Glycosaminoglycan binding facilitates entry of a bacterial pathogen into central nervous systems

Certain microbes invade brain microvascular endothelial cells (BMECs) to breach the blood-brain barrier (BBB) and establish central nervous system (CNS) infection. Here we use the leading meningitis pathogen group B Streptococcus (GBS) together with insect and mammalian infection models to probe a potential role of glycosaminoglycan (GAG) interactions in the pathogenesis of CNS entry. Site-directed mutagenesis of a GAG-binding domain of the surface GBS alpha C protein impeded GBS penetration of the Drosophila BBB in vivo and diminished GBS adherence to and invasion of human BMECs in vitro. Conversely, genetic impairment of GAG expression in flies or mice reduced GBS dissemination into the brain. These complementary approaches identify a role for bacterial-GAG interactions in the pathogenesis of CNS infection. Our results also highlight how the simpler yet genetically conserved Drosophila GAG pathways can provide a model organism to screen candidate molecules that can interrupt pathogen-GAG interactions for future therapeutic applications.     

Leukocyte-facilitated entry of intracellular pathogens into the central nervous system

Microbes use numerous strategies to invade the central nervous system. Leukocyte-facilitated entry is one such mechanism whereby intracellular pathogens establish infection by taking advantage of leukocyte trafficking to the central nervous system. Key components of this process include peripheral infection and activation of leukocytes, activation of cerebral endothelial cells with or without concomitant infection, and trafficking of infected leukocytes to and through the blood-brain or blood-cerebrospinal fluid barrier.     

Development and specificity of inhibitory terminal arborizations in the central nervous system

This study examined the morphological development of single inhibitory arborizations in the gerbil central auditory brain stem. Using a brain slice preparation, neurons of the medial nucleus of the trapezoid body (MNTB) were filled with horseradish peroxidase (HRP), and their complete arborizations were analyzed along the tonotopic axis of the lateral superior olive (LSO). The projections in neonatal animals displayed well-defined arbors that were ordered appropriately within the LSO. It was evident from the axonal pathways that the MNTB afferents could correct for projection errors after reaching the postsynaptic population. As development progressed, a number of arbors established diffuse or inappropriate projections within the LSO. These immature arborizations were no longer apparent by 18–25 days postnatal. The anatomical specificity of arbors at 12–13 and 18–25 days was quantified by measuring the distance that terminal boutons spread across the frequency axis. There was a significant reduction of this distance in older animals. In addition, there was a significant reduction in the mean number of boutons per arbor between 12–13 days and 18–25 days. The maximum nucleus cross-sectional area continued to increase through 15–16 days, indicating that the refined arbors occupied an even smaller fraction of the postsynaptic structure. Taken together, these observations suggest that central inhibitory arbors form exuberant contacts that must be eliminated during development.     

Effects of betel chewing on the central and autonomic nervous systems

Betel chewing has been claimed to produce a sense of well-being, euphoria, heightened alertness, sweating, salivation, a hot sensation in the body and increased capacity to work. Betel chewing also leads to habituation, addiction and withdrawal. However, the mechanisms underlying these effects remain poorly understood. Arecoline, the major alkaloid of Areca nut, has been extensively studied, and several effects of betel chewing are thought to be related to the actions of this parasympathomimetic constituent. However, betel chewing may produce complex reactions and interactions. In the presence of lime, arecoline and guvacoline in Areca nut are hydrolyzed into arecaidine and guvacine, respectively, which are strong inhibitors of GABA uptake. Piper betle flower or leaf contains aromatic phenolic compounds which have been found to stimulate the release of catecholamines in vitro. Thus, betel chewing may affect parasympathetic, GABAnergic and sympathetic functions. Betel chewing produces an increase in heart rate, blood pressure, sweating and body temperature. In addition, EEG shows widespread cortical desynchronization indicating a state of arousal. In autonomic function tests, both the sympathetic skin response and RR interval variation are affected. Betel chewing also increases plasma concentrations of norepinephrine and epinephrine. These results suggest that betel chewing mainly affects the central and autonomic nervous systems. Future studies should investigate both the acute and chronic effects of betel chewing. Such studies may further elucidate the psychoactive mechanisms responsible for the undiminished popularity of betel chewing since antiquity.     

