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Background: This study aimed to investigate the effects of low-level erbium-doped: yttrium, aluminum, and garnet (Er:YAG) laser irradiation on periodontal tissue healing and regeneration through angiogenesis in vivo and in vitro studies., Methods: Intrabony defects were surgically created in the bilateral maxilla molar of rats. The defects were treated by open flap debridement (OFD) with Er:YAG laser, including low-level laser irradiation (LLLI) to bone and blood clot surfaces, or conventional procedures. The mRNA expression of vascular endothelial growth factor (VEGF) in the surgical sites was quantified using real-time polymerase chain reaction. The decalcified specimens were prepared for histometric analysis. Also, LLLI was performed on human umbilical vein endothelial cells to evaluate the effects on angiogenesis. Cell proliferation, VEGF expression, and tube formation were assessed. In addition, capsazepine (CPZ), a selective inhibitor of transient receptor potential vanilloid 1 (TRPV1), treatment was performed before LLLI for the same assays., Results: OFD using Er:YAG laser did not generate thermal damage on bone or root surfaces. LLLI accelerated hemostasis by coagulation of the superficial layers of blood clots in the laser-treated group. Postoperative healing was sound in all animals in both groups. VEGF expression and bone formation were significantly increased in the laser-treated group compared to those in the conventional treatment group. In vitro, cell proliferation and VEGF expression were significantly increased in the LLLI group compared to the control group. Tube-formation assays showed that LLLI significantly promoted angiogenesis. CPZ treatment significantly suppressed VEGF expression and tube formation following LLLI., Conclusions: This study suggests that Er:YAG laser irradiation may promote periodontal tissue healing by enhancing angiogenetic effect of endothelial cells via TRPV1., (© 2023 American Academy of Periodontology.)

Objective: This study aims to investigate the mechanisms underlying the impaired healing response by diabetes after periodontal therapy., Background: Outcomes of periodontal therapy in patients with diabetes are impaired compared with those in patients without diabetes. However, the mechanisms underlying impaired healing response to periodontal therapy have not been sufficiently investigated., Materials and Methods: Zucker diabetic fatty (ZDF) and lean (ZL) rats underwent experimental periodontitis by ligating the mandibular molars for one week. The gingiva at the ligated sites was harvested one day after ligature removal, and gene expression was comprehensively analyzed using RNA-Seq. In patients with and without type 2 diabetes (T2D), the corresponding gene expression was quantified in the gingiva of the shallow sulcus and residual periodontal pocket after non-surgical periodontal therapy., Results: Ligation-induced bone resorption and its recovery after ligature removal were significantly impaired in the ZDF group than in the ZL group. The RNA-Seq analysis revealed 252 differentially expressed genes. Pathway analysis demonstrated the enrichment of downregulated genes involved in the peroxisome proliferator-activated receptor (PPAR) signaling pathway. PPARα and PPARγ were decreased in mRNA level and immunohistochemistry in the ZDF group than in the ZL group. In clinical, probing depth reduction was significantly less in the T2D group than control. Significantly downregulated expression of PPARα and PPARγ were detected in the residual periodontal pocket of the T2D group compared with those of the control group, but not in the shallow sulcus between the groups., Conclusions: Downregulated PPAR subtypes expression may involve the impaired healing of periodontal tissues by diabetes., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: This study aimed to investigate the effects of diabetes care on periodontal inflammation., Materials and Methods: This prospective cohort study included 51 Japanese patients with type 2 diabetes who underwent intensive diabetes care including educational hospitalization and regular outpatient treatment for 6 months. Dental prophylaxis without subgingival scaling was provided three times during the observational period. Associations between changes in periodontal parameters and glycaemic control levels were evaluated using multiple regression analysis., Results: Overall, 33 participants (mean age: 58.7 ± 12.9) were followed up for 6 months. At baseline examination, 82% were diagnosed with Stage III or IV periodontitis. Haemoglobin A1c (HbA1c) level changed from 9.6 ± 1.8% at baseline to 7.4 ± 1.3% at 6 months. The ratio of probing pocket depth (PPD) ≥4 mm, bleeding on probing (BOP), full-mouth plaque control record (PCR), periodontal epithelial surface area (PESA) and periodontal inflamed surface area (PISA) also significantly improved. The reduction in PPD and PESA was significantly associated with changes in both HbA1c and fasting plasma glucose (FPG) levels, and the reduction in PISA was significantly associated with an improvement in FPG after adjusting for smoking, change in body mass index and full-mouth PCR., Conclusions: This is the first study to report a significant improvement in PPD and BOP after intensive diabetes care and dental prophylaxis without subgingival scaling., Clinical Trial Registration Number: UMIN000040218., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Diabetes mellitus (DM) is associated with periodontal disease. Clinically, periodontal treatment is less effective for patients with DM. Oxidative stress is one of the mechanisms that link DM to periodontitis. The production of reactive oxygen species (ROS) is increased in the periodontal tissues of patients with DM and is involved in the development of insulin resistance in periodontal tissues. Insulin resistance decreases Akt activation and inhibits cell proliferation and angiogenesis. This results in the deterioration of wound healing and tissue repair in periodontal tissues. Antioxidants and insulin resistance ameliorants may inhibit ROS production and improve wound healing, which is worsened by DM. This manuscript provides a comprehensive review of the most recent basic and clinical evidence regarding the generation of ROS in periodontal tissues resulting from microbial challenge and DM. This study also delves into the impact of oxidative stress on wound healing in the context of periodontal and dental implant therapies. Furthermore, it discusses the potential benefits of administering antioxidants and anti-insulin resistance medications, which have been shown to counteract ROS production and inflammation. This approach may potentially enhance wound healing, especially in cases exacerbated by hyperglycemic conditions.

