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W F Hickey

Publications and source records attributed to W F Hickey.

At least 37 records · Page 2Linked to original sources
PubMed1999

Fatal poisoning from liquid dimethylmercury: a neuropathologic study.

Since ancient times, mercury has been recognized as a toxic substance. Dimethylmercury, a volatile liquid organic mercury compound, is used by a small number of chemistry laboratories as a reference material in nuclear magnetic resonance spectroscopy. To our knowledge, dimethylmercury has been reported in only three cases of human poisoning, each proving fatal. Very small amounts of this highly toxic chemical can result in devastating neurological damage and death. We report the neuropathologic findings in a fatal case of dimethylmercury intoxication occurring in a laboratory researcher that resulted from a small accidental spill. We compare these findings to those reported in one previously reported fatal case of dimethylmercury poisoning, and to earlier reports of monomethylmercury poisoning, and discuss the clinicopathologic correlation.

Atrophy↗
PubMed1999

Inflammatory thoughts about glioma gene therapy.

Gene therapy for treatment of glioma often involves delivery of herpes simplex virus-1 thymidine kinase gene. A new study shows that this approach can induce chronic inflammation, and raises important questions about current adenoviral-based clinical trials (pages 1256-1263).

Adenoviridae↗
PubMed1998

Humoral immunity in the central nervous system of Lewis rats infected with Borna disease virus.

The aim of this study was to investigate the humoral immune response to Borna disease (BD) virus in the brain of experimentally infected Lewis rats. Abundant IgG was detected in BD-rat brain with isotype variation throughout infection. IgG was locally produced as indicated by an intact blood-brain barrier, Ig kappa light chain mRNA-containing cells in brain and accumulation of virus-specific antibodies in cerebrospinal fluid. Treatment with BD-rat serum altered viral gene expression in persistently infected cultured rat glioblastoma cells. These data suggest that antibodies, produced in the brain, may influence viral gene expression.

Animals↗
PubMed1998

Evolution of the immune response in the central nervous system following infection with Borna disease virus.

Borna disease virus infection of Lewis rats results in an immune-mediated disease associated with transient meningoencephalitis and persistent viral infection. In the acute phase of disease, perivascular immune cell infiltrates consisted of CD4 + and CD8 + T cells, macrophages and NK cells with peak expression of mRNAs encoding the cytokines IL1alpha, IL2, IL6, TNFalpha, and IFNgamma. In the chronic phase of disease, numbers of NK cells, B cells and activated microglia increased in the brain parenchyma with peak expression of IL4 mRNA. These data were consistent with a switch from a Th1-like, cellular immune response to a Th2-like, humoral immune response.

Animals↗
PubMed1998

Antigen-dependent intrathecal antibody synthesis in the normal rat brain: tissue entry and local retention of antigen-specific B cells.

The intrathecal Ab response to Ag introduced into the normal brain has not been fully explored. Involvement of Ag-specific, peripheral B cells in an intrathecal response was studied using a normal rat model of Ag infusion through an indwelling cannula into defined brain sites, while maintaining a functionally intact blood-brain barrier. Specific Ab was detected in serum and cerebrospinal fluid. The intrathecal response is first detectable at day 14. Isoelectric focusing of cerebrospinal fluid reveals banding patterns consistent with local Ab production. To increase Ag-specific, circulating peripheral lymphocytes available for trafficking to Ag-stimulated brain and for enhancing intrathecal Ab synthesis, rats were preimmunized peripherally. Subsequently, Ag or saline (control) was infused through the cannula. Under this protocol, intrathecal synthesis is detectable earlier (day 5 postinfusion). Immunohistochemical studies at the infusion site assessed Ag-specific B cells, T cells, and activated APCs. Rats receiving peripheral preimmunization followed by Ag into caudate nucleus have far greater numbers of these cells, including plasma cells, within the infusion site compared with saline controls. Results confirm previous indirect evidence of intrathecal Ab synthesis in normal rat brain and provide the first direct evidence for B cell trafficking across normal brain barriers plus retention at the Ag deposition site. Our studies indicate that the normal brain microenvironment supports development of Ag-directed humoral immunity. We propose that immune privilege in normal brain is characterized by down-regulation of cell-mediated but not Ab immune responses within the central nervous system.

