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Biomedical subjects

David N Irani

Publications and source records attributed to David N Irani.

10 recordsLinked to original sources
PubMed2006

Cleavage of cystatin C in the cerebrospinal fluid of patients with multiple sclerosis.

OBJECTIVE: The diagnosis of multiple sclerosis (MS) can be challenging because of the lack of a specific diagnostic test. Recent advances in proteomics, however, offer new opportunities for biomarker discovery and the study of disease pathogenesis. METHODS: We analyzed cerebrospinal fluid (CSF) samples from 29 patients with MS or clinically isolated syndromes (CIS), 27 patients with transverse myelitis (TM), 50 patients with human immunodeficiency virus (HIV) infection, and 27 patients with other neurological diseases (ONDs) by surface-enhanced laser desorption/ionization time-of-flight mass spectroscopy. RESULTS: We found a unique protein of 12.5 kDa that was 100% specific for MS/CIS compared with TM or OND. Low levels of this protein were found in some patients with HIV infection. Tandem mass spectroscopy of a tryptic digest of this 12.5 kDa protein identified it as a cleavage product of full-length cystatin C (13.4 kDa), an important inhibitor of cysteine proteases including the cathepsins. Although total cystatin C levels in the MS patients was not different compared with controls, the patients with the highest 12.5/13.4 peak ratios also had the greatest cathepsin B inhibitory activity. INTERPRETATION: This suggests that cleavage of cystatin C may be an adaptive host response and may identify a subgroup of patients with MS.

Adolescent↗
PubMed2005

14-3-3 protein in CSF: an early predictor of SIV CNS disease.

In neurons, 14-3-3 proteins regulate diverse processes, including signal transduction, neurotransmitter production, and apoptosis by binding to target proteins, but the role 14-3-3 proteins play in the pathogenesis of central nervous system (CNS) disease remains unclear. To examine the relationship between presence of 14-3-3 protein in cerebrospinal fluid (CSF) and encephalitis in the SIV/macaque model of HIV CNS disease, CSF levels of 14-3-3 protein were measured by quantitative immunoblotting throughout infection in 6 SIV-infected pigtailed macaques. Beginning during asymptomatic infection and continuing until death, CSF levels of 14-3-3 were elevated in 4 of 6 SIV-infected animals. Animals with 14-3-3 protein in CSF had the highest viral loads in the CSF after acute infection and the highest levels of both viral RNA and protein in brain (p < 0.001). In contrast, the presence of 14-3-3 protein in CSF was not associated with CNS microglial/macrophage activation measured by quantitative immunohistochemical staining for CD68 (p = 0.13). CSF levels of 14-3-3 protein may be a valuable marker of early neuronal damage, CNS viral replication, and CNS disease progression in HIV-infected individuals.

14-3-3 Proteins↗
PubMed2004

Viral-induced spinal motor neuron death is non-cell-autonomous and involves glutamate excitotoxicity.

Neuroadapted Sindbis virus (NSV) is a neurotropic virus capable of inducing the death of spinal motor neurons in mice and rats. In this study we investigated the mechanisms that underlie NSV-induced motor neuron death. We found that many degenerating spinal motor neurons were not infected directly with NSV, suggesting that bystander cell death occurs. An excitotoxic mechanism was confirmed when blockade of calcium-permeable AMPA receptors attenuated motor neuron death both in vitro and in vivo. Blockade of astroglial glutamate reuptake potentiated NSV-induced motor neuron loss in vivo, suggesting that astrocyte-mediated removal of perisynaptic glutamate is important in limiting NSV-induced excitotoxic injury. Astroglial glutamate transport was reduced markedly in the spinal cord during NSV infection, in advance of motor neuron injury in susceptible mice. In contrast, we found 5.6-fold elevated glutamate uptake in the spinal cords of mice resistant to NSV-induced paralysis. Likewise, minocycline markedly increased spinal cord glutamate transport and protected mice from NSV-induced motor neuron death. These studies suggest that NSV infection triggers a cascade of events in the spinal cord resulting in impaired astrocytic glutamate transport and excitotoxic injury of motor neurons mediated via calcium-permeable AMPA receptors. Similar changes may occur in other motor neuron disorders such as amyotrophic lateral sclerosis or West Nile Virus-induced poliomyelitis, suggesting a common tissue injury pathway.

Alphavirus Infections↗
PubMed2004

Glutamate receptor antagonists protect from virus-induced neural degeneration.

Neuronal damage during acute viral encephalomyelitis can result directly from virus infection or indirectly from the host immune response to infection. In neurodegenerative diseases and stroke, neuronal death also can result from excess release of excitatory amino acid neurotransmitters, such as glutamate. To determine the role of glutamate excitotoxicity in fatal alphavirus-induced paralytic encephalomyelitis, we treated mice infected with neuroadapted Sindbis virus (NSV) with antagonists of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) subtypes of glutamate receptors. Both apoptotic and necrotic neurons in the hippocampus were decreased in animals treated with MK-801, an NMDA receptor antagonist, or GYKI-52466, an AMPA receptor antagonist. However, only AMPA receptor blockade prevented damage to spinal cord motor neurons and protected mice from paralysis and death due to NSV infection. Protection was not caused by altered virus replication because treatment did not affect virus distribution and actually delayed virus clearance. These results provide evidence that NSV infection activates neurotoxic pathways that result in aberrant glutamate receptor stimulation and neuronal damage. Furthermore, AMPA receptor-mediated motor neuron death is an important contributor to paralysis and mortality in acute alphavirus-induced encephalomyelitis.