Background: Kampo medicine is widely used in Japan; however, most physicians and pharmacists have insufficient knowledge and experience in it. Although a chatbot-style system using machine learning and natural language processing has been used in some clinical settings and proven useful, the system developed specifically for the Japanese language using this method has not been validated by research. The purpose of this study is to develop a novel drug information provision system for Kampo medicines using a natural language classifier® (NLC®) based on IBM Watson., Methods: The target Kampo formulas were 33 formulas listed in the 17th revision of the Japanese Pharmacopoeia. The information included in the system comes from the package inserts of Kampo medicines, Manuals for Management of Individual Serious Adverse Drug Reactions, and data on off-label usage. The system developed in this study classifies questions about the drug information of Kampo formulas input by natural language into preset questions and outputs preset answers for the questions. The system uses morphological analysis, synonym conversion by thesaurus, and NLC®. We fine-tuned the information registered into NLC® and increased the thesaurus. To validate the system, 900 validation questions were provided by six pharmacists who were classified into high or low levels of knowledge and experience of Kampo medicines and three pharmacy students., Results: The precision, recall, and F-measure of the system performance were 0.986, 0.915, and 0.949, respectively. The results were stable even with differences in the amount of expertise of the question authors., Conclusions: We developed a system using natural language classification that can give appropriate answers to most of the validation questions., (© 2023. The Author(s).)

