The immune-stromal cell interactions play a key role in health and diseases.In periodontitis,the most prevalent infectious disease in humans,immune cells accumulate in the oral mucosa and promote bone destruction by inducing receptor activator of nuclear factor-κB ligand(RANKL)expression in osteogenic cells such as osteoblasts and periodontal ligament cells.However,the detailed mechanism underlying immune-bone cell interactions in periodontitis is not fully understood.Here,we performed single-cell RNA-sequencing analysis on mouse periodontal lesions and showed that neutrophil-osteogenic cell crosstalk is involved in periodontitis-induced bone loss.The periodontal lesions displayed marked infiltration of neutrophils,and in silico analyses suggested that the neutrophils interacted with osteogenic cells through cytokine production.Among the cytokines expressed in the periodontal neutrophils,oncostatin M(OSM)potently induced RANKL expression in the primary osteoblasts,and deletion of the OSM receptor in osteogenic cells significantly ameliorated periodontitis-induced bone loss.Epigenomic data analyses identified the OSM-regulated RANKL enhancer region in osteogenic cells,and mice lacking this enhancer showed decreased periodontal bone loss while maintaining physiological bone metabolism.These findings shed light on the role of neutrophils in bone regulation during bacterial infection,highlighting the novel mechanism underlying osteoimmune crosstalk.

In stroke patients, excessive oxidative stress impairs brain nerve cells and leads to arteriosclerosis. On the other hand, rehabilitative exercise is necessary for the functional improvement and maintenance after stroke, and exercises themselves increase reactive oxygen species production simultaneously. Therefore, it is essential to elucidate how exercises influence oxidative stress in stroke patients. We assessed the effects of exercises on 29 Japanese subacute-phase stroke patients (exercise group, 20; control group, 9), in terms of oxidative stress by examining changes in reactive oxygen metabolite (ROM) level (i.e., oxidative stress) and biological antioxidant potential (BAP) level (i.e., antioxidant capacity) in blood plasma. The exercise group performed two sets of 1-hour exercises 6 days/week for 56 days. The control group performed the same 1-hour exercises, but only on days 1 and 56. ROM and BAP levels in blood plasma in both groups were measured immediately before and after the exercises and at rest on days 1 and 56. ROM level significantly decreased and BAP level significantly increased at rest from days 1 to 56 in the exercise group. However, no significant change was observed in these levels in the control group. Conclusion: Regular rehabilitative exercise can improve antioxidant capacity and attenuate oxidative stress even in stroke patients.
Oxidative Stress ; Stroke ; Arteriosclerosis

Characteristics of low attenuation area (LAA) of the lungs on HRCT were studied in 132 patients with asthma, and long-term spa therapy on the LAA of the lungs was observed in 5 patients with asthma, whose me an %LAA was more than 30%.
1. The morphology of LAA of the lungs on HRCT observed in asthma was different from that in pulmonary emphysema. 2. The LAA of the lungs in asthma was closely related to residual volume (RV). 3. The mean %LAA value significantly decreased from 33.5% before spa therapy to 24.5% at 24 months after beginning of the therapy. CT number also significantly increased after long-term spa therapy. 4. %FEV1.0 value significantly improved from 52.1% before spa therapy to 72.1% at 24 months after spa therapy. The RV value also decreased by spa therapy, however, the decrease was not significant. These results suggest that LAA of the lungs in asthma is associated with hyperinflation, and the LAA of the lungs decreases after long-term spa therapy.

Clinical effects of spa therapy for patients with pulmonary emphysema (PE) were evaluated by observing changes in %LAA of the lung on HRCT, %RV, %FVC, %FEV 1.0, and %DLco values after the long-term therapy. The subjects in this study 16 patients with PE. The subjects were divided into two groups according to the extent of %LAA<-950 HU of the lung on HRCT: %LAA<50% (N=6) and 50%≤%LAA (N=8). 1. Spa therapy significantly improved %LAA (42.5% at the initial stage to 36.3% 24 months after spa therapy), %RV (202.1% to 156.1%) and %DLco 71.0% to 85.7%), but not %FVC and %FEV 1.0, in patients with PE of %LAA<50%, however, significant. Improvement of these parameters was not observed in patients without spa therapy. 2. Spa therapy did not improve the values of %LAA, %RV, and %DLco, as well as %FVC and %FEV 1.0, in patients with PE of 50%≤%LAA. These parameters tended to decrease in the patients of 50%≤%LAA. These results suggest that spa therapy improves %LAA and parameters related to pulmonary function when they are at early stage of PE, however, the therapy was not remarkably effective for these parameters when they were at advanced stage of PE.

Spa therapy has been performed at our medical center for last 20 years. The changes in number and frequency of patients with respiratory disease were analyzed every 5 year for last 20 years. The total number of patients with respiratory disease who were admitted at our medical center for last 20 years was 1934, of whom the number of patients with asthma was 1226 (63.4%), and the number of those with COPD was 415 (21.5%). The number of patients with asthma treated with spa therapy showed a tendency to increase form 57 for the first 5 years (first stage) to 465 for the last 5 years (forth stage). The number of patients with COPD also increased from 26 for the first 5 years to 227 for the last 5 years. The frequency of SDIA decreased from 68.4% for the first 5 years to 29.0% for the last 5 years. In contrast, the frequency of pulmonary emphysema increased 19.2% at the first stage to 76.7% at the forth stage. The number and frequency of elderly patients with asthma and COPD over the age of 60 tended to increase for last 20 years.

