Persistent pathogens in the parenchyma of the brain.

It has recently been shown that bacteria and viruses can be delivered to the brain parenchyma without evoking an immune response. These experiments demonstrate that there are no cells within the brain parenchyma that can initiate a primary immune response, and that the drainage of pathogens from the brain parenchyma is distinct from that documented for soluble proteins. A persistent pathogen in the brain parenchyma can become a target for the immune system following peripheral sensitisation, and this may lead to bystander tissue damage.

Acral lipoblastoma.

Lipoblastomas are rare, benign childhood tumors. We report a case of lipoblastoma on the heel of a 5-year-old girl who presented with a progressively enlarging, xanthoerythematous plaque. Surgical excision with follow-up for possible recurrence is the treatment of choice.

The monoclonal antibody HB1 recognizes an adhesion molecule for macrophages in the brain.

The brain environment exerts a powerful influence on macrophage phenotype, as exemplified by microglia, but the mechanisms mediating this control are nuclear. Since adhesion molecules are known to transmit signals across cell membranes, we investigated adhesion receptors involved in macrophage interaction with brain tissue. We have demonstrated previously that macrophages adhere specifically to CNS neurones in an in vitro assay.

Cyclooxygenase-2 is highly expressed in microglial-like cells in a murine model of prion disease.

Prion diseases, or transmissible spongiform encephalopathies, are a relatively rare group of chronic degenerative disorders afflicting both animals and humans, characterized by typical histopathological signs such as amyloid deposition, neuronal loss and spongiform changes. Despite the absence of a typical acute inflammatory response, the consistent microglial activation and astrocytosis, that are found in human pathologies as well as in animal models, suggests the existence of an ongoing inflammatory response in these neurodegenerative diseases. To investigate the role of cyclooxygenase-2 (COX-2) activity in the pathogenesis of chronic neurodegenerative diseases, we studied immunohistochemically the expression of this key enzyme in the formation of prostaglandins during inflammatory responses in a well characterized murine model of prion disease.

Axon damage and repair in multiple sclerosis.

It is well known that within long-standing multiple sclerosis (MS) lesions there is axonal loss but whether it is an early or late event has been more difficult to establish. The use of immunocytochemical methods that reveal axonal end-bulbs is a valuable approach to investigating acute axonal injury in human pathological material. The application of these techniques to multiple sclerosis tissue reveals evidence of axonal injury in acute lesions; the distribution of the end-bulbs in acute and active-chronic lesions is associated with regions of maximal density of infiltrating macrophages.

In vivo expression of cyclooxygenase-2 in rat brain following intraparenchymal injection of bacterial endotoxin and inflammatory cytokines.

To clarify the role played by prostaglandins in acute brain inflammation we studied the expression of the key enzyme in their formation, cyclooxygenase-2 (COX-2), following microinjection of bacterial endotoxin (LPS), interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma), in the rat dorsal hippocampus. In spite of the extensive astrocyte and microglial reaction, at 24 hours after LPS injection COX-2 immunoreactivity (COX-2-ir) was exclusively associated with infiltrating neutrophils and with perivascular cells of blood vessels in the area surrounding the injection site. Microinjection of IFN-gamma did not alter COX-2-ir, whereas TNF-alpha or IL-1beta injection induced a moderate COX-2-ir in the perivascular cells of a few blood vessels close to the injection site, and in very few of the infiltrating neutrophils.

Non-nuclear histone H1 is upregulated in neurones and astrocytes in prion and Alzheimer's diseases but not in acute neurodegeneration.

A non-nuclear isoform of histone H1 is constitutively expressed in neurones. This protein is the major lipopolysaccharide (LPS)-binding protein in the brain. Since the major systemic LPS-binding protein is released in the liver and is an acute phase reactant, we were interested to learn whether this novel CNS histone showed altered expression following neuronal injury.

Acute inflammatory responses to mechanical lesions in the CNS: differences between brain and spinal cord.