Background: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a high probability of metastasis and a lack of specific targets and targeted therapeutics. Previously, we have reported that COL8A1, which is highly expressed in the mesenchymal stem-like (MSL) subtype of TNBC, facilitates TNBC growth via FAK/Src activation. Furthermore, we have found that COL8A1 enhances the invasion and metastasis of MDA-MB-231 cells, classified into MSL. However, the mechanism of invasion and metastasis by COL8A1 remains unclear. Here, we investigated the biological function of COL8A1 on the invasion and metastasis of MDA-MB-231 cells., Methods: The invasion and metastasis of MDA-MB-231 cells were evaluated using three-dimensional (3D) culture methods and xenograft mouse models. DNA microarray analysis examined the gene expression in COL8A1-overexpressing MDA-MB-231 cells and control cells. Gene expression was verified using RT-qPCR., Results: COL8A1-deficient cells showed little or no metastasis, whereas forced expression of COL8A1 in MDA-MB-231 cells, the MSL subtype of TNBC cell lines, significantly promoted distant metastasis after tumor resection. As with in vivo, 3D invasion assay revealed that COL8A1 increased the invasion capacity of MDA-MB-231 and Hs578T cells, classified into the MSL subtype of TNBC. DNA microarray analysis for COL8A1-overexpressing cells indicated that COL8A1 induces interleukin 1B (IL1B) and matrix metalloproteinase-1 (MMP1) expression, both of which are correlated with COL8A1 expression in the mesenchymal subtypes of TNBC, and the Kaplan-Meier plotter provided evidence that the prognosis in the MSL subtype was strongly associated with both gene expressions and COL8A1 expression. Pharmacological inhibitor treatment showed that COL8A1 regulated IL1B and MMP1 expression through a different pathway. Moreover, the knockdown of each gene expression reduced the invasion capacity of COL8A1-overexpressing MDA-MB-231 and Hs578T cells., Conclusion: Our findings indicate that COL8A1-induced IL1B and MMP1 enhanced the invasion and metastasis of the MSL subtype of TNBC. Considering our previous findings that COL8A1 promotes tumor growth, COL8A1 may be a prognostic and practical therapeutic target in TNBC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Diabetes involves metabolic disorders in various tissues via hyperglycemia-induced oxidative stress. This study aimed to investigate the antioxidative effect of enamel matrix derivative (EMD) on periodontal regeneration in diabetes., Methods: Twenty-two rats were equally divided into streptozotocin (STZ)-induced diabetes or control group. Two months after induction of hyperglycemia, systemic oxidative stress was measured using urinary 8-hydroxy-2'-deoxyguanosine. EMD or saline was applied into the intrabony defects created in the bilateral maxillary molar. mRNA expressions of inflammatory and oxidative stress markers were quantified (n = 6). Histometric analyses and immunohistochemistry of superoxide dismutase-1 (SOD-1) were performed 7 days postoperatively (n = 5). For in vitro experiments, the bone marrow-derived mesenchymal stem cells were isolated from rat femur and cultured in a high glucose (HG) or control medium. Reactive oxygen species (ROS) measurement and alizarin red staining were performed with/without EMD., Results: Systemic oxidative stress was significantly higher in the diabetic group. The connective tissue attachment and cementum formation were significantly increased at EMD-treated sites in both diabetic and non-diabetic groups. The expression of nicotinamide adenine dinucleotide phosphate oxidase two and four was significantly lower at EMD-treated sites than at EMD-untreated sites in both diabetic and non-diabetic rats. Immunohistochemistry showed significantly higher SOD-1 expression at the EMD-treated site. In vitro, HG culture had significantly higher ROS production compared with control, which was downregulated by EMD. EMD treatment significantly recovered the impaired calcification in HG., Conclusion: EMD promoted early-phase wound healing and periodontal tissue regeneration in the surgically created bony defect of STZ-induced diabetic rat by suppressing hyperglycemia-induced oxidative stress., (© 2021 American Academy of Periodontology.)

Objective: Few studies have reported on the impact of oxidative stress on the dental implant failure. The aim of this study was to investigate the impact of hyperglycemia-induced oxidative stress on dental implant osseointegration in diabetes mellitus (DM)., Methods: Acid-treated titanium implants were bilaterally placed in the maxillary alveolar ridge of streptozotocin-induced diabetic (DM group) and control rats after extraction of first molars. Histological analysis and micro-push-out test were performed 4 weeks after surgery. Oxidative stress and osteogenic markers in the surrounding bone were quantified by real-time polymerase chain reaction. In the in vitro study, rat bone marrow-derived mesenchymal stem cells (BMMSCs) were cultured on acid-treated titanium discs in a high-glucose (HG) or normal environment. Intracellular reactive oxygen species (ROS), cell proliferation, alkaline phosphatase (ALP) activity, and extracellular calcification were evaluated following antioxidant treatment with N-acetyl-L-cysteine (NAC)., Results: The implant survival rate was 92.9% and 75.0% in control and DM group, respectively. Bone-implant contact and push-out loads were significantly lower in the DM group. Expression of superoxide dismutase 1 at the mRNA level and on immunohistochemistry was significantly lower in the DM group. In vitro experiments revealed that the HG condition significantly increased ROS expression and suppressed the proliferation and extracellular calcification of BMMSCs, while NAC treatment significantly restored ROS expression, cell proliferation, and calcification. The ALP activity of both groups was not significantly different., Conclusion: In diabetes, high-glucose-induced oxidative stress downregulates proliferation and calcification of BMMSCs, impairing osseointegration and leading to implant failure., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: This study aimed to investigate the effects of metformin on gingival wound healing in insulin-resistant prediabetes., Methods: C57BL/6J mice were fed normal diet (ND) or high-fat diet (HFD) for 10 weeks; half of the HFD mice were treated with metformin (HFD+ Met) for the last 2 weeks. Insulin and glucose tolerance tests were performed. The palatal gingiva (2.0 × 0.5 mm) was surgically removed adjacent to the maxillary molars. Post-surgical wound closure was histomorphometrically evaluated for 1 week. The mRNA expression of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) in the tissue were quantified by real-time polymerase chain reaction. In vitro, the proliferation and migration of human gingival fibroblasts (HGFs) cultured under high-glucose or control conditions with/without metformin were analyzed. Akt phosphorylation and VEGF expression following the insulin stimulation were evaluated with/without metformin in high-glucose or control media., Results: HFD mice showed significantly higher plasma glucose levels and insulin resistance than ND mice. Gingival wound healing was delayed in HFD group compared with ND group but significantly improved in HFD + MET group. The decreased expression of VEGF and eNOS in HFD group was significantly elevated in the HFD + MET group. The proliferation and migration of HGFs were significantly impaired in high-glucose conditions compared with control; metformin treatment partially attenuated these effects. Metformin treatment significantly recovered the downregulated Akt phosphorylation and VEGF expression in high-glucose conditions., Conclusions: Metformin improved delayed gingival wound healing in insulin-resistant prediabetes by accelerating HGFs proliferation and migration via Akt phosphorylation in insulin signaling pathway., (© 2021 American Academy of Periodontology.)

