ENCEPHALITIS

encephalitis

Diagnosis, Diagnostics, Immunodiagnosis & Immunodiagnostics:

January 2003

6020. Athmanathan S, Vydehi B V, Sundaram C, Venuganti G K, Murthy J M K. Neuronal apoptosis in herpes simplex virus – 1 encephalitis (HSE). Indian J med Microbiol 2001; 19(3), 127-31. No abstract.

6021. Berger C, Schwarz S, Schaebitz WR, Aschoff A, Schwab S. Serum procalcitonin in cerebral ventriculitis. Crit Care Med. 2002 Aug;30(8):1778-81.

OBJECTIVES: The objective of this study was to test the hypothesis that serum procalcitonin is increased in patients with bacterial cerebral ventricular infections after the insertion of temporary external ventricular drains. PATIENTS AND METHODS: This open, prospective study included patients requiring temporary external ventricular drains for various neurologic conditions such as intracerebral hemorrhage with ventricular hemorrhage or space-occupying lesions in the posterior fossa (cerebellar infarctions or hemorrhages). Patients experiencing primary central nervous system infection or sepsis were excluded. Procalcitonin, C-reactive protein, and white blood cell count were measured daily. Cerebrospinal fluid was investigated every other day, including cerebrospinal fluid cell count, lactate, glucose, and cerebrospinal fluid culture. Results were categorized according to presence of bacterial cerebrospinal fluid infection as determined by positive cerebrospinal fluid cultures. RESULTS: A total of 34 consecutive patients were included. Procalcitonin was significantly higher (4.7 vs. 0.2 ng/mL) in patients with proven bacterial ventriculitis. Cerebrospinal fluid cell count (456 vs. 478 cells/microL) could not distinguish bacterial infection from abacterial reactions, mainly because of blood contamination of the cerebrospinal fluid. CONCLUSION: Cerebrospinal fluid of patients treated with temporary external ventricular drains is frequently characterized by blood contamination because of the insertion procedure, the underlying neurologic disorder such as ventricular hemorrhage, or the presence of an abacterial chemical ventriculitis. Thus, diagnosis of a bacterial ventricular infection requiring immediate antibiotic therapy is less certain. Serum procalcitonin adds to the diagnostic precision in bacterial ventriculitis.

6022. Chakrabarti S, Garvie D, RayChaudhuri K, Rao GG. Rationalizing the use of polymerase chain reaction based tests for diagnosis of common viral infections of the central nervous system. J Clin Pathol. 2002 Jul;55(7):560. No abstract.

6023. Garcia-Rivera EJ, Rigau-Perez JG. Encephalitis and dengue. Lancet. 2002 Jul 20;360(9328):261. No abstract.

6024. Juceviciene A, Vapalahti O, Laiskonis A, Ceplikiene J, Leinikki P. Prevalence of tick-borne-encephalitis virus antibodies in Lithuania. J Clin Virol. 2002 Jul;25(1):23-7.

BACKGROUND: Clinical infections caused by tick-borne encephalitis virus (TBEV) are quite common in Lithuania and cause significant disease burden not only as acute cases but as chronic sequealeae as well. In order to evaluate the spread of the disease and risk factors, a population based seroprevalence study was done. MATERIAL AND METHODS: about 1488 serum samples collected from healthy people from different parts of the country during the year 2000 were studied by hemagglutination inhibition (HI) method. For risk factor analysis detailed information was collected by a questionnaire. RESULTS: 44 samples (2.96%) were positive. This indicates that at least 1500 infections occur in the country annually. Seropositivity did not increase with increasing age. In certain areas, seropositivity was clearly higher than the average. Other living conditions or outdoor habits correlated poorly with seropositivity. Certain groups of people such as farmers, cattle breeders, or those having a summer cottage or spending time in the nature daily had increased risk. Seropositivity was significantly linked with meningoencephalitis without laboratory confirmation for TBE in the anamnesis, and drinking of goat milk. CONCLUSION: The study suggests that TBEV is prevalent in Lithuania. The data also supports the view that an increase in the incidence has occurred in the 1990s. The correlation between seropositivity and presumed risk factors do not seem strong enough to warrant a selective vaccination policy based on risk factors.

6025. Mickiene A, Laiskonis A, Gunther G, Vene S, Lundkvist A, Lindquist L. Tickborne encephalitis in an area of high endemicity in lithuania: disease severity and long-term prognosis. Clin Infect Dis. 2002 Sep 15;35(6):650-8.

Of 250 consecutively admitted patients with central nervous system (CNS) infections who were treated during a 1-year period, all 133 patients with tickborne encephalitis (TBE) were included in a prospective follow-up study. TBE presented as mild (meningeal) in 43.6% of patients and as moderate or severe (encephalitic) in 43.6% and 12.8% of patients, respectively. Paralytic disease was observed in 3.8% of the subjects, and cranial nerve injury was observed in 5.3%. One patient died of TBE. Permanent CNS dysfunction after 1 year was found in 30.8% of patients; in 8.5% of all TBE cases, severe disabilities required adjustment of daily activities. Corticosteroid treatment did not seem to improve outcome. A progressive course of TBE was noted in 2 patients. The risk of incomplete recovery was significantly higher among patients with the encephalitic form of TBE (odds ratio, 4.066; 95% confidence interval, 1.848-8.947). In conclusion, TBE is an important pathogen in CNS infection in the Kaunas region of Lithuania, and it causes long-lasting morbidity in one-third of cases.

6026. Raschilas F, Wolff M, Delatour F, Chaffaut C, De Broucker T, Chevret S, Lebon P, Canton P, Rozenberg F. Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study. Clin Infect Dis. 2002 Aug 1;35(3):254-60.

Management of herpes simplex encephalitis (HSE) has been considerably improved by the availability of acyclovir therapy and rapid polymerase chain reaction (PCR)-based diagnostic assays. Prognostic factors for this rare affliction are, however, misestimated. We conducted a large retrospective multicenter study that included 93 adult patients in whom HSE was diagnosed by PCR from 1991 through 1998 and who were treated with intravenous acyclovir. Among the 85 patients assessed at 6 months, 30 (35%) had a poor outcome, which led to death in 13 patients (15%) and severe disability in 17 (20%). The outcome was favorable for 55 patients (65%). A multivariate analysis identified 2 factors that were found to be independently associated with poor outcome: a Simplified Acute Physiology Score II >/=27 at admission and a delay of >2 days between admission to the hospital and initiation of acyclovir therapy. Early administration of antiviral therapy is the only parameter that can be modified to improve the prognosis of patients with HSE.

6027. Shinjoh M, Yoshikawa T, Li Y, Shiraishi K, Ueki H, Nerome K. Prophylaxis and treatment of influenza encephalitis in an experimental mouse model. J Med Virol. 2002 Jul;67(3):406-17.

A mouse model study using mouse brain-adapted influenza A virus was performed to establish the prophylaxis and treatment of influenza encephalitis and encephalopathy. All mice died after intranasal inoculation of the brain-adapted influenza A virus (H7N3), and the pathological findings indicated the presence of significant encephalitis. Viral antigen was also detected in the brain, both pathologically and virologically. By contrast, infected mice immunized with inactivated vaccine of the same strain did not lose weight, which is an indicator of the overall condition of the mice, and all of them survived. Similarly, antiserum treatment in the early period (0-1 day post-infection) resulted in 100% survival, and no pathological findings were observed in the brain. However, mice treated with antiserum 3 days post-infection showed encephalitis with viral antigens in both glial cells and neurocytes. Although amantadine treatment for 4 days delayed weight loss, it did not prevent death from encephalitis. These results show vaccination and early antiserum treatment to be highly effective, whereas 4-day treatment of amantadine was not very effective in treating or preventing influenza encephalitis. The life-prolonging effect of amantadine, however, suggests that use of amantadine together with other treatments may inhibit the progression of encephalitis. Copyright 2002 Wiley-Liss, Inc.

6028. Straight TM, Lazarus AA, Decker CF. Defending against viruses in biowarfare. How to respond to smallpox, encephalitides, hemorrhagic fevers. Postgrad Med. 2002 Aug;112(2):75-6, 79-80, 85-6. Review.

The threat of bioterrorism with use of viruses is increasing. Smallpox, encephalitis, and hemorrhagic fevers are the most likely diseases to result from viral deployment. It is critical that all healthcare professionals become familiar with the clinical presentation, diagnosis, management, and prevention of these diseases. Awareness and preparedness are instrumental in reducing viral transmission and improving survival of the victims.

6029. Wagner BP, Pfenninger J. Dynamic cerebral autoregulatory response to blood pressure rise measured by near-infrared spectroscopy and intracranial pressure. Crit Care Med. 2002 Sep;30(9):2014-21.

OBJECTIVES: Noninvasive near-infrared spectroscopy (NIRS) continuously monitors changes in cerebral hemoglobin saturation (Hb(Diff) ) and content (Hb(Total)). It may allow visualization of the dynamic cerebral autoregulatory response to rapid blood pressure increases without relevant contamination of the NIRS signal from extracerebral hemoglobin. DESIGN: Prospective cohort study. SETTINGS: Multidisciplinary pediatric intensive care unit. PATIENTS: Six consecutive children in coma due to severe encephalopathy (head trauma, five patients; mumps encephalitis, one patient) requiring artificial ventilation, invasive arterial blood, and intracranial pressure monitoring. INTERVENTIONS: Frontotemporal recording of Hb(Diff) and Hb(Total) while rapidly elevating blood pressure by bolus injection of phenylephrine. MEASUREMENTS AND RESULTS: During an increase of blood pressure of 13 +/- 1 mm Hg with a "rise time" of 16 +/- 1 secs (mean of a total of 31 injections +/- sem), a significant linear correlation was found between Hb(Diff) and intracranial pressure signals (mean coefficient, 0.46 +/- 0.04) but not between Hb(Total) and intracranial pressure. Three response patterns were observed. First, Hb(Diff) and intracranial pressure reduction, corresponding with vasoconstriction and normal dynamic autoregulation (n = 3); second, Hb(Diff) and intracranial pressure increase, corresponding with persistent vasodilation and abolished autoregulation (n = 11); and third, transient Hb(Diff) and intracranial pressure increase followed by a decrease at peak blood pressure elevation, called impaired autoregulation (n = 15). In one patient with fatal brain swelling, phenylephrine testing showed no effect on NIRS signals (n = 2). Furthermore, there were significant correlations between 31 pooled interindividual pairs of Hb(Diff) changes with intracranial pressure changes (values at baseline averaged over 60 secs subtracted from values at peak blood pressure elevation averaged over 5 secs), with a correlation coefficient of .82 (p <.001). CONCLUSIONS: NIRS represents a new and promising technique for bedside determination of dynamic cerebral autoregulation during acutely induced blood pressure rise. The significant correlations found between NIRS signals and intracranial pressure excluded relevant extracerebral contamination of the NIRS signals. In our patients with severe encephalopathy, dynamic autoregulation was in most instances not fully preserved.

6030. Yamamoto A, Nakayama M, Kurosawa Y, Sugo K, Karasawa H, Ogawa T, Takasaki T, Tashiro M, Kurane I. Development of a particle agglutination assay system for detecting Japanese encephalitis virus-specific human IgM, using hydroxyapatite-coated nylon beads. J Virol Methods. 2002 Jul;104(2):195-201.

Japanese encephalitis virus-specific IgM is a reliable indicator for serodiagnosis of Japanese encephalitis. A particle agglutination (PA) assay system was developed to detect anti-Japanese encephalitis virus IgM in human serum samples. The newly developed PA assay consisted of hydroxyapatite-coated nylon beads and V-bottom 96-well microplates. Hydroxyapatite-coated nylon beads were coated with Japanese encephalitis virus antigens. Japanese encephalitis virus antigen-coated, hydroxyapatite-coated nylon beads agglutinated in the IgM-captured wells when anti-Japanese encephalitis virus IgM-positive serum samples were used. A button pattern was formed at the bottom of the wells when anti-Japanese encephalitis virus IgM-negative serum samples were used. Thirty anti-Japanese encephalitis virus IgM-positive serum samples from Japanese encephalitis-confirmed cases were tested by the PA assay. All these serum samples were determined to be Japanese encephalitis virus IgM-positive. IgM titers determined by the PA assay corresponded to those determined by enzyme-linked immunosorbent assay. The titers were consistent in two independent PA assays. These results indicate that the newly developed PA assay is a reliable method for detecting anti-Japanese encephalitis virus IgM in human serum samples and that this assay will be a suitable diagnostic system especially in rural areas of Asia.

Pathogenesis:

6031. Dietrich JB. The adhesion molecule ICAM-1 and its regulation in relation with the blood-brain barrier. J Neuroimmunol. 2002 Jul;128(1-2):58-68. Review.

The blood-brain barrier (BBB) is formed by high resistance tight junctions within the capillary endothelium perfusing the vertebrate brain. Normal BBB maintains a unique microenvironment within the central nervous system (CNS). In neurodegenerative disorders (for example multiple sclerosis, MS), the BBB becomes impaired. Perivascular cells (astrocytes, macrophages and microglial cells) and brain microvascular endothelial cells (BMEC) produce various inflammatory factors that affect the BBB permeability and the expression of adhesion molecules. Indeed, cytokines can stimulate the expression of several adhesion molecules on brain microvascular endothelial cells. Among these adhesion molecules, the intercellular adhesion molecule-1 (ICAM-1) binds to its leukocyte ligands and allows activated leukocytes entry into the CNS.This review is dealing with the expression and regulation of ICAM-1 in relation with several properties of the BBB. Particularly, the role of ICAM-1 in the control of the leukocyte traffic into the CNS, as well as in cerebral malaria and in CNS infection by viruses, is discussed.

