Electrical Stimulation-Based Twitch Exercise Suppresses Progression of Immobilization-Induced Muscle Fibrosis via Downregulation of PGC-1?/VEGF Pathway.

This study aimed to determine whether electrical stimulation-based twitch exercise is effective in inhibiting the progression of immobilization-induced muscle fibrosis. 19 Wistar rats were randomly divided into a control group (n=6), an immobilization group (n=6; with immobilization only), and a Belt group (n=7; with immobilization and twitch exercise through the belt electrode device, beginning 2 weeks after immobilization). The bilateral soleus muscles were harvested after the experimental period. The right soleus muscles were used for histological analysis, and the left soleus muscles were used for biochemical and molecular biological analysis. As a result, in the picrosirius red images, the perimysium and endomysium were thicker in both the immobilization and Belt groups compared to the control group. However, the perimysium and endomysium thickening were suppressed in the Belt group. The hydroxyproline content and alpha-SMA, TGF-beta1, and HIF-1alpha mRNA expressions were significantly higher in the immobilization and belt groups than in the control group. These expressions were significantly lower in the Belt group than in the immobilization group. The capillary-to-myofiber ratio and the mRNA expressions of VEGF and PGC-1alpha were significantly lower in the immobilization and belt groups than in the control group, these were significantly higher in the Belt group than in the immobilization group. From these results, Electrical stimulation-based twitch exercise using the belt electrode device may prevent the progression of immobilization-induced muscle fibrosis caused by downregulating PGC-1alpha/VEGF pathway, we surmised that this intervention strategy might be effective against the progression of muscle contracture. Keywords: Immobilization, Skeletal muscle, Fibrosis, Electrical stimulation-based twitch exercise, PGC-1alpha/VEGF pathway.

Skeletal Muscle Electrical Stimulation Prevents Progression of Disuse Muscle Atrophy via Forkhead Box O Dynamics Mediated by Phosphorylated Protein Kinase B and Peroxisome Proliferator-Activated Receptor gamma Coactivator-1alpha.

Although electrical muscle stimulation (EMS) of skeletal muscle effectively prevents muscle atrophy, its effect on the breakdown of muscle component proteins is unknown. In this study, we investigated the biological mechanisms by which EMS-induced muscle contraction inhibits disuse muscle atrophy progression. Experimental animals were divided into a control group and three experimental groups: immobilized (Im; immobilization treatment), low-frequency (LF; immobilization treatment and low-frequency muscle contraction exercise), and high-frequency (HF; immobilization treatment and high-frequency muscle contraction exercise). Following the experimental period, bilateral soleus muscles were collected and analyzed. Atrogin-1 and Muscle RING finger 1 (MuRF-1) mRNA expression levels were significantly higher for the experimental groups than for the control group but were significantly lower for the HF group than for the Im group. Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) mRNA and protein expression levels in the HF group were significantly higher than those in the Im group, with no significant differences compared to the Con group. Both the Forkhead box O (FoxO)/phosphorylated FoxO and protein kinase B (AKT)/phosphorylated AKT ratios were significantly lower for the Im group than for the control group and significantly higher for the HF group than for the Im group. These results, the suppression of atrogin-1 and MuRF-1 expression for the HF group may be due to decreased nuclear expression of FoxO by AKT phosphorylation and suppression of FoxO transcriptional activity by PGC-1alpha. Furthermore, the number of muscle contractions might be important for effective EMS.

First Observation of Electron Scattering from Online-Produced Radioactive Target.

We successfully performed electron scattering off unstable nuclei which were produced online from the photofission of uranium. The target ^{137}Cs ions were trapped with a new target-forming technique that makes a high-density stationary target from a small number of ions by confining them in an electron storage ring. After developments of target generation and transportation systems and the beam stacking method to increase the ion beam intensity up to approximately 2×10^{7} ions per pulse beam, an average luminosity of 0.9×10^{26} cm^{-2} s^{-1} was achieved for ^{137}Cs. The obtained angular distribution of elastically scattered electrons is consistent with a calculation. This success marks the realization of the anticipated femtoscope which clarifies the structures of exotic and short-lived unstable nuclei.

The burden of heat-related mortality attributable to recent human-induced climate change.

