Effect of Porphyromonas gingivalis infection on gut dysbiosis and resultant arthritis exacerbation in mouse model.

BACKGROUND: Porphyromonas gingivalis (Pg) infection causes periodontal disease and exacerbates rheumatoid arthritis (RA). It is reported that inoculation of periodontopathogenic bacteria (i.e., Pg) can alter gut microbiota composition in the animal models. Gut microbiota dysbiosis in human has shown strong associations with systemic diseases, including RA, diabetes mellitus, and inflammatory bowel disease. Therefore, this study investigated dysbiosis-mediated arthritis by Pg oral inoculation in an experimental arthritis model mouse. METHODS: Pg inoculation in the oral cavity twice a week for 6 weeks was performed to induce periodontitis in SKG mice. Concomitantly, a single intraperitoneal (i.p.) injection of laminarin (LA) was administered to induce experimental arthritis (Pg-LA mouse). Citrullinated protein (CP) and IL-6 levels in serum as well as periodontal, intestinal, and joint tissues were measured by ELISA. Gut microbiota composition was determined by pyrosequencing the 16 s ribosomal RNA genes after DNA purification of mouse feces. Fecal microbiota transplantation (FMT) was performed by transferring Pg-LA-derived feces to normal SKG mice. The effects of Pg peptidylarginine deiminase (PgPAD) on the level of citrullinated proteins and arthritis progression were determined using a PgPAD knockout mutant. RESULTS: Periodontal alveolar bone loss and IL-6 in gingival tissue were induced by Pg oral infection, as well as severe joint destruction, increased arthritis scores (AS), and both IL-6 and CP productions in serum, joint, and intestinal tissues. Distribution of Deferribacteres and S24-7 was decreased, while CP was significantly increased in gingiva, joint, and intestinal tissues of Pg-inoculated experimental arthritis mice compared to experimental arthritis mice without Pg inoculation. Further, FMT from Pg-inoculated experimental arthritis mice reproduced donor gut microbiota and resulted in severe joint destruction with increased IL-6 and CP production in joint and intestinal tissues. The average AS of FMT from Pg-inoculated experimental arthritis was much higher than that of donor mouse. However, inoculation of the PgPAD knockout mutant inhibited the elevation of arthritis scores and ACPA level in serum and reduced CP amount in gingival, joint, and intestinal tissues compared to Pg wild-type inoculation. CONCLUSION: Pg oral infection affected gut microbiota dysbiosis and joint destruction via increased CP generation.

Randomized double-blind placebo-controlled multicenter trial of Yokukansan for neuropsychiatric symptoms in Alzheimer's disease.

AIM: Yokukansan (YKS), a traditional herbal medicine, has been used to treat behavioral and psychological symptoms of dementia (BPSD). The present study is the first double-blind, randomized, placebo-controlled trial to determine the efficacy and safety of YKS for the treatment of BPSD in Alzheimer's disease (AD). METHODS: A total of 22 sites consisting of clinics, hospitals and nursing homes participated. A total of 145 patients with AD were randomized. Active YKS (7.5 g/day) and placebo were supplied to 75 and 70 participants, respectively. The primary outcome measure was the 4-week change in total score of the Neuropsychiatric Inventory Brief Questionnaire Form (NPI-Q), an instrument that evaluates BPSD. Secondary outcome measures included 12-week changes in NPI-Q scores, changes in NPI-Q subcategory scores and total scores of the Mini-Mental-State Examination. RESULTS: Four-week changes in NPI-Q total scores did not differ significantly between the treatment and placebo groups. There were also no significant differences between groups in 12-week changes in total NPI-Q scores, NPI-Q subcategory scores or total Mini-Mental-State Examination scores. However, a subgroup with fewer than 20 points on the Mini-Mental-State Examination at baseline showed a greater decrease in "agitation/aggression" score in the YKS group than in the placebo group (P = 0.007). No serious adverse effects were observed during the study. CONCLUSIONS: Our data did not reach statistical significance regarding the efficacy of YKS against BPSD; however, YKS improves some symptoms including "agitation/aggression" and "hallucinations" with low frequencies of adverse events. Geriatr Gerontol Int 2017; 17: 211-218.

