Limited efficacy of an inactivated feline immunodeficiency virus vaccine.
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Animals↗
Biomedical subjects
S MacKay
Publications and source records attributed to S MacKay.
Transient human gene therapy: a novel cytokine regulatory strategy for experimental pancreatitis.
OBJECTIVE: The purpose of this study was to evaluate the ability to transfect a murine pancreas with a human cytokine regulatory gene (interleukin-10 [IL-10]) and examine the duration of transgene expression, its effect on the normal pancreas, and its antiinflammatory effect during acute pancreatitis. SUMMARY BACKGROUND DATA: Interleukin-1beta and tumor necrosis factor-alpha are known detrimental mediators during the progression of acute pancreatitis, and blockade of either cytokine results in decreased severity of pancreatitis and improved survival. Although gene therapy has been proposed as a method to deliver protein-based therapy during a number of conditions, no means of effectively transfecting the pancreas without inducing injury has been developed. METHODS: A plasmid-human IL-10 construct (pMP6-hIL-10) complexed with cationic liposomes was administered by single intraperitoneal injection to healthy mice. Effective transfection (reverse transcriptase-polymerase chain reaction for hIL-10 mRNA), transfected cell type (in situ polymerase chain reaction for hIL-10 DNA), and the effect on the normal pancreas were determined. Additional animals were transfected to determine the effects of this regulatory gene on the severity of pancreatitis. RESULTS: Nearly 80% of all pancreatic cells expressed human DNA that was subsequently transcribed into mRNA through day 14. The transfection event had no effect on amylase, lipase, or pancreatic histologic appearance. Successful transfection could attenuate subsequently induced pancreatitis (all parameters p < 0.05). CONCLUSIONS: Transient transfection of a human IL-10 gene can be accomplished into all cell types of murine pancreata using a plasmid/ liposome vector. The DNA is effectively transcribed into intact mRNA and does not cause inflammation or acinar cell damage. Transfer of this cytokine regulatory gene decreases the severity of pancreatitis, demonstrating a benefit of gene therapy during this acute inflammatory process.
Amylases↗
Event-related potential evidence for frontal cortex effects of chronic cocaine dependence.
We examined the effects of cocaine dependence and cocaine and alcohol codependence on the P3A event-related potential component. Ten chronic cocaine-dependent subjects, 10 chronic cocaine and alcohol codependent subjects, and 20 controls were studied in an auditory paradigm that included target, nontarget, and novel rare nontarget conditions. Substance-dependent subjects were abstinent from cocaine and/or alcohol for 2-6 weeks. Eighteen of these subjects (4 chronic cocaine-dependent subjects, 4 chronic cocaine/alcohol codependent subjects, and 10 normal controls) were also studied in an analogous visual paradigm. In the auditory modality, the latency of the P3A response in the novel rare nontarget condition was delayed and its amplitude was reduced in both substance-dependent samples compared to controls. Comparable results were found for the smaller samples studied in the visual modality. These results suggest that chronic cocaine dependence produces deficits in frontal cortex functions.
Acoustic Stimulation↗
Cocaine abusers have reduced auditory P50 amplitude and suppression compared to both normal controls and alcoholics.
The auditory P50 evoked response to click stimuli was recorded from 10 2-week abstinent African-American chronic cocaine abusers and 10 African-American non-substance-abusing controls. Stimuli consisted of pairs of clicks with a 500-msec interval between clicks in a pair, and a 7-8 sec interval between pairs of clicks. After averaging responses to 100 pairs of clicks and digital bandpass filtering between 10 and 50 Hz, P50 amplitude to the first and the second click was measured. The conditioning/testing (C/T) ratio, an index of P50 suppression, was computed as the ratio of P50 amplitude to the second compared to the first click. Chronic cocaine abusers had markedly diminished P50 amplitudes and increased C/T ratios (indicating decreased P50 suppression) in comparison to the controls. These P50 abnormalities were not seen in additional Caucasian gay/bisexual comparison groups of active alcoholics (n = 15) and non-substance-abusing controls (n = 10). Thus, decrements in P50 amplitude and P50 suppression appear to be specific to cocaine abuse, and to differentiate cocaine abuse from alcohol abuse. A response analogous to P50 can be measured in animals, facilitating the development of animal models of this cocaine effect.
Adult↗
Regional gray and white matter metabolite differences in subjects with AD, with subcortical ischemic vascular dementia, and elderly controls with 1H magnetic resonance spectroscopic imaging.
