from his car, a patient survived, probably because of low carbon monoxide levels in the emission gases of his modern car. The authors anticipate a reduction in fatalities when this method of suicide is used.

Neuropsychological performance in medicated and unmedicated patients with Tourette's disorder.

OBJECTIVE: To date, there have been no formal investigations of neuropsychological performance in patients with Tourette's disorder who are taking psychotropic medications. The authors conducted this study to provide such information. METHOD: They examined the neuropsychological performance of 96 patients 6-18 years old who met DSM-III-R criteria for Tourette's disorder; 51 of these patients were taking neuroleptic medications and 45 were not. The groups were well matched with regard to age, sex, education, and duration of symptoms. Each group was given a complete neuropsychological test battery as well as instruments rating symptoms of Tourette's disorder, obsessive-compulsive characteristics, and other behavioral disturbances. RESULTS: The patients taking medications did not differ from those not taking medications on any of the neuropsychological, intellectual, or educational measures. In addition, the groups did not differ with regard to level of Tourette's disorder symptoms. CONCLUSIONS: The results of this investigation suggest that patients with Tourette's disorder who do not experience intolerable side effects from neuroleptic medications are able to perform on educational, intellectual, and neuropsychological tests at a level comparable to that of unmedicated patients. These results have positive implications for patients with Tourette's disorder who respond to neuroleptic medications.

Depression and neuropsychological performance in asymptomatic HIV infection.

OBJECTIVE: The authors examined the effect of depression on neuropsychological performance in HIV-infected men. Previous studies have suggested that depression may account for the neuropsychological abnormalities observed in some patients with HIV infection, but few studies have specifically examined this question. METHOD: An extensive neuropsychological test battery was administered to 121 HIV-seropositive asymptomatic men and 42 HIV-seronegative comparison subjects. The seropositive subjects were grouped into depressed and non-depressed groups on the basis of scores on the Beck Depression Inventory, Hamilton Rating Scale for Depression, and Structured Clinical Interview for DSM-III-R. RESULTS: Statistical comparisons revealed very few measures on which the depressed seropositive subjects scored significantly worse than either of the nondepressed comparison groups. The nondepressed seropositive group differed consistently from the seronegative comparison subjects on measures of verbal memory and dexterity. CONCLUSIONS: These data indicate that the subtle neuropsychological abnormalities observed in some asymptomatic HIV-seropositive subjects cannot be attributed to depression. These data also indicate the advantages of a multifaceted approach to assessment of depression.

Central nervous system involvement in the eosinophilia-myalgia syndrome.

A patient with eosinophilia-myalgia syndrome developed progressive central nervosa system involvement that did not improve despite discontinuation of L-tryptophan therapy. Neurologic impairment was manifested initially by spastic monoparesis, which was improved by treatment with methyl-prednisolone and hydroxyurea. Recurrence of weakness was accompanied by gait ataxia, dysphagia, and complaints of a gradual decline in memory and concentration. Neuropsychological testing identified a broad pattern of cognitive deficits suggestive of a subcortical dementia, and magnetic resonance imaging demonstrated multiple high-signal lesions in the white matter. Cognitive deficits appear to be underrecognized in patients with the eosinophilia-myalgia syndrome. The response of our patient's initial symptoms to corticosteroid therapy suggests a possible role for autoimmune mechanisms in the pathogenesis of central nervous system involvement in the eosinophilia-myalgia syndrome. Neuropsychological evaluation should be performed in patients with cognitive complaints to delineate the full spectrum of central nervous system impairment associated with the eosinophilia-myalgia syndrome.

Effects of seizure type and waveform abnormality on memory and attention.

Deficits in memory, learning, and attention were examined in a sample of 57 patients admitted for investigation of intractable seizure disorder. The patients were grouped according to seizure type and nature of electroencephalographic abnormality. Patients with complex partial seizures were impaired in comparison with controls. Patients with spike-and-wave abnormalities were more impaired on some tests, while those with slow-wave abnormalities were impaired on other tests. These results suggest that, contrary to previous studies, patients with complex partial seizures have greater deficits than other seizure types in some areas of cognitive function.

Screening for cognitive dysfunction in multiple sclerosis.

BACKGROUND: With the use of comprehensive neuro-psychological assessments, a substantial proportion of patients with multiple sclerosis have been found to have substantial cognitive impairment. Although data generated from comprehensive examinations are useful in making recommendations for treatment interventions and compensatory strategies, the cost of such assessments prohibits their use with all patients. OBJECTIVE: To develop a screening battery to detect cognitive impairment in patients with multiple sclerosis that is sensitive, specific, brief, and cost-effective, and could identify patients who might benefit from a more comprehensive neuropsychological examination. DESIGN: On the basis of a comprehensive neuropsychological assessment battery, the presence of significant cognitive impairment was determined in patients with multiple sclerosis. The screening battery consisted of a subset of tests from the comprehensive battery. Performance on the screening battery was then used to predict presence of cognitive impairment on the comprehensive battery in validation and cross-validation samples. Severity of impairment on the screening battery was also regressed on ratings of functional impairment derived from the Expanded Disability Status Scale. RESULTS: In the validation sample, the screening battery had 100% sensitivity, 80% specificity, and 88.1% overall diagnostic accuracy. In the cross-validation sample, the screening battery had 100% sensitivity, 81.8% specificity, and an overall diagnostic accuracy rate of 90.7%. chi 2 tests showed that the accuracy of the screening battery was significantly better than chance in both samples. Performance on the screening battery also predicted the level of disability ratings on the Expanded Disability Status Scale and functional systems scales. CONCLUSIONS: The screening battery had a high degree of sensitivity, specificity, and diagnostic accuracy, while maintaining a brief administration time and high cost-effectiveness. The screening battery also predicted higher levels of disability and functional impairment as assessed by the Expanded Disability Status Scale, thereby enhancing its clinical utility. Despite its advantages, the findings do not suggest that the screening battery may be an effective substitute for a more detailed examination.

Rate of CD4 decline and neuropsychological performance in HIV infection.

This study examined the relationship between performance on a battery of neuropsychologic tasks and rate of CD4 lymphocyte decline in 47 gay or bisexual men infected with the human immunodeficiency virus type 1. Subjects were volunteers for a longitudinal study of the human immunodeficiency virus infection and were not selected because of neuropsychiatric symptoms. Subjects were at all stages of illness, although most were asymptomatic. Faster rates of decline in percent CD4 lymphocyte were related to poorer performance on measures of memory and reaction time. This relationship was independent of stage of illness and CD4 level at the time of neuropsychologic examination, and was not due to medication effects. The rate of percent CD4 lymphocyte cell loss is associated with and may represent a risk factor for the development of the human immunodeficiency virus-related neurobehavioral deficit.