Differentiation of PA from early PSP with different patterns of symptoms and CBF reduction.

OBJECTIVE: To clarify the features of pure akinesia (PA) and progressive supranuclear palsy (PSP) in the early stage of disease. METHODS: We investigated 15 PA and 41 PSP patients' clinical and radiologic features including head MRI, ethyl cysteinate dimmer-single photon emission-computed tomography (ECD-SPECT) and iodine-123 meta-iodobenzyl guanidine (123I-MIBG) myocardial scintigraphy. In ECD-SPECT study, cerebral blood flow (CBF) reduction was quantitatively expressed as Z-score, and that in the frontal lobe was evaluated. RESULTS: Many PSP patients claimed falls as the initial symptom but no PA patients did. Eye movement, as well as optokinetic nystagmus elicitation, was more frequently disturbed in PSP. Dementia, dysarthria and rigidity were also more frequent in PSP than in PA. Midbrain tegmentum atrophy in head MRI was more frequently observed in PSP. CBF in the frontal lobe, especially in the frontal eye field, was significantly lower in PSP than in PA. MIBG myocardial scintigraphy showed no difference between two groups. DISCUSSION: PA and PSP show distinct symptoms from the early stage, indicating that they are distinct disorders. The occurrence of falls and eye movement disturbance, as well as CBF reduction at the frontal eye field, is very important for distinguishing these disorders.

[A case of corticobasal degeneration that progressed from primary progressive aphasia].

A 65-year-old woman began to experience slowly progressive speech disturbance from 2001. She was admitted to our hospital for examination on May 2003. She had dysprosody, paragraphia, and mild disturbance in comprehension of spoken language. Repetition was preserved. No clear paraphasia was found. Calculation was disturbed, but there were no other neurological abnormalities including apraxia and agnosia. Brain MRI showed atrophy of the left frontal and parietal lobes. 99mTc-ECD SPECT showed decreased blood flow in the left frontal lobe and parietal lobe, especially in the Broca area and supplemental motor cortex. Primary progressive aphasia was diagnosed, because aphasia lasted for 2 years without other neurological deficits, and her daily activity was well preserved. During follow up, facial apraxia appeared from December 2003, and limb apraxia appeared from May 2004, followed by rigidity predominantly in the right upper limb and dementia. She was diagnosed as having corticobasal degeneration (CBD). The second SPECT on December 2004 showed progression of the decrease in cerebral flow at the same area showed by the first SPECT. SPECT is useful examination to predict the progress of the disease because the decrease of blood flow was recognized before the progression to CBD.

Potentiation of Akt and suppression of caspase-9 activations by electroacupuncture after transient middle cerebral artery occlusion in rats.

Electroacupuncture (EA) is an effective curative method for diseases including cerebral ischemia. In the current study, we investigated the effects of EA treatment on the activations of survival Akt and proapoptotic caspase-9 after 90 min of transient middle cerebral artery occlusion (tMCAO) in rat. Immunoreactivity of phospho-Akt (p-Akt) increased in the ipsilateral hemisphere after tMCAO with a peak at 8 h, and EA enhanced the Akt expression both in the number and the staining strength mainly in the ischemic penumbra (IP) at 8 and 24 h. Cleaved caspase-9 was strongly induced at 8 h in IP, which was suppressed with EA. The number of terminal deoxynucleotidyl transferase-mediated uridine 5' triphosphate-biotin nick end labelling positive cells reduced at 24 h in the cerebral cortex. These results suggest that EA potentiated the Akt and suppressed the caspase-9 activations, and may have a potential to reduce the number of neuronal cells undergoing apoptotic cell death.