Climate change affects human health; however, there have been no large-scale, systematic efforts to quantify the heat-related human health impacts that have already occurred due to climate change. Here, we use empirical data from 732 locations in 43 countries to estimate the mortality burdens associated with the additional heat exposure that has resulted from recent human-induced warming, during the period 1991-2018. Across all study countries, we find that 37.0% (range 20.5-76.3%) of warm-season heat-related deaths can be attributed to anthropogenic climate change and that increased mortality is evident on every continent. Burdens varied geographically but were of the order of dozens to hundreds of deaths per year in many locations. Our findings support the urgent need for more ambitious mitigation and adaptation strategies to minimize the public health impacts of climate change.

Filamentous fungi with high paraquat-degrading activity isolated from contaminated agricultural soils in northern Thailand.

The contamination of paraquat (1,1'-dimethyl-4,4'-bipyridylium dichloride) herbicide from the farming area has become a public concern in many countries. This herbicide harms to human health and negatively effects the soil fertility. Several methods have been introduced for the remediation of paraquat. In this study, 20 isolates of the paraquat-tolerant fungi were isolated from the contaminated soil samples in northern Thailand. We found that isolate PRPY-2 and PFCM-1 exhibited the highest degradation activity of paraquat on synthetic liquid medium. About 80 and 68% of paraquat were removed by PRPY-2 and PFCM-1 respectively after 15 days of cultivation. Based on the morphological characteristic and molecular analysis, the fungal isolate PRPY-2 and PFCM-1 were identified as Aspergillus tamarii and Cunninghamella sp. respectively. The biosorption of paraquat on these fungal mycelia was also investigated. It was found that only 8-10% of paraquat could be detected on their mycelia, while 24-46% of paraquat was degraded by fungal mycelia. This is the first report on paraquat degrading ability by A. tamarii and Cunninghamella sp. It is demonstrated that these filamentous fungi are promising microorganisms available for remediation of paraquat contaminated environment.

Nasogastric Tube Feeding Versus Total Parenteral Nutrition in Older Dysphagic Patients with Pneumonia: Retrospective Cohort Study.

OBJECTIVES: Many older patients with pneumonia cannot intake orally after admission and may need nutritional care such as nasogastric tube feeding or total parenteral nutrition. This study sought to compare in-hospital outcomes between patients receiving nasogastric tube feeding and total parenteral nutrition. DESIGN: This is a retrospective cohort study. SETTING: A hospital-based database constructed by the Diagnosis Procedure Combination survey data comprising more than 100 acute-care hospitals. PARTICIPANTS: The study included consecutive older inpatients aged >65 years admitted to participating hospitals with a diagnosis of pneumonia from 2014 through 2017. MEASUREMENTS: We compared patients who received total parenteral nutrition and those who received nasogastric tube feeding in terms of characteristics and outcomes. RESULTS: Among the included inpatients, a total of 336 (73.2%) patients received total parenteral nutrition and 123 (26.8%) patients received nasogastric tube feeding. Patients with nasogastric tube feeding had less in-hospital mortality (13.8% vs 27.1%, p = 0.003) and a smaller number of complications (mean; 0.71 vs 1.44, p <0.001), shorter length of hospital stay (mean; 27.6 vs 48.9, p <0.001), more discharges home (72.4% vs 35.1%, p <0.001), and more discharges without oral intake (65.9% vs 45.8%, p <0.001) than patients with total parenteral nutrition. The same results were obtained in propensity score analysis. CONCLUSIONS: Older patients with pneumonia treated with total parenteral nutrition were significantly more likely to have higher in-hospital mortality than those receiving nasogastric tube feeding.

Seasonality of suicide: a multi-country multi-community observational study.