N-3 fatty acids are reportedly effective for asthma. In addition, spa therapy has been reported to be effective for patients with asthma. In the present study, the effects of spa therapy combined with perilla seed oil-rich diet (rich in n-3 fatty acid) were examined on asthma. A total of 14 asthmatic patients had a complex spa therapy and consumed a perilla seed oil-rich diet-rich in α-linolenic acid (α-LNA) for 8 weeks. Generation of leukotriene (LT) C4 by leucocytes, respiratory function were analyzed. The generation of LTC4 by leucocytes decreased significantly for 2, 4 and 8 weeks (P<0.05). Peak expiratory flow (PEF) values increased significantly for 2, 4, 6 and 8 weeks (P<0.05). The values of ventilatory parameters [forced vital capacity (FVC), forced expiratory volume in one second (FEV₁), forced expiratory flow after 25% of expired FVC (FEF₂₅), forced expiratory flow after 75% of expired FVC (FEF₇₅), mean expiratory flow during the middle half of the FVC (FEF_25-75)] revealed a significant increase after 4 and 8 weeks of the modified diet (P<0.05). The results suggest that spa therapy combined with a perilla seed oil-rich diet are effective in the treatment of asthma in terms of its ability to suppress LTC4 generation by leucocytes, and in inducing an improvement of pulmonary function.

Effects of spa therapy on asthma were studied in 64 patients with asthma in relation to the generation of leukotrienes B4 (LTB4) and C4 (LTC4) and bronchial hyperresponsiveness. 1. The efficacy of spa therapy was marked in 12 (18.8%), and moderate in 45 (70.3%) of 64 patients with asthma, and slight or no efficacy of the therapy was observed in the residual 7 patients (10.9%). 2. Bronchial hyperresponsiveness to methacholine was the highest in patients with slight or no efficacy of spa therapy, however, there were no significant differences among the three groups classified by clinical efficacy. 3. The generation of LTC4 by leucocytes was significantly higher in patients with slight or no efficacy compared with the generation in those with marked (p<0.01) and moderate efficacy (p<0.001). However, there were no significant differences in the generation of LTB4 among them. 4. The generation of LTC4 before spa therapy significantly decreased in patients with marked (p<0.001) and moderate efficacy (p<0.01) after spa therapy, but not in those with slight or no efficacy. The generation of LTB4 was not significantly different before and after spa therapy among patients with marked, moderate, and slight or no efficacy. These results show that the efficacy of spa therapy for patients with asthma is closely related to the generation of LTC4 by leucocytes, and that the generation of LTC4 significantly decreases after spa therapy in patients with spa efficacy.

The patients with asthma or pulmonary emphysema who were admitted at our hospital for last 9 years (1992-2000) were examined in relation to frequency of disease, patient age, and areas where patients came.
1. Of 1271 patients (141.2 patients/year) with respiratory disease admitted for last 9 years, 808 (63.6%, 97.8 patients/year) were patients with asthma, and 157 (12.4%, 17.4 patients/year)) were those with pulmonary emphysema.
2. The frequency of patients with asthma for all patients with respiratory desease tended to decease from 82.1% in 1992 to 51.3% in 2000, while the frequency of those with pulmonary emphysema increased from 2.8% in 1992 to 24.4% in 2000.
3. The number of patients with asthma over the age of 70 years was larger in those inside Tottori prefecture, and the number of patients between the ages of 60 and 69 years was larger in those from distant areas. The age was more than 50 years in all patients with pulmonary emphysema.
4. The number of patients with asthma from distant areas (outside Tottori prefecture) was larger (456 patients; 56.4%) than the number of those inside Tottori prefecture (352 patients) for 9 years. The number of patients from Okayama, Hiroshima, Hyogo and Osaka was larger than the number from other distant areas.

We studied the effects of electro acupuncture stimulation of Baxie on local tolerance as an index of cold induced vasodilation (CIVD). The subjects consisted of 22 healthy adult volunteers. The skin temperature and skin blood flow in the middle finger were simultaneously examined before, during, and after immersion of the finger in cold water. Electroacupuncture stimulation at 1 Hz with a 66 to 100V intensity was performed for 5 minutes. Experiments of no stimulation and electroacupuncture stimulation were conducted on the same subject on different days.
The results revealed the following:
1. CIVD was caused by rapid increase of skin blood flow during immersion of the finger in cold water.
2. The minimum skin temperature, minimum skin blood flow, maximum skin blood flow, mean skin temperature in the rising phase of skin temperature, and the index of resistance to frostbite of the electroacupuncture stimulated group were higher than those of the unstilmulated group, and rates of skin temperature increase and decrease during immersion of the finger in cold water in the electroacupuncture stimulated group were significantly higher. These results show that electroacupuncture stimulation increases local cold tolerance in the finger.