Discordance between hyposalivation and xerostomia

Individuals with an objective decrease in salivary flow (objective dry mouth) may not be aware of subjective dry mouth (xerostomia). However, no clear evidence exists to explain the discordance between subjective and objective dry mouth. Therefore, this cross-sectional study aimed to assess the prevalence of xerostomia and decreased salivary flow among community-dwelling elderly adults. In addition, this study assessed several potential demographic and health status determinants of the discrepancy between xerostomia and reduced salivary flow. The 215 participants in this study were community-dwelling older people aged 70 years and above who underwent dental health examinations between January-February 2019. Symptoms of xerostomia were collected in the form of a questionnaire. The unstimulated salivary flow rate (USFR) was measured by a dentist using visual inspection. The stimulated salivary flow rate (SSFR) was measured using the Saxon test. We identified 19.1% of participants as having mild-severe USFR decline with xerostomia and 19.1% as having mild-severe USFR decline without xerostomia. Additionally, 26.0% of participants had low SSFR and xerostomia, and 40.0% had low SSFR without xerostomia. Except for the age trend, no factors could be associated with the discordance between USFR measurement and xerostomia. Furthermore, no significant factors were associated with the discordance between the SSFR and xerostomia. However, females were significantly associated (OR = 2.608, 95% CI = 1.174–5.791) with low SSFR and xerostomia, as compared to males. Age was a factor that was also significantly associated (OR = 1.105, 95% CI = 1.010–1.209) with low SSFR and xerostomia. Our findings indicate that approximately 20% of the participants had low USFR without xerostomia, and 40% had low SSFR without xerostomia. This study showed that age, sex, and the number of medications may not be factors in the discrepancy between the subjective feeling of dry mouth and reduced salivary flow

UCP3 ト Hax-1 ノ ソウゴ サヨウ ニヨル ミトコンドリア ノ カルシウム ノ ウド ノ チョウセツ

Mitochondrial Ca２＋ plays an important role in the regulations of various cellular functions. Uncoupling protein ３ （UCP３） is primarily expressed in the inner membrane of skeletal muscle mitochondria. Recently, it has been reported that UCP３ is associated with Ca２＋ uptake into mitochondria. However, the mechanisms by which UCP３ regulates mitochondrial Ca２＋ uptake are not well understood. Here we report that UCP３interacts with HS‐１associated protein X‐１ （Hax‐１）, an anti-apoptotic protein that is localized in mitochondria, which is involved in cellular responses to Ca２＋. The hydrophilic sequences within the loop２, matrix-localized hydrophilic domain of mouse UCP３are necessary for binding to Hax‐１of the C-terminal domain in adjacent to mitochondrial innermembrane. Interestingly, interaction of these proteins occurs the calciumdependent manner. Moreover, NMR spectrum of the C-terminal domain of Hax‐１was dramatically changed by removal of Ca２＋, suggesting that the C-terminal domain of Hax‐１ underwent a Ca２＋-induced conformation change. In the Ca２＋-free states, C-terminal Hax‐１ didn’t change the structure, suggesting that Ca２＋ binding may induce the change of protein structure of Hax‐１ C-terminus. These studies identify a novel UCP３‐Hax‐１complex regulates the influx of Ca２＋ into mitochondria. Thus, the efficacy of UCP３‐Hax‐１in mitochondrial calcium regulation may provide a novel therapeutic approach against mitochondrial dysfunction-related disease

Chronic exposure of VEGF inhibitors promotes the malignant phenotype of colorectal cancer cells