6032. Graham PL, Ampofo K, Saiman L. Linezolid treatment of vancomycin-resistant Enterococcus faecium ventriculitis. Pediatr Infect Dis J. 2002 Aug;21(8):798-800.

The successful treatment of a 7-month-old infant with shunt-associated ventriculitis caused by vancomycin-resistant Enterococcus faecium is presented. Linezolid was administered intravenously every 8 h; children have a greater volume of distribution and total body clearance than adults and therefore require more frequent dosing. The patient tolerated the therapy without adverse effects.

6033. Johnson JJ, Roberts CW, Pope C, Roberts F, Kirisits MJ, Estes R, Mui E, Krieger T, Brown CR, Forman J, McLeod R. In vitro correlates of Ld-restricted resistance to toxoplasmic encephalitis and their critical dependence on parasite strain. J Immunol. 2002 Jul 15;169(2):966-73.

Resistance to murine toxoplasmic encephalitis has been precisely and definitively mapped to the L(d) class I gene. Consistent with this, CD8(+) T cells can adoptively transfer resistance to toxoplasmic encephalitis. However, cytotoxic CD8(+) T cells, capable of killing class I-matched, infected target cells, are generated during the course of Toxoplasma gondii infection even in mice lacking the L(d) gene. L(d)-restricted killing could not be demonstrated, and the functional correlate of the L(d) gene has therefore remained elusive. Herein, L(d)-restricted killing of T. gondii-infected target cells is demonstrated for the first time. L(d)-restricted killing is critically dependent on the strain of T. gondii and is observed with all the derivatives of type II strains tested, but not with a type I strain. These results have important implications for vaccine development.

6034. Malakoff D. Infectious disease. Bird advocates fear that West Nile virus could silence the spring. Science. 2002 Sep 20;297(5589):1989. No abstract.

6035. Nath SK, Kelly JA, Reid J, Lam T, Gray-McGuire C, Namjou B, Aston CE, Harley JB. SLEB3 in systemic lupus erythematosus (SLE) is strongly related to SLE families ascertained through neuropsychiatric manifestations. Hum Genet. 2002 Jul;111(1):54-8.

Seizures and psychosis are neuropsychiatric (NP) manifestations of a large number of systemic lupus erythematosus (SLE) patients. Since NP manifestations were part of the SLE phenotype for some, but not all SLE affecteds, we hypothesized that those SLE patient families with NP manifestations might be more genetically homogeneous at loci important to NP-related SLE, and hence have increased power to detect linkage. We identified 23 families of European-American (EA) origin and 20 families of African-American (AA) origin, in which at least one SLE patient in each family was diagnosed with the presence of NP manifestations. A total of 318 microsatellite markers at an average marker density of 11 cM were genotyped. Uncertainty of the genetic model led us to perform the initial genome scan by a multipoint non-parametric allele sharing linkage method. Once the evidence of linkage was suggestive, we then performed parametric model-based linkage by maximizing the relevant parameters to define a parsimonious genetic model. We found the maximum multipoint parametric LOD score was 5.19 and the non-parametric linkage score (Zlr) was 3.12 ( P=9x10(-4)) for EA NP pedigrees at 4p16, previously identified as SLEB3. The segregation behavior of this linked locus suggests a dominant mode of inheritance with an almost 100% homogeneous genetic effect in these pedigrees. The results demonstrated a significant increase of LOD score to detect SLEB3 when the families were further ascertained through NP, compared with the analysis of all EA SLE families together.

6036. Schuster FL. Cultivation of pathogenic and opportunistic free-living amebas. Clin Microbiol Rev. 2002 Jul;15(3):342-54. Review.

Free-living amebas are widely distributed in soil and water, particularly members of the genera Acanthamoeba and NAEGLERIA: Since the early 1960s, they have been recognized as opportunistic human pathogens, capable of causing infections of the central nervous system (CNS) in both immunocompetent and immunocompromised hosts. Naegleria is the causal agent of a fulminant CNS condition, primary amebic meningoencephalitis; Acanthamoeba is responsible for a more chronic and insidious infection of the CNS termed granulomatous amebic encephalitis, as well as amebic keratitis. Balamuthia sp. has been recognized in the past decade as another ameba implicated in CNS infections. Cultivation of these organisms in vitro provides the basis for a better understanding of the biology of these amebas, as well as an important means of isolating and identifying them from clinical samples. Naegleria and Acanthamoeba can be cultured axenically in cell-free media or on tissue culture cells as feeder layers and in cultures with bacteria as a food source. Balamuthia, which has yet to be isolated from the environment, will not grow on bacteria. Instead, it requires tissue culture cells as feeder layers or an enriched cell-free medium. The recent identification of another ameba, Sappinia diploidea, suggests that other free-living forms may also be involved as causal agents of human infections.

6037. Tanaka M, Maruyama Y, Sugie M, Motizuki H, Kamakura K, Tanaka K. Cytotoxic T cell activity against peptides of Hu protein in anti-Hu syndrome. J Neurol Sci. 2002 Sep 15;201(1-2):9-12.

Half of all patients with limbic encephalitis and small cell lung carcinoma (SCLC) have anti-Hu antibodies that react with all of central and peripheral nervous system neuronal nuclei in immunohistochemical studies and 35- to 40-kDa reactive bands on western blots of extracts from isolated central nervous system neurons. The roles of anti-Hu antibodies in neuronal damage, however, have yet to be shown. Evidence of infiltration of CD8-positive T cells to tumors and affected nervous tissues and limited use of the T cell receptor repertoire in the central nervous system suggests that CD8-positive cytotoxic T cells (CTL) cause neuronal loss. We found the HLA B7 supertype in all of seven Japanese patients with anti-Hu syndrome. We identified HLA class I-restricted, CD 8-positive cytotoxic T cell activity in peripheral blood from three patients with anti-Hu syndrome for five peptides with binding motifs for the HLA B7 supertype in the amino acid sequence of the Hu protein. This study support the involvement of CD8-positive cytotoxic T cells in the development of paraneoplastic neurological syndrome with anti-Hu antibodies.

6038. Vojdani A, Campbell AW, Anyanwu E, Kashanian A, Bock K, Vojdani E. Antibodies to neuron-specific antigens in children with autism: possible cross-reaction with encephalitogenic proteins from milk, Chlamydia pneumoniae and Streptococcus group A. J Neuroimmunol. 2002 Aug;129(1-2):168-77.

We measured autoantibodies against nine different neuron-specific antigens and three cross-reactive peptides in the sera of autistic subjects and healthy controls by means of enzyme-linked immunosorbent assay (ELISA) testing. The antigens were myelin basic protein (MBP), myelin-associated glycoprotein (MAG), ganglioside (GM1), sulfatide (SULF), chondroitin sulfate (CONSO4), myelin oligodendrocyte glycoprotein (MOG), alpha,beta-crystallin (alpha,beta-CRYS), neurofilament proteins (NAFP), tubulin and three cross-reactive peptides, Chlamydia pneumoniae (CPP), streptococcal M protein (STM6P) and milk butyrophilin (BTN). Autistic children showed the highest levels of IgG, IgM and IgA antibodies against all neurologic antigens as well as the three cross-reactive peptides. These antibodies are specific because immune absorption demonstrated that only neuron-specific antigens or their cross-reactive epitopes could significantly reduce antibody levels. These antibodies may have been synthesized as a result of an alteration in the blood-brain barrier. This barrier promotes access of preexisting T-cells and central nervous system antigens to immunocompetent cells, which may start a vicious cycle. These results suggest a mechanism by which bacterial infections and milk antigens may modulate autoimmune responses in autism.

Vaccines:

6039. Shlim DR, Solomon T. Japanese encephalitis vaccine for travelers: exploring the limits of risk. Clin Infect Dis. 2002 Jul 15;35(2):183-8. Review.

The prevention of Japanese encephalitis in travelers presents the juxtaposition of 4 factors: a disease that is widespread throughout Asia, a disease with a low incidence in travelers, a vaccine about which there are safety concerns, and a clinical course that can result in death or permanent disability in two-thirds of symptomatic cases. Travel medicine practitioners often seem to be polarized into 2 groups: a group that gives more weight to the severity of the disease (and therefore often recommend vaccination) and another group that is more persuaded by the low occurrence of cases in travelers (and therefore rarely recommend vaccination). This review assesses the known risks of contracting Japanese encephalitis and the risks associated with the vaccine and tries to develop an appropriate way to recommend this vaccine to travelers who may be at significant risk.

Therapy:

6040. Acosta MT, Montanez P, Leon-Sarmiento FE. Half brain but not half function. Lancet. 2002 Aug 24;360(9333):643. No abstract.

6041. Gupta SK; Verma VK; Parihar A. Department of Medicine, GMC, Jammu, Srinagar. India Herpes simplex encephalitis JK Practitioner. 2002 Jan-Mar; 9(1): 53-4

ABSTRACT: Herpes simplex encephalitis is the commonest and the gravest form of acute encephalitis, seen sporadically throughout the year & in patients of all ages and in all parts of the world. It carries a mortality rate of 30-70 percent and those who survive are left with serious neurologic abnormalities. It is due almost always to Herpes Simplex Virus-I (HSV-I) which is also the cause of the common herpetic lesions of the oral mucosa. Rarely, however, do the oral and encephalitic lesions coincide. We report here a case of Herpes simplex encephalitis who presented with behaviour disturbances followed by seizures and coma and this patient had full recovery following acyclovir therapy.

6042. Mayo DR, Beckwith WH 3rd. Inactivation of West Nile virus during serologic testing and transport. J Clin Microbiol. 2002 Aug;40(8):3044-6.

Inactivation of West Nile virus (WNV) in enzyme-linked immunosorbent assay (ELISA) wash buffer at 37 degrees C was studied, as well as inactivation of WNV in cell culture medium over several days at an ambient temperature (28 degrees C). Aliquots of WNV were removed from the 37 degrees C ELISA wash buffer at 5, 15, 30, and 60 min for the former experiment, while daily aliquots of medium were sampled for the latter experiment. No virus was detected in the wash buffer at 30 and 60 min, while virus was readily detected from cell culture medium over this time. In addition, titers of WNV consistently dropped over a 7-day period at 28 degrees C compared to control suspensions of virus held at 4 degrees C. These observations indicate that WNV is readily inactivated in the presence of detergent-containing buffers. Furthermore, the viability loss at ambient temperature suggests that WNV is easily inactivated during routine transportation and testing of human body fluids such as serum and cerebrospinal fluid.

6043. Singh N; Syed Sadiq A; Singh V; Singh A National Institute of Pharmaceutical Education and Research S.A.S. Nagar Punjab Adaptogens anti stress agents a study focusing Indian plants Antiseptic. 2002 Jun; 99(6): 198-201.

ABSTRACT: This article has been presented with a view to acquaint the readers about plant adaptogens/antistress agent. Although relation of stress has been recognized in genesis of diseases long back, a scientific database is still missing. The pharmaco-clinical studies carried out in this regard are a new venture in Stress-Pharmacology. It is meant to provide new research awareness in the field regarding the fact about stress, Stress-disease and their prevention and treatment. This is more important in view of the fact that there are no drugs for such stress-related diseases in the armamentarium of modern drug therapy. Simple animal models like swimming endurance, immobilization induced gastric ulcers, adrenal function during stress, CCI4 hepatotoxicity, anoxia tolerance test, brain neurotransmitters and enzyme and CNS receptors levels of neurohumorals after swimming immobilization and gravitational stress, milk induced leucocytosis, lipid peroxidase assessment for prevention of cell damage through anti-oxidant activity were carried out to evaluate the adaptogenic activity of these plants in rats and mice. Clinical trial in diseases related to stress like bronchial asthma, hypertension, cellular immunity, viral encephalitis, chronic fatigue syndrome were carried out in man.

April 2003

6651. Bell JE, Arango JC, Robertson R, Brettle RP, Leen C, Simmonds P. HIV and drug misuse in the Edinburgh cohort. J Acquir Immune Defic Syndr. 2002 Oct 1;31 Suppl 2:S35-42.

The Edinburgh cohort of intravenous drug users (IVDUs) became infected with HIV between 1983 and 1984. Before the era of effective therapy, many of these infected IVDUs displayed cognitive impairments on progressing to AIDS and were found to have HIV encephalitis (HIVE). Full autopsies were conducted on these patients, providing an opportunity to study the intersecting pathology of pure HIVE and drug use. High proviral load in the brain correlated well with the presence of giant cells and HIV p24 positivity. In presymptomatic HIV infection, IVDUs were found to have a lymphocytic infiltrate in the central nervous system (CNS). Apart from the expected microglial activation in the presence of HIV infection of the CNS, drug use in its own right was found to be associated with microglial activation. Examination of HIV-negative IVDUs revealed a number of neuropathologic features, including microglial activation, which may underpin HIV-related pathology in the CNS. HIV isolated from different regions of the brain was exclusively of R5-tropic type throughout the course of infection. Detailed studies of p17 and V3 sequences suggest that viral sequestration occurs in the CNS before the onset of AIDS and that increasing diversity of HIV variants within the brain is associated with increasing severity of HIVE. Because brain isolates have proved to be different from those in lymphoid tissue (and blood), it is likely that selective neuroadaptive pressures operate before HIVE supervenes. Drug abuse may be synergistic in this process through activation of microglia, breakdown of the blood-brain barrier, and direct neurotoxicity. Collections of clinically well-characterized HIV-infected tissues such as those in the Edinburgh Brain Bank are a vital resource to support ongoing studies of viral pathogenesis in the CNS and interactions with drug abuse.

