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Endotoxaemia has been described in cases of Human African trypanosomiasis (HAT), but it is unclear if this phenomenon influences inflammatory pathology either in the periphery or central nervous system (CNS). We studied endotoxin concentrations in the plasma and cerebrospinal fluid (CSF) of Trypanosoma brucei rhodesiense patients using the chromogenic Limulus Amoebocyte lysate assay. The relationship of endotoxin concentration to the presentation of gross signs of inflammation and the inflammatory/counter-inflammatory cytokine profile of the relevant compartments were analysed. We demonstrate that HAT patients exhibit parasitaemia-independent plasma endotoxaemia, and that this is associated with splenomegaly and lymphadenopathy. Endotoxin concentrations normalize rapidly after treatment. There was no evidence of endotoxin release in the CNS. A rapid normalization of endotoxin levels after treatment and lack of association with parasitaemia suggest that gut leakage is the main source of endotoxin in the circulation. Low CSF endotoxin concentrations and a lack of any association with neuroinflammatory markers or neurological sequelae suggest that endotoxin does not play a role in the pathogenesis of the disease in the CNS. [ABSTRACT FROM PUBLISHER]

Multiple sclerosis is an inflammatory demyelinating disease of the CNS, the aetiology of which is believed to have both genetic and environmental components. We have investigated one of the candidate viruses for the environmental component of multiple sclerosis, the neurotropic human herpesvirus 6 (HHV-6). Utilizing fluorescent in situ hybridization (FISH) techniques, we have examined human post-mortem tissues for the presence of immediate early and late viral gene expression in multiple sclerosis patient normal appearing white matter (NAWM), lesional tissue and normal control brain samples. HHV-6 gene transcription was detected in all tissue samples and was restricted to oligodendrocytes, as determined by double mRNA FISH analysis. Quantitative analysis of viral mRNA expression indicated that both NAWM and lesional multiple sclerosis samples exhibited significantly higher levels of HHV-6 expression compared with the normal control samples. Lesional samples exhibited the highest levels of viral gene expression, with NAWM exhibiting an intermediate level between lesional and control tissues. Immunofluorescence against early and late HHV-6 proteins verified active translation of HHV-6 viral mRNA in oligodendrocytes. Southern blot analysis of nested polymerase chain reactions using extracted genomic DNA and cDNA confirmed the presence of the HHV-6 genome in all individuals, with the active expression profile mirroring the FISH results. The frequent high level of HHV-6 infection in multiple sclerosis samples suggests a possible role in pathogenesis.

Human African trypanosomiasis, also known as sleeping sickness, affects the CNS at the late stage of the disease. Untreated the disease is invariably fatal, and melarsoprol, the only available and effective treatment for CNS disease, is associated in up to 10% of cases with a severe post-treatment reactive encephalopathy (PTRE), which can itself cause death. We used a reproducible mouse model of the PTRE to investigate the pathogenesis and treatment of this condition. Mice infected with Trypanosoma brucei brucei and treated subcuratively with diminazene aceturate develop a severe meningoencephalitis that closely resembles PTRE. We previously reported that substance P plays an important role in PTRE. We investigated the effect of disrupting the gene encoding for the NK1 receptor in mice on the clinical and neuroinflammatory response in this model. After induction of PTRE, NK1-/- mice showed a significant reduction in clinical impairment compared with NK1+/+ mice, but the severity of the neuroinflammatory response was significantly greater in NK1-/- mice. To explore the mechanisms of this dissociated phenotype, we treated infected NK1-/- mice with antagonists to NK2 and NK3 receptors, either singly or in combination. While none of these antagonist treatments altered the clinical score, combined treatment with the NK2 and NK3 antagonists significantly reduced the neuroinflammatory grading score in the NK1-/- mice. Thus, the clinical and neuroinflammatory responses to parasite invasion can be mediated by different pathways, and, importantly, the neuroinflammatory response is altered by alternative tachykinin receptor usage. These findings could be exploited to develop novel anti-inflammatory therapies in Human African trypanosomiasis by modulating the NK1 receptor as well as the parasite.

APOEpolymorphism may influence risk for cold sores and, by interacting with latent HSV-1, risk for Alzheimer's disease (AD). APOEgenotype also influences outcome after brain injury. We sought to determine whether APOEgenotype influences risk for herpes simplex encephalitis (HSE), whether apoE is involved in the response to HSE and if APOEgenotype influences outcome from HSE. There was increased immunoreactivity of neurons, neuropil and glia for apoE areas of brain damaged by HSE. APOEgenotypes for cases of HSE (n57) were similar to those of controls (n41). APOEgenotypes for survivors of HSE were similar to those of patients who died. We conclude that apoE is involved in the response to damage associated with HSE, as in other forms of brain injury. However, APOEgenotype does not appear to influence either the risk of developing HSE or subsequent mortality.