Animals↗
PubMed1998

A common immunoregulatory locus controls susceptibility to actively induced experimental allergic encephalomyelitis and experimental allergic orchitis in BALB/c mice.

Previous studies have shown that differential susceptibility to actively induced experimental allergic encephalomyelitis (EAE) and experimental allergic orchitis (EAO) exists among various BALB/c substrains. Of eight substrains studied for EAE and 13 for EAO, BALB/cJ mice are phenotypically the most resistant to disease induction. Resistance to both diseases is controlled by single recessive mutations unlinked to any of the known alleles distinguishing BALB/cJ mice. In this study, segregation analysis employing a second generation backcross population shows that resistance to both EAE and EAO is due to a mutation in a common immunoregulatory gene. The role of immunoregulatory cells in controlling EAE resistance was examined using adoptive transfer protocols. BALB/cJ mice immunized with spinal cord homogenate plus adjuvants generate immunoregulatory spleen cells (SpC) that, when transferred to naive BALB/cByJ recipients, reduce the incidence and severity of EAE. Treatment of such cells with either cytotoxic monoclonal anti-Thy1.2 or anti-CD4 plus C' before transfer abrogates the ability of BALB/cJ SpC to inhibit disease. In contrast, neither SpC from adjuvant-immunized BALB/cJ nor spinal cord homogenate- plus adjuvant-primed BALB/cByJ donors influences the incidence or severity of disease observed in recipients. In addition, the role of environment in influencing susceptibility to EAE and EAO in BALB/c mice is documented. Taken together, these results support the existence of a common disease susceptibility locus in the pathways leading to two autoantigenically distinct CD4+ T cell-mediated, organ-specific, autoimmune diseases.

Animals↗
PubMed1998

Acute hemodynamic and coronary circulatory effects of experimental autoimmune myocarditis.

Myocarditis and progression to cardiomyopathy is associated with focal spasm and reperfusion of the coronary microcirculation. Experimental autoimmune myocarditis (EAM), induced with cardiomyosin peptide-specific T cells in Lewis rats, was hypothesized to cause acute hemodynamic and coronary vasculature changes. Fifteen experimental animals (5 each at 1, 2, and 3 weeks after T-cell injection) and eight controls were studied using the constant pressure variant of the isolated heart. Coronary resistant decreased while coronary flow increased (P < 0.05) in EAM hearts after the first week. Rate-pressure product, +dP/dt and -dP/dt, decreased while the heart/body weight ratio increased (P < 0.05) compared with controls at 1 week but not at 2 or 3 weeks. Mean local myocardial PO2, which reflects local oxygen delivery and consumption, and MVO2 were not different for EAM hearts. However, compared with controls EAM myocardial PO2 varied more widely and was often beyond the usual range, suggesting the occurrence of localized hypoxic and hyperoxic areas. In summary, after the first week there was a significant decrease in coronary resistance in the EAM animals, which required higher flow to maintain a similar perfusion pressure. These changes in coronary resistance and flow along with the heterogeneity and extremes of local myocardial PO2 levels without a significant change in MVO2 may be explained by postulating development of low-resistance, high-flow hyperoxic areas which steal flow, thus causing hypoxia in other areas.

Acute Disease↗
PubMed1998

Noncontusive segmental spinal cord injury using radiofrequency current.

