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Biomedical subjects

A Nath

Publications and source records attributed to A Nath.

At least 73 records · Page 4Linked to original sources
PubMed1999

Paroxysmal dyskinesias in patients with HIV infection.

OBJECTIVE: To determine the clinical features of paroxysmal dyskinesias among HIV type 1 (HIV-1)-seropositive patients. BACKGROUND: Movement disorders have been associated with HIV infection, although the full spectrum of these disorders remains uncertain. METHODS: Six adult HIV-1-seropositive patients presenting with paroxysmal dyskinesias were identified. Each patient underwent metabolic, CSF, EEG, and neuroimaging studies. RESULTS: Mean age at onset was 34.5 years and five of six patients were AIDS defined. Dyskinesias were focal, multifocal, or hemidystonic in four patients and generalized in another two patients. Two of the six patients had paroxysmal kinesigenic dyskinesias and the remaining four patients had paroxysmal nonkinesigenic dyskinesias. Choreoathetosis (n = 3), myoclonus (n = 2), postural tremor (n = 5), and dysarthria (n = 3) were observed. Benzodiazepines appeared beneficial in three of six patients. Two patients with HIV-associated dementia and paroxysmal nonkinesigenic dyskinesia had a progressive course to death. Autopsy of a patient with paroxysmal nonkinesigenic dyskinesias revealed intense astrogliosis and loss of calbindin-positive neurons in the subcortical gray matter. CONCLUSIONS: Paroxysmal dyskinesias may present as a primary HIV-1-induced neurologic syndrome. The occurrence of paroxysmal dyskinesias is associated with neuronal injury and loss in the subcortical gray matter but the mechanism remains unknown.

AIDS Dementia Complex↗
PubMed1999

Evidence that Par-4 participates in the pathogenesis of HIV encephalitis.

Progressive neuronal degeneration in brain regions involved in learning and memory processes is a common occurrence in patients infected with human immunodeficiency virus type 1 (HIV-1). We now report that levels of Par-4, a protein recently linked to neuronal apoptosis in Alzheimer's disease, are increased in neurons in hippocampus of human patients with HIV encephalitis and in monkeys infected with a chimeric strain of HIV-1 and simian immunodeficiency virus. Par-4 levels increased rapidly in cultured hippocampal neurons following exposure to the neurotoxic HIV-1 protein Tat, and treatment of the cultures with a Par-4 antisense oligonucleotide protected the neurons against Tat-induced apoptosis. Additional findings show that Par-4 participates at an early stage of Tat-induced neuronal apoptosis before caspase activation, oxidative stress, and mitochondrial dysfunction. Our data suggest that Par-4 may be a mediator of neuronal apoptosis in HIV encephalitis and that therapeutic approaches targeting the Par-4 apoptotic cascade may prove beneficial in preventing neuronal degeneration and associated dementia in patients infected with HIV-1.

Animals↗
PubMed1999

Role of Na+/H+ exchangers, excitatory amino acid receptors and voltage-operated Ca2+ channels in human immunodeficiency virus type 1 gp120-mediated increases in intracellular Ca2+ in human neurons and astrocytes.

Human immunodeficiency virus type 1 (HIV-1) dementia is the commonest form of dementia in North American people less than 60 years of age. HIV-1 envelope glycoprotein gp120 has been implicated in the neurotoxicity observed in, and the pathogenesis of, HIV-1 dementia. Recombinant gp120 (gp120) was pressure-applied on to cultured human fetal neurons and astrocytes and, by using single-cell calcium imaging, we determined the mechanisms responsible for gp120-induced increases in the levels of intracellular calcium ([Ca2+]i). Significant dose-related increases in [Ca2+]i were observed in neurons and astrocytes. In neurons, 5 pM gp120 increased [Ca2+]i by 290+/-13 nM and increases of 2210+/-211 nM were found at 209 nM, the highest concentration of gp120 tested. The apparent EC50 value for gp120 of 223+/-40 pM in neurons was not significantly different from that in astrocytes. Immunoelution of gp120 with polyclonal anti-gp120 and Ca2+-free conditions blocked increases in [Ca2+]i by gp120. Increases in [Ca2+]i were significantly (P < 0.005) attenuated by the Na+/H+ exchange blocker 5-(N-methyl-N-isobutyl)-amiloride in neurons and astrocytes. The L-type calcium channel blockers nimodipine, diltiazem and CdCl2 + NiCl2 significantly (P < 0.005) reduced increases in [Ca2+]i in neurons, but not astrocytes. Increases in [Ca2+]i by gp120 were not significantly affected by blockers of N-, P- and Q-type calcium channels. The N-methyl-D-aspartate receptor antagonists (+/-)-2-amino-5-phosphonopentanoic acid (AP5), memantine and dizocilpine significantly (P < 0.01) lowered gp120-induced increases in [Ca2+]i in neurons. AP5 and memantine, but not dizocilpine, significantly (P < 0.01) reduced increases in [Ca2+]i by gp120 in astrocytes. Gp120 appears to activate astrocyte Na+/H+ exchangers to release glutamate and potassium and, subsequent to this, increases in [Ca2+]i in neurons and astrocytes result from activation of excitatory amino acid receptors on astrocytes and neurons, and voltage-operated calcium channels on neurons. Drugs that block gp120-induced changes in [Ca2+]i in neurons and astrocytes may help in the treatment of HIV-1 dementia.