6652. Bosma GP, Middelkoop HA, Rood MJ, Bollen EL, Huizinga TW, van Buchem MA. Association of global brain damage and clinical functioning in neuropsychiatric systemic lupus erythematosus. Arthritis Rheum. 2002 Oct;46(10):2665-72.

OBJECTIVE: To investigate the relationship between quantitative estimates of global brain damage based on magnetization transfer imaging (MTI) and cerebral functioning, as measured by neurologic, psychiatric, and cognitive assessments, as well as disease duration in patients with a history of neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: In a clinically heterogeneous group of 24 female patients (age range 19-65 years, mean age 35 years) with a history of NPSLE, the correlation values of several volumetric MTI measures and an estimate of cerebral atrophy, neurologic functioning (Kurtzke's Expanded Disability Status Scale [EDSS]), psychiatric functioning (the Hospital Anxiety and Depression Scale [HADS]), and cognitive functioning (cognitive impairment score [CIS] derived from the revised Wechsler Adult Intelligence Scale), as well as several measures of disease duration were assessed using Pearson's correlation coefficient.

RESULTS: Quantitative volumetric estimates of global brain damage based on MTI and a measure of global brain atrophy correlated significantly with the EDSS, HADS, and CIS scores. No significant correlation was found between the quantitative estimates of global brain damage and the measures of disease duration. CONCLUSION: The results of this study demonstrate that volumetric MTI parameters and cerebral atrophy reflect functionally relevant brain damage in patients with NPSLE. Furthermore, the absence of a linear relationship between disease duration and results of volumetric MTI measures and atrophy suggests a complicated pattern of accumulating brain damage in patients with NPSLE.

6653. Bsibsi M, Ravid R, Gveric D, van Noort JM. Broad expression of Toll-like receptors in the human central nervous system. J Neuropathol Exp Neurol. 2002 Nov;61(11):1013-21.

The family of Toll-like receptors (TLRs) plays a key role in controlling innate immune responses to a wide variety of pathogen-associated molecules. In this study we investigated expression of TLRs in vitro by purified human microglia, astrocytes, and oligodendrocytes, and in vivo by immunohistochemical examination of brain and spinal cord sections. Cultured primary microglia were found to express mRNA encoding a wide range of different TLR family members while astrocytes and oligodendrocytes primarily express TLR2 and TLR3. Comparisons between microglia derived from a series of control subjects and neurodegenerative cases indicate distinct differences in levels of mRNA encoding the different TLRs indifferent microglia samples. Interestingly, expression of TLR proteins in cultured microglia as revealed by immunocytochemistry was restricted to intracellular vesicles, whereas in astrocytes they were exclusively localized on the cell surface. Finally, in vivo expression of TLR3 and TLR4 was examined by immunohistochemical analysis of brain and spinal cord sections from both control and multiple sclerosis brains, revealing enhanced expression of either TLR in inflamed CNS tissues. Together, our data reveal broad and regulated expression of TLRs both in vitro and in vivo by human glia cells.

6654. Burudi EM, Marcondes MC, Watry DD, Zandonatti M, Taffe MA, Fox HS. Regulation of indoleamine 2,3-dioxygenase expression in simian immunodeficiency virus-infected monkey brains. J Virol. 2002 Dec;76(23):12233-41.

The human immunodeficiency virus type 1-associated cognitive-motor disorder, including the AIDS dementia complex, is characterized by brain functional abnormalities that are associated with injury initiated by viral infection of the brain. Indoleamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme in tryptophan catabolism in extrahepatic tissues, can lead to neurotoxicity through the generation of quinolinic acid and immunosuppression and can alter brain chemistry via depletion of tryptophan. Using the simian immunodeficiency virus (SIV)-infected rhesus macaque model of AIDS, we demonstrate that cells of the macrophage lineage are the main source for expression of IDO in the SIV-infected monkey brain. Animals with SIV encephalitis have the highest levels of IDO mRNA, and the level of IDO correlates with gamma interferon (IFN-gamma) and viral load levels. In vitro studies on mouse microglia reveal that IFN-gamma

is the primary inducer of IDO expression. These findings demonstrate the link between IDO expression, IFN-gamma levels, and brain pathology signs observed in neuro-AIDS.

6655. Gain P, Chiquet C, Thuret G, Drouet E, Antoine JC. Herpes simplex virus type 1 encephalitis associated with acute retinal necrosis syndrome in an immunocompetent patient. Acta Ophthalmol Scand. 2002 Oct;80(5):546-9.

PURPOSE: The onset of acute retinal necrosis secondary to herpes simplex encephalitis is exceptional. We report such an association in an immunocompetent patient, in whom the genome of herpes simplex virus type 1 (HSV-1) was identified successively at both sites of infection. METHODS: Polymerase chain reaction (PCR) assay of HSV-1 in cerebrospinal fluid (CSF) and aqueous humour. RESULTS: An immunocompetent patient aged 40 years presented with HSV-1 encephalitis, which was confirmed by imaging, viral serology and identification of the HSV-1 genome in the CSF. The subject's immunological profile was normal. The patient was treated with foscavir. Six weeks after clinical recovery and negative PCR, the patient presented with a unilateral acute retinal necrosis syndrome. Polymerase chain reaction of the aqueous humour was positive, while

serology and PCR of the CSF remained negative. CONCLUSION: Identification of the HSV-1 genome at the two successive sites of infection stresses the possibility of brain-to-eye transmission of HSV-1.

6656. Hadden PW, Barry CJ. Images in clinical medicine. Herpetic encephalitis and acute retinal necrosis. N Engl J Med. 2002 Dec 12;347(24):1932. No abstract.

6657. Hill D, Dubey JP. Toxoplasma gondii: transmission, diagnosis and prevention. Clin Microbiol Infect. 2002 Oct;8(10):634-40.

Toxoplasmosis, caused by the protozoan parasite Toxoplasma gondii, is one of the most common parasitic infections of man and other warm-blooded animals. It has been found world-wide from Alaska to Australia. Nearly one-third of humanity has been exposed to this parasite. In most adults it does not cause serious illness, but it can cause blindness and mental retardation in congenitally infected children and devastating disease in immunocompromised individuals.

6658. Horie T, Shen Y, Kajino K, Gaubin M, Bonomi G, Mani JC, Berezov A,Piatier-Tonneau D, Guardiola J, Hillard B, Rostami A, Greene M, Murali R. Study of disabling T-cell activation and inhibiting T-cell-mediated immunopathology reveals a possible inverse agonist activity of CD4 peptidomimetics. Exp Mol Pathol. 2002 Oct;73(2):93-103.

We designed a new class of aromatically modified exocyclic peptides based on the structure of CD4 by engineering one of the cysteine residues in a peptidomimetic derived from the CDR3 region of the CD4 molecule. All three species mediate inhibition of T-cell proliferation at concentrations ranging from 10 to 100 microM. The mimetics CD4-Cys and CD4-Met bind to sCD4 with affinities ranging from 1 to 2 microM, while CD4-Ser shows poor binding in radioisotope assay. Though these mimetics have similar structures, they exhibit different biochemical and biological functions. Activation of T-cells as measured by thymidine incorporation or IL-2 production revealed that CD4-Cys and CD4-Ser mimetics behave as classical antagonists. On the other hand, the CD4-Met species inhibited T-cell proliferation with an IC(50) of 30 microM but unexpectedly increased IL-2 secretion modestly at a less than 3 microM concentration. In experimental autoimmune encephalitis (EAE), CD4-Ser and CD4-Cys mimetics reduced the severity of EAE symptoms while the CD4-Met mimetic exacerbated the conditions. We propose that CD4-Cys and CD4-Ser are classical antagonists, but CD4-Met may possess properties of an inverse agonist. The structure-activity relationship of mimetics reveals that a minor change in the net hydropathic value is enough to alter the dynamic nature of the receptor-ligand complex.

6659. Lee KH, McKie VC, Sekul EA, Adams RJ, Nichols FT. Unusual encephalopathy after acute chest syndrome in sickle cell disease: acute necrotizing encephalitis. J Pediatr Hematol Oncol. 2002 Oct;24(7):585-8.

Stroke is the most common neurologic complication of sickle cell disease. Acute chest syndrome (ACS) is a known risk factor for stroke in this population. Two patients (a 12-year-old boy and a 6-year-old girl) developed acute change of mental status and focal neurologic signs during episodes of ACS. The clinical and radiologic findings were compatible with acute necrotizing encephalitis, a variant of acute demyelinating encephalomyelitis. Patients with acute neurologic deterioration in conjunction with ACS should be evaluated thoroughly for other causes of central nervous system disease including infectious/parainfectious processes as well as stroke.

6660. Ljungman P. Beta-herpesvirus challenges in the transplant recipient. J Infect Dis. 2002 Oct 15;186 Suppl 1:S99-S109.

Cytomegalovirus (CMV) has major consequences after allogeneic stem cell and solid organ transplantation. CMV may cause significant morbidity and mortality, and monitoring to detect reactivation to reduce disease or management of end organ disease is associated with increased resource utilization. Two other members of the beta-herpesvirus family, human herpesvirus (HHV) type 6 and HHV-7, are increasingly recognized as important pathogens in transplant recipients, either by direct infection (e.g., encephalitis, hepatitis, or pneumonitis) or via interaction with CMV. In addition to direct effects of CMV infection, such indirect effects as an increased risk for bacterial and fungal infections or impaired graft acceptance and function are important research topics. Diagnosis and treatment of CMV infection is currently more advanced than for HHV-6 and HHV-7.

6661. Mantegazza R, Bernasconi P, Baggi F, Spreafico R, Ragona F, Antozzi C, Bernardi G, Granata T. Antibodies against GluR3 peptides are not specific for Rasmussen's encephalitis but are also present in epilepsy patients with severe, early onset disease and intractable seizures. J Neuroimmunol. 2002 Oct;131(1-2):179-85.

Rasmussen's encephalitis (RE) is a rare condition characterized by drug-resistant seizures, recurrent status epilepticus and progressive lateralized neurological deterioration. There is evidence of autoimmune involvement in the pathogenesis. We investigated the presence of anti-GluR3 antibodies against peptides A and B in patients with RE (n=11), partial and generalized epilepsy (n=85) and other neurological diseases (n=30). The antibodies were specific for epilepsy and are thus not a marker of RE, while particularly high antibody titers characterized a subgroup of non-RE patients with "catastrophic" epilepsy. Antibodies against GluR3B peptide were significantly associated with frequent seizures compared to occasional or drug-controlled seizures.

6662. Martin K, Franco-Paredes C. Herpes encephalitis. Lancet. 2002 Oct 26;360(9342):1286. No abstract.

Pathogenesis:

6663. Baum S. West Nile virus: time for prevention, not panic. As the virus spreads, the risk of severe illness remains low. Health News. 2002 Oct;8(10):3. No abstract.

6664. Chase P. Ethical concerns with organ donation. S C Nurse. 2002 Oct-Dec;9(4):23. No abstract.

6665. Colangelo V, Schurr J, Ball MJ, Pelaez RP, Bazan NG, Lukiw WJ. Gene expression profiling of 12633 genes in Alzheimer hippocampal CA1: transcription and neurotrophic factor down-regulation and up-regulation of apoptotic and pro-inflammatory signaling. J Neurosci Res. 2002 Nov 1;70(3):462-73.

Alterations in transcription, RNA editing, translation, protein processing, and clearance are a consistent feature of Alzheimer's disease (AD) brain. To extend our initial study (Alzheimer Reports [2000] 3:161-167), RNA samples isolated from control and AD hippocampal cornu ammonis 1 (CA1) were analyzed for 12633 gene and expressed sequence tag (EST) expression levels using DNA microarrays (HG-U95Av2 Genechips; Affymetrix, Santa Clara, CA). Hippocampal CA1 tissues were carefully selected from several hundred potential specimens obtained from domestic and international brain banks. To minimize the effects of individual differences in gene expression, RNA of high spectral quality (A(260/280) > or= 1.9) was pooled from CA1 of six control or six AD subjects. Results were compared as a group; individual gene expression patterns for the most-changed RNA message levels were also profiled. There were no significant differences in age, postmortem interval (mean < or = 2.1 hr) nor tissue pH (range 6.6-6.9)

between the two brain groups. AD tissues were derived from subjects clinically classified as CDR 2-3 (CERAD/NIA). Expression data were analyzed using GeneSpring (Silicon Genetics, Redwood City, CA) and Microarray Data Mining Tool (Affymetrix) software. Compared to controls and 354 background/alignment markers, AD brain showed a generalized depression in brain gene transcription, including decreases in RNA encoding transcription factors (TFs), neurotrophic factors, signaling elements involved in synaptic plasticity such as synaptophysin, metallothionein III, and metal regulatory factor-1. Three- or morefold increases in RNAs encoding DAXX, cPLA(2), CDP5, NF-kappaBp52/p100, FAS, betaAPP, DPP1, NFIL6, IL precursor, B94, HB15, COX-2, and CEX-1 signals were strikingly apparent. These data support the hypothesis of widespread

transcriptional alterations, misregulation of RNAs involved in metal ion homeostasis, TF signaling deficits, decreases in neurotrophic support and activated apoptotic and neuroinflammatory signaling in moderately affected AD hippocampal CA1. Copyright 2002 Wiley-Liss, Inc.

6666. Gnann JW Jr. Varicella-zoster virus: atypical presentations and unusual complications. J Infect Dis. 2002 Oct 15;186 Suppl 1:S91-8. Review.