VEGF-targeting anti-angiogenic drugs have enabled significant advances in cancer therapy. However, acquired resistance to VEGF-targeting drugs occurs, leading to disease progression. How tumors become the resistance remains fully uncertain. One of possible mechanisms for the resistance may be the direct effect of VEGF inhibitors on tumor cells expressing VEGF receptors (VEGF-R). We investigated here the direct effect of chronic VEGF inhibition on phenotype changes in cancer cells. To chronically inhibit cancer cell-derived VEGF, human colon cancer HCT116 cells were chronically exposed (3 months) to anti-VEGF neutralizing monoclonal antibody (HCT/mAb cells, blockade of VEGF alone) or VEGF-R tyrosine kinase inhibitor foretinib (HCT/fore cells, blockade of all VEGF family). HCT/mAb cells redundantly increased VEGF family member (VEGF, PlGF, VEGF-B, VEGF-R1 and VEGF-R2) and induced a resistance to hypoxia-induced apoptosis. By contrast, HCT/fore cells did not show the redundant increase in VEGF family member, but significantly increased a VEGF-independent pro-angiogenic factor FGF-2. HCT/fore cells showed increased migration and invasion activities in addition to a resistance to hypoxia-induced apoptosis. The resistance to apoptosis was significantly suppressed by inhibition of hypoxia-inducible factor-1α in HCT/mAb cells, but not in HCT/fore cells. These findings suggest that chronic inhibition of VEGF/VEGF-R accelerates malignant phenotypes of colon cancer cells

The malignant progression effects of regorafenib in human colon cancer cells

A number of anti-angiogenic drugs targeting vascular endothelial growth factor receptors (VEGF-R) have developed and enabled significant advances in cancer therapy including colorectal cancer. However, acquired resistance to the drugs occurs, leading to disease progression, such as invasion and metastasis. How tumors become the resistance and promote their malignancy remains fully uncertain. One of possible mechanisms for the resistance and the progression may be the direct effect of VEGF-R inhibitors on tumor cells expressing VEGF-R. We investigated here the direct effect of a VEGF-R-targeting agent, regorafenib, which is the first small molecule inhibitor of VEGF-Rs for the treatment of patients with colorectal cancer, on phenotype changes in colon cancer HCT116 cells. Treatment of cells with regorafenib for only 2 days activated cell migration and invasion, while vehicle-treated control cells showed less activity. Intriguingly, chronic exposure to regorafenib for 90 days dramatically increased migration and invasion activities and induced a resistance to hypoxia-induced apoptosis. These results suggest that loss of VEGF signaling in cancer cells may induce the acquired resistance to VEGF/VEGF-R targeting therapy by gaining two major malignant phenotypes, apoptosis resistance and activation of migration/invasion

食生活の多様性とうつ病および自殺の有病率との関連 ―26年間の国際比較研究―

Purpose: This study aimed to determine the associations of dietary diversity with depression and suicide rates by an ecological analysis using 26-years worldwide statistics.Methods: Average food supply and energy supply by country, excluding loss between production and household, were obtained from the Food and Agriculture Organization of the United Nations Statistics Division database (FAOSTAT). Dietary diversity scores were calculated from food group classifications. Age-standardized depression prevalence and suicide rates per 100,000 people by country were obtained from the Global Burden of Disease (GBD) 2017 database. The association between food diversity scores and depression prevalence and suicide rates was analyzed by a mixed effects model controlling for covariates in 137 countries with populations of 1 million or greater.Results: A significant negative association was found in the analysis of the relationship between dietary diversity and the prevalence of major depression in the model controlled for all covariates [β (se) = –225.6 (61.9), p < 0.001]. In addition, a significant negative association between dietary diversity and the suicide rate was also found in the model controlled for all covariates [β (se) = –3.08 (1.50), p < 0.05].Conclusion: Dietary diversity was significantly negatively associated with the rates of major depression and suicide. Diets rich in foods may reduce the prevalence of depression and suicide rate.【目的】本研究は、26年間の世界的な統計を用いた生態学的分析により、食生活の多様性とうつ病や自殺率との関連を明らかにすることを目的とした。【方法】生産と家庭間の喪失を除く国別平均食料供給量とエネルギー供給量を国連食糧農業機関統計局データベース（FAOSTAT）から入手した。食物群分類から食事多様性スコアを算出した。年齢標準化された国別の人口10万人当たりのうつ病有病率と自殺率は、Global Burden of Disease（GBD）2017データベースから取得した。人口100万人以上の137カ国を対象に、食品多様性スコアとうつ病有病率および自殺率との関連を、共変量を制御した混合効果モデルで解析した。【結果】食生活の多様性とうつ病の有病率との関係を分析したところ、すべての共変量を調整したモデルにおいて、有意な負の関連が認められた［β（se）＝－225.6（61.9）、p < 0.001］。さらに、食生活の多様性と自殺率との間の有意な負の関連も、すべての共変量を調整したモデルで認められた［β（se）= －3.08（1.50）、p < 0.05］。【結論】食生活の多様性は、うつ病および自殺の発生率と有意に負の関連があった。食物を豊富に含む食事は、うつ病や自殺を減少させる可能性がある