Astrocytes↗
PubMed1999

Involvement of inositol 1,4,5-trisphosphate-regulated stores of intracellular calcium in calcium dysregulation and neuron cell death caused by HIV-1 protein tat.

HIV-1 infection commonly leads to neuronal cell death and a debilitating syndrome known as AIDS-related dementia complex. The HIV-1 protein Tat is neurotoxic, and because cell survival is affected by the intracellular calcium concentration ([Ca2+]i), we determined mechanisms by which Tat increased [Ca2+]i and the involvement of these mechanisms in Tat-induced neurotoxicity. Tat increased [Ca2+]i dose-dependently in cultured human fetal neurons and astrocytes. In neurons, but not astrocytes, we observed biphasic increases of [Ca2+]i. Initial transient increases were larger in astrocytes than in neurons and in both cell types were significantly attenuated by antagonists of inositol 1,4,5-trisphosphate (IP3)-mediated intracellular calcium release [8-(diethylamino)octyl-3,4,5-trimethoxybenzoate HCI (TMB-8) and xestospongin], an inhibitor of receptor-Gi protein coupling (pertussis toxin), and a phospholipase C inhibitor (neomycin). Tat significantly increased levels of IP3 threefold. Secondary increases of neuronal [Ca2+]i in neurons were delayed and progressive as a result of excessive calcium influx and were inhibited by the glutamate receptor antagonists ketamine, MK-801, (+/-)-2-amino-5-phosphonopentanoic acid, and 6,7-dinitroquinoxaline-2,3-dione. Secondary increases of [Ca2+]i did not occur when initial increases of [Ca2+]i were prevented with TMB-8, xestospongin, pertussis toxin, or neomycin, and these inhibitors as well as thapsigargin inhibited Tat-induced neurotoxicity. These results suggest that Tat, via pertussis toxin-sensitive phospholipase C activity, induces calcium release from IP3-sensitive intracellular stores, which leads to glutamate receptor-mediated calcium influx, dysregulation of [Ca2+]i, and Tat-induced neurotoxicity.

2-Amino-5-phosphonovalerate↗
PubMed1999

Primary headaches in HIV-infected patients.

Headache in patients with human immunodeficiency virus (HIV) infection may indicate life-threatening illnesses such as opportunistic infections or neoplasms. Alternatively, such patients may develop benign self-limiting headaches. Hence, defining the various types of headache in these patients is essential for proper management. This study describes the clinical characteristics of primary headaches occurring in a group of HIV-infected patients. Of 115 patients seen from 1990 to 1996, 44 (38%) had headaches. Primary headaches were present in 29 (66%) patients and secondary causes were identified in 15 (34%). Among those with primary headaches, migraine occurred in 22 (76%), tension-type headache in 4 (14%), and cluster headache in 3 (10%) patients. Half of those with migraine (n=ll), 1 patient with tension-type headache, and 1 patient with cluster headache developed chronic daily headaches which were severe and refractory to conventional headache or antiretroviral therapy. We conclude that primary headaches in patients with HIV infection are: (1) the commonest type of headache; (2) may present for the first time in individuals with severe immunosuppression; (3) usually bear no relationship to antiretroviral drug therapy; (4) polypharmacy, depression, anxiety, and insomnia are commonly associated comorbidities; (5) frequently do not respond to conventional management and carry a poor prognosis; and (6) do not require neuroradiological and/or cerebrospinal fluid evaluations.

Adult↗
PubMed1999

Pathobiology of human immunodeficiency virus dementia.