Background: Registered dietitians are rarely employed at community pharmacies in Japan, even though dietetic advice might benefit some patients., Objective: To clarify the present status of dietetic consultation provided by registered dietitians and their collaboration with pharmacists in community pharmacies., Methods: We conducted a cross-sectional questionnaire-based survey of pharmacists and registered dietitians who work in community pharmacies. The surveyed items were: frequency of dietetic consultation, awareness of one's knowledge and ability to conduct dietetic consultation, concerns, pharmacists' recognition of the need for nutritional support at community pharmacies, and cooperation between registered dietitians and pharmacists., Results: Sixty-six registered dietitians, 53 pharmacists in pharmacies with registered dietitians/dietitians, and 110 pharmacists in pharmacies without registered dietitians/dietitians responded. The frequency of dietetic consultation regarding obesity and hypertension was significantly higher for registered dietitians than for pharmacists. The ability to conduct dietetic consultation regarding diseases/conditions such as kidney disease not requiring dialysis, hyperuricemia, gout, obesity and hypertension was also significantly higher for dietitians than pharmacists. More than 70% of pharmacists recognized the importance of nutritional support at community pharmacies, while 56.1% of registered dietitians noted that they were not able to fully utilize their occupational abilities. Registered dietitians were divided into two groups: registered dietitians who answered that they were able to utilize their occupational abilities and those that answered they were not. The former group was more likely to ask pharmacists about patients' medication for dietetic consultation and to be asked to provide dietetic consultation to patients. The latter group was more likely to find difficulty in scheduling dietetic consultation., Conclusion: Our results suggest that registered dietitians in community pharmacies have a greater explanatory ability than pharmacists concerning nutritional and dietary management for patients. It may be important for pharmacists to improve cooperation with registered dietitians by providing more opportunities for dietetic consultation., (© 2021. The Author(s).)

Abstract: Polypharmacy influences malnutrition and activities of daily living (ADL) in older individuals owing to side effects such as anorexia. This study aimed to examine whether polypharmacy (5 or more drugs) is associated with malnutrition and ADL disability among daycare facility users.This cross-sectional study was performed in a daycare facility specializing in rehabilitation. Malnutrition was defined according to the Global Leadership Initiative on Malnutrition criteria and ADL disability according to the "criteria for determination of the daily life independence level (bedridden level) of elderly with disabilities."In total, 103 of the 134 included individuals were analyzed. Thirty-three (32.0%) participants were malnourished, 46 (44.7%) had ADL disability, 58 (56.3%) qualified as cases of polypharmacy, and 9 (8.7%) experienced loss of appetite. Multivariable logistic regression analysis showed that polypharmacy was independently associated with malnutrition and ADL disability. Separate analyses of each type of drug revealed that proton pump inhibitors (that impair protein absorption and assimilation), anticonstipation drugs, and antihypertensive drugs were associated with malnutrition, whereas proton pump inhibitors, anticonstipation drugs, antidyslipidemia drugs, and antidiabetic drugs were associated with ADL disability. The only factor related to anorexia was the loss of pleasure of eating, which in turn was related to psychological stress.The side effects of polypharmacy among individuals with malnutrition and ADL disability may include impaired protein absorption and assimilation caused by proton pump inhibitors, but not anorexia. Further multicenter prospective studies are required to confirm these findings., Competing Interests: The authors declare that there is no conflict of interest., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

