PubMed Health⌕ Search

Biomedical subjects

Alan C Jackson

Publications and source records attributed to Alan C Jackson.

At least 19 recordsLinked to original sources
PubMed2006

Comparative pathogenesis of recombinant rabies vaccine strain SAD-L16 and SAD-D29 with replacement of Arg333 in the glycoprotein after peripheral inoculation of neonatal mice: less neurovirulent strain is a stronger inducer of neuronal apoptosis.

Less neurovirulent strains of rabies virus have been recognized to be stronger inducers of neuronal apoptosis in vitro than more neurovirulent strains, but few studies have clarified whether this also applies in vivo. A comparative study was performed in two-day-old ICR mice inoculated in a hindlimb thigh muscle with recombinant rabies virus vaccine strain SAD-L16 (L16) or SAD-D29 (D29), which contains an attenuating substitution of Arg333 in the rabies virus glycoprotein. Histopathological and immunohistochemical analyses of brains were performed at early daily time points and in moribund animals. Both viruses caused progressive limb weakness; mortality with L16 was 100% at day 7 post-inoculation (p.i.) and 75% at 17 days p.i. for D29 and Kaplan-Meyer survival curves were significantly different. L16 spread to the brain more quickly than D29, and both viruses produced multifocal lesions in the brainstem and cerebellum associated with inflammatory changes and neuronal apoptosis. There was more disseminated involvement of the brain and many more infected neurons in L16 infection, particularly in the neostriatum, hippocampus, and cerebral cortex. Both viruses induced neuronal apoptosis, which was most marked in the brainstem tegmentum and internal granular layer of the cerebellum. In light of the lower burden of infection and smaller number of neurons infected with D29, this less virulent virus was a stronger inducer of neuronal apoptosis than the more virulent L16. These findings support previous in vitro studies indicating that there is an inverse relationship between pathogenicity and apoptosis. Induction of apoptosis, which is an innate mechanism in which the host restricts viral spread, may contribute to severe clinical neurological disease when there is viral invasion into the central nervous system.

Animals↗
PubMed2006

Expression of Toll-like receptor 3 in the human cerebellar cortex in rabies, herpes simplex encephalitis, and other neurological diseases.

There is recent in vitro evidence that human neurons express the innate immune response receptor, Toll-like receptor-3 (TLR-3), and that expression is enhanced in viral infections. The authors examined the immunohistochemical expression of TLR-3 in the cerebellar cortex of postmortem human brains. Purkinje cells were found to express TLR-3 in all cases of rabies (4 of 4) and herpes simplex encephalitis (2 of 2) as well as in cases of amyotrophic lateral sclerosis (1 of 2), stroke (1 of 2), and Alzheimer's disease (3 of 3). In cases of viral infection, direct viral infection was not necessary for enhanced neuronal TLR-3 expression, suggesting that soluble factors likely play an important role in inducing TLR-3 expression. In addition to neurons, occasional Bergmann glia expressed TLR-3 in some cases. This study has provided evidence that human brain neurons can express TLR-3 in vivo and suggests that neurons may play an important role in initiating an inflammatory reaction in a variety of neurological diseases.

Adolescent↗
PubMed2006

Failure of therapeutic coma and ketamine for therapy of human rabies.

The recent success in treating a human rabies patient in Milwaukee prompted the use of a similar therapeutic approach in a 33-year-old male Thai patient who was admitted in the early stages of furious rabies. He received therapeutic coma with intravenous diazepam and sodium thiopental to maintain an electroencephalographic burst suppression pattern, which was maintained for a period of 46 h, as well as intravenous ketamine (48 mg/kg/day) as a continuous infusion and ribavirin (48 to 128 mg/kg/day) via a nasogastric tube. He never developed rabies virus antibodies and he died on his 8th hospital day. At least three other patients have been treated unsuccessfully with a similar therapeutic approach. Because of the lack of a clear scientific rationale, high associated costs, and potential complications of therapeutic coma, the authors recommend caution in taking this approach for the therapy of rabies outside the setting of a clinical trial. More experimental work is also needed in cell culture systems and in animal models of rabies in order to develop effective therapy for human rabies.

Adult↗
PubMed2006

Rabies: new insights into pathogenesis and treatment.