OBJECTIVE: To develop a nondisruptive model for the study of spinal cord injury. METHODS: A 2-MHz radiofrequency heating chamber was mounted over the rat T13-L1 vertebral column via a short dorsal incision. Epidural temperature at chamber level was monitored via a small proximal laminotomy. Forty-three rats were studied using time-temperature heating regimens from 45 to 48.5 degrees C and 4 to 15 minutes. A blinded numerical hind limb impairment score (Neurologic Impairment Score) was determined at intervals up to 2 weeks after injury. Segmental spinal cord blood flow was measured using [14C]butanol tissue uptake in injured and control rats. RESULTS: Above the injury threshold, increasing the time-temperature regimens was associated with a progressively worse Neurologic Impairment Score (r = 0.73-0.87 up to 24 hours after injury). Cord blood flow was unchanged at 2 hours but was 44% depressed at the injury level 6 hours after injury (p < 0.01). Histologically, injury extended minimally beyond the injured segment. Vascular thrombosis was not seen. CONCLUSION: This comparatively noninvasive model does not mechanically disrupt cord components and results in progressive neurologic impairment that correlates with the time-temperature regimen used for injury. It should be useful in identifying secondary phenomena that worsen functional status after cord trauma.

Animals↗
PubMed1998

Autoimmune orchitis, epididymitis, and vasitis are immunogenetically distinct lesions.

Experimental allergic orchitis (EAO), the principle animal model of noninfectious testicular inflammatory disease, is a genetically determined phenotype. Classical EAO, induced by inoculation with testicular homogenate and the appropriate adjuvants, is characterized by inflammatory infiltrates in the testis (orchitis), epididymis (epididymitis), and vas deferens (vasitis). In this study, the genetic control of susceptibility and resistance to these three lesions was analyzed in the mouse. The results obtained with independent inbred strains and H2 congenic mice show that the genetic control of all three lesions is complex and involves both H2 and non-H2-linked genes. Whole-genome exclusion mapping was performed on a backcross population segregating for all three phenotypes. Permutation-derived thresholds provided experimentwise, chromosomewise, comparisonwise, and marker-specific chromosomewise thresholds for declaration of significant regions linked to marker loci. Unique loci were identified on chromosome 8 for orchitis, chromosome 16 for epididymitis, and chromosome 1 for vasitis and have been designated as Orch6, Epd1, and Vas1, respectively. These results show that autoimmune orchitis, epididymitis, and vasitis are immunogenetically distinct lesions.

Animals↗
PubMed1997

Intravenous lipopolysaccharide induces cyclooxygenase 2-like immunoreactivity in rat brain perivascular microglia and meningeal macrophages.

Production of prostaglandins is a critical step in transducing immune stimuli into central nervous system (CNS) responses, but the cellular source of prostaglandins responsible for CNS signalling is unknown. Cyclooxygenase catalyzes the rate-limiting step in the synthesis of prostaglandins and exists in two isoforms. Regulation of the inducible isoform, cyclooxygenase 2, is thought to play a key role in the brain's response to acute inflammatory stimuli. In this paper, we report that intravenous lipopolysaccharide (LPS or endotoxin) induces cyclooxygenase 2-like immunoreactivity in cells closely associated with brain blood vessels and in cells in the meninges. Neuronal staining was not noticeably altered or induced in any brain region by endotoxin challenge. Furthermore, many of the cells also were stained with a perivascular microglial/macrophage-specific antibody, indicating that intravenous LPS induces cyclooxygenase in perivascular microglia along blood vessels and in meningeal macrophages at the edge of the brain. These findings suggest that perivascular microglia and meningeal macrophages throughout the brain may be the cellular source of prostaglandins following systemic immune challenge. We hypothesize that distinct components of the CNS response to immune system activation may be mediated by prostaglandins produced at specific intracranial sites such as the preoptic area (altered sleep and thermoregulation), medulla (adrenal corticosteroid response), and cerebral cortex (headache and encephalopathy).

Animals↗
PubMed1997

Dissociation of microglial activation and neuropathic pain behaviors following peripheral nerve injury in the rat.