This review investigated whether the adjunctive use of antioxidants with periodontal therapy improves periodontal parameters in patients with type 2 diabetes. A systematic and extensive literature search for randomized controlled trials (RCTs) conducted before April 2021 was performed on the PubMed, Cochrane Library, and Web of Science databases. The risk of bias was assessed using the Cochrane risk-of-bias tool. A meta-analysis was performed to quantitatively evaluate the clinical outcomes following periodontal therapy. After independent screening of 137 initial records, nine records from eight RCTs were included. The risk-of-bias assessment revealed that all RCTs had methodological weaknesses regarding selective bias, although other risk factors for bias were not evident. This meta-analysis of two RCTs showed that periodontal pocket depths were significantly reduced in the groups treated with combined non-surgical periodontal therapy and melatonin than in those treated with non-surgical periodontal therapy alone. The present systematic review and meta-analysis suggest that the adjunctive use of melatonin, resveratrol, omega-3 fatty acids with cranberry juice, propolis, and aloe vera gel with periodontal therapy significantly improves periodontal disease parameters in patients with type 2 diabetes, and melatonin application combined with non-surgical periodontal therapy might significantly reduce periodontal pocket depth. However, there are still limited studies of melatonin in combination with non-surgical periodontal therapy in Type 2 diabetic patients, and more well-designed RCTs are required to be further investigated.

This study aimed to analyze population flow using global positioning system (GPS) location data and evaluate influenza infection pathways by determining the relationship between population flow and the number of drugs sold at pharmacies. Neural collective graphical models (NCGMs; Iwata and Shimizu 2019) were applied for 25 cell areas, each measuring 10 × 10 km 2 , in Osaka, Kyoto, Nara, and Hyogo prefectures to estimate population flow. An NCGM uses a neural network to incorporate the spatiotemporal dependency issue and reduce the estimated parameters. The prescription peaks between several cells with high population flow showed a high correlation with a delay of one to two days or with a seven-day time-lag. It was observed that not much population flows from one cell to the outside area on weekdays. This observation may have been due to geographical features and undeveloped transportation networks. The number of prescriptions for anti-influenza drugs in that cell remained low during the observation period. The present results indicate that influenza did not spread to areas with undeveloped traffic networks, and the peak number of drug prescriptions arrived with a time lag of several days in areas with a high amount of area-to-area movement due to commuting.

Introduction: The aim was to investigate the relationship of full-mouth inflammatory parameters of periodontal disease with diabetes and obesity., Research Design and Methods: This cross-sectional study conducted diabetes-related examinations and calculated periodontal inflamed and epithelial surface area (PISA and PESA) of 71 Japanese patients with type 2 diabetes. Multiple linear regression analyses were performed to evaluate associations between PISA or PESA and diabetes and obesity parameters., Results: Median value of body mass index (BMI), hemoglobin A1c (HbA1c) level, fasting plasma glucose (FPG) level, and visceral fat area (VFA) were 25.7 kg/m 2 , 9.1%, 151 mg/L, and 93.3 cm 2 , respectively. PISA and PESA were significantly associated with HbA1c after adjusting for age, sex, BMI, smoking status, and full-mouth plaque control level (PISA: coefficient=38.1, 95% CI 8.85 to 67.29, p=0.001; PESA: coefficient=66.89, 95% CI 21.44 to 112.34, p=0.005). PISA was also significantly associated with the highest FPG tertile (>175 mg/dL) after adjusting for confounders (coefficient=167.0, 95% CI 48.60 to 285.4, p=0.006). PISA and PESA were not significantly associated with BMI or VFA., Conclusion: PISA was associated with FPG and HbA1c, but not with obesity parameters, independent from confounders such as full-mouth plaque control level in patients with type 2 diabetes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This study offers an analysis of the elderly (over 65 years of age) among a general community population in terms of the percentages of: (i) persons with recurring thoughts of death and/or of committing suicide, and (ii) people who have consulted others, including medical professionals, with regard to these problems. Among 433 elderly over the age of 65 in one community in a town in Aomori Prefecture, 358 agreed to participate in the project. Forty-four participants (12.3%) responded that they had either 'thoughts of death' or 'thoughts of suicide', and these thoughts had continued for more than 2 weeks in 12 participants (3.4%). Only 15 of the 44 suicidal elderly responded that they had consulted someone about their problems. Although there are many elderly people exhibiting a subclinical depressive state with recurring thoughts of death or thoughts of suicide, the number of people who consult family members, professionals, or others is very low. This suggests the importance of community networking through educational activities so that people can more readily talk to and support one another.