The pathobiology of dementia that accompanies infection with the human immunodeficiency virus involves complex interactions of the virus with the host. The virus enters the brain either as free viral particles or hidden in infected monocytes (the "Trojan Horse" mechanism). Within the brain it infects microglial cells, causing a productive and cytopathic infection, and infects astrocytes, causing a latent or restricted infection. The brain thus acts as an important reservoir for the virus. These infected cells release several viral proteins, some of which are toxic to neurons and are called "virotoxins." These virotoxins activate glial cells to release a number of soluble factors that are either toxic to neurons or cause chemotaxis of monocytes into the brain. Because the glial cells outnumber the neurons by 10:1, this is an important mechanism by which the virotoxins amplify their toxic potential and initiate a self-perpetuating cascade of events, resulting in a "domino effect" on the brain. Only a transient exposure to virotoxins is necessary to initiate these positive feedback loops. Thus, a "hit and run" phenomenon may be operative within the brain. Therapeutic approaches are based on decreasing the viral burden in the brain and blocking the actions of the key neurotoxic substances at various levels within the various cascades.

AIDS Dementia Complex↗
PubMed1999

Human immunodeficiency virus type 1 TAT protein induces adhesion molecule expression in astrocytes.

AIDS encephalitis is a frequent consequence of CNS HIV infection, especially in children. One of its many characteristics is a leukocyte infiltrate that is believed to contribute to the production of cytokines, chemokines and neurotoxic factors resulting in CNS damage. Entry of such leukocytes into the CNS is mediated in part by the expression of adhesion molecules by blood - brain barrier (BBB) endothelial cells. Expression of these proteins by astrocytes, the other main component of the BBB, also serves to target leukocytes to the CNS parenchyma. We now demonstrate that HIV-1-derived Tat, a soluble protein secreted by infected cells, induced astrocyte VCAM-1 and ICAM-1 expression in a dose- and time-dependent manner. The functional role of Tat in monocyte binding in vitro was also demonstrated. These data suggest that the presence of extracellular Tat may be a significant factor in the trafficking of HIV-infected and inflammatory cells into the CNS via its effect on adhesion molecule expression by astrocytes.

Astrocytes↗
PubMed1998

Induction of monocyte chemoattractant protein-1 in HIV-1 Tat-stimulated astrocytes and elevation in AIDS dementia.

Activated monocytes release a number of substances, including inflammatory cytokines and eicosanoids, that are highly toxic to cells of the central nervous system. Because monocytic infiltration of the central nervous system closely correlates with HIV-1-associated dementia, it has been suggested that monocyte-derived toxins mediate nervous system damage. In the present study, we show that the HIV-1 transactivator protein Tat significantly increases astrocytic expression and release of monocyte chemoattractant protein-1 (MCP-1). Astrocytic release of beta-chemokines, which are relatively less selective for monocytes, including RANTES, macrophage inflammatory protein-1alpha, and macrophage inflammatory protein-1beta, was not observed. We also show that MCP-1 is expressed in the brains of patients with HIV-1-associated dementia and that, of the beta-chemokines tested, only MCP-1 could be detected in the cerebrospinal fluid of patients with this condition. Together, these data provide a potential link between the presence of HIV-1 in the brain and the monocytic infiltration that may substantially contribute to dementia.

AIDS Dementia Complex↗
PubMed1998

Infrequent detection of human herpesvirus 6 DNA in peripheral blood mononuclear cells from multiple sclerosis patients.

Several studies have suggested an association between human herpesvirus 6 (HHV-6) infection and multiple sclerosis. As HHV-6 is predominantly a T-cell tropic virus, we examined the frequency of detection of HHV-6 genome in peripheral blood mononuclear cells from relapsing-remitting (n = 32) and chronic progressive (n = 14) patients and from healthy (n = 17) and neurological (n = 7) controls. Two sensitive polymerase chain reaction assays were used to target different regions within the HHV-6 genome. Depending on the polymerase chain reaction assay used, the detection of HHV-6 genome ranged from 11.7 to 23.5% (controls), 3.1 to 23.0% (relapsing-remitting), and 14.2 to 28.5% (chronic progressive). Although these observations do not exclude a pathogenic role for HHV-6 in multiple sclerosis, they indicate a lack of correlation between HHV-6 infection of peripheral blood mononuclear cells and the development of multiple sclerosis.

Adult↗
PubMed1998

Parkinsonism with HIV infection.

