Lipoteichoic acid (LTA) is a cell surface glycoconjugate of gram-positive bacteria and is reported to activate the innate immune system. We previously reported that purified LTA obtained from Enterococcus hirae has no immunostimulating activity, but a subfraction (Eh-AF) in an LTA fraction possesses activity. In this study, we established a mouse monoclonal antibody neutralizing the activity of Eh-AF and investigated its inhibitory effects. Monoclonal antibody (MAbEh1) was established by the immunization of BALB/c mice with Eh-AF, followed by hybridoma screening based on its inhibitory effect for the production of interleukin-6 (IL-6) induced by Eh-AF. MAbEh1 neutralized the production of IL-6 by LTA fraction from not only E. hirae but also Staphylococcus aureus, while it failed to block that of lipopolysaccharide, suggesting that the antibody recognized a common active structure(s) in LTA fractions. Synthetic glycolipids in these LTAs did not induce cytokine production, at least in our system. Interestingly, the antibody was found to inhibit the activity of immunostimulating synthetic lipopeptides, Pam 3 CSK 4 and FSL-1. These results suggest that MAbEh1 neutralizes the activity of lipoprotein-like compounds which is responsible for the activity of the LTA fraction of E. hirae and S. aureus.Lipoteichoic acid (LTA) is a macroamphiphile distributing on the cell surfaces of gram-positive bacteria and is reported to exhibit immunostimulatory and inflammatory activities. LTA has been shown to have an antitumor effect (34, 36) and to induce inflammatory cytokines, such as tumor necrosis factor (TNF), interleukin-1 (IL-1), and 31,33). Recent research showed that such immunostimulatory activities of bacterial compounds were mediated by Toll-like receptor (TLR), a type I transmembrane receptor for innate immune activation (32). To date, more than 10 members of the TLR family have been discovered and most of their ligands were identified: TLR4 in combination with the adapter molecule MD-2 for lipopolysaccharide (LPS)/lipid A, an outer membrane component of gram-negative bacteria (21, 24); TLR9 for unmethylated CpG DNA (15); TLR3 and TLR7/8 for double-and single-stranded RNA (1, 14); TLR5 for bacterial flagellin (13); and TLR2 subfamily (TLR1, Ϫ2, and Ϫ6) for bacterial lipoprotein/lipopeptide (29, 30). LTA was also reported to be a ligand of TLR2 (22).The structures of LTAs have been well studied and proposed as a glycoconjugates generally composed of a glycolipid anchor part, such as ␤-kojibiosyldiacylglycerol for Enterococcus hirae and Streptococcus pyogenes and ␤-gentiobiosyldiacylglycerol for Staphylococcus aureus, and a 1,3-linked poly(glycerophosphate) substituted by sugars and D-alanine at position 2 of the glycerol (4). Previously, we attempted to determine a structure of the LTA responsible for these activities. Fukase et al. prepared chemically synthetic glycoconjugates having fundamental structures of LTA from E. hirae and S. pyogenes and their glycolipid anchor parts (5, 6). However, these synthetic compounds ...

In order to clarify mechanisms underlying dopaminergic neuronal death in Parkinson's disease (PD), a gene expression profiling study was performed in a rodent model of PD. In this model, mice are intrastriatally injected with 6-hydroxydopamine (6-OHDA) and dopaminergic neurons in the substantia nigra (SN) gradually die by retrograde degeneration. The SN were removed 2 h, 24 h, or 14 days after 6-OHDA administration. Levels of mRNAs related to cell death or survival were quantified using adaptor-tagged competitive PCR (ATAC-PCR). The cyclin D1 gene showed an immediate increase in mRNA expression. After 24 h, when dopaminergic neurons were under intense degeneration, levels of caspase 8 mRNA and p53 apoptosis effecter related to pmp 22 (PERP) mRNA increased and, conversely, FAS mRNA decreased. After 14 days, when the degeneration was attenuated, levels of PERP mRNA and serum- and glucocorticoid-regulated kinase (SGK) mRNA still increased. SGK has a similarity to AKT, which is an important molecule involved in nerve growth factor signal transduction. AKT mRNA levels are low in dopaminergic neurons. These results suggest that an increase in cyclin D1 mRNA triggers dopaminergic neurons to enter an abnormal cell cycle, which leads to neuronal degeneration and cell death, possibly induced by PERP and caspase 8. In addition to cell death-related genes, several survival-related genes are activated. SGK might function as a key enzyme for the survival of dopaminergic neurons.

The mechanism of L-DOPA for antinociception was investigated. Nociceptive behaviors in mice after an intrathecal (i.t.) administration of substance P were evaluated. L-DOPA (i.t.) dose-dependently attenuated the substance P-induced nociceptive behaviors. Co-administration of benserazide (i.t.), a DOPA decarboxylase inhibitor, abolished the antinociceptive effect of L-DOPA. The L-DOPA-induced antinociception was antagonized by sulpiride, a D2 blocker, but not by SCH 23390, a D1 blocker. These results suggest that L-DOPA relieves pain after conversion to dopamine, with the dopamine sedating pain transmission by way of the dopamine D2 receptor.

No abstract

We report the cases of two patients with psychiatric stupor who developed venous thrombosis. A 29‐year‐old schizophrenic woman had been hospitalized in psychiatric institutions three times because of stupor associated with auditory hallucinations and thought blocking. These symptoms recurred and she was admitted to our hospital with deep venous thrombosis of her left leg. The other patient was a 67‐year‐old woman with depression. She had also suffered from insomnia. Following admission to our hospital, she developed a depressive stupor complicated by deep venous thrombosis of her left leg. Both cases were treated with sodium heparin and urokinase, and completely resolved. It is well known that dehydration, infection and decubitus ulcers are important physical complications of psychiatric stupor, but there have been few reports of deep venous thrombosis as a physical complication of stupor.