AIMS: We aimed to investigate the heterogeneity of seasonal suicide patterns among multiple geographically, demographically and socioeconomically diverse populations. METHODS: Weekly time-series data of suicide counts for 354 communities in 12 countries during 1986-2016 were analysed. Two-stage analysis was performed. In the first stage, a generalised linear model, including cyclic splines, was used to estimate seasonal patterns of suicide for each community. In the second stage, the community-specific seasonal patterns were combined for each country using meta-regression. In addition, the community-specific seasonal patterns were regressed onto community-level socioeconomic, demographic and environmental indicators using meta-regression. RESULTS: We observed seasonal patterns in suicide, with the counts peaking in spring and declining to a trough in winter in most of the countries. However, the shape of seasonal patterns varied among countries from bimodal to unimodal seasonality. The amplitude of seasonal patterns (i.e. the peak/trough relative risk) also varied from 1.47 (95% confidence interval [CI]: 1.33-1.62) to 1.05 (95% CI: 1.01-1.1) among 12 countries. The subgroup difference in the seasonal pattern also varied over countries. In some countries, larger amplitude was shown for females and for the elderly population (≥65 years of age) than for males and for younger people, respectively. The subperiod difference also varied; some countries showed increasing seasonality while others showed a decrease or little change. Finally, the amplitude was larger for communities with colder climates, higher proportions of elderly people and lower unemployment rates (p-values < 0.05). CONCLUSIONS: Despite the common features of a spring peak and a winter trough, seasonal suicide patterns were largely heterogeneous in shape, amplitude, subgroup differences and temporal changes among different populations, as influenced by climate, demographic and socioeconomic conditions. Our findings may help elucidate the underlying mechanisms of seasonal suicide patterns and aid in improving the design of population-specific suicide prevention programmes based on these patterns.

Search for η

We measured missing mass spectrum of the ^{12}C(γ,p) reaction for the first time in coincidence with potential decay products from η^{'} bound nuclei. We tagged an (η+p) pair associated with the η^{'}N→ηN process in a nucleus. After applying kinematical selections to reduce backgrounds, no signal events were observed in the bound-state region. An upper limit of the signal cross section in the opening angle cosθ_{lab}^{ηp}<-0.9 was obtained to be 2.2 nb/sr at the 90% confidence level. It is compared with theoretical cross sections, whose normalization ambiguity is suppressed by measuring a quasifree η^{'} production rate. Our results indicate a small branching fraction of the η^{'}N→ηN process and/or a shallow η^{'}-nucleus potential.

Functional analysis of a novel G87V TNFRSF1A mutation in patients with TNF receptor-associated periodic syndrome.

Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autoinflammatory disease that is caused by heterozygous mutations in the TNFRSF1A gene. Although more than 150 TNFRSF1A mutations have been reported to be associated with TRAPS phenotypes only a few, such as p.Thr79Met (T79M) and cysteine mutations, have been functionally analyzed. We identified two TRAPS patients in one family harboring a novel p.Gly87Val (G87V) mutation in addition to a p.Thr90Ile (T90I) mutation in TNFRSF1A. In this study, we examined the functional features of this novel G87V mutation. In-vitro analyses using mutant TNF receptor 1 (TNF-R1)-over-expressing cells demonstrated that this mutation alters the expression and function of TNF-R1 similar to that with the previously identified pathogenic T79M mutation. Specifically, cell surface expression of the mutant TNF-R1 in transfected cells was inhibited with both G87V and T79M mutations, whereas the T90I mutation did not affect this. Moreover, peripheral blood mononuclear cells (PBMCs) from TRAPS patients harboring the G87V and T90I mutations showed increased mitochondrial reactive oxygen species (ROS). Furthermore, the effect of various Toll-like receptor (TLR) ligands on inflammatory responses was explored, revealing that PBMCs from TRAPS patients are hyper-responsive to TLR-2 and TLR-4 ligands and that interleukin (IL)-8 and granulocyte-macrophage colony-stimulating factor (GM-CSF) are likely to be involved in the pathogenesis of TRAPS. These findings suggest that the newly identified G87V mutation is one of the causative mutations of TRAPS. Our findings based on unique TRAPS-associated mutations provide novel insight for clearer understanding of inflammatory responses, which would be basic findings of developing a new therapeutic and prophylactic approach to TRAPS.

