There is no established genetic model of bipolar disorder or major depression, which hampers research of these mood disorders. Although mood disorders are multifactorial diseases, they are sometimes manifested by one of pleiotropic effects of a single major gene defect. We focused on chronic progressive external ophthalmoplegia (CPEO), patients with which sometimes have comorbid mood disorders. Chronic progressive external ophthalmoplegia is a mitochondrial disease, which is accompanied by accumulation of mitochondrial DNA (mtDNA) deletions caused by mutations in nuclear-encoded genes such as POLG (mtDNA polymerase). We generated transgenic mice, in which mutant POLG was expressed in a neuron-specific manner. The mice showed forebrain-specific defects of mtDNA and had altered monoaminergic functions in the brain. The mutant mice exhibited characteristic behavioral phenotypes, a distorted day-night rhythm and a robust periodic activity pattern associated with estrous cycle. These abnormal behaviors resembling mood disorder were worsened by tricyclic antidepressant treatment and improved by lithium, a mood stabilizer. We also observed antidepressant-induced mania-like behavior and long-lasting irregularity of activity in some mutant animals. Our data suggest that accumulation of mtDNA defects in brain caused mood disorder-like mental symptoms with similar treatment responses to bipolar disorder. These findings are compatible with mitochondrial dysfunction hypothesis of bipolar disorder.

The population pharmacokinetic parameters of vancomycin obtained here can be used to individualize the dosage of vancomycin in institutions with similar patient population characteristics.

No abstract

Host-derived factors alter gut microenvironment, and changes in gut microbiota also affect biological functions of host. Alterations of gut microbiota have been reported in a wide variety of diseases, but the whole picture of alterations in pancreatic diseases remains to be clarified. In particular, the gut microbiota may be affected by malnutrition or impaired exocrine pancreas function that is associated with pancreatic diseases. We here conducted comprehensive analysis of gut microbiota in patients with type 1 autoimmune pancreatitis (AIP), a pancreatic manifestation of the systemic IgG4-related disease, and chronic pancreatitis (CP). The two diseases were selected, because altered immune reactions in AIP and/ or long-standing malnutrition in CP may influence the gut microbiota. Fecal samples were obtained from 12 patients with AIP before the steroid therapy and 8 patients with CP. Metagenome DNA was extracted, and microbiota was analyzed by next generation sequencing. Gut microbiota profiles were different between patients with AIP and those with CP; namely, the proportions of Bacteroides, Streptococcus and Clostridium species were higher in patients with CP. The reasons for the increased proportion of these bacterial species remain unknown, but may reflect malabsorption and/or decreased pancreatic enzymes, both of which are associated with CP. Incidentally, the identified Streptococcus species are oral cavity inhabitants and also known as pathogens for endocarditis. Despite the small sample size, this study has shown the differences in gut microbiota profiles between AIP and CP. Comprehensive analysis of the gut microbiota may be useful for the differential diagnosis of pancreatic diseases.