Biomedical subjects
D W Kimberlin
Publications and source records attributed to D W Kimberlin.
Herpes simplex viruses.
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Human herpesviruses 6 and 7: identification of newly recognized viral pathogens and their association with human disease.
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Human herpesvirus-6: neurologic implications of a newly-described viral pathogen.
Discovered only 12 years ago, human herpesvirus-6 (HHV-6) has been associated with central nervous system (CNS) findings such as febrile seizures, encephalitis, meningitis, and possibly multiple sclerosis. These manifestations have been reported in both immunocompetent and immunocompromised individuals. The applications of such sophisticated laboratory tools as polymerase chain reaction, in situ hybridization, immunohistochemical staining, and representational difference analysis have expanded knowledge of the spectrum of CNS disease attributable to HHV-6 while delineating pathogenic mechanisms of both primary HHV-6 infection and reactivation from latency. This article reviews existing knowledge of the CNS manifestations of HHV-6, focusing on both clinical aspects of HHV-6 infection and its pathogenesis on neurologic diseases.
Treatment of viral infections during pregnancy and the neonatal period.
Over the past 15 years, successful antiviral therapy of herpes simplex virus (HSV) infection has emerged with safe therapeutics. Despite the major impact of acyclovir on the severity of HSV infection, morbidity and mortality from neonatal herpes exist. The development of therapeutics that impact on the natural history of HIV and AIDS just now are being realized, nearly a decade after the first beneficial effects of therapy were reported. Early investigations of antiviral agents in pregnant women and children must occur more promptly as the field of antiviral therapy advances. Improved therapeutics are likely to emerge over the next decade for both pregnant women and their offspring.
Application of the polymerase chain reaction to the diagnosis and management of neonatal herpes simplex virus disease. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group.
Cerebrospinal fluid (CSF) specimens from 77 neonates with herpes simplex virus (HSV) disease were evaluated retrospectively by polymerase chain reaction (PCR). Samples were collected from 202 infants enrolled in a National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group trial that compared vidarabine with acyclovir for the treatment of neonatal HSV infection. HSV DNA was detected in the CSF of 26 (76%) of 34 infants with CNS disease, in 13 (93%) of 14 infants with disseminated infection, and in 7 (24%) of 29 with skin, eye, or mouth (SEM) involvement. One of the 7 PCR-positive SEM patients subsequently developed severe neurologic impairment. Eighteen (95%) of 19 infants with positive CSF PCR results after the completion of 10 days of antiviral therapy experienced significant morbidity or mortality. Application of PCR to neonatal HSV disease may provide additional information on which clinical decisions may be based, although its diagnostic utility outside the research setting is unproven.
Antiviral resistance: mechanisms, clinical significance, and future implications.
The increased awareness of antiviral resistance over the past decade has paralleled the development of new antiviral agents. While such resistant viral isolates are of clinical significance primarily in immunocompromised individuals, the development and transmission of such mutants have been reported in immunocompetent persons as well. As antiviral agents are increasingly utilised by the clinician, the incidence of such occurrences is likely to increase. Issues relating to mechanisms of antiviral resistance, clinical manifestations and significance of resistance, and implications for future antiviral development and utilisation are reviewed in this article. Viruses that are discussed include herpes simplex virus, varicella-zoster virus, cytomegalovirus, influenza A virus, and human immunodeficiency virus.
Protein synthesis-dependent induction of interleukin-1 beta by lipopolysaccharide is inhibited by dexamethasone via mRNA destabilization in human astroglial cells.
Dexamethasone inhibits lipopolysaccharide-induced synthesis of the cytokine, interleukin-1 beta, in cerebrospinal fluid of patients with bacterial meningitis. Along with monocytes, astrocytes are capable of producing lipopolysaccharide-induced interleukin-1 beta in the central nervous system. The objective of this study was to investigate the induction of interleukin-1 beta mRNA by lipopolysaccharide, and the inhibition of this process by dexamethasone, in human astrocytes using the astrocytoma cell line U-373MG as a model system. Dexamethasone-mediated inhibition of induction of interleukin-1 beta mRNA by lipopolysaccharide required a functional glucocorticoid receptor. In contrast to monocytes, lipopolysaccharide induction of interleukin-1 beta mRNA in U-373MG cells required de novo protein synthesis. Dexamethasone also had no effect on lipopolysaccharide-induced interleukin-1 beta transcriptional initiation in U-373MG cells. U-373MG cells were similar to monocytes, however, with respect to the ability of dexamethasone to decrease interleukin-1 beta mRNA half-life. These findings demonstrate that the mode of lipopolysaccharide induction of interleukin-1 beta mRNA, and inhibition of this process by dexamethasone, can vary in different cell types.
Antiviral resistance--an emerging problem.
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Molecular mechanisms of antiviral resistance.
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Assays for antiviral drug resistance.
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Research initiatives in studies of antiviral resistance and consensus points and recommendations.
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Models of antiviral resistance.
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Antiviral resistance in clinical practice.
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Modulation of expression of genes involved in the inflammatory response by lipopolysaccharide and temperature in cultured human astroglial cells.
In bacterial sepsis and meningitis, large concentrations of interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) correlate directly with morbidity and mortality. This laboratory has reported previously that elevated temperature in the physiologic range is associated with down regulation of IL-1 beta and TNF alpha expression in cultured astroglia after lipopolysaccharide (LPS) stimulation. To further investigate the role of elevated temperature in the CNS inflammatory response, the effects of LPS and elevated temperature on the expression of genes that participate in the inflammatory response were determined in cultured transformed human fetal astrocytes and in an astrocytoma cell line. The effect of physiologic temperature elevation on cytokine concentrations in cerebrospinal fluid (CSF) was also investigated in a rabbit meningitis model. The findings indicate that astrocytes express a wide variety of cytokines, growth factors, growth factor receptors, and other genes that could play important roles in CNS inflammation. Furthermore, temperature elevation in the febrile range can lead to alterations in the patterns of expression of many genes involved in the inflammatory response of these cells.