Alphavirus Infections↗
PubMed2003

Human embryonic germ cell derivatives facilitate motor recovery of rats with diffuse motor neuron injury.

We have investigated the potential of human pluripotent cells to restore function in rats paralyzed with a virus-induced motor neuronopathy. Cells derived from embryonic germ cells, termed embryoid body-derived (EBD) cells, introduced into the CSF were distributed extensively over the rostrocaudal length of the spinal cord and migrated into the spinal cord parenchyma in paralyzed, but not uninjured, animals. Some of the transplanted human cells expressed the neuroglial progenitor marker nestin, whereas others expressed immunohistochemical markers characteristic of astrocytes or mature neurons. Rare transplanted cells developed immunoreactivity to choline acetyltransferase (ChAT) and sent axons into the sciatic nerve as detected by retrograde labeling. Paralyzed animals transplanted with EBD cells partially recovered motor function 12 and 24 weeks after transplantation, whereas control animals remained paralyzed. Semi-quantitative analysis revealed that the efficiency of neuronal differentiation and extension of neurites could not account for the functional recovery. Rather, transplanted EBD cells protected host neurons from death and facilitated reafferentation of motor neuron cell bodies. In vitro, EBD cells secrete transforming growth factor-alpha (TGF-alpha) and brain-derived neurotrophic factor (BDNF). Neutralizing antibodies to TGF-alpha and to BDNF abrogated the ability of EBD-conditioned media to sustain motor neuron survival in culture, whereas neutralizing antibodies to BDNF eliminated the axonal outgrowth from spinal organotypics observed with direct coculture of EBD cells. We conclude that cells derived from human pluripotent stem cells have the capacity to restore neurologic function in animals with diffuse motor neuron disease via enhancement of host neuron survival and function.

Alphavirus Infections↗
PubMed2003

The classic and variant forms of Creutzfeldt-Jakob disease.

Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, are a group of progressive neurodegenerative disorders that affect both animals and humans. These diseases take part of their name from a striking and common neuropathological feature: spongiform ("sponge-like") degeneration of the brain. As the name also implies, TSEs can literally be transmitted from one host to another much like any other infectious disease. In these situations, however, symptoms may take months or years to appear in the recipient host. Otherwise, TSEs either develop spontaneously or rarely arise through genetic mutation and therefore occur as familial disorders. Regardless of their origin, all TSEs progress over a period of months inevitably leading to the death of the affected individual. From a neuropsychiatric perspective, it is notable that the newly identified variant form of Creutzfeldt-Jakob disease (vCJD) typically occurs in younger adults causing prominent psychiatric and/or behavioral abnormalities as important early manifestations of disease. This has forced a heightened awareness of vCJD among mental health professionals throughout the United Kingdom where the disorder occurs. Relevant features of both the classic and variant forms of Creutzfeldt-Jakob disease (CJD) will be reviewed.

Animals↗
PubMed2002

West Nile virus encephalitis in the United States.

West Nile virus appeared in New York City in 1999 and has subsequently spread over the eastern United States. The mode of transport across the Atlantic Ocean is unknown. During the past decade, encephalitis has been a more prominent feature of West Nile virus infection in Europe, the Middle East, and the United States, suggesting the emergence of more neurovirulent strains. The rapid spread of the virus and more serious disease caused by the virus have spurred vaccine development.

Animals↗
PubMed2002

BCL-2 and BAX protect adult mice from lethal Sindbis virus infection but do not protect spinal cord motor neurons or prevent paralysis.

Cellular proteins that regulate apoptotic cell death can modulate the outcome of Sindbis virus (SV) encephalitis in mice. Both endogenous and overexpressed BCL-2 and BAX proteins protect newborn mice from fatal SV infection by blocking apoptosis in infected neurons. To determine the effects of these cellular factors on the course of infection in older animals, a more neurovirulent SV vector (dsNSV) was constructed from a viral strain that causes both prominent spinal cord infection with hind-limb paralysis and death in weanling mice. This vector has allowed assessment of the effects of BCL-2 and BAX on both mortality and paralysis in these hosts. Similar to newborn hosts, weanling mice infected with dsNSV encoding BCL-2 or BAX survived better than animals infected with control viruses. This finding indicates that BCL-2 and BAX both protect neurons that mediate host survival. Neither cellular factor, however, could suppress the development of hind-limb paralysis or prevent the degeneration of motor neurons in the lumbar spinal cord. Infection of BAX knockout mice with dsNSV demonstrated that endogenous BAX also enhances the survival of animals but has no effect on paralysis. These findings for the spinal cord are consistent with earlier data showing that dying lumbar motor neurons do not exhibit an apoptotic morphology. Thus, divergent cell death pathways are activated in different target populations of neurons during neurovirulent SV infection of weanling mice.

Alphavirus Infections↗
PubMed2001

Diagnosis and prevention of bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease.

An outbreak of bovine spongiform encephalopathy (BSE) arose in the United Kingdom as a result of prions entering and being recycled through the ruminant food chain. Humans have since developed a variant form of Creutzfeldt-Jakob disease (vCJD), also mostly in the United Kingdom, that occurs in younger individuals and causes prominent psychiatric and/or behavioral manifestations early in disease. Laboratory studies now provide strong evidence that the causative agent of BSE in cattle and vCJD in humans share a common origin. Because of a lack of information regarding the incubation period of vCJD and the number of people who may have been exposed, the future scope of this disease remains unknown. Control of the current and any future outbreaks in cattle requires strict measures to prevent contamination of the animal food chain with prions of any species. Prevention of human exposure mandates the avoidance of neural tissue in all human foods.

Animals↗