自発的高運動ラットの安静時遺伝子発現パターンと野生型ラット運動時遺伝子発現パターンの違い

The Spontaneously-Running Tokushima Shikoku (SPORTS) strain is an original line derived from Wistar rats, which spontaneously runs >6 km/day on wheels, and has better glucose tolerance and less fat than Wistar rats. However, the molecular mechanism that contributes to the increased metabolic activity in SPORTS rats is unknown. The present study aimed to characterize the gene expression profiles of skeletal muscles in SPORTS rats housed under sedentary (SED) conditions. We found that the expression levels of genes encoding mitochondrial respiratory chain enzymes such as ATP synthase 6 (mt-Atp6) and cytochrome c oxidase subunit 6c (Cox 6c), were higher in the soleus (SOL) muscles of SED SPORTS than in SED Wistar rats. The ratio of type IIa myofibers was higher and glucose tolerance was better in SED SPORTS than in Wistar rats that were sedentary and trained daily on treadmills, respectively. We then investigated candidate genes that might contribute to the better glucose tolerance of SED SPORTS rats using DNA microarray analysis. Among 116 upregulated genes in the SOL muscles of SED SPORTS rats, only 19 were also increased in trained Wistar rats. We focused on v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (Erbb3), which was associated with glucose transport in myocytes, and found higher expression levels in the SOL muscles of SED SPORTS than in SED Wistar rats. The SOL muscles of SED SPORTS rats also contained more activity of β-hydroxy-acylCoA dehydrogenase, a key enzyme of β-oxidation, indicating enhanced lipid oxidation. These findings suggest that increased metabolic activity in skeletal muscle (especially the SOL muscle) of SPORTS rats is congenital and that gene expression profiles of SPORTS rats and Trained Wistar rats are different

Genetic polymorphism of pleiotrophin is associated with pain experience in Japanese adults Case-control study

Genetic factors play a role in individual differences in pain experience. Here, we performed a genome-wide association study (GWAS) to identify novel loci regulating pain processing. We conducted a 2-stage GWAS and the candidate single-nucleotide polymorphisms (SNPs) association study on pain experience using an exploratory cohort of patients with cancer pain. The confirmatory cohort comprised of participants from the general population with and without habitual use of analgesic medication. In the exploratory cohort, we evaluated pain intensity using a numerical rating scale, recorded daily opioid dosages, and calculated pain reduction rate. In the confirmatory cohort, pain experience was defined as habitual nonsteroidal anti-inflammatory drug usage. Using linear regression models, we identified candidate SNP in the exploratory samples, and tested the association between phenotype and experienced pain in the confirmatory samples. We found 1 novel SNP (rs11764598)—located on the gene encoding for pleiotrophin on chromosome 7—that passed the genome-wide suggestive significance at 20% false discovery rate (FDR) correction in the exploratory samples of patients with cancer pain (P = 1.31 × 10-7, FDR = 0.101). We confirmed its significant association with daily analgesic usage in the confirmatory cohort (P = .028), although the minor allele affected pain experience in an opposite manner. We identified a novel genetic variant associated with pain experience. Further studies are required to validate the role of pleiotrophin in pain processing

Nationwide retrospective observational study of idiopathic dendriform pulmonary ossification : clinical features with a progressive phenotype