PURPOSE OF REVIEW: The occurrences of transmission of rabies virus by organ and vascular conduit transplantation, and recovery from rabies by a patient in Wisconsin, will be addressed. Perspectives will be given on the prevention of rabies by organ transplantation and on the management of patients with rabies. RECENT FINDINGS: In 2004 transplantation of organs and a vascular conduit was responsible for the transmission of rabies virus, resulting in seven fatal cases of rabies in the USA and Germany. Likely infectious rabies virus was present within nerves of the transplanted organs and arterial segment and productive infection developed in the immunosuppressed recipients. In 2004 a young patient, who did not receive postexposure rabies prophylaxis after a bat bite, survived rabies in Wisconsin. The importance of therapy she received on her favorable outcome remains unknown. SUMMARY: Recent transmissions of rabies virus from organ-transplantation donors highlight the importance of clinical recognition of rabies. Laboratory screening of potential donors for rabies prior to organ transplantation would be associated with logistical problems and serious consequences due to false-positive results. The survival of a patient with rabies has offered hope that effective therapy of rabies may become a reality in the future.

Animals↗
PubMed2006

Rabies virus infection of primary neuronal cultures and adult mice: failure to demonstrate evidence of excitotoxicity.

Cultures derived from the cerebral cortices and hippocampi of 17-day-old mouse fetuses infected with the CVS strain of rabies virus showed loss of trypan blue exclusion, morphological apoptotic features, and activated caspase 3 expression, indicating apoptosis. The NMDA (N-methyl-D-aspartate acid) antagonists ketamine (125 microM) and MK-801 (60 microM) were found to have no significant neuroprotective effect on CVS-infected neurons, while the caspase inhibitor Ac-Asp-Glu-Val aspartic acid aldehyde (25 microM) exerted a marked neuroprotective effect. Glutamate-stimulated increases in levels of intracellular calcium were reduced in CVS-infected hippocampal neurons. Ketamine (120 mg/kg of body weight/day intraperitoneally) given to CVS-infected adult mice produced no beneficial effects. We have found no supportive evidence that excitotoxicity plays an important role in rabies virus infection.

Animals↗
PubMed2005

Overlap of pathology in paralytic rabies and axonal Guillain-Barre syndrome.

We describe clinical and pathological features of a case of paralytic rabies with acute axonal neuropathy that closely resembled axonal Guillain-Barre syndrome. This case emphasizes that there is overlap of both clinical and pathological features in paralytic rabies and axonal Guillain-Barre syndrome. These findings raise the possibility that infectious and autoimmune etiologies can lead to similar morphological changes in the nerves.

Campylobacter jejuni↗
PubMed2005

Comparative pathogenesis of the SAD-L16 strain of rabies virus and a mutant modifying the dynein light chain binding site of the rabies virus phosphoprotein in young mice.

Recent reports have suggested that rabies virus phosphoprotein (P) interaction with dynein minus-end-directed microtubule motor proteins may be of fundamental importance in the axonal transport of rabies virus. A deletion of 11 amino acids was introduced into recombinant rabies virus SAD-L16 (L16) that modified the dynein light chain (LC8) binding site of the rabies virus P, producing mutant L-DeltaP11. This mutant is a useful tool for determining the role of P-LC8 interaction in viral spread and pathogenesis. Seven-day-old ICR mice were inoculated into a hindlimb thigh muscle with L16 or L-DeltaP11. Histopathological and immunohistochemical analyses of their brains were performed at serial time points in order to determine the pattern of viral spread. L16 spread to the brain and caused a severe encephalitis with apoptotic neuronal changes. L-DeltaP11 infected specific brain areas (brainstem and hippocampus) 1-2 days later than L16 and involved a smaller number of neurons in some brain regions. However, the neuronal apoptotic changes produced by both viruses were similar in most brain regions. Following peripheral inoculation, deletions modifying the LC8 binding site had an effect on delaying viral spread, but did not significantly alter the pattern of rabies virus encephalitis. The precise role of the rabies virus P-dynein interaction in the axonal transport of rabies virus, particularly the importance of this interaction during natural infection, merits further study.

Animals↗
PubMed2005

Glycoprotein-mediated induction of apoptosis limits the spread of attenuated rabies viruses in the central nervous system of mice.

