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Biomedical subjects

W I Lipkin

Publications and source records attributed to W I Lipkin.

At least 19 recordsLinked to original sources
PubMed2006

Use of a short fragment of the C-terminal E gene for detection and characterization of two new lineages of dengue virus 1 in India.

Here we propose the use of a 216-nucleotide fragment located in the carboxyl terminus of the E gene (E-COOH) and a pairwise-based comparison method for genotyping of dengue virus 1 (DENV-1) strains. We have applied this method to the detection and characterization of DENV-1 in serum samples from travelers returning from the tropics. The results obtained with the typing system correlate with the results obtained by comparison of the sequences of the entire E gene of the strains. The approach demonstrates utility in plotting the distribution and circulation of different genotypes of DENV-1 and also suggests the presence of two new clades of Indian strains. The integration of the method with an online database and a typing characterization tool enhances its strength. Additionally, the analysis of the complete E gene of DENV-1 strains suggested the occurrence of a nondescribed recombination event in the China GD23-95 strain. We propose the use of this methodology as a tool for real-time epidemiological surveillance of dengue virus infections and their pathogenesis.

DNA, Viral↗
PubMed2006

Endoplasmic reticulum stress and neurodegeneration in rats neonatally infected with borna disease virus.

Borna disease virus infection of neonatal rats results in a characteristic behavioral syndrome and apoptosis of subsets of neurons in the hippocampus and cerebellum (neonatal Borna disease [NBD]). The cellular mechanisms leading to neurodevelopmental damage in NBD have not been fully elucidated. Insights into this model may have general implications for understanding the pathogenesis of virus-associated neurodevelopmental damage. Here we report the presence of endoplasmic reticulum (ER) stress markers and activation of the unfolded protein response in the NBD hippocampus and cerebellum. Specific findings included enhanced PERK-mediated phosphorylation of eif2alpha and concomitant regulation of ATF4 translation; IRE1-mediated splicing of XBP1 mRNA; and cleavage of the ATF6 protein in NBD rat brains. We found evidence for regional and cell type-specific divergence in the expression of ER stress-induced proapoptotic and quality control signals. Our results demonstrate that ER stress induction in death-susceptible Purkinje neurons in NBD is associated with the expression of the proapoptotic molecule CHOP in the absence of compensatory expression of the ER quality control molecules Bip and protein disulfide isomerase. In contrast, ER stress in death-resistant astrocytes is associated with complementary expression of CHOP and ER quality control signals. These results implicate an imbalance between ER stress-mediated apoptosis and survival signaling as a critical determinant of neural cell fate in NBD.

Animals↗
PubMed2005

Molecular identification of adenoviruses in clinical samples by analyzing a partial hexon genomic region.

Here we present a system for adenovirus detection and genotyping based on PCR amplification and phylogenetic analysis of a conserved hexon gene fragment. The system was validated using 157 sequences (86 previously typed and 71 clinical samples) and correctly identified species and serotype in 100% and 84% of sequences, respectively. Known associations between specific serotypes and clinical syndromes are verified. Possible new associations are described to allow further independent testing.

Adenovirus Infections, Human↗
PubMed2005

Molecular identification of mumps virus genotypes from clinical samples: standardized method of analysis.

A sensitive nested reverse transcription-PCR assay, targeting a short fragment of the gene encoding the small hydrophobic protein (SH gene), was developed to allow rapid characterization of mumps virus in clinical samples. The sensitivity and specificity of the assay were established using representative genotypes A, B, C, D, E, and F. Mumps virus RNA was characterized directly from cerebrospinal fluid (CSF) samples and in extracts of mumps virus isolates from patients with various clinical syndromes. Direct sequencing of products and subsequent phylogenetic analysis enabled genetic classification. A simple web-based system of sequence analysis was established. The study also allowed characterization of mumps virus strains from Argentina as part of a new subgenotype. This PCR assay for characterization of mumps infections coupled to a web-based analytical program provides a rapid method for identification of known and novel strains.

Amino Acid Sequence↗
PubMed2004

Neurotoxic effects of postnatal thimerosal are mouse strain dependent.

The developing brain is uniquely susceptible to the neurotoxic hazard posed by mercurials. Host differences in maturation, metabolism, nutrition, sex, and autoimmunity influence outcomes. How population-based variability affects the safety of the ethylmercury-containing vaccine preservative, thimerosal, is unknown. Reported increases in the prevalence of autism, a highly heritable neuropsychiatric condition, are intensifying public focus on environmental exposures such as thimerosal. Immune profiles and family history in autism are frequently consistent with autoimmunity. We hypothesized that autoimmune propensity influences outcomes in mice following thimerosal challenges that mimic routine childhood immunizations. Autoimmune disease-sensitive SJL/J mice showed growth delay; reduced locomotion; exaggerated response to novelty; and densely packed, hyperchromic hippocampal neurons with altered glutamate receptors and transporters. Strains resistant to autoimmunity, C57BL/6J and BALB/cJ, were not susceptible. These findings implicate genetic influences and provide a model for investigating thimerosal-related neurotoxicity.