We describe six patients with parkinsonism and another 10 patients with parkinsonian features with human immunodeficiency virus (HIV) infection. In 50% of these patients, the symptoms were precipitated by neuroleptics. In the remaining patients, no obvious cause other than HIV infection was identified. Discontinuation of the neuroleptics produced complete recovery in one patient and partial or no response in others. Rapid progression of parkinsonism was noted in two patients, one of whom was treated with high-dose zidovudine (AZT) and benztropine. We conclude that patients with AIDS are at risk of developing an akinetic parkinsonism which may be precipitated by the use of neuroleptics, response to treatment is variable, and parkinsonism may be another primary HIV-induced syndrome.

AIDS Dementia Complex↗
PubMed1998

HIV-1 protein Tat induces apoptosis of hippocampal neurons by a mechanism involving caspase activation, calcium overload, and oxidative stress.

Patients infected with HIV-1 often exhibit cognitive deficits that are related to progressive neuronal degeneration and cell death. The protein Tat, which is released from HIV-1-infected cells, was recently shown to be toxic toward cultured neurons. We now report that Tat induces apoptosis in cultured embryonic rat hippocampal neurons. Tat induced caspase activation, and the caspase inhibitor zVAD-fmk prevented Tat-induced neuronal death. Tat induced a progressive elevation of cytoplasmic-free calcium levels, which was followed by mitochondrial calcium uptake and generation of mitochondrial-reactive oxygen species (ROS). The intracellular calcium chelator BAPTA-AM and the inhibitor of mitochondrial calcium uptake ruthenium red protected neurons against Tat-induced apoptosis. zVAD-fmk suppressed Tat-induced increases of cytoplasmic calcium levels and mitochondrial ROS accumulation, indicating roles for caspases in the perturbed calcium homeostasis and oxidative stress induced by Tat. An inhibitor of nitric oxide synthase, and the peroxynitrite scavenger uric acid, protected neurons against Tat-induced apoptosis, indicating requirements for nitric oxide production and peroxynitrite formation in the cell death process. Finally, Tat caused a delayed and progressive mitochondrial membrane depolarization, and cyclosporin A prevented Tat-induced apoptosis, suggesting an important role for mitochondrial membrane permeability transition in Tat-induced apoptosis. Collectively, our data demonstrate that Tat can induce neuronal apoptosis by a mechanism involving disruption of calcium homeostasis, caspase activation, and mitochondrial calcium uptake and ROS accumulation. Agents that interupt this apoptotic cascade may prove beneficial in preventing neuronal degeneration and associated dementia in AIDS patients.

AIDS Dementia Complex↗
PubMed1998

Antiallergic/antiasthmatic activity of oligopeptide related to IgE.

In spite of continuous research in the field of bronchial asthma, still no satisfactory drug is available. Recently a new class of oligopeptide exhibited antiallergic activity by inhibiting the synthesis of IgE antibody. The analogue of ADSDGK (94-335) has shown antiallergic activity in experimental models. The 94-335 inhibited the passive cutaneous anaphylaxis (PCA) reactions in rats in a dose-dependent manner (0.5-10 mg kg-1 p.o.) by 47-90%. There was a 70-87% protection of mast cell degranulation induced by compound 48/80 with peptide 94-335 at 0.5-1.5 mg kg-1 p.o. in rats. This peptide also inhibited antigen- induced contraction in sensitised guinea pig ileum. There was 18 and 72% protection to bronchoconstriction induced by histamine and egg albumin, respectively, in an aerosol test in guinea pigs. These effects of compound 94-335 were comparable with that of the clinically-used antiallergic drug disodium cromoglycate (DSCG). The results suggest that peptide 94-335 possesses potent antiallergic activity.

Animals↗
PubMed1998

Anti-allergic and anti-anaphylactic activity of picroliv--a standardised iridoid glycoside fraction of Picrorhiza kurroa.

Picroliv, a standardised iridoid glycoside fraction from the root and rhizome of Picrorhiza kurroa at a dose of 25 mg kg-1 p.o. inhibited passive cutaneous anaphylaxis in mice (82%) and rats (50-85%) and protected mast cells from degranulation (60-80%) in a concentration-dependent manner. Its effect was also studied in sensitised guinea pig ileum preparation in vitro (Schultz-Dale study) and in normal guinea pigs in vivo (Konzett-Rossler, in preparation). There was inhibition of the Schultz-Dale response in sensitised guinea pig ileum, but the bronchospasm induced by histamine could not be antagonised or prevented by Picroliv, indicating the absence of a direct post-synaptic histamine receptor blocking activity.

Animals↗
PubMed1998

Neurobiological aspects of human immunodeficiency virus infection: neurotoxic mechanisms.