OBJECTIVE: To use 1H magnetic resonance spectroscopic imaging to study differences in neuron density (N-acetylaspartate [NAA]), membrane phospholipid metabolites (choline [Cho]), and creatine-containing metabolites (creatine plus phosphocreatine [Cr]) in subjects with Alzheimer's disease (AD), with subcortical ischemic vascular dementia (SIVD), and elderly controls. DESIGN: Cross-sectional, between groups. SETTING: A Veterans Affairs medical center and university memory clinic. PARTICIPANTS: Forty elderly subjects with AD (n = 14), with SIVD (n = 8), and elderly controls (n = 18). MAIN OUTCOME MEASURES: We used 1H magnetic resonance spectroscopic imaging to acquire spectra from a 80 x 100 x 17-mm volume superior to the lateral ventricles. Spectra were analyzed from voxels in anterior, medial, and posterior gray and white matter using nuclear magnetic resonance-1 and the results were compared between groups using repeated measures analysis of variance (ANOVA), Tukey's test, and individual Student's t tests. RESULTS: Using ANOVA, significantly lower levels of NAA/Cho and NAA/Cr and significantly higher levels of Cho/Cr were observed across both gray and white matter voxels in subjects with AD. Using individual Student's t tests, a significantly lower level of NAA/Cho and a higher level of Cho/Cr were observed in the posterior gray matter in subjects with AD. Using ANOVA in subjects with SIVD, significantly lower gray and white matter NAA/Cr levels were observed. Using Tukey's test, the NAA/Cr level was significantly lower in frontal white matter voxels in subjects with SIVD compared with controls. CONCLUSIONS: Our findings in subjects with AD suggest neuron loss in gray matter, axon loss in white matter, and altered Cho metabolism in posterior brain regions. Our findings in subjects with SIVD are consistent with higher levels of creatine-containing metabolites and/or lower levels of NAA in frontal white matter.
Aged↗
Tumor cell nitric oxide inhibits cell growth in vitro, but stimulates tumorigenesis and experimental lung metastasis in vivo.
Arginine-derived nitric oxide (NO) has been identified in some tumor cell lines and solid human tumors. The effect of tumor cell NO on tumor biology is poorly understood. The purpose of this study was to investigate the effect of NO production by EMT-6 murine breast cancer cells on tumor cell growth in vitro and subcutaneous tumor growth and experimental pulmonary metastasis in vivo. EMT-6 cells were incubated with endotoxin (LPS, 10 microgram/ml) and interferon-gamma (IFN, 50 U/ml), in the presence or absence of the NO synthase inhibitor, omega-nitro-L-arginine methyl ester (L-NAME, 2 mM), and NO production and cell number were assessed 24 hr later. EMT-6 cells were also treated overnight with LPS/IFN, in the presence or absence of L-NAME, washed and injected either subcutaneously in the dorsal flank (n = 40) or via the tail vein (n = 40) of syngeneic BALB/c mice. Two weeks following tumor cell injection, tumor size and number of pulmonary metastases were assessed. LPS/IFN stimulated NO production in EMT-6 cells and inhibited cell growth in vitro by 50%. L-NAME blocked LPS/IFN stimulation of NO production and restored cell growth to near control levels. When injected into BALB/c mice, LPS/IFN-stimulated tumor cells demonstrated a two-fold increase in subcutaneous tumor growth and experimental pulmonary metastases over control cells. L-NAME reduced tumor size and number of lung metastases to control levels, suggesting that tumor cell NO production was responsible for this effect. In summary, LPS/IFN-stimulated NO production in EMT-6 tumor cells inhibits tumor cell growth in vitro, yet paradoxically augments tumor growth and metastasis in vivo.
Analysis of Variance↗
Alzheimer disease and subcortical ischemic vascular dementia: evaluation by combining MR imaging segmentation and H-1 MR spectroscopic imaging.
PURPOSE: To determine the association between H-1 magnetic resonance (MR) spectroscopic imaging and MR imaging differences in subjects with Alzheimer disease (AD) or subcortical ischemic vascular dementia (SIVD) versus control subjects and if both studies combined enable discrimination of AD from control subjects better than either study alone. MATERIALS AND METHODS: Measures were obtained in nine AD, eight SIVD, and 11 control subjects with MR imaging segmentation software. RESULTS: Statistically significantly lower N-acetylaspartate/choline-containing metabolites (Cho) and higher Cho/creatine-containing metabolites in posterior mesial gray matter in AD versus control subjects were independent of MR imagining differences. Combined measures allowed correct classification of AD and control subjects, but none of the MR measures allowed accurate discrimination between AD and SIVD subjects. CONCLUSION: Between-group differences in tissue-type contributions to H-1 MR spectroscopic imaging voxels must be accounted for when reporting H-1 MR spectroscopic imaging data in AD, SIVD, and control subjects. Combined studies allowed more accurate discrimination between AD and control subjects than either study alone.