Precision Analysis of the

We present a precision analysis of the ^{136}Xe two-neutrino ßß electron spectrum above 0.8 MeV, based on high-statistics data obtained with the KamLAND-Zen experiment. An improved formalism for the two-neutrino ßß rate allows us to measure the ratio of the leading and subleading 2νßß nuclear matrix elements (NMEs), ξ_{31}^{2ν}=-0.26_{-0.25}^{+0.31}. Theoretical predictions from the nuclear shell model and the majority of the quasiparticle random-phase approximation (QRPA) calculations are consistent with the experimental limit. However, part of the ξ_{31}^{2ν} range allowed by the QRPA is excluded by the present measurement at the 90% confidence level. Our analysis reveals that predicted ξ_{31}^{2ν} values are sensitive to the quenching of NMEs and the competing contributions from low- and high-energy states in the intermediate nucleus. Because these aspects are also at play in neutrinoless ßß decay, ξ_{31}^{2ν} provides new insights toward reliable neutrinoless ßß NMEs.

Dedifferentiated Fat (DFAT) cells: A cell source for oral and maxillofacial tissue engineering.

Tissue engineering is a promising method for the regeneration of oral and maxillofacial tissues. Proper selection of a cell source is important for the desired application. This review describes the discovery and usefulness of dedifferentiated fat (DFAT) cells as a cell source for tissue engineering. Dedifferentiated Fat cells are a highly homogeneous cell population (high purity), highly proliferative, and possess a multilineage potential for differentiation into various cell types under proper in vitro inducing conditions and in vivo. Moreover, DFAT cells have a higher differentiation capability of becoming osteoblasts, chondrocytes, and adipocytes than do bone marrow-derived mesenchymal stem cells and/or adipose tissue-derived stem cells. The usefulness of DFAT cells in vivo for periodontal tissue, bone, peripheral nerve, muscle, cartilage, and fat tissue regeneration was reported. Dedifferentiated Fat cells obtained from the human buccal fat pad (BFP) are a minimally invasive procedure with limited esthetic complications for patients. The BFP is a convenient and accessible anatomical site to harvest DFAT cells for dentists and oral surgeons, and thus is a promising cell source for oral and maxillofacial tissue engineering.

Full-layer mucosal histology in achalasia: Histological epithelial wave is characteristic in "pinstripe pattern"-positive achalasia.

BACKGROUND: Previously, the mucosal histology in achalasia has only been investigated using superficial biopsy or surgically resected esophageal specimens in end-stage cases. We investigated the histology of the full-layer mucosa in early and advanced achalasia. METHODS: Endoscopy was performed for the pinstripe pattern (PSP) (an early achalasia indicator) and dilation and thickening of the mucosa (advanced achalasia indicators). A mucosal entry site for peroral endoscopic myotomy was created using cap-fitted endoscopic mucosal resection to access the full-layer mucosa and the submucosa. KEY RESULTS: Mucosal histology was compared between 32 patients with achalasia and 15 controls. Histological esophagitis with findings of inflammatory cell infiltration and dilated intercellular spaces was observed more in patients with achalasia than in controls (87.5% vs 13.3%, P<.001; 84.4% vs 46.7%, P=.049). Muscularis mucosae (MM) atrophy and epithelial wave were only observed in achalasia (40.6% vs 0%, P=.005; 28.1% vs 0%, P=.043). Fibrosis was more common in achalasia, but without statistical significance (31.3% vs 20.0%, P=.503). In achalasia with endoscopic dilation and thickening of the mucosa, MM atrophy was observed histologically, and in cases involving endoscopic PSP, the histological epithelial wave was observed. CONCLUSIONS & INFERENCES: Histological findings of esophagitis were observed endoscopically even in early achalasia. Pinstripe pattern corresponds to the epithelial wave observed histologically in achalasia, whereas endoscopic findings in advanced achalasia correspond to MM atrophy. Appropriate management is necessary during early achalasia to prevent progression to advanced achalasia with more severe histological changes.

Simulation training for medical emergencies in the dental setting using an inexpensive software application.