Varicella-zoster virus (VZV) is the etiologic agent of varicella (primary infection) and herpes zoster (reactivation of latent infection). Although varicella is most often a relatively benign and self-limited childhood illness, the disease can be associated with a variety of serious and potentially lethal complications in both immunocompetent and immunocompromised persons. One complication of varicella that appears to be increasing in frequency is serious bacterial soft tissue infections caused by group A streptococci. Issues related to management of varicella become especially complex when varicella involves pregnant women or susceptible neonates. Herpes zoster can be associated with a variety of neurologic complications, including a syndrome of delayed contralateral hemiparesis. Neurologic complications of herpes zoster, including chronic encephalitis, occur with increased frequency in AIDS patients. VZV retinitis is a potentially sight-threatening complication that occurs in both immunocompetent and immunocompromised persons. Current knowledge regarding pathogenesis and antiviral therapy is reviewed.

6667. Rodriguez JJ, Parisien JP, Horvath CM. Nipah virus V protein evades alpha and gamma interferons by preventing STAT1 and STAT2 activation and nuclear accumulation. J Virol. 2002 Nov;76(22):11476-83.

Characterization of recent outbreaks of fatal encephalitis in southeast Asia identified the causative agent to be a previously unrecognized enveloped negative-strand RNA virus of the Paramyxoviridae family, Nipah virus. One feature linking Nipah virus to this family is a conserved cysteine-rich domain that is the hallmark of paramyxovirus V proteins. The V proteins of other paramyxovirus species have been linked with evasion of host cell interferon (IFN) signal transduction and subsequent antiviral responses by inducing proteasomal degradation of the IFN-responsive transcription factors, STAT1 or STAT2. Here we demonstrate that Nipah virus V protein escapes IFN by a distinct mechanism involving direct inhibition of STAT protein function. Nipah virus V protein differs from other paramyxovirus V proteins in its subcellular distribution but not in its ability to inhibit cellular IFN responses. Nipah virus V protein does not induce STAT degradation but instead inhibits IFN responses by forming high-molecular-weight complexes with both STAT1 and STAT2. We demonstrate that Nipah virus V protein accumulates in the cytoplasm by a Crm1-dependent mechanism, alters the STAT protein subcellular distribution in the steady state, and prevents IFN-stimulated STAT redistribution. Consistent with the formation of complexes, STAT protein tyrosine phosphorylation is inhibited in cells expressing the Nipah virus V protein. As a result, Nipah virus V protein efficiently prevents STAT1 and STAT2 nuclear translocation in response to IFN, inhibiting cellular responses to both IFN-alpha and IFN-gamma.

Vaccines:

6668. Harrington PR, Lindesmith L, Yount B, Moe CL, Baric RS. Binding of Norwalk virus-like particles to ABH histo-blood group antigens is blocked by antisera from infected human volunteers or experimentally vaccinated mice. J Virol 2002 Dec;76(23):12335-43

Attachment of Norwalk (NV), Snow Mountain (SMV), and Hawaii (HV) virus-like particles (VLPs) to specific ABH histo-blood group antigens was investigated by using human saliva and synthetic biotinylated carbohydrates. The three distinct Norwalk-like viruses (NLVs) have various capacities for binding ABH histo-blood group antigens, suggesting that different mechanisms for NLV attachment likely exist. Importantly, antisera from NV-infected human volunteers, as well as from mice inoculated with packaged Venezuelan equine encephalitis virus replicons expressing NV VLPs, blocked the ability of NV VLPs to bind synthetic H type 1, Le(b), and H type 3, suggesting a potential mechanism for antibody-mediated neutralization of NV.

Therapy:

6669. Gupta SK; Verma VK; Parihar A. Herpes simplex encephalitis JK Practitioner. 2002 Jan-Mar; 9(1): 53-4

6670. Quirk M. First treatment trial for West Nile infection begins. Lancet Infect Dis. 2002 Oct;2(10):589. No abstract.

6671. Singh N; Syed Sadiq A; Singh V; Singh A Adaptogens anti stress agents a study focusing Indian plants. Antiseptic. 2002 Jun; 99(6): 198-201

July 2003

7167. Aboul-Enein F, Rauschka H, Kornek B, Stadelmann C, Stefferl A, Bruck W, Lucchinetti C, Schmidbauer M, Jellinger K, Lassmann H. Preferential loss of myelin-associated glycoprotein reflects hypoxia-like white matter damage in stroke and inflammatory brain diseases. J Neuropathol Exp Neurol. 2003 Jan;62(1):25-33.

Destruction of myelin and oligodendrocytes leading to the formation of large demyelinated plaques is the hallmark of multiple sclerosis (MS) pathology. In a subset of MS patients termed pattern III, actively demyelinating lesions show preferential loss of myelin-associated glycoprotein (MAG) and apoptotic-like oligodendrocyte destruction, whereas other myelin proteins remain well preserved. MAG is located in the most distal periaxonal oligodendrocyte processes and primary "dying back" oligodendrogliopathy may be the initial step of myelin degeneration in pattern III lesions. In the present study, various human white matter pathologies, including acute and chronic white matter stroke, virus encephalitis, metabolic encephalopathy, and MS were studied. In addition to a subset of MS cases, a similar pattern of demyelination was found in some cases of virus encephalitis as well as in all lesions of acute white matter stroke. Brain white matter lesions presenting with MAG loss and apoptotic-like oligodendrocyte destruction, irrespective of their primary disease cause, revealed a prominent nuclear expression of hypoxia inducible factor-1alpha in various cell types, including oligodendrocytes. Our data suggest that a hypoxia-like tissue injury may play a pathogenetic role in a subset of inflammatory demyelinating brain lesions.

7168. Azad R, Gupta RK, Kumar S, Pandey CM, Prasad KN, Husain N, Husain M. Is neurocysticercosis a risk factor in coexistent intracranial disease? An MRI based study. J Neurol Neurosurg Psychiatry. 2003 Mar;74(3):359-61.

BACKGROUND: Previous reports have suggested that neurocysticercosis is associated with glioma and Japanese encephalitis, and that it is a risk factor for stroke. OBJECTIVE: To determine if neurocysticercosis has a significant association with, or is a risk factor for, coexistent pathologies such as Japanese encephalitis, glioma, abscess, tuberculoma, or infarction. SUBJECTS: 10 350 patients from the hospital population who underwent 1.5 T cranial magnetic resonance imaging during the previous 12 years were evaluated for the presence of neurocysticercosis and coexisting pathology. DESIGN: Retrospective cohort analysis. RESULTS: The prevalence of neurocysticercosis in cases with dual pathology was significantly less than in a control group (1.1% v 8.3%; z = 11.05; p < 0.001, power of test = 1). Neurocysticercosis lesions were less common (p < 0.05) in the different subgroups of coexistent pathology than in the control group except in the case of Japanese encephalitis, where the difference was non-significant (z = 0.69, p = 0.49). The relative risk was less than 1 in all subgroups except Japanese encephalitis, where it was 1.23. The location of neurocysticercosis lesions and the presence of perilesional oedema did not affect coexistent lesion location or severity on a particular side (p = 0.413 and 0.623 for location and perilesional oedema, respectively). When the above factors were analysed separately in patients with Japanese encephalitis, they also did not affect coexistent lesion location or severity (p = 0.659 and 0.548, respectively). CONCLUSIONS: The coexistence of neurocysticercosis and other lesions may be an incidental observation in a few patients referred from areas of high prevalence and endemicity. It appears unlikely that neurocysticercosis is a risk factor for other intracerebral pathology. The location of neurocysticercosis lesions and whether or not there is surrounding perilesional oedema do not appear to affect the location or severity of coexisting lesions.

7169. Behzad-Behbahani A, Klapper PE, Vallely PJ, Cleator GM. BK virus DNA in CSF of immunocompetent and immunocompromised patients. Arch Dis Child 2003 Feb;88(2):174-5

AIM: To investigate the possible aetiological role of BK and JC viruses in immunocompetent and immunocompromised children with suspected encephalitis and meningoencephalitis. METHODS: The polymerase chain reaction and microplate hybridisation method was employed for the detection of polyomavirus DNA in 266 CSF specimens collected from immunocompetent and immunocompromised patients. RESULTS: BK virus DNA was detected in three (2.1%) CSF samples taken from patients aged 2-5 years; two were patients with acute lymphocytic leukaemia without overt neurological symptoms, the other was a patient with suspected encephalitis. BK virus DNA was also detected in two (1.6%) CSF samples taken from older children in the age range 10-16 years; both children had suspected encephalitis. JC virus DNA was not found in any CSF sample from either age group. CONCLUSIONS: Detection of BK virus in the CSF of immunocompromised and immunocompetent patients with suspected neurological disease suggests that this virus may have had a pathogenic role in the aetiology of this condition

7170. Bernal F, Shams'ili S, Rojas I, Sanchez-Valle R, Saiz A, Dalmau J, Honnorat J, Sillevis Smitt P, Graus F. Anti-Tr antibodies as markers of paraneoplastic cerebellar degeneration and Hodgkin's disease. Neurology. 2003 Jan 28;60(2):230-4.

BACKGROUND: Preliminary studies suggested that anti-Tr antibodies identify patients with paraneoplastic cerebellar degeneration (PCD) and Hodgkin disease (HD). OBJECTIVE: To extend the clinical-immunologic analysis to 28 patients with anti-Tr antibodies. METHODS: Anti-Tr antibodies were detected by immunohistochemistry. A competitive inhibition assay was used to ascertain if anti-Tr antibodies of different sera identify common epitopes. Anti-Tr immunoglobulin G (IgG) subclass distribution was determined by immunohistochemistry using monoclonal antibodies against human IgG isotypes. Tr immunoreactivity was analyzed in tumor sections using biotinylated anti-Tr IgG. RESULTS: Median age of the 28 patients was 61 years (range 14 to 75 years) and 22 were male. A cerebellar syndrome was present in 27 patients and a possible limbic encephalitis in one. HD was diagnosed in 25 patients. No tumor was found in three patients; the autopsy of one of them disclosed severe loss of Purkinje cells without inflammatory infiltrates. Anti-Tr antibodies spontaneously disappeared in all patients without tumor and in 10/10 patients after successful HD treatment. Anti-Tr antibodies were absent in the serum but positive in the CSF of two patients. All positive anti-Tr sera inhibited the immunoreactivity of biotinylated anti-Tr IgG. The predominant isotypes of anti-Tr were IgG1 and IgG3. Only 1 out of the 15 HD samples studied presented anti-Tr positivity that was localized in some Reed-Sternberg cells. CONCLUSIONS: This study confirms the strong association between anti-Tr antibodies and PCD associated with HD. Anti-Tr antibodies from different patients recognize similar epitopes. Unlike other antineuronal antibodies, anti-Tr antibodies can be detected in the CSF but not in the serum and may spontaneously disappear during the follow-up, and Tr immunoreactivity is usually lacking in the tumor.

7171. Dong M, Zhang PF, Grieder F, Lee J, Krishnamurthy G, VanCott T, Broder C, Polonis VR, Yu XF, Shao Y, Faix D, Valente P, Quinnan GV Jr. Induction of primary virus-cross-reactive human immunodeficiency virus type 1-neutralizing antibodies in small animals by using an alphavirus-derived in vivo expression system. J Virol. 2003 Mar;77(5):3119-30.

We have studied the induction of neutralizing antibodies by in vivo expression of the human immunodeficiency virus type 1 (HIV-1) envelope by using a Venezuelan equine encephalitis virus (VEE) replicon system with mice and rabbits. The HIV-1 envelope, clone R2, has broad sensitivity to cross-reactive neutralization and was obtained from a donor with broadly cross-reactive, primary virus-neutralizing antibodies (donor of reference serum, HIV-1-neutralizing serum 2 [HNS2]). It was expressed as gp160, as secreted gp140, and as gp160deltaCT with the cytoplasmic tail deleted. gp140 was expressed in vitro at a high level and was predominantly uncleaved oligomer. gp160deltaCT was released by cells in the form of membrane-bound vesicles. gp160deltaCT induced stronger neutralizing responses than the other forms. Use of a helper plasmid for replicon particle packaging, in which the VEE envelope gene comprised a wild-type rather than a host range-adapted sequence, also enhanced immunogenicity. Neutralizing activity fractionated with immunoglobulin G. This activity was cross-reactive among a panel of five nonhomologous primary clade B strains and a Chinese clade C strain and minimally reactive against a Chinese clade E (circulating recombinant form 1) strain. The comparative neutralization of these strains by immune mouse sera was similar to the relative neutralizing effects of HNS2, and responses induced in rabbits were similar to those induced in mice. Together, these results demonstrate that neutralizing antibody responses can be induced in mice within 2 to 3 months that are similar in potency and cross-reactivity to those found in the chronically infected, long-term nonprogressive donor of HNS2. These findings support the expectation that induction of highly cross-reactive HIV-1 primary virus-neutralizing activity by vaccination may be realized.

7172. Hamprecht K, Eckle T, Prix L, Faul C, Einsele H, Jahn G. Ganciclovir-resistant cytomegalovirus disease after allogeneic stem cell transplantation: pitfalls of phenotypic diagnosis by in vitro selection of an UL97 mutant strain. J Infect Dis. 2003 Jan 1;187(1):139-43.

