Discovery of treatment for nerve agents targeting a new metabolic pathway.

The inhibition of acetylcholinesterase is regarded as the primary toxic mechanism of action for chemical warfare agents. Recently, there have been numerous reports suggesting that metabolic processes could significantly contribute to toxicity. As such, we applied a multi-omics pipeline to generate a detailed cascade of molecular events temporally occurring in guinea pigs exposed to VX.

Cigarette smoking, stress-induced analgesia and pain perception in men and women.

This study examined gender differences in smoking-related analgesia and stress-induced analgesia (SIA), as a function of pain modality. Forty men (20 smokers, 20 nonsmokers) and 37 women (17 smokers) were tested twice for pain sensitivity to tourniquet ischemia, thermal heat, and cold pressor tests; once following mental stress and once following rest control, counterbalancing order. Cardiovascular and neuroendocrine responses to mental stress were also examined.

Transponder-induced sarcoma in the heterozygous p53+/- mouse.

Heterozygous p53+/- transgenic mice are being studied for utility as a short-term alternative model to the 2-yr rodent carcinogenicity bioassay. During a 26-wk study to assess the potential carcinogenicity of oxymetholone using p-cresidine as a positive control, glass/polypropylene microchips (radio transponder identification devices) were subcutaneously implanted into male and female p53+/- mice. During week 15, the first palpable mass was clinically observed at an implant site.

Dynamic expression of L-selectin in cell-to-cell interactions between neutrophils and endothelial cells in vitro.

Neutrophil-endothelial cell interactions are regulated by cell adhesion molecules and their cognate ligands. It has been proposed that L-selectin and Mac-1 (CD11b/CD18), two neutrophil adhesion receptors, have sequential roles in neutrophil extravasation during inflammation. In this model, L-selectin mediates rolling and initial adherence of neutrophils to endothelial cells, while Mac-1 strengthens this initial adherence and also facilitates migration of neutrophils through endothelial cells.

Mechanisms of inflammatory cell attachment in chronic relapsing experimental allergic encephalomyelitis: a scanning and high-voltage electron microscopic study of the injured mouse blood-brain barrier.

Brain and spinal cord blood vessels from mice subjected to chronic relapsing experimental allergic encephalomyelitis were examined by scanning (SEM) and high-voltage electron microscopy (HVEM). SEM analysis of veins and venules from affected tissue regions demonstrated inflammatory cells (ICs), primarily lymphocytes or monocytes, attached to the luminal endothelial cell (EC) surface adjacent to the junctional complexes. In transverse section these cells were shown by HVEM to extend and to insert filopodia (lymphocytes) or flap-like lamellapodia (monocytes) into the luminal EC surfaces.

Laminar analysis of the number of neurons, astrocytes, oligodendrocytes and microglia in the visual cortex (area 17) of 3-month-old rhesus monkeys fed a human infant soy-protein formula with or without taurine supplementation from birth.

The effect of taurine addition to a commercial (taurine-free) soy-protein formula on the development of the visual cortex has been examined in 3-month-old rhesus monkeys. The thickness, number of neurons, astrocytes, oligodendrocytes and microglia have been measured in the different laminae. There were no significant differences in cortical thickness, total number of neurons, astrocytes, oligodendrocytes, or microglia between the groups, but there were some significant differences in some laminae as well as some qualitative differences.

Combined conventional transmission, scanning, and high-voltage electron microscopy of the same blood vessel for the study of targeted inflammatory cells in blood-brain barrier inflammation.

The microvasculature of brains and spinal cords from mice subjected to chronic relapsing experimental autoimmune encephalomyelitis (CREAE) was studied using three different electron microscopic techniques. Blood vessels were initially examined by scanning electron microscopy. This allowed for the investigation of topographical changes of the luminal aspects of endothelial cells (ECs) and identification of targeted inflammatory cells (ICs) attached to the ECs.

Aluminum neurotoxicity in mammals.

Although aluminum comprises a large percentage of the Earth's crust, it is excluded from body tissues, and especially from the central nervous system. When aluminum is experimentally introduced to the central nervous system, several neurotoxic effects are observed:i.e.

Microanalysis of Alzheimer disease NFT and plaques.

Electron probe energy dispersive microanalysis of isolated andin situ neurofibrillary tangles (NFT) and neuritic (senile) plaque cores have been done to investigate the levels of Al, Si, Ca and Fe in the leading lesions of Alzheimer disease neuropathology. Varying levels of Si and Al, and to a lesser extent Ca, have been co-localized in about one half of the NFT and plaques examined using X-ray mapping. The variability of detection and the low levels of Al present indicates that aluminum is not required for the formation of the NFT and that aluminosilicates are not involved in the formation of the plaque core.

Sites of egress of inflammatory cells and horseradish peroxidase transport across the blood-brain barrier in a murine model of chronic relapsing experimental allergic encephalomyelitis.