INTRODUCTION: Every dental provider needs to be educated about medical emergencies to provide safe dental care. Simulation training is available with simulators such as advanced life support manikins and robot patients. However, the purchase and development costs of these simulators are high. We have developed a simulation training course on medical emergencies using an inexpensive software application. The purpose of this study was to evaluate the educational effectiveness of this course. MATERIALS AND METHODS: Fifty-one dental providers participated in this study from December 2014 to March 2015. Medical simulation software was used to simulate a patient's vital signs. We evaluated participants' ability to diagnose and treat vasovagal syncope or anaphylaxis with an evaluation sheet and conducted a questionnaire before and after the scenario-based simulation training. RESULTS: The median evaluation sheet score for vasovagal syncope increased significantly from 7/9 before to 9/9 after simulation training. The median score for anaphylaxis also increased significantly from 8/12 to 12/12 (P < .01). For the item "I can treat vasovagal syncope/anaphylaxis adequately," the percentage responding "Strongly agree" or "Agree" increased from 14% to 56% for vasovagal syncope and from 6% to 42% for anaphylaxis with simulation training. CONCLUSIONS: This simulation course improved participants' ability to diagnose and treat medical emergencies and improved their confidence. This course can be offered inexpensively using a software application.

The influence of aging on the effectiveness of heat stress in preventing disuse muscle atrophy.

This study examined the aging effect on disuse muscle atrophy prevention using heat stress. Wistar rats aged 7 and 60 weeks were divided into three groups as follows: control, immobilized (Im), and immobilized and heat stressed (ImH). Heat stress was given by immersing the hindlimbs in hot water (42 °C) for 60 min, once in every 3 days and the gastrocnemius (GAS) and soleus (SOL) muscles were extracted after 14 days. Muscle-fiber types were classified using ATPase staining. Heat shock protein 70 (HSP70) was assessed through Western blotting. In GAS muscle of both groups and SOL muscle of 7-week-old rats, the fiber diameter of each muscle type in the ImH group significantly increased compared with that in the Im group. However, this could not be observed in the SOL muscle of the 60-week-old rats. The increased percentage of type-I fibers and variability of types I and II muscle-fiber diameter were evident in the SOL muscle of the 60-week rats. HSP70 was significantly elevated in the ImH group compared with in the Im group in both muscle types of both age groups. Thus, effectiveness of heat stress in the prevention of disuse muscle atrophy appears unsatisfactory in aging muscle fibers.

Changes in esophageal motility after endoscopic submucosal dissection for superficial esophageal cancer: a high-resolution manometry study.

The effect of endoscopic submucosal dissection (ESD) on esophageal motility remains unknown. Therefore, the aim of this study is to elucidate changes in esophageal motility after ESD along with the cause of dysphagia using high-resolution manometry (HRM). This is a before-and-after trial of the effect of ESD on the esophageal motility. Twenty patients who underwent ESD for superficial esophageal carcinoma were enrolled in this study. Patients filled out a questionnaire about dysphagia and underwent HRM before and after ESD. Results before and after ESD were compared. Data were obtained from 19 patients. The number of patients who complained of dysphagia before and after ESD was 1/19 (5.3%) and 6/19 (31.6%), respectively (P = 0.131). Scores from the five-point Likert scale before and after ESD were 0.1 ± 0.5 and 1.0 ± 1.6, respectively (P = 0.043). The distal contractile integral (DCI) before and after ESD and the number of failed, weak, or fragmented contractions were not significantly different. However, in five patients with circumferential ESD, DCI was remarkably decreased and the frequency of fail, weak, or fragmented contractions increased. Univariate regression analysis showed a relatively strong inverse correlation of ΔDCI with the circumferential mucosal defect ratio {P < 0.01, standardized regression coefficient (r) = -0.65}, the number of stricture preventions (P < 0.01, r = -0.601), and the number of stricture resolutions (P < 0.01, r = -0.77). This HRM study showed that impairment of esophageal motility could be caused by ESD. The impairment of esophageal motility was conspicuous, especially in patients with circumferential ESD and subsequent procedures such as endoscopic triamcinolone injection and endoscopic balloon dilatation. Impaired esophageal motility after ESD might explain dysphagia.

Relationship between sudden natural death and abdominal fat evaluated on postmortem CT scans.