Development and specificity of inhibitory terminal arborizations in the central nervous system.

This study examined the morphological development of single inhibitory arborizations in the gerbil central auditory brain stem. Using a brain slice preparation, neurons of the medial nucleus of the trapezoid body (MNTB) were filled with horseradish peroxidase (HRP), and their complete arborizations were analyzed along the tonotopic axis of the lateral superior olive (LSO). The projections in neonatal animals displayed well-defined arbors that were ordered appropriately within the LSO. It was evident from the axonal pathways that the MNTB afferents could correct for projection errors after reaching the postsynaptic population. As development progressed, a number of arbors established diffuse or inappropriate projections within the LSO. These immature arborizations were no longer apparent by 18-25 days postnatal. The anatomical specificity of arbors at 12-13 and 18-25 days was quantified by measuring the distance that terminal boutons spread across the frequency axis. There was a significant reduction of this distance in older animals. In addition, there was a significant reduction in the mean number of boutons per arbor between 12-13 days and 18-25 days. The maximum nucleus cross-sectional area continued to increase through 15-16 days, indicating that the refined arbors occupied an even smaller fraction of the postsynaptic structure. Taken together, these observations suggest that central inhibitory arbors form exuberant contacts that must be eliminated during development.     

Compounds from the sea with actions on the cardiovascular and central nervous systems

Recent efforts at probing into the oceans have produced evidence that marine invertebrates such as gorgonians and sponges offer a rich reserve of pharmacologically interesting molecules. Our investigations indicate that it is possible to obtain novel compounds both structurally and pharmacologically. For example, autonomium from a sponge is a dual adrenergic combined with cholinergic molecule, with a structure that may be considered a hybrid between a catecholamine and choline. Various terpenoids and indole derivatives from marine organisms have been found to possess activities on the central nervous system. Several peptides from sea anemones are cardiotonic and have initiated a new concept of chemical structure believed to be associated with cardiac activity. A number of closely related halogenated cyclic ethers are good inhibitors of drug metabolism. Thus, there seems little doubt that the sea warrants an extensive chemical and pharmacological examination.     

Evolution of flatworm central nervous systems: Insights from polyclads

The nervous systems of flatworms have diversified extensively as a consequence of the broad range of adaptations in the group. Here we examined the central nervous system (CNS) of 12 species of polyclad flatworms belonging to 11 different families by morphological and histological studies. These comparisons revealed that the overall organization and architecture of polyclad central nervous systems can be classified into three categories (I, II, and III) based on the presence of globuli cell masses -ganglion cells of granular appearance-, the cross-sectional shape of the main nerve cords, and the tissue type surrounding the nerve cords. In addition, four different cell types were identified in polyclad brains based on location and size. We also characterize the serotonergic and FMRFamidergic nervous systems in the cotylean Boninia divae by immunocytochemistry. Although both neurotransmitters were broadly expressed, expression of serotonin was particularly strong in the sucker, whereas FMRFamide was particularly strong in the pharynx. Finally, we test some of the major hypothesized trends during the evolution of the CNS in the phylum by a character state reconstruction based on current understanding of the nervous system across different species of Platyhelminthes and on up-to-date molecular phylogenies.     

Upper trapezius muscle activity patterns during repetitive manual material handling and work with with a computer mouse.