Peripheral nerve injury commonly leads to neuropathic pain states fostered, in part, by neuroimmunologic events. We used two models of neuropathic pain (L5 spinal nerve cryoneurolysis (SPCN) and chronic constriction injury (CCI)) to assess the role of spinal glial activation responses in producing pain behaviors. Scoring of glial responses subjectively encompassed changes in cell morphology, cell density and intensity of immunoreactivity with specific activation markers (OX-42 and anti-glial fibrillary acidic protein (GFAP) for microglia and astrocytes, respectively). Glial responses were compared with tactile sensitivity (mechanical allodynia) at 1, 3 or 10 days following SPCN and with thermal hyperalgesia at 10 days in the CCI group. Neuropathic pain behaviors preceded and did not closely correlate with microglial responses in either model. Perineural application of bupivacaine prior to SPCN prevented spinal microglial responses but not pain behaviors. Spinal astrocytic responses to SPCN were early, robust and not altered by bupivacaine. The current findings support the use of bupivacaine as a tool to suppress microglial activation and challenge the putative role of microglia in initiating or potentiating pain behaviors which result from nerve injury.

Anesthetics, Local↗
PubMed1997

Unmasking of an unusual myelin basic protein epitope during the process of myelin degeneration in humans: a potential mechanism for the generation of autoantigens.

A rabbit antiserum (anti-EP), induced against a synthetic peptide corresponding to residues 68 to 86 of guinea pig myelin basic protein, powerfully immunostained abnormal-appearing oligodendrocytic processes and cell bodies in demyelinating areas associated with multiple sclerosis plaques. However, it failed to recognize any structures in normal human, rat, or guinea pig brain. The antiserum recognized the synthetic peptide QDENPVV, which corresponds to human myelin basic protein residues 82 to 88. Immunoabsorption with this peptide eliminated immunohistochemical staining. By contrast, several commercial antibodies recognizing nearby sequences of human myelin basic protein intensely stained all myelinated structures in both normal and multiple sclerosis tissue. The unusual epitope recognized by anti-EP appears to be accessible only in areas of myelin degeneration. If insults occur that repeatedly expose a region of MBP normally sheltered from immunosurveillance, a self-sustaining immune reaction might result.

Adult↗
PubMed1996

PECAM-1 (CD31) expression in the central nervous system and its role in experimental allergic encephalomyelitis in the rat.

The role of T cell activation associated adhesion molecules on lymphocyte traffic and the initiation of inflammation has received considerable attention. This study, using a new monoclonal antibody (mAb) TLD-3A12, describes the distribution of PECAM-1 (CD31), an Ig supergene family adhesion molecule thought to be important in leukocyte transmigration during inflammation, in rat lymphoid organs and spinal cord. PECAM expression within the CNS is confined to endothelial cells of the blood brain barrier (BBB). Induction of inflammation within the CNS using the adoptive transfer of myelin reactive CD4+ T cells results in the de novo expression of immune adhesion and accessory molecules in the spinal cord, while the level of PECAM appeared only mildly increased. The distribution of PECAM on CNS endothelial cells became more diffuse during EAE induction, possibly the result of endothelial cell activation. In vitro studies demonstrate a partial inhibition of antigen-specific CD4+ T cell proliferation following anti-PECAM mAb treatment. Treatment of Lewis rats with TLD-3A12 antibody prior to T cell injection and throughout EAE induction does not result in a delay in the onset of clinical signs or weight loss, nor does it decrease the incidence and severity of disease. These data suggest that the expression of PECAM by CNS endothelial cells is not a requirement for the initiation of inflammation and clinical signs of EAE following the adoptive transfer of encephalitogenic lymphocytes. Thus, cells requiring PECAM-1 to migrate and perform their pathogenic functions are not critical to the development of rat EAE.

Animals↗
PubMed1996

Inhibition by CTLA4Ig of experimental allergic encephalomyelitis.