Aged↗
Alcohol abuse and HIV infection have additive effects on frontal cortex function as measured by auditory evoked potential P3A latency.
Both alcohol and human immunodeficiency virus (HIV) infection have been shown to produce central nervous system (CNS) morbidity in frontal brain regions. The degree to which the CNS morbidity in HIV infection, as it affects frontal cortex function, may be preferentially increased by alcohol abuse was examined using the auditory P3A evoked potential. The P3A indexes an orienting response, maximal over frontal cortex that occurs when novel nontarget stimuli are presented in the midst of a target detection paradigm. Four groups of subjects were compared: HIV+ alcohol abusers, HIV+ light/nondrinkers, HIV- alcohol abusers, and HIV- light/nondrinkers. The alcohol abuser and light/nondrinker HIV+ groups were matched on percent CD4 lymphocytes, insuring that the results reflected specific CNS effects and were not a result of differences between the groups in the degree of systemic immune suppression. Alcohol abuse and HIV infection had at least additive effects on P3A latency, consistent with alcohol abuse worsening the effect of HIV disease on frontal cortex function. Post-hoc analyses suggested that concomitant alcohol abuse results in the effects of HIV infection on P3A latency becoming manifest earlier in the HIV disease process.
AIDS Dementia Complex↗
Delayed latency of the event-related brain potential P3A component in HIV disease. Progressive effects with increasing cognitive impairment.
OBJECTIVE: To examine the degree to which P3A latency was sensitive to the early and progressive effects of human immunodeficiency virus (HIV) disease on frontal cortex function by studying HIV-positive subjects who varied in degree of cognitive impairment. DESIGN: Event-related brain potential studies of four groups of subjects: cognitively nonimpaired high-risk HIV-negative subjects, cognitively nonimpaired HIV-positive subjects, cognitively mildly to moderately impaired HIV-positive subjects, and cognitively severely impaired HIV-positive subjects. SETTING: Voluntarily participating subjects on an outpatient basis at a medical center facility. PARTICIPANTS: Seventy-one community-residing gay or bisexual HIV-positive male volunteers were compared with 17 HIV-negative male gay or bisexual subjects used as a control sample. The HIV-positive subjects were stratified with regard to severity of cognitive impairment into the following three subsamples: subjects who were cognitively normal (n = 35), subjects with mild to moderate cognitive impairment (n = 20), and subjects with severe cognitive impairment (n = 16), with the samples closely matched in age. The HIV-positive subsamples were closely matched on percentage of CD4 lymphocytes. Subjects were excluded if they reported a history of drug or alcohol abuse, a major mental disorder, a head injury with loss of consciousness, or brain disease other than HIV related. MAIN OUTCOME MEASURE: P3A latency. RESULTS: P3A latency was significantly delayed in HIV-positive subjects compared with HIV-negative control subjects, with a delay of 12 milliseconds in the cognitively normal group (P < .02) and the magnitude of delay increasing with increasing severity of HIV-associated cognitive impairments (P < .001). Delayed P3A was primarily associated with the progression of HIV-associated cognitive impairment, with a secondary and additive association with severity of HIV-associated medical illness. CONCLUSION: This finding suggests that delayed P3A latency is sensitive to the relatively early central nervous system effects of HIV and progresses with worsening of the central nervous system effects of HIV.
Adult↗
Delayed P3A in abstinent elderly male chronic alcoholics.
Significant central nervous system toxicity in frontal brain regions has been demonstrated with chronic alcohol consumption both on autopsy and using neuropsychological testing. This study examined the latency of an objective and reproducible brain event-related potential measure of frontal cortex function in chronic elderly male alcoholics who were abstinent 3 months-2 years, a patient group in whom the central nervous system effects of chronic alcohol abuse are thought to be largest and most persistent. We examined the latency of the P3A event-related potential component, which reflects a frontal maximum orienting response to novel stimuli. Twelve elderly abstinent chronic alcoholic males and 11 elderly male controls were studied in an auditory and a visual paradigm, each of which included target, nontarget, and novel rare nontarget conditions. In both modalities, the P3A response to the novel rare nontarget stimuli was significantly delayed in the chronic alcoholics. P3B delays to the target stimuli were also present in the alcoholics, with the P3A and P3B effects being independent of each other. For both P3A and P3B, the effects were larger and more consistent in the visual compared with the auditory modality. Our conclusions are as follows: (1) both P3A and P3B latency delays are evident in elderly abstinent chronic alcoholics; (2) separate mechanisms are responsible for these effects; (3) these effects are more sensitively detected in the visual versus the auditory modality; and (4) delayed P3A latency may be an objective and reproducible index of the frontal cortex effects of chronic alcohol abuse.