Animals↗
PubMed2001

Infectious and immune factors in the pathogenesis of neurodevelopmental disorders: epidemiology, hypotheses, and animal models.

Both genetic and environmental factors contribute to the pathogenesis of a wide variety of neurodevelopmental disorders, including autism, mental retardation, and schizophrenia. Some heritable disorders approach 100% penetrance; nonetheless, even in these disorders, subtle aspects of clinical disease expression may be influenced by the environment. In other disorders with genetic influences, exogenous factors, and the timepoint(s) during nervous system development at which they are introduced, modulate expression of disease. Elucidation of the mechanisms guiding this intricate interplay between host response genes, environmental agents, and the neurodevelopmental context within which these interactions occur, is necessary to understand the continuum of clinical outcomes. This chapter will review the evidence that infectious and immune factors may contribute to the pathogenesis of neurodevelopmental disorders, describe an animal model of neurodevelopmental disorders based upon viral infection, identify processes by which neural circuitry may be compromised, and outline areas for future research.

Animals↗
PubMed2001

Borna disease virus infection of adult and neonatal rats: models for neuropsychiatric disease.

Animal models provide unique opportunities to explore interactions between host and environment. Two models have been established based on Borna disease virus infection that provide new insights into mechanisms by which neurotropic agents and/or immune factors may impact developing or mature CNS circuitry to effect complex disturbances in movement and behavior. Note in press: Since this chapter was submitted, several manuscripts have been published that extend findings reported here and support the relevance of BDV infections of neonatal Lewis rats as models for investigating mechanisms of neurodevelopmental damage in autism. Behavioral abnormalities, including disturbed play behavior and chronic emotional overactivity, have been described by Pletnikov et al. (1999); inhibition of responses to novel stimuli were described by Hornig et al. (1999); loss of Purkinje cells following neonatal BDV infection has been demonstrated by Eisenman et al. (1999), Hornig et al. (1999), and Weissenböck et al. (2000); and alterations in cytokine gene expression have been reported by Hornig et al. (1999), Plata-Salaman et al. (1999) and Sauder et al. (1999).

Animals↗
PubMed2001

Bornavirus tropism and targeted pathogenesis: virus-host interactions in a neurodevelopmental model.

Animal models provide unique opportunities to explore interactions between host and environment. Two models have been established based on Bornavirus infection that provide new insights into mechanisms by which neurotropic agents and/or immune factors may impact developing or mature CNS circuitry to effect complex disturbances in movement and behavior. Distinct losses in DA pathways in the adult infection model, and the associated dramatic movement disorder that accompanies it, make it an intriguing model for tardive dyskinesia and dystonic syndromes. The neuropathologic, physiologic, and neurobehavioral features of BDV infection of neonates indicate that it not only provides a useful model for exploring the mechanisms by which viral and immune factors may damage developing neurocircuitry, but also has significant links to the range of biologic, neurostructural, locomotor, cognitive, and social deficits observed in serious neuropsychiatric illnesses such as autism.

Animals↗
PubMed2001

Borna disease virus and neuropsychiatric disease--a reappraisal.

Despite progress in understanding the molecular biology and pathobiology of Borna disease virus, its epidemiology and role in human disease remain controversial. The challenges encountered in this field are a paradigm for the investigation of diseases potentially linked to complex host-microorganism interactions.

Animals↗
PubMed2001

Absence of echovirus sequences in brain and spinal cord of amyotrophic lateral sclerosis patients.

The role of enteroviruses in pathogenesis of amyotrophic lateral sclerosis (ALS) is controversial. A recent study, based on reverse transcription-polymerase chain reaction (RT-PCR) analysis of spinal cord, reported identification of a novel echovirus in 15 of 17 French subjects with ALS and only 1 of 29 subjects with other neurologic diseases. We established a real-time RT-PCR method based on this novel echovirus sequence and used this method and that previously employed for analysis of the French subjects to determine the prevalence of echoviral sequences in spinal cord and motor cortex of sporadic ALS subjects from the United States. No echoviral sequences were found in 20 spinal cord and 10 motor cortex samples from autopsy-confirmed cases of ALS or 13 spinal cord and 5 motor cortex samples from subjects with no motor neuron disease.