Firstly, upper trapezius EMG activity patterns were recorded on the dominant side of 6 industrial production workers and on the side operating a computer mouse of 14 computer-aided design (CAD) operators to study differences in acute muscular response related to the repetitiveness of the exposure. The work tasks were performed with median arm movement frequencies ranging from 5 min(-1) to 13 min(-1) and were characterized by work cycle times ranging from less than 30 sec to several days. However, the static and median EMG levels and EMG gap frequencies were similar for all work tasks indicating that shoulder muscle loads may be unaffected by large variations in arm movement frequencies and work cycle times. An exposure variation analyses (EVA) showed that the EMG activity patterns recorded during production work were more repetitive than during CAD work, whereas CAD work was associated with more static muscle activity patterns, both may be associated with a risk of developing musculoskeletal symptoms. Secondly, upper trapezius EMG activity patterns recorded on the mouse side of the CAD operators were compared with those recorded on the non-mouse side to study differences in muscular responses potentially related to the risk of developing shoulder symptoms which were more prevalent on the mouse side. The number of EMG gaps on the mouse side were significantly lower than the values for the upper trapezius on the non-mouse side indicating that more continuous activity was present in the upper trapezius muscle on the mouse side and EVA analyses showed a more repetitive muscle activity pattern on the mouse side. These findings may be of importance to explain differences in the prevalence of shoulder symptoms.     

The peptide molecular links between the central nervous and the immune systems

Summary. The central nervous system (CNS) and the immune system were for many years considered as two autonomous systems. Now, the reciprocal connections between them are generally recognized and very well documented. The links are realized mainly by various immuno- and neuropeptides. In the review the influence of the following immunopeptides on CNS is presented: tuftsin, thymulin, thymopoietin and thymopentin, thymosins, and thymic humoral factor. On the other side, the activity in the immune system of such neuropeptides as substance P, neurotensin, some neurokinins, enkephalins, and endorphins is discussed.     

On the evolution of central nervous systems: Implications from polyclad turbellarian neurobiology

The nervous system of the polyclad turbellarian Notoplana acticola consists of a series of nerve plexuses and a central ganglion, the brain. The brain contains a variety of cell types including multipolar heteropolar and bipolar neurons. These cell types are rare in other invertebrate ganglia. Individual neurons also contain a variety of different ion channels. both spiking and nonspiking neurons are found. Some neurons are multimodal interneurons. Habituation appears to be a postsynaptic phenomenon. Sensitization and long-term potentiation have not been demonstrated. Polyclads appear to represent a stage in the evolution of centralized nervous systems where much of the neuronal machinery underlying behavior occurs in the peripheral nervous system and the brain's main functions are the coordination and sequencing of peripherally placed reflexes. Even at this stage, however, the brain already contains cells that seem as advanced as those found in higher organisms.     

Icam-1 participates in the entry of west nile virus into the central nervous system

Determining how West Nile virus crosses the blood-brain barrier is critical to understanding the pathogenesis of encephalitis. Here, we show that ICAM-1(-/-) mice are more resistant than control animals to lethal West Nile encephalitis. ICAM-1(-/-) mice have a lower viral load, reduced leukocyte infiltration, and diminished neuronal damage in the brain compared to control animals. This is associated with decreased blood-brain barrier leakage after viral infection. These data suggest that ICAM-1 plays an important role in West Nile virus neuroinvasion and that targeting ICAM-1 signaling may help control viral encephalitis.     

Direct entry of rabies virus into the central nervous system without prior local replication.

Rabies virus pathogenesis was studied in a mouse model by inoculation of the masseter muscle. At different intervals, the masseter muscle, trigeminal ganglia, and brain were analyzed for virus-specific RNA with a polymerase chain reaction assay, which revealed that as early as 18 h postinfection (p.i.), virus-specific RNA was present in the trigeminal ganglia, and at 24 h p.i., viral RNA was identified in the brain stem. Analysis of the masseter muscle demonstrated virus at 1 h p.i. but no virus-specific RNA between 6 and 30 h p.i., indicating that virus invaded the nerve ending directly, without prior replication in the muscle. At 36 h p.i., viral RNA was detected again in the masseter muscle. Selective amplification of plus- and minus-strand RNA isolated from the masseter muscle at 96 h p.i. revealed that the majority of the rabies virus-specific RNA was in the positive sense, suggesting virus replication in muscle tissue during late stages of infection.