Aged↗
Effects of chronic alcohol abuse and HIV infection on brain phosphorus metabolites.
We examined the effects of human immunodeficiency virus (HIV) infection and chronic alcohol consumption on cerebral phosphorus metabolites to determine if chronic alcohol abuse is a risk factor for the progression of neurological effects of HIV infection. We studied 15 HIV- alcoholics, 8 HIV- light/nondrinkers, 32 HIV+ alcoholics, and 41 HIV+ light/nondrinking men, with both HIV+ groups having similar CD4 lymphocyte counts. We used localized 31-phosphorus magnetic resonance spectroscopy after magnetic resonance imaging to examine two brain volumes in superior white matter and subcortical gray matter. Chronic alcohol consumption was associated with reduced white matter concentrations of phosphodiester (PDE) and phosphocreatine (PCr). Also in the white matter, acquired immune deficiency syndrome (AIDS) and AIDS-related complex (ARC) were associated with reduced concentrations of PDE and PCr, compared with both HIV- and clinically asymptomatic HIV+ subjects. Because no alcohol-by-HIV interactions were detected, the effects of HIV infection and alcohol abuse were cumulative. This is reflected in a successive decrease of white matter PDE and PCr concentrations in the order HIV- light/nondrinkers/HIV- alcoholics/HIV+ light/nondrinkers/HIV+ alcoholics. Subcortical gray matter PDE concentrations were lower in ARC/AIDS alcoholics than in HIV- light/nondrinking individuals. These findings suggest altered brain phospholipid metabolites and energy metabolites with alcohol abuse and HIV infection. They demonstrate that the adverse metabolic effects of HIV on the brain are augmented by chronic alcohol abuse.
AIDS Dementia Complex↗
Brain atrophy and cognitive function in older abstinent alcoholic men.
We used computer-aided magnetic resonance image analysis and an age-normed battery of neuropsychological tests to measure brain atrophy and cognitive function in 14 older abstinent alcoholic men and 11 older controls in the expectation that these subject groups would show the greatest and most persistent cerebral effects consequent to chronic alcoholism. The abstinent alcoholics exhibited cognitive impairments (primarily in memory and visual-spatial-motor skills) compared with the controls. In contrast, we found no difference in global cerebral atrophy between the groups, although two alcoholics had extensive atrophy compared with all other subjects. However, there was a stronger association between age and ventricular dilation in the alcoholic sample compared with controls. We conclude that a substrate other than magnetic resonance imaging-detectable global atrophy must underlie the persistent cognitive impairments evident in the sampled alcoholics. Furthermore, if there are global atrophic changes in the brain associated with chronic alcoholism, these effects are not ubiquitous and/or may be reversible in most patients with sufficient abstinence.
Aged↗
H-1 MR spectroscopic imaging of white matter signal hyperintensities: Alzheimer disease and ischemic vascular dementia.
PURPOSE: To investigate the association of white matter signal hyperintensities (WMSHs) with changes in hydrogen-1 metabolites. MATERIALS AND METHODS: T2-weighted magnetic resonance (MR) imaging and H-1 MR spectroscopic imaging were performed in 21 elderly control subjects without or with minimal WMSHs, eight elderly subjects with substantial WMSHs, 11 probable Alzheimer disease patients with WMSHs, and eight ischemic vascular dementia (IVD) patients with WMSHs. N-acetylaspartate (NAA), choline-containing metabolites (Cho), and creatine-containing metabolites (Cr) were analyzed. RESULTS: Differences in regional metabolite levels were found within the supraventricular brain of elderly control subjects. In Alzheimer disease patients, extensive WMSHs showed a lower percentage of NAA and a higher percentage of Cho compared with contralateral normal-appearing white matter (NAWM); in IVD patients, extensive and large WMSHs were associated with a higher percentage of Cho and a lower percentage of Cr compared with contralateral NAWM. CONCLUSION: Regional metabolite variation and the presence of WMSHs are important covariants that must be accounted for in analysis of MR spectroscopic data.