Lesion-induced inflammatory responses in both brain and spinal cord have recently become a topic of active investigation. Using C57BL/6J mice, we compared the tissue reaction in these two central nervous system (CNS) compartments with mechanical lesions of similar size involving both grey and white matter. This evaluation included the quantitative assessment of neutrophils, lymphocytes and activated macrophages/microglia, as well as astrocyte activation, upregulation of vascular cell adhesion molecules (ICAM-1, VCAM-1, PECAM) and the extent of blood-brain barrier (BBB) breakdown.

Variation in the immune response to adenoviral vectors in the brain: influence of mouse strain, environmental conditions and priming.

E1-deleted adenoviral vectors expressing the bacterial beta-galactosidase gene were inoculated into the brain of unprimed and primed C3H.He or C57BL/6J mice housed under either conventional or specific-pathogen-free (SPF) conditions. The kinetics of immune responses to both the vector and the transgene were investigated.

Restricted cyclooxygenase-2 expression in the central nervous system following acute and delayed-type hypersensitivity responses to bacillus Calmette-Guérin.

The expression of cyclooxygenase-2, a key enzyme in prostaglandin and thromboxane synthesis in inflammation, was studied immunohistochemically in in vivo models of acute and chronic inflammatory responses in rat central nervous system. In the acute inflammatory response to intracranial injection of heat-killed bacillus Calmette-Guérin as well as in the immune-mediated, delayed-type hypersensitivity response to the same pathogen, cyclooxygenase-2 expression was restricted to major infiltrating haematogenous cell populations such as neutrophils and mononuclear phagocytes, while the expression of the enzyme by brain non-neuronal resident cells (astrocytes, microglia, perivascular cells) appeared to be limited to perivascular cells of the blood vessels in the vicinity of the lesion and in the surrounding area. On the basis of their morphology and location, these perivascular cells were identified as perivascular macrophages, but we could not rule out the possibility that some endothelial cells also expressed cyclooxygenase-2.

Inflammatory response and retinal ganglion cell degeneration following intraocular injection of ME7.

Scrapie is a prion disease which occurs naturally in sheep and which can be transmitted experimentally to rodents. After intracerebral injection of ME7 into mouse, an atypical inflammatory response, characterized by T-lymphocytes and activated microglia is present early in the course of the disease. In the present work, we have investigated the relationship between this inflammatory response, astrocytosis and neuronal loss along the visual pathway after intraocular injection (intraocular) of ME7 in C57BL/6J mice.

Induction of hyperphosphorylated tau in living slices of rat hippocampal formation and subsequent detection using an ELISA.

Although hyperphosphorylated tau is an established feature of Alzheimer's Disease, its role in the disease process is poorly understood, partly because of lack of suitable animal models. We describe the use of living slices of rat hippocampal formation to study tau phosphorylation. Using the AT8 antibody in an ELISA, phosphorylated tau was detected in freshly frozen slices and it increased significantly in slices that were incubated in an electrophysiological recording chamber; the amount detected was greatest when the homogenisation buffer contained phosphatase and kinase inhibitors.

The major brain isoform of kif1b lacks the putative mitochondria-binding domain.

Kinesin and kinesin superfamily proteins are molecular motors involved in important intracellular functions such as organelle transport and cell division. They are microtubule-activated ATPases composed of a motor domain that binds to microtubules and a cargo-binding domain that binds to specific organelles. While searching for the slow Wallerian degeneration mutation (WldS) on distal mouse Chromosome (Chr) 4, we have identified a member of the kinesin superfamily whose predicted gene product has the N-terminal motor domain of Kif1b and a novel C-terminal cargo-binding domain homologous to Kif1a.

Delayed symptom onset and increased life expectancy in Sandhoff disease mice treated with N-butyldeoxynojirimycin.

Sandhoff disease is a neurodegenerative disorder resulting from the autosomal recessive inheritance of mutations in the HEXB gene, which encodes the beta-subunit of beta-hexosaminidase. GM2 ganglioside fails to be degraded and accumulates within lysosomes in cells of the periphery and the central nervous system (CNS). There are currently no therapies for the glycosphingolipid lysosomal storage diseases that involve CNS pathology, including the GM2 gangliosidoses.