B7-1 and B7-2 are well characterized costimulatory ligands on Ag presentation cells for the CD28 and CTLA4 receptors on T cells. The fusion protein CTLA4Ig can block this interaction and prevent specific T cell activation. The development of fatal CD4+ T cell-mediated experimental allergic encephalomyelitis (EAE) in susceptible female Lewis rats was optimized by immunization with 20 mg of guinea pig spinal cord homogenate in CFA on day 0 with three doses of 1 microgram pertussis toxin given i.v. on days 0, 3, and 7. This immunization regimen uniformly resulted in the development of severe clinical neurologic signs of EAE with 100% mortality by day 17 postimmunization. Treatment with 0.5 mg/dose of rhCTLA4-Ig on days - 2, 0, 3, 6, 9, 12, 15 and 18 significantly decreased the incidence, delayed the onset, and reduced the severity of clinical EAE (p = 0.0002 vs control by the Mann-Whitney U test) enough to completely prevent fatal EAE, whereas treatment with control human IgG had no effect. Histologically, perivascular neutrophilic infiltrates were also dramatically decreased in the spinal cords of animals treated with CTLA4 but not in those treated with control human IgG. The proliferative response to encephalitogenic Ags (guinea pig myelin basic protein and proteolipid protein) by lymph node cells from animals immunized with guinea pig spinal cord 10 days before was also significantly suppressed in vitro by CTLA4Ig (1 microg/ml). However, the protective effect of CTLA4Ig could be completely prevented by the daily i.p. administration, from day 0 to 10, of exogenous human rIL-2 (180,000 IU). These results indicate a critical requirement of the costimulatory B7/CD28 pathway early in the development of CD4+ T cell-mediated EAE in the rat.

Abatacept↗
PubMed1996

Experimental allergic encephalomyelitis in the rat is inhibited by aminoguanidine, an inhibitor of nitric oxide synthase.

This study assessed the role of de novo nitric oxide (NO) production in the pathogenesis of experimental allergic encephalomyelitis (EAE) by using aminoguanidine (AG), an inhibitor of nitric oxide synthase (NOS), which preferentially inhibits the cytokine- and endotoxin-inducible isoform of NOS versus the constitutive isoforms consisting of endothelial and neuronal NOS. The maximum clinical severity of EAE and the duration of illness were significantly reduced or totally inhibited by twice daily subcutaneous injection of 100 mg/kg body weight AG. Histochemical staining for NADPH diaphorase, which detects enzymatic activity of NOS, revealed positive reactivity in untreated EAE rats both in parenchymal blood vessel walls and in anterior horn cell neurons, while normal rats and rats with EAE treated with AG showed predominantly the neuronal positivity. Moreover, this NADPH staining pattern was further supported by the immunohistochemical findings that endothelial NOS (eNOS) expression was increased in blood vessels in the inflamed lesions of untreated EAE rats and that inducible NOS (iNOS) was detected in some inflammatory cells, while treatment with AG could significantly reduce both iNOS and eNOS production. These results suggest that: (i) both iNOS and eNOS are upregulated in inflamed areas of the rat central nervous system in EAE; (ii) increased NO production plays a role in the development of clinical signs in EAE; and (iii) selective inhibitors of iNOS and/or eNOS may have therapeutic potential for the treatment of certain autoimmune diseases.

Animals↗
PubMed1996

Co-localization of secretoneurin immunoreactivity and macrophage infiltration in the lesions of experimental autoimmune encephalomyelitis.

Secretoneurin, a novel neuropeptide, has recently been shown to attract monocytes. In our present study we have tested whether the local presence of secretoneurin within the CNS of the rat may influence the topographical distribution of inflammatory infiltrates in acute T-cell mediated encephalomyelitis. Experimental allergic encephalomyelitis was induced by passive transfer of myelin basic protein-reactive T-lymphocytes and the distribution of T-cells and macrophages was studied at day 3, 4 and 7 after transfer. In the same sections secretoneurin immunoreactivity was visualized by immunohistochemistry. A clustering of macrophages, but not of T-lymphocytes, was seen at sites of secretoneurin immunoreactivity in all stages of experimental autoimmune encephalomyelitis. Our data indicate for the first time that local neuropeptides may play a role in leucocyte recruitment into inflammatory lesions of the CNS.

Animals↗