Aged↗
Axonal injury and membrane alterations in Alzheimer's disease suggested by in vivo proton magnetic resonance spectroscopic imaging.
We used spin-echo magnetic resonance imaging and proton magnetic resonance spectroscopic imaging in 8 patients with probable Alzheimer's disease and in 10 age-matched elderly control subjects to assess the effects of Alzheimer's disease on the brain. On magnetic resonance images the patients showed significant ventricular enlargements relative to the control subjects. We measured the distribution and relative signal intensities of N-acetylaspartate (a putative neuronal marker), of choline residues representing lipid metabolites, and of creatine-containing metabolites in a large section of the centrum semiovale containing white and mesial gray matter. Throughout the white matter of the patients with Alzheimer's disease compared to elderly control subjects, N-acetylaspartate was decreased relative to choline (N-acetylaspartate-choline ratio) and creatine-containing metabolites (N-acetylaspartate-creatine ratio) with no changes in the choline-creatine ratio. The N-acetylaspartate-choline ratio was lower and choline-creatine higher in the mesial gray matter of AD patients relative to elderly controls. The posterior section of the centrum semiovale in the patients showed increased choline-creatine and choline-N-acetylaspartate ratios with the N-acetylaspartate-creatine ratio unchanged between the patients and control subjects. These spectroscopic findings give suggestive evidence of diffuse axonal injury and membrane alterations in gray and white matter of the centrum semiovale in patients with Alzheimer's disease.
Aged↗
N-acetylaspartate reductions measured by 1H MRSI in cognitively impaired HIV-seropositive individuals.
We used magnetic resonance imaging (MRI) and water-suppressed proton MR spectroscopic imaging (1H MRSI) to study the effects of human immunodeficiency virus (HIV) infection on the brain. Our recent in vivo finding of lower N-acetylaspartate (NAA), a putative marker of neurons, in the supraventricular brain of cognitively impaired HIV-seropositive patients (CISP) compared to noninfected controls was replicated in a new cohort of 13 CISP patients and extended to include 10 high-risk homosexual HIV-seronegative controls. Throughout the supraventricular brain the ratio of NAA to choline-containing metabolites (NAA/Cho) was lower in CISP subjects than in high-risk controls (1.98 +/- 0.36 vs. 2.35 +/- 0.29, p = 0.016), and the ratio of NAA to creatine-containing metabolites (NAA/Cr) was also lower in CISP subjects than in high-risk controls (3.02 +/- 0.44 vs. 3.56 +/- 0.39, p = 0.007) with Cho/Cr unchanged in both groups. These findings indicate a NAA reduction which suggests neuron loss and/or dendritic and axonal damage. Homosexual high-risk HIV-seronegative controls had metabolite measures similar to previously studied heterosexual HIV-seronegative controls. NAA measures in six cognitively normal HIV-seropositive subjects (CNSP) (NAA/Cho = 2.34 +/- 0.39, NAA/Cr = 3.42 +/- 0.69) were similar to those of controls and tended to be increased relative to those in cognitively impaired HIV-seropositive subjects. This study demonstrates that reduced NAA in the supraventricular brain is associated with the development of severe cognitive impairments secondary to HIV infection and that 1H MRSI methodology reliably detects HIV effects on the brain.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Alteration of brain phospholipid metabolites in cocaine-dependent polysubstance abusers.
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Adult↗
Reduced brain N-acetylaspartate suggests neuronal loss in cognitively impaired human immunodeficiency virus-seropositive individuals: in vivo 1H magnetic resonance spectroscopic imaging.
We used magnetic resonance imaging (MRI) and water-suppressed proton magnetic resonance spectroscopic imaging to study the effects of human immunodeficiency virus (HIV) infection on the brains of 10 individuals with cognitive impairment due to HIV and seven normal controls. 1H spectra from nine 2.5-ml volumes in the centrum semiovale and the mesial cortex showed significantly reduced N-acetylaspartate (NAA) relative to choline and creatine in the cognitively impaired HIV-infected subjects. This reduction was due to a nonlocalized decrease of NAA in these patients, only two of whom had moderate atrophy and white matter signal hyperintensities on MRI. Since NAA is a putative neuronal marker, the findings suggest neuronal damage in early stages of HIV infection that is not evident on standard MRI and are consistent with the neuropathologically known neuronal loss.
Adult↗
Pain corner. Duragesic.
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Administration, Cutaneous↗