OBJECTIVE: This study examined the association between sudden natural death and abdominal fat using postmortem computed tomography (CT) scans. SUBJECTS AND METHODS: Postmortem CT images at the umbilical level of 241 subjects were used to measure abdominal areas of subcutaneous- and visceral fat, the rate of visceral fat and the waist circumference. Of the study subjects, 174 died of sudden natural death (130 men and 44 women), and 67 died of different causes (46 men and 21 women). All were between 40 and 75 years of age. Logistic regression analysis was performed to identify independent abdominal parameters associated with sudden natural death. RESULTS: By univariate analysis, the areas of subcutaneous and visceral fat were significantly larger in sudden natural death than who died of different causes (subcutaneous fat, odds ratio [OR] = 1.004, 95% confidence interval [CI] = 1.000-1.007, p = 0.03; visceral fat, OR = 1.008, 95% CI = 1.003-1.013, p < 0.01). Multivariate analysis showed that the area of visceral fat was an independent factor associated with the risk of sudden natural death (OR = 1.008, 95% CI = 1.002-1.015, p = 0.02). CONCLUSIONS: Postmortem CT revealed that sudden natural death was related to abdominal fat deposits.

Capnography Prevents Hypoxia during Sedation for Dental Treatment: A Randomized Controlled Trial.

Intravenous sedation is useful for dental treatment in patients with intellectual disabilities. However, it is often necessary to manage such patients with deep sedation because their cooperation cannot be obtained. During deep sedation, undetected hypoventilation can lead to severe complications, such as hypoxia. Recently, capnographic monitoring has been advocated as a useful technique for preventing hypoxia during sedation. This randomized control trial evaluated whether the use of capnography reduces the incidence of hypoxia during the deep sedation of patients for dental treatment. This study involved patients with intellectual disabilities who underwent dental treatment under sedation. The subjects were randomized to the intervention group (I-group) or control group (C-group). All of the patients underwent routine monitoring, as well as bispectral index (BIS) and capnographic monitoring; however, only an independent observer had access to the patients' capnographic data during the dental procedures. Sedation was maintained at a BIS of 50 to 70 by administration of propofol. In the I-group, the independent observer signaled to the dental anesthesiologist if the capnogram indicated that the patient had been suffering from alveolar hypoventilation or apnea for >15 s. In the C-group, the observer signaled to the dental anesthesiologist if the capnogram indicated that the patient had been suffering from alveolar hypoventilation or apnea for >60 s. In both groups, the dental anesthesiologists responded to the signals using appropriate airway management strategies. The primary endpoint of this study was the incidence of hypoxia during dental treatment, which was defined as oxygen saturation of <95%. Hypoxemic episodes occurred in 13.4% and 34.8% of cases in the I-group and C-group, respectively. The incidence of hypoxia was significantly lower in the I-group. These results suggest that capnographic monitoring during deep sedation for dental treatment prevents hypoxemic episodes by allowing the early detection of hypoventilation. Knowledge Transfer Statement: This is the first randomized controlled trial to examine whether the use of capnography reduces the incidence of hypoxia during deep sedation for dental treatment. The findings of this study can be used by clinicians to aid decision-making regarding dental sedation standards at individual clinics. Moreover, they can be used as high-level evidence during the production or updating of clinical guidelines for dental sedation by leading associations.

Habitual intake of fermented milk products containing Lactobacillus casei strain Shirota and a reduced risk of hypertension in older people.

This study investigated relationships between the frequent intake of fermented milk products containing Lactobacillus casei strain Shirota (LcS) and the onset of hypertension (resting systemic pressure ≥140 mmHg [systolic]/≥90 mmHg [diastolic], a doctor's diagnosis and/or antihypertensive medicine use) during a 5-year period in 352 communityliving Japanese aged 65 to 93 years (125 men and 227 women). Initially normotensive subjects were divided into two groups (n=254 and n=98) on the basis of their intake of fermented milk products (<3 or ≥3 times/week, respectively), as estimated during an interview by a certified nutritionist. The incidence of hypertension over the 5-year interval was significantly lower in those who took fermented milk products ≥3 rather than <3 times/week (6.1 vs 14.2%, P=0.037). A multivariate-adjusted proportional hazards model predicted that blood pressures were significantly more likely to remain normal over 5 years in subjects who took ≥3 fermented milk products rather than <3 times/ week (relative risk 0.398 [95% confidence interval 0.167-0.948], P=0.037). These results suggest that after adjustment for potential confounders, the risk of developing hypertension is substantially lower in elderly people who take fermented milk products containing LcS at least 3 times a week.