A 9-month posttransplantation course of an allogeneic stem-cell transplant recipient (human cytomegalovirus [HCMV] serostatus, donor positive/recipient negative), in whom ganciclovir (GCV) resistance developed (UL97 mutations M460V, L595S, and C603W) on day 164 after transplantation and who developed HCMV retinitis and fatal HCMV encephalitis is presented. Virus strains isolated from secondary cultures were analyzed by UL97 restriction assays and sequencing and were compared with primary DNA extracts of the same specimens, which resulted in molecular proof of an initial HCMV strain-specific in vitro selection of the in vivo nondominant UL97 L595S-C603 mutant strain from 3 viral variants present in vivo. In addition, compartmentalization of virus present in blood and cerebrospinal fluid was found. The influence of rapidly increasing plasma virus load (to >10(6) copies/mL) and oral administration of GCV on the emergence of GCV resistance is shown. These findings have strong implications for the diagnosis of HCMV drug resistance.

7173. Hertzig T, Weber M, Greiffenberg L, Holthausen BS, Goebel W, Kim KS, Kuhn M. Antibodies present in normal human serum inhibit invasion of human brain microvascular endothelial cells by Listeria monocytogenes. Infect Immun. 2003 Jan;71(1):95-100.

Listeria monocytogenes causes meningitis and encephalitis in humans and crosses the blood-brain barrier by yet unknown mechanisms. The interaction of the bacteria with different types of endothelial cells was recently analyzed, and it was shown that invasion into, but not adhesion to, human brain microvascular endothelial cells (HBMEC) depends on the product of the inlB gene, the surface molecule InlB, which is a member of the internalin multigene family. In the present study we analyzed the role of the medium composition in the interaction of L. monocytogenes with HBMEC, and we show that invasion of HBMEC is strongly inhibited in the presence of adult human serum. The strong inhibitory activity, which is not present in fetal calf serum, does not inhibit uptake by macrophage-like J774 cells but does also inhibit invasion of Caco-2 epithelial cells. The inhibitory component of human serum was identified as being associated with L. monocytogenes-specific antibodies present in the human serum. Human newborn serum (cord serum) shows only a weak inhibitory activity on the invasion of HBMEC by L. monocytogenes.

7174. Hurley RA, Ernst T, Khalili K, Del Valle L, Simone IL, Taber KH. Identification of HIV-associated progressive multifocal leukoencephalopathy: magnetic resonance imaging and spectroscopy. J Neuropsychiatry Clin Neurosci. 2003 Winter;15(1):1-6. No abstract available.

7175. Kossmann T, Morganti-Kossmann MC, Orenstein JM, Britt WJ, Wahl SM, Smith PD. Cytomegalovirus production by infected astrocytes correlates with transforming growth factor-beta release. J Infect Dis. 2003 Feb 15;187(4):534-41.

Cytomegalovirus (CMV) encephalitis is well documented in immunosuppressed persons, but its pathogenesis has received little investigative attention. The examination of brain tissue from 2 patients with acquired immunodeficiency syndrome who had CMV encephalitis showed colocalization of CMV inclusions and transforming growth factor (TGF)-beta in cells that contained astrocyte-specific glial filaments. To investigate the relationship between CMV and TGF-beta in the brain, an ex vivo murine model of CMV-infected astrocytes was established. Cultures of primary murine (strain FVB/N) astrocytes inoculated with murine (Smith strain) CMV expressed, over time, increasing amounts of infectious CMV in parallel with increasing levels of TGF-beta mRNA and peptide. Astrocyte release of CMV declined in the presence of antibody to TGF-beta and increased substantially after the addition of exogenous TGF-beta. These findings suggest that CMV infection of astrocytes induces the production of TGF-beta, which in turn enhances productive CMV expression.

7176. Lin TY, Hsia SH, Huang YC, Wu CT, Chang LY. Proinflammatory cytokine reactions in enterovirus 71 infections of the central nervous system. Clin Infect Dis. 2003 Feb 1;36(3):269-74.

Enterovirus 71 (EV71) infection can lead to devastating clinical outcomes. An appreciation of the scientific relationship between cytokine response and patient mortality may help limit the risks posed by this deadly illness. We present the results of a study that compared the cerebrospinal fluid (CSF) and serum levels of interleukin-6 (IL-6) and interleukin-1beta (IL-1beta) in 24 patients with EV71 infection. Cases in this study involved diverse manifestations or complications, including encephalitis, poliomyelitis-like syndrome, meningitis, and pulmonary edema. CSF levels of IL-6 in study patients were found to be consistently higher during the first 2 days of central nervous system (CNS) involvement than afterward. Compared with patients who did not have pulmonary edema, patients who experienced pulmonary edema had dramatically varied blood values, including IL-6, white blood cell counts, and glucose levels. Our findings suggest that the combination of CNS and systemic inflammatory response may trigger EV71-related cardiopulmonary collapse.

7177. Mishra OP, Batra P, Ali Z, Anupurba S, Das BK. Cerebrospinal fluid lysozyme level for the diagnosis of tuberculous meningitis in children. J Trop Pediatr. 2003 Feb;49(1):13-6.

Lysozyme activity was assayed in the cerebrospinal fluid (CSF) of 32 tuberculous meningitis (TBM), 17 bacterial meningitis, 10 partially treated bacterial meningitis, 18 encephalitis and 18 control subjects. The mean CSF lysozyme activity was significantly raised (p < 0.001) in TBM patients compared with other study groups. A cut-off CSF lysozyme level of > or = 26 U/l had a sensitivity and specificity of 93.7 and 84.1 per cent, respectively for the diagnosis of TBM. Overall, it was found to be a better test than any other single test and thus can be used for rapid and early diagnosis of TBM in children.

7178. Potula R, Badrinath S, Srinivasan S. Japanese encephalitis in and around Pondicherry, South India: a clinical appraisal and prognostic indicators for the outcome. J Trop Pediatr. 2003 Feb;49(1):48-53.

Japanese encephalitis (JE) is numerically one of the most important causes of viral encephalitis worldwide, with an estimated 50,000 cases and 15,000 deaths annually. About one-third of patients die and half of the survivors have severe neuropsychiatric sequelae. Three hundred patients clinically suspected of JE were tested in the present study. Laboratory confirmation of JE was on the basis of detection of antigen or presence of JE-specific IgM antibody and/or neutralizing antibody in a single CSF sample. The risk factors that were associated with fatal outcome were determined. Japanese encephalitis infection was confirmed in 70.7 per cent (212/300) of the patients. All patients were from rural areas and with low socioeconomic background. Prominent clinical findings were: fever in 100 per cent (212/212) patients, altered sensorium in 87.73 per cent (186/212), convulsion in 85.84 per cent (182/212), headache in 50 per cent (106/212), and vomiting in 47.64 per cent (101/212). The final clinical outcome was available for only 68.39 per cent (145/212) of patients, as children were taken home against medical advice. Of these, 35.86 per cent (52) died while 63.44 per cent (92) of patients survived. Correlations of investigative findings with the final outcome revealed that absence of virus-specific IgM and neutralizing antibodies in CSF were associated with fatal outcome. In patients diagnosed with Japanese encephalitis the presence of a virus-specific immune response is associated with a favourable outcome and an important parameter in recovery from illness.

7179. Schauble B, Castillo PR, Boeve BF, Westmoreland BF. EEG findings in steroid-responsive encephalopathy associated with autoimmune thyroiditis. Clin Neurophysiol. 2003 Jan;114(1):32-7.

OBJECTIVE: To analyze the electroencephalogram (EEG) findings of patients with steroid-responsive encephalopathy associated with autoimmune (Hashimoto) thyroiditis. METHODS: We reviewed 51 EEGs and the clinical records of 17 patients (5 men and 12 women, 27-84 years old). RESULTS: All patients had mild to severe generalized slowing on the EEG which corresponded to the clinical severity of the underlying encephalopathy. Other findings included triphasic waves, epileptiform abnormalities, photomyogenic response, and photoparoxysmal response. Follow-up EEGs of 13 patients showed slowing in 7 and a return to normal in 6. Myoclonic jerks were recorded during the EEG study of 8 patients but did not have an EEG correlate. The EEG and clinical condition improved after treatment with corticosteroids. When encephalopathy recurred, the EEG showed corresponding abnormalities. CONCLUSIONS: EEG findings in steroid-responsive encephalopathy associated with autoimmune thyroiditis consist mainly of slow wave abnormalities that reflect the degree of severity of the underlying encephalopathy. The EEG findings often paralleled the course of the disease, showing improvement with improvement in the clinical condition and worsening with recurrence of symptoms. SIGNIFICANCE: The EEG is helpful in evaluating and following patients with steroid-responsive encephalopathy associated with autoimmune thyroiditis in reflecting the degree of central nervous system (CNS) involvement, in determining whether their condition is better or worse, and in ruling out other causes of encephalopathy.

7180. Sibbald B. Canada will check donor blood for West Nile virus if test available. CMAJ. 2003 Jan 21;168(2):207. No abstract available.

7181. Singhal AB, Newstein MC, Budzik R, Cha JH, Rordorf G, Buonanno FS, Panzara MA. Diffusion-weighted magnetic resonance imaging abnormalities in Bartonella encephalopathy. J Neuroimaging. 2003 Jan;13(1):79-82.

The authors describe 2 patients with new-onset, refractory status epilepticus and serological evidence for Bartonella infection. Brain magnetic resonance imaging (MRI) in patient 1 showed transient diffusion abnormalities in the posterior (pulvinar) thalami. In patient 2, brain MRI showed several enhancing cortical lesions, of which one lesion was bright on diffusion-weighted imaging (DWI). In patients with unexplained, refractory seizures, the presence of DWI abnormalities warrants a search for unusual infectious or inflammatory disorders, like Bartonella encephalitis.

7182. Thomas P, Zifkin B, Ghetau G, Delalande O. Persistence of ictal activity after functional hemispherectomy in Rasmussen syndrome. Neurology. 2003 Jan 14;60(1):140-2.

A 15-year-old girl with a 3-year history of Rasmussen syndrome (RS) underwent left functional hemispherectomy by central disconnection. Clinical seizures then ceased. Five months postoperatively, ictal EEG discharges were associated with focal hyperperfusion on SPECT within the disconnected hypoperfused left hemisphere, suggesting that the basic mechanisms of RS may continue, only to remit later. EEG and SPECT may complement studies of these in seizure-free surgically treated patients in whom clinical follow-up may be unrevealing.

7183. Turchan J, Pocernich CB, Gairola C, Chauhan A, Schifitto G, Butterfield DA, Buch S, Narayan O, Sinai A, Geiger J, Berger JR, Elford H, Nath A. Oxidative stress in HIV demented patients and protection ex vivo with novel antioxidants. Neurology. 2003 Jan 28;60(2):307-14.

OBJECTIVE: To determine the role of oxidative stress in mediating HIV dementia and to identify novel therapeutic compounds that may block this oxidative stress. METHODS: Brain tissue from patients with HIV encephalitis and macaques with simian immune deficiency virus encephalitis was immunostained for lipid peroxidation. Oxidized proteins in CSF of patients with various stages of HIV dementia were quantitated and we determined whether CSF from these patients could alter mitochondrial function. Several novel compounds with antioxidant effects were screened to determine their relative efficacy in protecting against CSF-induced neurotoxicity. RESULTS: Evidence for oxidative stress was present both in brain and in CSF. The presence of oxidized proteins in the CSF and CSF-induced progressive decrease in mitochondrial activity correlated with the severity of cognitive impairment, but only the group of patients with moderate to severe dementia reached statistical significance. L-deprenyl, didox, imidate, diosgenin, and ebselen blocked the CSF-induced toxicity. No effect of trimidox, ruthenium red, or Quercetin was seen. CONCLUSIONS: Increased oxidative stress is present in brain and CSF of HIV-infected patients. There is also an accumulation of toxic substances in the CSF that are capable of inducing oxidative stress. The authors have identified several novel compounds that are capable of blocking the CSF-induced toxicity, the therapeutic potential of which is worthy of further exploration.

7184. Warnatz K, Peter HH, Schumacher M, Wiese L, Prasse A, Petschner F, Vaith P, Volk B, Weiner SM. Infectious CNS disease as a differential diagnosis in systemic rheumatic diseases: three case reports and a review of the literature. Ann Rheum Dis. 2003 Jan;62(1):50-7.

BACKGROUND: Immunosuppressive treatment of rheumatic diseases may be associated with several opportunistic infections of the brain. The differentiation between primary central nervous system (CNS) involvement and CNS infection may be difficult, leading to delayed diagnosis. OBJECTIVE: To differentiate between CNS involvement and CNS infection in systemic rheumatic diseases. Methods and results: Three patients with either longstanding or suspected systemic rheumatic diseases (systemic lupus erythematodes, Wegener's granulomatosis, and cerebral vasculitis) who presented with various neuropsychiatric symptoms are described. All three patients were pretreated with different immunosuppressive drugs (leflunomide, methotrexate, cyclophosphamide) in combination with corticosteroids. Magnetic resonance imaging of the brain was suggestive of infectious disease, which was confirmed by cerebrospinal fluid analysis or stereotactic brain biopsy (progressive multifocal leucoencephalopathy (PML) in two and nocardiosis in one patient). DISCUSSION: More than 20 cases of PML or cerebral nocardiosis in patients receiving corticosteroids and cytotoxic drugs for rheumatic disease have been reported. The clinical aspects of opportunistic CNS infections and the role of brain imaging, cerebrospinal fluid analysis and stereotactic brain biopsy in the differential diagnosis are reviewed.

Pathogenesis:

7185. Booton GC, Carmichael JR, Visvesvara GS, Byers TJ, Fuerst PA. Genotyping of Balamuthia mandrillaris based on nuclear 18S and mitochondrial 16S rRNA genes.Am J Trop Med Hyg. 2003 Jan;68(1):65-9.