Adult↗
PubMed2000

Neurotrophic factor expression after CNS viral injury produces enhanced sensitivity to psychostimulants: potential mechanism for addiction vulnerability.

Hypothesized risk factors for psychostimulant, amphetamine, and cocaine abuse include dopamine (DA) receptor polymorphisms, HIV infection, schizophrenia, drug-induced paranoias, and movement disorders; however, the molecular, cellular, and biochemical mechanisms that predispose to drug sensitivity or drive the development of addiction are incompletely understood. Using the Borna disease rat, an animal model of viral-induced encephalopathy wherein sensitivity to the locomotor and stereotypic behavioral effects of d-amphetamine and cocaine is enhanced (Solbrig et al., 1994, 1998), we identify a specific neurotrophin expression pattern triggered by striatal viral injury that increases tyrosine hydroxylase activity, an early step in DA synthesis, to produce a phenotype of enhanced amphetamine sensitivity. The reactive neurotrophin pattern provides a molecular framework for understanding how CNS viral injury, as well as other CNS adaptations producing similar growth factor activation profiles, may influence psychostimulant sensitivity.

Animals↗
PubMed2000

Ribavirin inhibits West Nile virus replication and cytopathic effect in neural cells.

West Nile virus (WNV) is an emerging mosquito-borne pathogen that was reported for the first time in the Western hemisphere in August 1999, when an encephalitis outbreak in New York City resulted in 62 clinical cases and 7 deaths. WNV, for which no antiviral therapy has been described, was recently recovered from a pool of mosquitoes collected in New York City. In anticipation of the recurrence of WNV during the summer of 2000, an analysis was made of the efficacy of the nucleoside analogue ribavirin, a broad-spectrum antiviral compound with activity against several RNA viruses, for treatment of WNV infection. High doses of ribavirin were found to inhibit WNV replication and cytopathogenicity in human neural cells in vitro.

Antiviral Agents↗
PubMed2000

Detection of West Nile virus sequences in cerebrospinal fluid.

We have established a sensitive and specific real-time PCR method for detection of West Nile virus. Analysis of specimens obtained during the 1999 New York outbreak indicated the presence of viral sequences In cerebrospinal fluid of all of four Individuals with fatal outcomes, and in only one of four who survived.

Adolescent↗
PubMed2000

Microglial activation and neuronal apoptosis in Bornavirus infected neonatal Lewis rats.

Lewis rats neonatally infected with Borna disease virus have a behavioral syndrome characterized by hyperactivity, movement disorders, and abnormal social interactions. Virus is widely distributed in brain; however, neuropathology is focused in dentate gyrus, cerebellum, and neocortex where granule cells, Purkinje cells and pyramidal cells are lost through apoptosis. Although a transient immune response is present, its distribution does not correlate with sites of damage. Neuropathology is instead colocalized with microglial proliferation and expression of MHC class I and class II, ICAM, CD4 and CD8 molecules. Targeted pathogenesis in this system appears to be linked to microglial activation and susceptibility of specific neuronal populations to apoptosis rather than viral tropism or virus-specific immune responses.

Animals↗
PubMed2000

Expression and characterization of the Borna disease virus polymerase.

Borna disease virus is the prototype of a new family, Bornaviridae, within the order Mononegavirales, that is characterized by nuclear transcription, splicing, low level replication, and neurotropism. The products of five open reading frames predicted from the genomic sequence have been confirmed; however, expression of the sixth, corresponding to the putative viral polymerase (L), has not been demonstrated. Here, we describe expression and characterization of a 190-kDa protein proposed to represent L. Expression of this protein from the third transcription unit of the viral genome is dependent on a splicing event that fuses a small upstream open reading frame in frame with the larger downstream continuous open reading frame. The protein is detected by serum antibodies from infected rats and is present in the nucleus, where it colocalizes with the phosphoprotein. L is also shown to be phosphorylated by cellular kinases and to interact with the viral phosphoprotein in coimmunoprecipitation studies. These findings are consistent with the identity of the 190-kDa protein as the viral polymerase and provide insights and describe reagents that will be useful for Bornavirus molecular biology and pathobiology.

Amino Acid Sequence↗
PubMed1999

Genetic analysis of West Nile New York 1999 encephalitis virus.

Analysis of the genome of the flavivirus responsible for the 1999 New York City encephalitis epidemic cloned from human brain by reverse-transcription polymerase chain reaction Indicates its identity as a lineage I West Nile virus (WNV; WNV-NY1999) closely related to WNVs previously isolated In the Middle East.

Amino Acid Sequence↗