Hirofumi Morioka

Antinociceptive mechanism of l-DOPA

&NA; 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.

Evidence of immunostimulating lipoprotein existing in the natural lipoteichoic acid fraction

ABSTRACT 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, Pam3CSK4 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.

The Genetic Basis of Phenotypic Diversity: Autism as an Extreme Tail of a Complex Dimensional Trait

Autism is a developmental lifelong condition of the human brain, and a behavioral characterization as a spectrum (autism spectrum disorder: ASD) is the best way to illustrate this complex trait (Frith, 2001; Rapin, 1997; Wing, 1997). The predominant presence of autistic cases without comorbidity (idiopathic or primary ASD) (Freitag, 2007) clearly means that the biological effects associated with the known concomitant medical conditions (cytogenic abnormalities, fragile X syndrome, tuberous sclerosis, congenital infections, maternal thalidomide use, epilepsy, etc.) cannot be the common prerequisite for ASD at least in the majority of the cases. The presence of a strong genetic contribution is evident from the results of twin studies, which demonstrated that 70-90% of monozygotic twins are concordant for ASD, and the concordance in dizygotic twins and the recurrence rate in the proband’s siblings are both less than 10% (Rapin & Katzman, 1998). A broadening of the criteria of diagnosis leads the monozygotic concordance ratio to more than 90%, but 100% concordance is never obtained (Rapin & Katzman, 1998). Therefore, it is claimed that genetic factors contribute about 90% to ASD with environmental factors contributing no more than 10% (Garber, 2007). Although a flood of genetic information in the field of ASD is continuously growing, even the newest genome-wide molecular studies cannot detect the universal genetic prerequisite for idiopathic cases with ASD, compelling some researchers to speculate that ASD has a huge inter-case heterogeneity of the related gene variants. Many gene variants, which seem to affect brain development and synaptic functions, have been reported in association with the autistic development (Betancur, 2011; Garber, 2007; Persico & Bourgeron, 2006; Pinto et al., 2010). In families with the candidates for autism gene variants, however, the strict co-segregation, in which the gene variant is found only in individuals with ASD among family members including parents, is still exceptional (Table 1). To explain this fact, the broader distribution of the more primary phenotype or prebehavioral phenotype (endophenotype) beyond the categorical border is introduced as the speculative solution through this research maze (Viding & Blakemore, 2007). It may be quite difficult to detect and evaluate such endophenotypes because of the configurational or hierarchical structures of human cognitions and behaviors. Even if such speculations were

Quantitative Nature of Social Vulnerability and Autism: An Important Paradigm Shift in the DSM-5 for Autism Spectrum Disorder.

In the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), autistic characteristics in social interaction and communication are described as qualitative impairments. However, the difference between autistics and nonautistics in the draft of the 5th edition (DSM-5 draft) is quantitative rather than qualitative. The word “qualitative” is deleted in the draft text, and it is specified that the relation between social demands and individual limited capacities is critical for symptom manifestation (criterion C). Because the proposed levels of support requirement in the draft are mere observable outcomes of social vulnerability, the boundary between level 1 and nonautistic condition is determined by the relation between social demands and individual capacities. In addition to the introduction of the single category (autism spectrum disorder (ASD)) to cover the entire case spectrum, the DSM-5 draft is clearly based on a conviction that ASD is indistinguishable from the normal behavioral range. This concise review provides an explanation for this implicit paradigm shift from qualitative to quantitative. Importantly, the conditional role of social demands for symptom manifestation in the draft can be plausibly interpreted using a unique liability-probability model.