Dementia due to human immunodeficiency virus (HIV) infection is the commonest cause of dementia in children, young adults and middle-aged people. Its incidence continues to rise despite the use of newer antiretroviral agents. The study of the pathogenesis of HIV dementia has lead to the discovery of novel mechanisms of neural dysfunction and toxicity, and holds promise for further discovery of new molecules and pathways involved in maintaining cerebral function and enabling dysfunction. New to the field of neurovirology is the emerging concept that proteins that are part of the virus may themselves be neurotoxic by virtue of their abilities to be either directly toxic to brain cells or may, through their actions on glial cells or macrophages, release neurotoxic products coded by the host genome. These mechanisms have been demonstrated for HIV-1 and accordingly we propose a new term, virotoxins, to describe such actions. This review provides an in-depth analysis of the pathophysiological mechanisms by which these viral and cellular products affected by HIV virotoxins cause neural dysfunction.

HIV Infections↗
PubMed1998

Neuronal excitatory properties of human immunodeficiency virus type 1 Tat protein.

Neuronal dysfunction and cell death in patients with human immunodeficiency virus type-1 (HIV-1) infection may be mediated by HIV-1 proteins and products released from infected cells. Two HIV-1 proteins, the envelope glycoprotein gp120 and nonstructural protein Tat, are neurotoxic. We have determined the neuroexcitatory properties of HIV-1 tat protein using patch-clamp recording techniques. When fmoles of Tat were applied extracellularly, it elicited dose-dependent depolarizations of human fetal neurons in culture and rat CA1 neurons in slices, both in the absence and presence of tetrodotoxin. These responses were voltage-dependent, reversed at approximately 0 mV, and were significantly increased by repetitive applications with no evidence of desensitization. That these responses to Tat were due to direct actions on neurons was supported by observations that Tat dose-dependently depolarized outside-out patches excised from cultured human neurons. Removal of extracellular Ca2+ decreased the responses both in neurons and membrane patches. This is the first demonstration that an HIV-1 protein can, in the absence of accessory cells, directly excite neurons and leads us to speculate that Tat may be a causative agent in HIV-1 neurotoxicity.

Animals↗
PubMed1998

Intraventricular injection of human immunodeficiency virus type 1 (HIV-1) tat protein causes inflammation, gliosis, apoptosis, and ventricular enlargement.

To determine the role of the Tat protein of the human immunodeficiency virus type 1 (HIV-1) in the pathogenesis of HIV-1 associated dementia, recombinant Tat was injected intraventricularly as a single or repeated dose into male Sprague-Dawley rats. Histopathological evaluation showed an initial infiltration of neutrophils one day after Tat injection, followed by macrophages and lymphocytes by 7 days. Tat-injected brains also exhibited astrocytosis, apoptotic cells, and ventricular enlargement 7 days following the last injection. Nuclear magnetic resonance spectroscopic analysis of tissue extracts of hippocampi from Tat-injected rats showed a decrease in the glutamate/g aminobutyric acid ratio. We conclude that the transient extracellular exposure of the central nervous system to Tat protein of HIV can cause a cascade of events leading to the influx of inflammatory cells, glial cell activation, and neurotoxicity.

Animals↗
PubMed1998

Neuronal death induced by brain-derived human immunodeficiency virus type 1 envelope genes differs between demented and nondemented AIDS patients.

Human immunodeficiency virus type 1 (HIV-1) infection of the brain results in viral replication primarily in macrophages and microglia. Despite frequent detection of viral genome and proteins in the brains of AIDS patients with and without HIV dementia, only 20% of AIDS patients become demented. To investigate the role of viral envelope gene variation in the occurrence of dementia, we examined regions of variability in the viral envelope gene isolated from brains of AIDS patients. Brain-derived HIV-1 V1-V2 envelope sequences from seven demented and six nondemented AIDS patients displayed significant sequence differences between clinical groups, and by phylogenetic analysis, sequences from the demented group showed clustering. Infectious recombinant viruses containing brain-derived V3 sequences from both clinical groups were macrophagetropic, and viruses containing brain-derived V1, V2, and V3 sequences from both clinical groups spread efficiently in macrophages. In an indirect in vitro neurotoxicity assay using supernatant fluid from HIV-1-infected macrophages, recombinant viruses from demented patients induced greater neuronal death than viruses from nondemented patients. Thus, the HIV-1 envelope diversity observed in these patient groups appeared to influence the release of neurotoxic molecules from macrophages and might account in part for the variability in occurrence of dementia in AIDS patients.

AIDS Dementia Complex↗