ABSTRACTA consistent feature of varicella-zoster virus (VZV) latency is the restricted pattern of viral gene expression in human ganglionic tissues. To understand further the significance of this gene restriction, we used in situ hybridization (ISH) to detect the frequency of RNA expression for nine VZV genes in trigeminal ganglia (TG) from 35 human subjects, including 18 who were human immunodeficiency virus (HIV) positive. RNA for VZV gene 21 was detected in 7 of 11 normal and 6 of 10 HIV-positive subjects, RNA for gene 29 was detected in 5 of 14 normal and 11 of 11 HIV-positive subjects, RNA for gene 62 was detected in 4 of 10 normal and 6 of 9 HIV-positive subjects, and RNA for gene 63 was detected in 8 of 17 normal and 12 of 15 HIV-positive subjects. RNA for VZV gene 4 was detected in 2 of 13 normal and 4 of 9 HIV-positive subjects, and RNA for gene 18 was detected in 4 of 15 normal and 5 of 15 HIV-positive subjects. By contrast, RNAs for VZV genes 28, 40, and 61 were rarely or never detected. In addition, immunocytochemical analysis detected the presence of VZV gene 63-encoded protein in five normal and four HIV-positive subjects. VZV RNA was also analyzed in explanted fresh human TG and dorsal root ganglia from five normal human subjects over a period of up to 11 days in culture. We found a very different pattern of gene expression in these explants, with transcripts for VZV genes 18, 28, 29, 40, and 63 all frequently detected, presumably as a result of viral reactivation. Taken together, these data provide further support for the notion of significant and restricted viral gene expression in VZV latency.

The olfactory ensheathing cell (OEC) has attracted much interest recently because of its potential for transplantation-based therapy of CNS disease. Rat OECs are able to remyelinate demyelinated axons and support regeneration of damaged axons. Although OECs can be grown readily from the rat, a macrosmatic species, it has been uncertain whether it would be similarly straightforward to obtain these cells from the human, a microsmatic species with a relatively poorly developed olfactory system. In this study, we have identified a human OEC which shares many properties with its rat counterpart, including expression of the low-affinity nerve growth factor receptor (L-NGFr) and similar growth factor requirements. Purified populations of human OECs obtained by selection with L-NGFr antibodies have extremely high viability in tissue culture, and are capable of remyelinating persistently demyelinated CNS axons following transplantation into experimentally induced demyelinating lesions in the rat spinal cord. Thus, the human OEC represents an important new cell for the development of transplant therapy of CNS diseases.

The clinical features, investigative profiles and outcome of 46 patients with biopsy or autopsy-proven herpes simplex encephalitis admitted to the Institute of Neurological Sciences, Glasgow between 1962 and 1985 were analysed retrospectively. The protean presenting symptoms and signs included a history of a prodromal influenza-like illness (48 per cent), rapid onset of headache, clouding of consciousness and confusion (52 per cent), meningism (65 per cent), raised intracranial pressure (33 per cent), deep coma (35 per cent), mutism or aphasia (46 per cent), focal neurological signs (89 per cent), and seizures (61 per cent). When seizures occurred they were almost always focal. The electroencephalogram was the most useful diagnostic test being abnormal in all cases, the majority showing focal changes in one or other hemisphere. Of the neuroradiological procedures employed, computerized tomographic and isotope brain scanning most frequently demonstrated localizing abnormalities in one or both temporal and/or frontal lobes. Midline shift was seen in half the cases. The cerebrospinal fluid was abnormal in every case but was not diagnostic. Cerebral biopsy of one temporal lobe was performed in 40 cases and a positive diagnosis of acute necrotizing encephalitis was made in 37 of these. Herpes simplex virus was isolated from the brains of 29 of the 40 cases in which the procedure was attempted, but immunofluorescence assays for antigens to herpes simplex virus were only positive in 11 out of 25 cases. Serological assays showed a greater than four-fold rise in the anti-herpes simplex virus antibody litre in 13 out of 22 patients tested. A total of 19 patients (41 per cent) survived and 27 (59 per cent) died and the mean survival time from the onset of symptoms to death was 23 days. Both the level of consciousness and the degree of speech deficit on admission were related to eventual outcome, but the age of the individuals did not have as great an effect on the outcome as found in previous studies. Antiviral treatment was given in 27 patients. Eight of the 15 patients (53 per cent) who had received idoxuridine survived and two of these made a useful recovery. Three out of the five (60 per cent) of the patients treated with vidarabine survived and two had a useful outcome. Of the seven cases treated with acyclovir five (71 per cent) survived, three of whom had a useful outcome. Only three (16 per cent) of the 19 patients who did not receive any antiviral treatment survived. Only five individuals were able to return to work and most survivors were left with permanent neurological and/or psychological impairment. The policy widely adopted in the United Kingdom for treating suspected cases of herpes simplex encephalitis empirically with acyclovir now seems justified, but it is critical that such patients be treated early in the disease before either coma or mutism develops.