Cytokine-induced acute inflammation in the brain and spinal cord.

Different compartments in the central nervous system mount distinct inflammatory responses. The meninges and choroid plexus respond to pro-inflammatory stimuli in a manner reminiscent of a peripheral inflammatory response, whereas the brain parenchyma is refractory. Trauma-induced lesions in brain and in spinal cord are associated with leukocyte infiltration, blood-brain barrier (BBB) breakdown, and secondary tissue destruction.

The acute inflammatory response in CNS following injection of prion brain homogenate or normal brain homogenate.

The neuropathological hallmarks of end-stage prion disease are vacuolation, neuronal loss, astrocytosis and deposition of PrPSc amyloid. We have also shown that there is an inflammatory response in the brains of scrapie-affected mice from 8 weeks post-injection. In this study we have investigated the acute CNS response to the intracerebral injection of scrapie-affected brain homogenate.

Low dietary protein during early pregnancy alters bovine placental development.

To determine if low dietary protein concentration in the first two trimesters of pregnancy alters placental development, genetically similar heifers from closed herd were fed diets containing different levels of protein in the first and second trimesters of gestation. There were four animals per treatment group, the groups being: L/L = fed a diet containing 7% crude protein (CP) (low protein) in the first and second trimesters; H/H = fed a diet containing 14% CP (high protein) in the first and second trimesters; L/H = fed low protein in the first trimester and high in the second trimester and vice versa for the H/L group. Low protein diets in the first trimester increased dry cotyledon weight at term.

Heparin injection into the adult rat hippocampus induces seizures in the absence of macroscopic abnormalities.

The pathological hallmarks of Alzheimer's disease include neurofibrillary tangles, neuropil threads and neuritic plaques. Neurofibrillary tangles and neuropil threads are comprised of paired helical filaments which are themselves composed of a hyperphosphorylated form of the microtubule-associated protein tau. Neuritic plaques are extracellular deposits of aggregated beta amyloid associated with neurites containing hyperphosphorylated tau.

Differential blood-brain barrier breakdown and leucocyte recruitment following excitotoxic lesions in juvenile and adult rats.

Acute neuronal degeneration can be induced by intracerebral injections of the glutamate receptor agonists kainic acid (KA) and NMDA (N-methyl-D-aspartate). It is accompanied by an inflammatory response that has not yet been fully investigated. We have previously demonstrated that the juvenile rat brain is more susceptible to an inflammatory challenge when compared to adult rat brain.

Immunochemical detection of arylamine N-acetyltransferase during mouse embryonic development and in adult mouse brain.

Arylamine N-acetyltransferases (NATs) are important in susceptibility to xenobiotic-induced disorders (e.g., drug-induced autoimmune disease, bladder cancer), but their role in endogenous metabolism is yet to be elucidated.

The role of the thalamus and basal ganglia in parkinsonian tremor.

The mechanism of parkinsonian tremor may involve a central oscillator, peripheral feedback to the central nervous system (CNS), or both. The thalamus or the globus pallidus is the most likely site for a central oscillator and would be predicted to generate thalamic tremor-related activity characterized, respectively, by calcium spike-associated bursts and by maximal tremor-related activity in the pallidal relay nucleus of thalamus. Thalamic spike trains demonstrate neither of these characteristics.

A revised view of the central nervous system microenvironment and major histocompatibility complex class II antigen presentation.

There are numerous observations reporting that phagocytes expressing major histocompatibility complex (MHC) Class II molecules are associated with the central nervous system (CNS) in normal and pathological conditions. Although MHC Class II expression is necessary for antigen presentation to CD4 + T-cells, it is not sufficient and co-stimulatory molecules are also required. We review here recent in vivo studies demonstrating that the microglia and perivascular macrophages are unable to initiate a primary immune response in the CNS microenvironment, but may support secondary immune responses.