Balamuthia mandrillaris is an opportunistically pathogenic ameba that causes fatal granulomatous amebic encephalitis (GAE) in vertebrates. Previous phylogenetic analyses that included the sequence of a single nuclear small subunit ribosomal RNA gene (18S or ssu rDNA) from this ameba suggested that Balamuthia is closely related to Acanthamoeba, another opportunistically pathogenic amebic genus, which includes multiple ssu rDNA genotypes. We tested whether this also is true for Balamuthia. The nuclear ssu rDNA from 4 isolates and the mitochondrial ssu rDNA from 7 isolates of B. mandrillaris have been sequenced. No variation in the nuclear rDNA sequences and low levels of variation in the mitochondrial rDNA were found. Both gene sequences were consistent with a single genotype for B. mandrillaris. The mitochondrial sequences of B. mandrillaris are unique and should be useful for development of genus-specific diagnostic probes for use with clinical, environmental, and archived specimens.

7186. Cucchiara BL, Forman MS, McGarvey ML, Kasner SE, King D. Fatal subacute cytomegalovirus encephalitis associated with hypogammaglobulinemia and thymoma. Mayo Clin Proc. 2003 Feb;78(2):223-7.

Parathymic syndromes are systemic disorders that occur in association with thymoma. One such parathymic syndrome, hypogammaglobulinemia, was initially identified by Good in 1954 and has been referred to as Good syndrome. Patients with this syndrome develop a variety of recurrent infections due to the associated immunodeficiency. We describe a patient with cytomegalovirus encephalitis associated with Good syndrome and discuss the pathologic findings present on autopsy. The possibility of a cytomegalovirus infection should be considered early in the evaluation of patients with Good syndrome if appropriate clinical symptoms are present.

7187. Gritsun TS, Frolova TV, Zhankov AI, Armesto M, Turner SL, Frolova MP, Pogodina VV, Lashkevich VA, Gould EA. Characterization of a siberian virus isolated from a patient with progressive chronic tick-borne encephalitis. J Virol. 2003 Jan;77(1):25-36.

A strain of Tick-borne encephalitis virus designated Zausaev (Za) was isolated in Siberia from a patient who died of a progressive (2-year) form of tick-borne encephalitis 10 years after being bitten by a tick. The complete genomic sequence of this virus was determined, and an attempt was made to correlate the sequence with the biological characteristics of the virus. Phylogenetic analysis demonstrated that this virus belongs to the Siberian subtype of Tick-borne encephalitis virus. Comparison of Za virus with two related viruses, a Far Eastern isolate, Sofjin, and a Siberian isolate, Vasilchenko, revealed differences among the three viruses in pathogenicity for Syrian hamsters, cytopathogenicity for PS cells, plaque morphology, and the electrophoretic profiles of virus-specific nonstructural proteins. Comparative amino acid alignments revealed 10 individual amino acid substitutions in the Za virus polyprotein sequence that were different from those of other tick-borne flaviviruses. Notably, the dimeric form of the Za virus NS1 protein migrated in polyacrylamide gels as a heterogeneous group of molecules with a significantly higher electrophoretic mobility than those of the Sofjin and Vasilchenko viruses. Two amino acid substitutions, T(277)-->V and E(279)-->G, within the NS1 dimerization domain are probably responsible for the altered oligomerization of Za virus NS1. These studies suggest that the patient from whom Za virus was isolated died due to increased pathogenicity of the latent virus following spontaneous mutagenesis.

7188. Kathula SK, Kamana M, Mall S. Rectal carcinoma with dementia. Psychosomatics. 2003 Jan-Feb;44(1):82-3. No abstract available.

7189. Kumar S. Inadequate research facilities fail to tackle mystery disease. BMJ. 2003 Jan 4;326(7379):12. No abstract available.

7190. Pola R, Flex A, Gaetani E, Santoliquido A, Serricchio M, Pola P, Bernabei R. Intercellular adhesion molecule-1 K469E gene polymorphism and Alzheimer's disease. Neurobiol Aging. 2003 Mar-Apr;24(2):385-7.

Inflammatory processes are considered important in the pathogenesis of Alzheimer's disease (AD). Intercellular adhesion molecule-1 (ICAM-1) is an important mediator of inflammatory response and immune cell activation, is expressed on cerebrovascular endothelium and neuritic plaques in brain of AD patients, and seems to be implicated in the process of neuro-degeneration. A common polymorphism of the ICAM-1 gene (K469E) has been recently reported. In this case-control study, we evaluated the distribution of E/K alleles and genotypes of the ICAM-1 gene in 98 patients affected by sporadic AD and 115 age- and sex-matched controls. The frequency of the EE genotype was significantly higher in AD patients (P<0.01). Logistic regression analysis indicated that the presence of EE genotype significantly increased the risk of AD (odds ratio 3.01 [1.1-8.0], P<0.05). This study shows for the first time an association between ICAM-1 E/K gene polymorphism and AD, suggesting that polymorphisms of the ICAM-1 gene may be clinically important and confirming that inflammatory mechanisms may be crucial in the pathophysiology of neuro-degenerative diseases.

7191. Ryan J, Dave K, Emmerich E, Fernandez B, Turell M, Johnson J, Gottfried K, Burkhalter K, Kerst A, Hunt A, Wirtz R, Nasci R. Wicking assays for the rapid detection of West Nile and St. Louis encephalitis viral antigens in mosquitoes (Diptera: Culicidae). J Med Entomol. 2003 Jan;40(1):95-9.

The recent outbreaks of West Nile (WN) encephalitis and St. Louis encephalitis (SLE) in the United States have highlighted the need for rapid and specific methods of detecting arboviral antigens in mosquitoes. We evaluated rapid, field-usable assays for detecting and differentiating WN and SLE viruses in mosquito pools, based on a patent-pending, immunochromatographic technology (VecTest) formatted on a dipstick. The device provides results in less than 20 min and can be used in laboratories with adequate containment facilities. In laboratory assessments, both the SLE and WN virus tests demonstrated sensitivity comparable with that of an antigen capture ELISA, but less than can be achieved with Vero cell plaque or reverse-transcriptase polymerase chain reaction assays. There was no evidence of cross-reaction when tested with high concentrations of heterologous flavivirus antigens or with Eastern equine encephalitis or Western equine encephalitis viruses. Both the WN and SLE dipstick tests delivered a clear positive result with a single positive specimen in a pool of 50 mosquitoes. This virus assay technology reduces the time required to obtain test results and will allow rapid medical threat assessment and effective targeting of vector control measures.

7192. Teunissen CE, van Boxtel MP, Bosma H, Bosmans E, Delanghe J, De Bruijn C, Wauters A, Maes M, Jolles J, Steinbusch HW, de Vente J. Inflammation markers in relation to cognition in a healthy aging population. J Neuroimmunol. 2003 Jan;134(1-2):142-50.

The relation between serum inflammatory protein levels and cognitive performance was investigated in a healthy population.Individuals were tested during 6 years of follow-up. Serum concentrations of 10 inflammatory proteins were correlated to cognitive speed (Letter-Digit Coding Test, LDCT), attention and information processing (Stroop) and memory (Word Learning). Haptoglobin levels at baseline correlated negatively with cognitive performance on the Stroop and Word Learning Recall test over the 6 years follow-up period. C-reactive protein (CRP) levels at baseline correlated negatively with performance on the Word Learning tests over the 6 years follow-up period. Thus, relatively high concentrations of haptoglobin and C-reactive protein may be indicative for impaired cognitive performance.

7193. Twiddy SS, Holmes EC. The extent of homologous recombination in members of the genus Flavivirus. J Gen Virol. 2003 Feb;84(Pt 2):429-40.

The family Flaviviridae includes important human pathogens, such as dengue (DEN) virus, yellow fever (YF) virus and hepatitis C virus, many of which have emerged or re-emerged in recent years. Until recently, flavivirus evolution was thought to proceed in a clonal manner, with diversity generated mainly through the accumulation of mutational changes. However, this assumption has now been shown to be invalid, with homologous recombination demonstrated in all three genera of the FLAVIVIRIDAE: Since recombination has important implications for the study of virus evolution, a survey of recombination in the viruses of the genus Flavivirus was carried out. Using envelope gene sequence data and a combination of graphical and phylogenetic analyses, hitherto unreported recombination in Japanese encephalitis virus and St Louis encephalitis virus was detected, as well as further recombinants in DEN virus. However, no evidence for recombination was found in West Nile or YF viruses, or in the tick-borne flavivirus group. It is proposed that the difference between the mosquito- and tick-borne viruses can be accounted for by their differing modes of transmission, whilst the variation among the mosquito-borne flaviviruses reflects both the ecology of the particular host and vector species and also bias in the sampling process.

7194. Xiong H, Boyle J, Winkelbauer M, Gorantla S, Zheng J, Ghorpade A, Persidsky Y, Carlson KA, Gendelman HE. Inhibition of long-term potentiation by interleukin-8: implications for human immunodeficiency virus-1-associated dementia. J Neurosci Res. 2003 Feb 15;71(4):600-7.

Human immunodeficiency virus type 1 (HIV-1)-infected mononuclear phagocytes (MP; brain macrophages and microglia) secrete a number of toxic factors that affect the pathogenesis of HIV-1-associated dementia (HAD). The identification and relative role of each MP toxin for neuronal dysfunction during HAD are not well understood. Interleukin-8 (IL-8), a CXC chemokine involved in leukocyte activation and chemotaxis, is constitutively produced by MP, and elevated levels of IL-8 mRNA were detected in the brains of patients with HIV-1 encephalitis (HIVE) by both ribonuclease protection assays and real-time PCR. To determine the role that IL-8 might play in the neuronal dysfunction in HAD, we studied its effect on synaptic transmission and plasticity in the CA1 region of hippocampus, the seat of learning and memory. Bath application of IL-8 (50 ng/ml) to rat hippocampal slices had no effect on basal synaptic transmission. However, IL-8 was shown to inhibit long-term potentiation (LTP) in a concentration-dependent manner. In control and IL-8-treated slices, the LTP magnitudes were 167.8% +/- 11.9% (mean +/- SE; n = 17) and 122.2% +/- 16.2% of basal levels (n = 13), respectively. These differences were statistically significant (P < 0.05). Preincubation of hippocampal slices with a monoclonal CXCR2 antibody (2 microg/ml) but not control IgG (2 microg/ml) blocked IL-8-induced inhibition of LTP. The expression of CXCR2 receptors in the CA1 region was shown by Western blot assays. The induction of IL-8 in HAD, its inhibition of LTP, and the expression of its receptor, CXCR2, in the hippocampus all suggest that it plays a role in the cognitive dysfunction associated with HAD. Copyright 2002 Wiley-Liss, Inc.

Vaccines:

7195. Kleymann G.Novel agents and strategies to treat herpes simplex virus infections. Expert Opin Investig Drugs 2003 Feb;12(2):165-83.

The quiet pandemic of herpes simplex virus (HSV) infection has plagued humanity since ancient times, causing mucocutaneous infection, such as herpes labialis and herpes genitalis. Disease symptoms often interfere with everyday activities and occasionally HSV infections are the cause of life-threatening or sight-impairing disease, especially in neonates and the immunocompromised patient population. After primary or initial infection the virus persists for life in a latent form in neurons of the host, periodically reactivating and often resulting in significant psychosocial distress for the patient. Currently, no cure is available. In the mid-1950s the first antiviral, idoxuridine, was developed for topical treatment of herpes disease and, in 1978, vidarabine was licensed for systemic use to treat HSV encephalitis. Acyclovir (Zovirax), a potent, specific and tolerable nucleosidic inhibitor of the herpes DNA polymerase, was a milestone in the development of antiviral drugs in the late 1970s. In the mid-1990s, when acyclovir became a generic drug, valacyclovir (Valtrex) and famciclovir (Famvir), prodrugs of the gold standard and penciclovir (Denavir), Vectavir), a close analogue, were launched. Though numerous approaches and strategies were tested and considerable effort was expended in the search of the next generation of an antiherpetic therapy, it proved difficult to outperform acyclovir. Notable in this regard was the award of a Nobel Prize in 1988 for the elucidation of mechanistic principles which resulted in the development of new drugs such as acyclovir. Vaccines, interleukins, interferons, therapeutic proteins, antibodies, immunomodulators and small-molecule drugs with specific or nonspecific modes of action lacked either efficacy or the required safety profile to replace the nucleosidic drugs acyclovir, valacyclovir, penciclovir and famciclovir as the first choice of treatment. Recently though, new inhibitors of the HSV helicase-primase with potent in vitro antiherpes activity, novel mechanisms of action, low resistance rates and superior efficacy against HSV in animal models have been discovered. This review summarises the current therapeutic options, discusses the potential of preclinical or investigational drugs and provides an up-to-date interpretation of the challenge to establish novel treatments for herpes simplex disease.

7196. Lin CW, Wu SC. A functional epitope determinant on domain III of the Japanese encephalitis virus envelope protein interacted with neutralizing-antibody combining sites. J Virol 2003 Feb;77(4):2600-6.

The envelope (E) protein of Japanese encephalitis virus (JEV) is associated with viral binding to cellular receptors, membrane fusion, and the induction of protective neutralizing-antibody responses in hosts. Most previous studies have not provided detailed molecular information about the spatial configuration of the functional epitopes on domain III of the E protein. Here site-directed mutagenesis was performed to demonstrate that the functional epitope determinants at Ser331 and Asp332 on domain III of the JEV E protein interacted with neutralizing monoclonal antibody (MAb) E3.3. Bacterial expression of the recombinant Fab E3.3 confirmed the molecular interactions of Arg94 in complementary determining region H3 with Ser331 and Asp332 on domain III. This study elucidates the detailed molecular structures of the neutralizing epitope determinants on JEV domain III, which can provide useful information for designing new vaccines.