Results are reported of experiments designed to focus at attachment sites of inflammatory cells (ICs) on the luminal surface of brain endothelial cells (ECs) and on the mechanisms of horseradish peroxidase (HRP) transport across the altered blood-brain barrier (BBB) in a murine model of chronic relapsing experimental allergic encephalomyelitis. Cationized ferritin (CF) served as a marker for evaluating the electrostatic nature of brain microblood vessels (MBVs) on the plasma membranes of ICs or normal mouse peripheral white blood cells and erythrocytes. SJL/J mice demonstrating clinical illness were given HRP or CF, in vivo or in situ, respectively.

Genetic control of scrapie: incubation period and plaque formation in I mice.

The host component of control of scrapie incubation period in the mouse is manifested largely through the action of the Sinc gene. Only one mouse strain (VM) has been found that is p7p7 (prolonged incubation for ME7 agent) and two other strains have been derived from VM. All other strains, designated s7s7, have a short incubation for ME7.

Ultrastructural observations of spinal cord lesions and blood-brain barrier changes in scrapie-infected mice.

Spinal cord samples from IM or VM mice injected intracerebrally with the 87V scrapie agent were examined ultrastructurally at the clinical stage of disease for changes in blood vessel permeability and for pathological alterations. In several animals, (3 of 16), massive changes were noted in the cervical spinal cords in the subependymal area of the cortical gray matter immediately surrounding the central canal including ependymal cell changes, the presence of amyloid plaque in close association with microglial cells, extensive neuropil vacuolation, the appearance of reactive astrocytes, degenerating neurites and vacuolated neurons. In those regions showing structural damage, localized increased permeability to horseradish peroxidase across the blood-brain barrier was noticed along with the appearance of numerous vesiculo-canalicular profiles in micro-blood vessel endothelial cells with extravasation of the tracer to the neuropil.

Retinal degeneration in 3-month-old rhesus monkey infants fed a taurine-free human infant formula.

Rhesus monkey infants were raised from birth on a taurine-free soy protein-based human infant formula or on the same formula supplemented with taurine. The monkeys were killed 3 months after birth and the retinas examined by light and electron microscopy. All of the monkeys raised on formula alone showed degenerative ultrastructural changes in photoreceptor outer segments that ranged from swelling and disorientation to fragmentation and disorganization.

Feline maternal taurine deficiency: effects on retina and tapetum of the offspring.

The retina and tapetum of kittens born to taurine-deficient and taurine-supplemented mothers were compared. Retinal taurine concentrations typically reach adult levels 6 weeks postnatally. When measured at weaning at 8 postnatal weeks, the taurine concentrations in retina and tapetum of taurine-deficient kittens were 40% of normal levels.

Abnormal visual cortex development in the kitten associated with maternal dietary taurine deprivation.

We have examined the visual cortex of newborn and 8-week-old kittens born to mothers consuming a taurine-supplemented or taurine-free diet using the rapid Golgi technique. Kittens from taurine-supplemented mothers exhibited normal development of the visual cortex. Kittens from taurine-depleted mothers showed striking differences.

Postnatal taurine deficiency in the kitten results in a persistence of the cerebellar external granule cell layer: correction by taurine feeding.

Dietary deprivation of taurine in pregnant cats from approximately 1 week prior to giving birth is sufficient to reduce substantially the taurine concentration in feline milk but does not result in any abnormalities in kittens at birth. Kittens nursing on this low taurine milk have a lower growth rate than normal, have lower tissue taurine concentrations, and 8 weeks after birth have a persistence of cells in the cerebellar external granule cell layer. Mitotic figures are present also, indicating that cell division is occurring still, an event which normally is completed 3-4 weeks after birth.

Taurine deficiency in the developing cat: persistence of the cerebellar external granule cell layer.

Dietary taurine deprivation adversely affects feline pregnancy and is associated with the frequent occurrence of fetal resorption, abortion, stillbirth, and low birthweight of live kittens at term. Taurine-deprived, live-born kittens have a poor postnatal survival rate and grow less well than kittens from taurine-supplemented queens. The postnatal dietary taurine intake of such kittens is reduced if they are nursed by their biologic mothers; the concentration of taurine in milk of taurine-deprived mothers is less than 10% of that in milk from taurine-supplemented queens.

Preclinical changes in weight of scrapie-infected mice as a function of scrapie agent-mouse strain combination.

Several inbred strains of mice were injected with different scrapie agents and their total body weight was monitored throughout the incubation period. As a control, mice were injected with normal mouse brain homogenate. For most combinations of scrapie agent and mouse strain, weights during the preclinical phase were similar to or lower than the average weight of controls.

Increased blood-brain barrier permeability in scrapie-infected mice.

The present investigation was designed to study the ultrastructural integrity of the blood-brain barrier (BBB) in the cerebral microvasculature of scrapie-infected mice showing clinical illness. Cerebral microvessels from either IM, VM, or C57BL/6J mice, terminally affected with various strains of scrapie agent showed a focal leakage of horseradish peroxidase (HRP) in all agent-strain and mouse-strain combinations. This leakage was most pronounced in and near the primary site of agent inoculation, but was also observed in microvessels scattered throughout the brain.