Background: Diffuse pulmonary ossification is a specific lung condition that is accompanied by underlying diseases. However, idiopathic dendriform pulmonary ossification (IDPO) is extremely rare, and the clinical features remain unclear. In this study, we aimed to report the clinical characteristics of IDPO. Methods: We conducted a nationwide survey of patients with IDPO from 2017 to 2019 in Japan and evaluated the clinical, radiological, and histopathological findings of patients diagnosed with IDPO. Results: Twenty-two cases of IDPO were identified. Most subjects (82%) were male, aged 22-56 years (mean (SD), 37.9 (9.1)) at diagnosis. Nearly 80% of the subjects were asymptomatic, and the condition was discovered during a medical check-up. However, 36% of the subjects showed a decline in forced vital capacity (%FVC) predicted <80% at diagnosis. The typical radiological features of high-resolution CT (HRCT) are calcified branching structures that are predominantly distributed in the lower lung fields without any other conspicuous finding. Histopathological analysis also showed dendriform ossified lesions from the intraluminal areas to interstitial areas. Notably, during the follow-up period of 20 years, disease progression was found in 88% on HRCT and more than 50% on pulmonary function tests (FVC and/or forced expiratory volume in 1s). Two cases with rapid decline of 10% /year in %FVC predicted were observed.)) at diagnosis. Nearly 80% of the subjects were asymptomatic, and the condition was discovered during a medical check-up. However, 36% of the subjects showed a decline in forced vital capacity (%FVC) predicted <80% at diagnosis. The typical radiological features of high-resolution CT (HRCT) are calcified branching structures that are predominantly distributed in the lower lung fields without any other conspicuous finding. Histopathological analysis also showed dendriform ossified lesions from the intraluminal areas to interstitial areas. Notably, during the follow-up period of 20 years, disease progression was found in 88% on HRCT and more than 50% on pulmonary function tests (FVC and/or forced expiratory volume in 1s). Two cases with rapid decline of 10% /year in %FVC predicted were observed. )) at diagnosis. Nearly 80% of the subjects wereasymptomatic, and the condition was discovered during a medical check-up. However, 36% of the subjects showed a decline in forced vital capacity (%FVC) predicted <80% at diagnosis. The typical radiological features of high-resolution CT (HRCT) are calcified branching structures that are predominantly distributed in the lower lung fields without any other conspicuous finding. Histopathological analysis also showed dendriform ossified lesions from the intraluminal areas to interstitial areas. Notably, during the follow-up period of 20 years, disease progression was found in 88% on HRCT and more than 50% on pulmonary function tests (FVC and/or forced expiratory volume in 1s). Two cases with rapid decline of 10% /year in %FVC predicted were observed. Conclusions: IDPO develops at a young age with gradually progressive phenotype. Further research and long-term (>20 years) follow-up are required to clarify the pathogenesis and clinical findings in IDPO

On the origin and evolution of the asteroid Ryugu: A comprehensive geochemical perspective

Presented here are the observations and interpretations from a comprehensive analysis of 16 representative particles returned from the C-type asteroid Ryugu by the Hayabusa2 mission. On average Ryugu particles consist of 50% phyllosilicate matrix, 41% porosity and 9% minor phases, including organic matter. The abundances of 70 elements from the particles are in close agreement with those of CI chondrites. Bulk Ryugu particles show higher δ18O, Δ17O, and ε54Cr values than CI chondrites. As such, Ryugu sampled the most primitive and least-thermally processed protosolar nebula reservoirs. Such a finding is consistent with multi-scale H-C-N isotopic compositions that are compatible with an origin for Ryugu organic matter within both the protosolar nebula and the interstellar medium. The analytical data obtained here, suggests that complex soluble organic matter formed during aqueous alteration on the Ryugu progenitor planetesimal (several 10’s of km), <2.6 Myr after CAI formation. Subsequently, the Ryugu progenitor planetesimal was fragmented and evolved into the current asteroid Ryugu through sublimation