Therapy:

7197. Atwood CS, Perry G, Smith MA. Cerebral hemorrhage and amyloid-beta. Science. 2003 Feb 14;299(5609):1014. No abstract available.

October 2003

7915. Aronica E, Troost D, Rozemuller AJ, Yankaya B, Jansen GH, Isom LL, Gorter JA. Expression and regulation of voltage-gated sodium channel beta1 subunit protein in human gliosis-associated pathologies. Acta Neuropathol (Berl). 2003 May;105(5):515-23. Epub 2003 Feb 20.

Auxiliary beta1 subunits of voltage-gated sodium channels (NaChs) critically regulate channel activity and may also act as cell adhesion molecules (CAMs). In a recent study we have shown that the expression of beta1 NaCh protein is increased in reactive astrocytes in a rat epilepsy model of mesial temporal lobe epilepsy. The present study was undertaken to examine whether changes of NaCh beta1 subunit protein expression are also associated with structural changes occurring in human reactive astrocytes under different pathological conditions in vivo, as well as in response to changing environmental conditions in vitro. Strong beta1 astroglial immunoreactivity was present in human brain tissue from patients with astrogliosis. The over-expression of beta1 protein in reactive glia was observed in both epilepsy-associated brain pathologies (temporal lobe epilepsy, cortical dysplasia), as well as non-epileptic (cerebral infarction, multiple sclerosis, amyotrophic lateral sclerosis, meningo-encephalitis) disorders. The up-regulation of beta1 subunit protein in astrocytes can be reproduced in vitro. beta1 protein is highly expressed in human astrocytes cultured in the presence of trophic factors, under conditions in which they show morphology similar to the morphology of cells undergoing reactive gliosis. The growth factor-induced overexpression of beta1 protein was abrogated by PD98059, which inhibits the mitogen-activated protein kinase pathway. These findings demonstrate that the expression of NaCh beta1 subunit protein in astrocytes is plastic, and indicate a novel mechanism for modulation of glial function in gliosis-associated pathologies.

7916. Berenguer J, Miralles P, Arrizabalaga J, Ribera E, Dronda F, Baraia-Etxaburu J, Domingo P, Marquez M, Rodriguez-Arrondo FJ, Laguna F, Rubio R, Lacruz Rodrigo J, Mallolas J, de Miguel V; GESIDA 11/99 Study Group. Clinical course and prognostic factors of progressive multifocal leukoencephalopathy in patients treated with highly active antiretroviral therapy. Clin Infect Dis. 2003 Apr 15;36(8):1047-52. Epub 2003 Apr 02.

We analyzed survival rates, neurologic function, and prognostic factors for 118 consecutive patients with acquired immunodeficiency syndrome-associated progressive multifocal leukoencephalopathy (PML) treated with highly active antiretroviral therapy (HAART) in 11 hospitals throughout Spain. Seventy-five patients (63.6%) remained alive for a median of 114 weeks (2.2 years) after diagnosis of PML. Neurologic function of the survivors was categorized as cure or improvement in 33, stabilization or worsening in 40, and unknown in 2. The baseline CD4+ cell count was the only variable found with prognostic significance. The odds ratio of death was 2.71 (95% confidence interval, 1.19-6.15) for patients with CD4+ cell counts of <100 cells/microL, compared with patients who had CD4+ cell counts of > or =100 cells/microL. One-third of patients with PML died despite receipt of HAART; neurologic function improved in approximately one-half of the survivors. A CD4+ cell count of <100 cells/microL was associated with higher mortality.

7917. De Tiege X, Heron B, Lebon P, Ponsot G, Rozenberg F. Limits of early diagnosis of herpes simplex encephalitis in children: a retrospective study of 38 cases. Clin Infect Dis. 2003 May 15;36(10):1335-9. Epub 2003 May 01.

The prognosis of herpes simplex encephalitis (HSE) depends on the early and appropriate administration of specific antiviral therapy. We retrospectively reviewed 38 cases of children with proven HSE, to evaluate the reliability of polymerase chain reaction results, according to the time of cerebrospinal fluid (CSF) sampling. Initial negative results were observed in 8 of 33 CSF samples drawn before day 3 of the disease and were significantly associated with a low level of protein and <10 leukocytes/mm3 in the CSF.

7918. Dunand AC, Jallon P. EEG-mediated diagnosis of an unusual presentation of SSPE. Clin Neurophysiol. 2003 Apr;114(4):737-9.

OBJECTIVE: To highlight the role of EEG in the diagnosis of SSPE. METHODS: EEG was performed in an 18 month old girl who had a 1 week history of repeated episodes of sudden flexion of the head and trunk and frequent falls. RESULTS: EEG abnormalities consisted of stereotyped, generalized and synchronous high amplitude periodic complexes. These abnormalities correlated with brief episodes of axial and upper limb atonia on electromyogram examination. They persisted during sleep although abnormal movements disappeared. Biological results and cerebral MRI confirmed the diagnosis of subacute sclerosing panencephalitis. CONCLUSIONS: This case is exceptional because of the age of the patient, the clinical presentation and the mode of contamination and it highlights the role of EEG in this diagnosis.

7919. Heneka MT, Gavrilyuk V, Landreth GE, O'Banion MK, Weinberg G, Feinstein DL. Noradrenergic depletion increases inflammatory responses in brain: effects on IkappaB and HSP70 expression. J Neurochem. 2003 Apr;85(2):387-98.

The inflammatory responses in many cell types are reduced by noradrenaline (NA) binding to beta-adrenergic receptors. We previously demonstrated that cortical inflammatory responses to aggregated amyloid beta (Abeta) are increased if NA levels were first depleted by lesioning locus ceruleus (LC) noradrenergic neurons, which replicates the loss of LC occurring in Alzheimer's disease. To examine the molecular basis for increased responses, we used the selective neurotoxin DSP4 to lesion the LC, and then examined levels of putative anti-inflammatory molecules. Inflammatory responses were achieved by injection of aggregated Abeta1-42 peptide and IL-1beta into frontal cortex, which induced neuronal inducible nitric oxide synthase (iNOS) and microglial IL-1beta expression. DSP4-treatment reduced basal levels of nuclear factor kappa B (NF-kappaB) inhibitory IkappaB proteins, and of heat shock protein (HSP)70. Inflammatory responses were prevented by co-injection (ibuprofen or ciglitzaone) or oral administration (pioglitazone) of peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. Treatment with PPARgamma agonists restored IkappaBalpha, IkappaBbeta, and HSP70 levels to values equal or above those observed in control animals, and reduced activation of cortical NF-kappaB. These results suggest that noradrenergic depletion reduces levels of anti-inflammatory molecules which normally limit cortical responses to Abeta, and that PPARgamma agonists can reverse that effect. These findings suggest one mechanism by which PPARgamma agonists could provide benefit in neurological diseases having an inflammatory component.

7920. Jorgensen GE, Hammarin AL, Bratt G, Grandien M, Flaegstad T, Johnsen JI. Identification of a unique BK virus variant in the CNS of a patient with AIDS. J Med Virol. 2003 May;70(1):14-9.

Human polyomavirus BK (BKV; GenBank or EMBL or DDBJ accession no. NC001538) is often reactivated in immunosuppressed patients. Reactivation has been associated primarily with excretion of the virus in the urine, and there have been few reports of renal and/or neurological disease caused by BKV in patients with acquired immunodeficiency syndrome (AIDS). Polymerase chain reaction, Southern blotting, and sequencing were used to detect and identify the noncoding control region (NCCR) of BKV in different tissues in an AIDS patient with meningoencephalitis, retinitis, and nephritis. An undescribed reorganized NCCR variant of the virus, completely different from the variants detected in peripheral blood leukocytes (PBLs) and urine, was identified in the cerebrospinal fluid (CSF) and CNS tissues. These results suggest that rearrangements in the NCCR of the virus have resulted in a BKV variant, which is better adapted to the host cell machinery of the cells in CNS tissue. The rearranged variant (BKV CNS) might have been involved in the initiation and/or development of the pathological lesions observed in the CNS-related tissues of this patient. Copyright 2003 Wiley-Liss, Inc.

7921. Lassmann H, Reindl M, Rauschka H, Berger J, Aboul-Enein F, Berger T,Zurbriggen A, Lutterotti A, Bruck W, Weber JR, Ullrich R, Schmidbauer M, Jellinger K, Vandevelde M. A new paraclinical CSF marker for hypoxia-like tissue damage in multiple sclerosis lesions. Brain. 2003 Jun;126(Pt 6):1347-57.

Recent studies on the immunopathology of multiple sclerosis revealed a heterogeneity in the patterns of demyelination, suggesting interindividual differences in the mechanism responsible for myelin destruction. One of these patterns of demyelination, characterized by oligodendrocyte dystrophy and apoptosis, closely mimics myelin destruction in acute white matter ischaemia. In the course of a systematic screening for virus antigen expression in multiple sclerosis brains, we identified a monoclonal antibody against canine distemper virus, which detects a cross-reactive endogenous brain epitope, highly expressed in this specific subtype of actively demyelinating multiple sclerosis lesions with little or no immunoreactivity in other active multiple sclerosis cases. The respective epitope, which is a phosphorylation-dependent sequence of one or more proteins of 50, 70 and 115 kDa, is also expressed in a subset of active lesions of different virus-induced inflammatory brain diseases, but is present most prominently and consistently in acute lesions of white matter ischaemia. Its presence is significantly associated with nuclear expression of hypoxia-inducible factor-1 alpha within the lesions of both inflammatory and ischaemic brain diseases. The respective epitope is liberated into the CSF and, thus, may become a useful diagnostic tool to identify clinically a defined multiple sclerosis subtype.

7922. Lednicky JA, Vilchez RA, Keitel WA, Visnegarwala F, White ZS, Kozinetz CA, Lewis DE, Butel JS. Polyomavirus JCV excretion and genotype analysis in HIV-infected patients receiving highly active antiretroviral therapy. AIDS. 2003 Apr 11;17(6):801-7.

OBJECTIVE: To assess the frequency of shedding of polyomavirus JC virus (JCV) genotypes in urine of HIV-infected patients receiving highly active antiretroviral therapy (HAART). METHODS: Single samples of urine and blood were collected prospectively from 70 adult HIV-infected patients and 68 uninfected volunteers. Inclusion criteria for HIV-infected patients included an HIV RNA viral load < 1000 copies, CD4 cell count of 200-700 x 106 cells/l, and stable HAART regimen. PCR assays and sequence analysis were carried out using JCV-specific primers against different regions of the virus genome. RESULTS: JCV excretion in urine was more common in HIV-positive patients but not significantly different from that of the HIV-negative group [22/70 (31%) versus 13/68 (19%); P = 0.09]. HIV-positive patients lost the age-related pattern of JCV shedding (P = 0.13) displayed by uninfected subjects (P = 0.01). Among HIV-infected patients significant differences in JCV shedding were related to CD4 cell counts (P = 0.03). Sequence analysis of the JCV regulatory region from both HIV-infected patients and uninfected volunteers revealed all to be JCV archetypal strains. JCV genotypes 1 (36%) and 4 (36%) were the most common among HIV-infected patients, whereas type 2 (77%) was the most frequently detected among HIV-uninfected volunteers. CONCLUSION: These results suggest that JCV

shedding is enhanced by modest depressions in immune function during HIV infection. JCV shedding occurred in younger HIV-positive persons than in the healthy controls. As the common types of JCV excreted varied among ethnic groups, JCV genotypes associated with progressive multifocal leukoencephalopathy may reflect demographics of those infected patient populations.

7923. Mani J, Reddy BC, Borgohain R, Sitajayalakshmi S, Sundaram C, Mohandas S. Magnetic resonance imaging in rabies. Postgrad Med J. 2003 Jun;79(932):352-4.

Rabies encephalitis has a classical clinical presentation and its diagnosis is unmistakable. In about a fifth of cases rabies occurs as its paralytic form, which lacks the classic symptoms and may mimic other diseases, especially acute disseminated encephalomyelitis (ADEM). Magnetic resonance imaging of the brain in rabies shows a distinct abnormal pattern that differentiates it from ADEM. Hence it may be a useful tool in diagnosis of paralytic rabies. Failure to administer post-exposure rabies immunoglobulin along with the rabies vaccine may result in vaccine failure.

7924. Martin WJ. Complex intracellular inclusions in the brain of a child with a stealth virus encephalopathy. Exp Mol Pathol. 2003 Jun;74(3):197-209.

Unusual pigmented intracellular inclusions are commonly seen in cultures

-obtained from patients infected with stealth viruses. Some of these structures may potentially provide a source of chemical energy for the infected cells to help compensate for the apparent damage to the cells' mitochondria. They have accordingly been termed alternative cellular energy pigments (ACE pigments). In keeping with this suggestion, the present paper illustrates the diversity of extraneous materials present in vacuolated, mitochondria-damaged cells seen in the brain biopsy of a child with a stealth-virus-associated encephalopathy. Many of the intracellular inclusions show highly ordered structuring, while others have a more amorphous appearance. These structures may provide a target for energy-based therapeutic intervention in stealth-virus-infected patients.

7925. Overholser ED, Coleman GD, Bennett JL, Casaday RJ, Zink MC, Barber SA, Clements JE. Expression of simian immunodeficiency virus (SIV) nef in astrocytes during acute and terminal infection and requirement of nef for optimal replication of neurovirulent SIV in vitro. J Virol. 2003 Jun;77(12):6855-66.