Induction of apoptosis by rabies virus (RV) has been reported to be associated with the expression of the glycoprotein (G), but inversely correlated with pathogenicity. To further delineate the association between the expression of the G and the induction of apoptosis, recombinant RVs with replacement of only the G gene were used to infect mice by the intracerebral route. Recombinant viruses expressing the G from attenuated viruses expressed higher level of the G and induced more apoptosis in mice than recombinant RV expressing the G from wild-type (wt) or pathogenic RV, demonstrating that it is the G gene that determines the level of G expression and, consequently, the induction of apoptosis. Likewise, recombinant viruses expressing the G from wt or pathogenic RV are more pathogenic in mice than those expressing G from attenuated RV, confirming the inverse correlation between RV pathogenicity and the induction of apoptosis. To investigate the mechanism by which induction of apoptosis attenuates viral pathogenicity, mice were infected with wt or attenuated RV by the intramuscular route. It was found that low doses of attenuated RV induced apoptosis in the spinal cord and failed to spread to the brain or produce neurological disease. On the other hand, apoptosis was not observed in the spinal cord of mice infected with the same doses of wt RV and the virus spread to various parts of the brain and induced fatal neurologic disease. These results suggest that glycoprotein-mediated induction of apoptosis limits the spread of attenuated rabies viruses in the central nervous system (CNS) of mice.

Animals↗
PubMed2005

Neuronal dysfunction and death in rabies virus infection.

Because morphologic changes in natural rabies are usually relatively mild, it is thought that the severe clinical disease with a fatal outcome must be due to neuronal dysfunction of rabies virus-infected neurons. The precise bases of this functional impairment are unknown, and current knowledge on electro-physiological alterations, effects on ion channels and neurotransmission, and neurotoxicity are reviewed. Rabies virus may induce neuronal death, possibly through apoptotic mechanisms. Neuronal apoptosis has been observed in vitro and also in vivo under particular experimental conditions. The relevance of neuronal apoptosis in these situations to natural rabies has not yet been fully elucidated.

Animals↗
PubMed2005

Recombinant rabies virus vaccine strain SAD-l16 inoculated intracerebrally in young mice produces a severe encephalitis with extensive neuronal apoptosis.

Seven-day-old ICR mice were infected by intracerebral inoculation with recombinant rabies virus vaccine strain SAD-L16. Infected mice developed severe and fatal encephalitis with rabies virus-infected neurons in widespread regions of the brain. There was extensive neuronal death with predominant features of apoptosis, as assessed by light and electron microscopy, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining, and immunohistochemical staining for activated caspase-3. Although SAD-L16 is a neuroattenuated rabies virus, it is fully capable of spreading efficiently and inducing widespread neuronal apoptosis in the immature mouse brain.

Animals↗
PubMed2004

Neuronal apoptosis in immunodeficient mice infected with the challenge virus standard strain of rabies virus by intracerebral inoculation.

The challenge virus standard-11 strain (CVS) of fixed rabies virus produces neuronal apoptosis in widespread areas of the brain of mice after intracerebral inoculation. The role of the adaptive immune response in producing neuronal apoptosis in this model was evaluated by comparing the infections in adult C57BL/6J mice with nude mice (T cell deficient) and Rag1 mice (T and B cell deficient). Both strains of immunodeficient mice showed very similar clinical disease and neuropathological findings, including marked neuronal apoptosis. The adaptive immune response is unlikely of fundamental importance in producing neuronal apoptosis in the brains of mice in this model.

Animals↗
PubMed2003

Rabies virus infection: an update.

There are still many unanswered questions in the pathogenesis of rabies, but recent progress has been made. During most of the long incubation period of rabies, the virus likely remains close the site of viral entry. Centripetal spread to the central nervous system and spread within the central nervous system occur by fast axonal transport. Neuronal dysfunction, rather than neuronal death, is responsible for the clinical features and fatal outcome in natural rabies. Recent work has changed our perspective on the ecology of rabies virus under particular circumstances in certain species. Hopefully, advances in our understanding of rabies pathogenesis will lead to advances in the treatment of this dreaded disease.

Animals↗
PubMed2002

Management of rabies in humans.

Rabies is a fatal disease in humans, and, to date, the only survivors of the disease have received rabies vaccine before the onset of illness. The approach to management of the rabies normally should be palliative. In unusual circumstances, a decision may be made to use an aggressive approach to therapy for patients who present at an early stage of clinical disease. No single therapeutic agent is likely to be effective, but a combination of specific therapies could be considered, including rabies vaccine, rabies immunoglobulin, monoclonal antibodies, ribavirin, interferon-alpha, and ketamine. Corticosteroids should not be used. As research advances, new agents may become available in the future for the treatment of human rabies.

Adrenal Cortex Hormones↗