-As the most numerous cells in the brain, astrocytes play a critical role in maintaining central nervous system homeostasis, and therefore, infection of astrocytes by human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) in vivo could have important consequences for the development of HIV encephalitis. In this study, we establish that astrocytes are infected in macaques during acute SIV infection (10 days postinoculation) and during terminal infection when there is evidence of SIV-induced encephalitis. Additionally, with primary adult rhesus macaque astrocytes in vitro, we demonstrate that the macrophage-tropic, neurovirulent viruses SIV/17E-Br and SIV/17E-Fr replicate efficiently in astrocytes, while the lymphocyte-tropic, nonneurovirulent virus SIV(mac)239 open-nef does not establish productive infection. Furthermore, aminoxypentane-RANTES abolishes virus replication, suggesting that these SIV strains utilize the chemokine receptor CCR5 for entry into astrocytes. Importantly, we show that SIV Nef is required for optimal replication in primary rhesus macaque astrocytes and that normalizing input virus by particle number rather than by infectivity reveals a disparity between the ability of a Nef-deficient virus and a virus encoding a nonmyristoylated form of Nef to replicate in these central nervous system cells. Since the myristoylated form of Nef has been implicated in functions such as CD4 and major histocompatibility complex I downregulation, kinase association, and enhancement of virion infectivity, these data suggest that an as yet unidentified function of Nef may exist to facilitate SIV replication in astrocytes that may have important implications for in vivo pathogenesis.

7926. Trillo-Pazos G, Diamanturos A, Rislove L, Menza T, Chao W, Belem P, Sadiq S, Morgello S, Sharer L, Volsky DJ. Detection of HIV-1 DNA in microglia/macrophages, astrocytes and neurons isolated from brain tissue with HIV-1 encephalitis by laser capture microdissection. Brain Pathol. 2003 Apr;13(2):144-54.

In HIV-1 encephalitis, HIV-1 replicates predominantly in macrophages and

- microglia. Astrocytes also carry HIV-1, but the infection of oligodendrocytes and neurons is debated. In this study we examined the presence of HIV-1 DNA in different brain cell types in 6 paraffin embedded, archival post-mortem pediatric and adult brain tissues with HIV-1 encephalitis by Laser Capture Microdissection (LCM). Sections from frontal cortex and basal ganglia were stained by immunohistochemistry for CD68 (microglia), GFAP (astrocytes), MAP2 (neurons), and p24 (HIV-1 positive cells) and different cell types were microdissected by LCM. Individual cells or pools of same type of cells were lysed, the cell lysates were subjected to PCR using HIV-1 gag SK38/SK39 primers, and presence of HIV-1 DNA was confirmed by Southern blotting. HIV-1 gag DNA was consistently detected by this procedure in the frontal cortex and basal ganglia in 1 to 20 p24 HIV-1 capsid positive cells, and in pools of 50 to 100 microglia/macrophage cells, 100 to 200 astrocytes, and 100 to 200 neurons in HIV-1 positive cases but not in HIV-1 negative controls. These findings suggest that in addition to microglia, the infection of astrocytes and neurons by HIV-1 may contribute to the development of HIV-1 disease in the brain.

7927. Vallat-Decouvelaere AV, Chretien F, Gras G, Le Pavec G, Dormont D, Gray F. Expression of excitatory amino acid transporter-1 in brain macrophages and microglia of HIV-infected patients. A neuroprotective role for activated microglia? J Neuropathol Exp Neurol. 2003 May;62(5):475-85.

Recent experimental studies showed that activated macrophages/microglia (AMM) express excitatory amino acid transporters (EAATs), suggesting that, in addition to their neurotoxic properties, they also have a neuroprotective role by clearing extracellular glutamate and producing antioxidant glutathione. To test this hypothesis in human, the brain of 12 HIV-positive patients and 3 controls were immunostained for EAAT-1. EAAT-1 was expressed by AMM in all HIV-infected cases but not in HIV-negative controls. Expression varied according to the disease stage. In 5 cases with active HIV-encephalitis (HIVE), AMM strongly expressed EAAT-1 in the white matter and basal ganglia, analogous to HLA-DR and CD68 expression. There was weaker expression in the cortex and perineuronal microglial cells were not involved. In a case with "burnt out" HIVE following highly active antiretroviral therapy (HAART), EAAT-1 expression was mild, identical to that of HLA-DR and CD68 in the white matter and cortex and involved perineuronal microglial cells. In 3 AIDS patients without HIVE and in 3 pre-AIDS cases, EAAT-1 expression in the white matter was weaker than HLA-DR and CD68 expression; there was stronger correlation in the gray matter where perineuronal microglial cells were stained predominantly. Our findings in humans tend to confirm that AMM, particularly perineuronal microglial cells, play a neuroprotective role in the early stages of HIV infection and, possibly, following treatment. This is in keeping with the early microglial activation seen in pre-AIDS cases, and the late occurrence of neuronal loss. It may also explain the reversible cognitive disorders following treatment in some cases.

Pathogenesis

7928. Oku K, Atsumi T, Furukawa S, Horita T, Sakai Y, Jodo S, Amasaki Y, Ichikawa K, Amengual O, Koike T. Cerebral imaging by magnetic resonance imaging and single photon emission computed tomography in systemic lupus erythematosus with central nervous system involvement. Rheumatology (Oxford). 2003 Jun;42(6):773-7. Epub 2003 Mar 31.

7929. Ortega-Aznar A, Romero-Vidal FJ, Castellvi J, Ferrer JM, Codina A. Adult-onset subacute sclerosing panencephalitis: clinico-pathological findings in 2 new cases. Clin Neuropathol. 2003 May-Jun;22(3):110-8.

7930. Pretorius PM, Quaghebeur G. The role of MRI in the diagnosis of MS. Clin Radiol. 2003 Jun;58(6):434-48.

7931. Soragna D, Tupler R, Ratti MT, Montalbetti L, Papi L, Sestini R. An Italian family affected by Nasu-Hakola disease with a novel genetic mutation in the TREM2 gene. J Neurol Neurosurg Psychiatry. 2003 Jun;74(6):825-6. No abstract

Vaccines:

7932. Gangolli SS, Vasilakis N, Kovacs GR, Zamb TJ, Kowalski J. A method of alphavirus replicon particle titration based on expression of functional replicase/transcriptase. J Virol Methods. 2003 May;109(2):133-8.

Alphavirus replicon particles are being exploited for a variety of purposes both in vitro as gene expression vectors, and in vivo as vaccines or gene therapy vectors. There is a need for a simple and universal method of titration of replicon particles that is independent of expression of the foreign protein. We devised a method that uses modified vaccinia virus Ankara (MVA) as an indicator virus, to deliver a Venezuelan equine encephalitis virus (VEE) defective helper RNA encoding green fluorescent protein (GFP). Co-infection of cells with the MVA-based indicator and Venezuelan equine encephalitis virus replicon particles (VRP) results in expression of the GFP gene. VRP titer is readily determined by counting fluorescent cells.

7933. Nel LH, Niezgoda M, Hanlon CA, Morril PA, Yager PA, Rupprecht CE. A comparison of DNA vaccines for the rabies-related virus, Mokola. Vaccine. 2003 Jun 2;21(19-20):2598-606.

Mokola virus, a rabies-related virus, has been reported to date from the African continent only. Like rabies virus, it is highly pathogenic, causes acute encephalitis, and zoonotic events have been documented. Although believed to be rare, there has been an unexplained increase in the number of isolations of the virus in South Africa in recent years. We have cloned and sequenced the glycoprotein (G) and nucleoprotein (N) genes from a South African Mokola virus, and used these in the construction of different DNA vaccines for immunization against Mokola virus. Four vaccines, utilizing different promoters and DNA backbone compositions, were generated and compared for efficacy in protection against Mokola virus. In one of these, both the Mokola virus G and N genes were co-expressed. Two of the single G-expressing DNA vaccines (based on pSG5 and pCI-neo, respectively) protected laboratory mice against lethal challenge, despite major differences in their promoters. However, neither vaccine was fully protective in a single immunization only. Serological assays confirmed titers of virus-neutralizing antibodies after immunization, which increased upon booster vaccine administration. A third construct (based on pBudCE4) was less effective in inducing a protective immune response, despite employing a strong CMV enhancer/promoter also used in the pCI-neo plasmid. Dual expression of Mokola virus G and N genes in pBudCE4 did not enhance its efficacy, under the conditions described. In addition, no significant utility could be demonstrated for a combined prime-boost approach, as no cross-protective immunity was observed against rabies or Mokola viruses from the use of pSG5-mokG or vaccinia-rabies glycoprotein recombinant virus vaccines, respectively, even though both vaccines provided 60-100% protection against homologous virus challenge.

7934. Theophilides CN, Ahearn SC, Grady S, Merlino M. Identifying West Nile virus risk areas: the Dynamic Continuous-Area Space-Time system. Am J Epidemiol. 2003 May 1;157(9):843-54.

The Dynamic Continuous-Area Space-Time (DYCAST) system was developed to identify and prospectively monitor high-risk areas for West Nile virus in New York, New York (New York City). The system is based on a geographic model that uses a localized Knox test to capture the nonrandom space-time interaction of dead birds, as an indicator of an intense West Nile virus amplification cycle, within a 1.5-mile (2.41-km) buffer area and 21-day moving window. The Knox analysis is implemented as an interpolation function to create a surface of probabilities over a grid of 1,400 cells overlaying New York City. The model's parameters were calibrated using year 2000 data and information on the vector-host transmission cycle. The DYCAST system was implemented in a geographic information system and used operationally in year 2001. It successfully identified areas of high risk for human West Nile virus infection in areas where five of seven human cases resided, at least 13 days prior to the onset of illness, and proved that it can be used as an effective tool for targeting remediation and control efforts.

Therapy:

7935. Barker CM, Reisen WK, Kramer VL. California state Mosquito-Borne Virus Surveillance and Response Plan: a retrospective evaluation using conditional simulations. Am J Trop Med Hyg. 2003 May;68(5):508-18.

The California Mosquito-Borne Virus Surveillance and Response Plan recently was developed to provide a semi-quantitative means for assessing risk for western equine encephalomyelitis (WEE) or St. Louis encephalitis (SLE) viruses and to provide intervention guidelines for mosquito control and public health agencies during periods of heightened risk for human infection. West Nile virus recently has arrived in California, and the response plan also will provide a baseline for assessing the risk for human and equine infection with this virus. In the response plan, overall risk is calculated by averaging risk due to 1)environmental conditions, 2) adult mosquito vector abundance, 3) vector infection rates, 4) sentinel chicken seroconversion rates, 5) equine cases (for WEE), 6) human cases, and 7) the proximity of virus activity to populated areas. Overall risk is categorized into three levels: normal season, emergency planning, or epidemic conditions. We evaluated this response plan using historical data from years with no, enzootic, and epidemic activity of WEE and SLE in several areas of California to determine whether calculated risk levels approximated actual conditions. Multiple methods of risk calculation were considered for both viruses. Assessed risk based on cumulative temperature, rainfall, and runoff levels over the entire season provided more or equally

accurate assessments than biweekly assessments based solely on the previous

half-month. For WEE, during years with enzootic activity or early-season periods of years with WEE epidemic activity, combining horse and human cases as a single risk factor improved the model's ability to forecast pending WEE activity, but separating the two factors allowed a better indication of WEE activity during epidemics and periods with no activity. For SLE, assignment of higher risk to drier conditions as measured by rainfall and runoff yielded the most accurate representation of actual virus activity during all recent study periods.

7936. Langford TD, Letendre SL, Larrea GJ, Masliah E. Changing patterns in the neuropathogenesis of HIV during the HAART era. Brain Pathol. 2003 Apr;13(2):195-210.

Rapid progress in the development of highly active antiretroviral therapy has changed the observed patterns in HIV encephalitis and AIDS-related CNS opportunistic infections. Early in the AIDS epidemic, autopsy studies pointed to a high prevalence of these conditions. With the advent of nucleoside reverse transcriptase inhibitors, the prevalence at autopsy of opportunistic infections, such as toxoplasmosis and progressive multifocal leukoencephalopathy, declined while that of HIV encephalitis increased. After the introduction of protease inhibitors, a decline in both HIV encephalitis and CNS opportunistic infections was observed. However, with the increasing resistance of HIV strains to antiretrovirals, there has been a resurgence in the frequency of HIV encephalitis and HIV leukoencephalopathy. HIV leukoencephalopathy in AIDS patients failing highly active antiretroviral therapy is characterized by massive infiltration of HIV infected monocytes/macrophages into the brain and extensive white matter destruction. This condition may be attributable to interactions of anti-retrovirals with cerebrovascular endothelium, astroglial cells and white matter of the brain. These interactions may lead to cerebral ischemia, increased blood-brain barrier permeability and demyelination. Potential mechanisms of such interactions include alterations in host cell signaling that may result in trophic factor dysregulation and mitochondrial injury. We conclude that despite the initial success of combined anti-retroviral therapy, more severe forms of HIV encephalitis appear to be emerging as the epidemic matures. Factors that may contribute to this worsening include the prolonged survival of HIV-infected patients, thereby prolonging the brain's exposure to HIV virions and proteins, the use of increasingly toxic combinations of poorly penetrating drugs in highly antiretroviral-experienced AIDS patients, and selection of more virulent HIV strains with higher replication rates and greater virulence in neural tissues.

7937. Mitka M. As West Nile virus season heats up, blood safety testing lags behind. JAMA. 2003 May 14;289(18):2341-2. No abstract.

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