Decreased Proteasomal Function Exacerbates Endoplasmic Reticulum Stress-Induced Chronic Inflammation in Obese Adipose Tissue.

Low-grade chronic inflammation contributes to both aging and the pathogenesis of age-related diseases. White adipose tissue (WAT) in obese individuals exhibits chronic inflammation, which is associated with obesity-related disorders. Aging exacerbates obesity-related inflammation in WAT; however, the molecular mechanisms underlying chronic inflammation and its exacerbation by aging remain unclear. Age-related decline in activity of the proteasome, a multisubunit proteolytic complex, has been implicated in age-related diseases. This study employed a mouse model with decreased proteasomal function that exhibits age-related phenotypes to investigate the impact of adipocyte senescence on WAT inflammation. Transgenic mice expressing proteasomal subunit ß5t with weak chymotrypsin-like activity experience reduced lifespan and develop age-related phenotypes. Mice fed with a high-fat diet and experiencing proteasomal dysfunction exhibited increased WAT inflammation, increased infiltration of proinflammatory M1-like macrophages, and increased proinflammatory adipocytokine-like monocyte chemoattractant protein-1, plasminogen activator inhibitor-1, and tumor necrosis factor-α, which are all associated with activation of endoplasmic reticulum (ER) stress-related pathways. Impaired proteasomal activity also activated ER stress-related molecules and induced expression of proinflammatory adipocytokines in adipocyte-like cells differentiated from 3T3-L1 cells. Collectively, the results suggesed that impaired proteasomal activity increases ER stress and that subsequent inflammatory pathways play pivotal roles in WAT inflammation. Because proteasomal function declines with age, age-related proteasome impairment may be involved in obesity-related inflammation among elderly individuals.

Divergent ecological responses to typhoon disturbance revealed via landscape-scale acoustic monitoring.

Climate change is increasing the frequency, intensity, and duration of extreme weather events across the globe. Understanding the capacity for ecological communities to withstand and recover from such events is critical. Typhoons are extreme weather events that are expected to broadly homogenize ecological dynamics through structural damage to vegetation and longer-term effects of salinization. Given their unpredictable nature, monitoring ecological responses to typhoons is challenging, particularly for mobile animals such as birds. Here, we report spatially variable ecological responses to typhoons across terrestrial landscapes. Using a high temporal resolution passive acoustic monitoring network across 24 sites on the subtropical island of Okinawa, Japan, we found that typhoons elicit divergent ecological responses among Okinawa's diverse terrestrial habitats, as indicated by increased spatial variability of biological sound production (biophony) and individual species detections. This suggests that soniferous communities are capable of a diversity of different responses to typhoons. That is, spatial insurance effects among local ecological communities provide resilience to typhoons at the landscape scale. Even though site-level typhoon impacts on soundscapes and bird detections were not particularly strong, monitoring at scale with high temporal resolution across a broad spatial extent nevertheless enabled detection of spatial heterogeneity in typhoon responses. Further, species-level responses mirrored those of acoustic indices, underscoring the utility of such indices for revealing insight into fundamental questions concerning disturbance and stability. Our findings demonstrate the significant potential of landscape-scale acoustic sensor networks to capture the understudied ecological impacts of unpredictable extreme weather events.

Decreased proteasome function increases oxidative stress in the early stage of pressure ulcer development.

The aging process in the elderly results in heightened skin fragility associated with various disorders, including pressure ulcers (PUs). Despite the high incidence of PUs in the elderly population, there is a limited body of research specifically examining the impact of aging on the development of pressure ulcers. Therefore, investigating age-related physiological abnormalities is essential to elucidate the pathogenesis of PUs. Ischemia-reperfusion (I/R) injury and the subsequent oxidative stress caused by reactive oxygen species (ROS) play essential roles in the early stage of PUs. In this study, we used a mouse model of proteasomal dysfunction with an age-related phenotype to examine the role of proteasome activity in cutaneous I/R injury in vivo. Decreased proteasome function did not affect the expression of inflammatory cytokines and adhesion molecules in the I/R area in transgenic mice; however, proteasome inhibition increased oxidative stress that was not attenuated by activation of the oxidative stress response mediated by NF-E2-related factor 2 (Nrf2). In dermal fibroblasts (FCs) subjected to hypoxia-reoxygenation (H/R), proteasome inhibition induced oxidative stress and ROS production, and Nrf2 activation did not adequately upregulate antioxidant enzyme expression, possibly leading to antioxidant/oxidant imbalance. The free radical scavenger edaravone had protective effects against I/R injury in vivo and decreased oxidative stress in FCs treated with a proteasome inhibitor and subjected to H/R in vitro. The results suggest that the age-related decline in proteasome activity promotes cutaneous I/R injury-induced oxidative stress, and free radical scavengers may exert protective effects by preventing oxidative stress in the early stage of PUs.

Conventional versus underwater endoscopic resection for superficial non-ampullary duodenal epithelial tumours.

BACKGROUND AND OBJECTIVE: Several endoscopic resection methods have been developed as less invasive treatments for superficial non-ampullary duodenal epithelial tumours. This study aimed to compare outcomes of conventional endoscopic mucosal resection and underwater endoscopic mucosal resection for superficial non-ampullary duodenal epithelial tumours, including resection depth and rate of the muscularis mucosa contained under the lesion. METHODS: This single-centre retrospective cohort study conducted from January 2009 to December 2021 enrolled patients who underwent conventional endoscopic mucosal resection and underwater endoscopic mucosal resection for superficial non-ampullary duodenal epithelial tumours and investigated their clinicopathological outcomes using propensity score matching. RESULTS: Of the 285 superficial non-ampullary duodenal epithelial tumours, 98 conventional endoscopic mucosal resections and 187 underwater endoscopic mucosal resections were included. After propensity score matching, 64 conventional endoscopic mucosal resections and 64 underwater endoscopic mucosal resections were analysed. The R0 resection rate was significantly higher in underwater endoscopic mucosal resection cases than in conventional endoscopic mucosal resection cases (70.3% vs. 50.0%; P = 0.030). In the multivariate analysis, a lesion diameter > 10 mm (odds ratio 7.246; P = 0.001), being in the 1st-50th treatment period (odds ratio 3.405; P = 0.008), and undergoing conventional endoscopic mucosal resection (odds ratio 3.617; P = 0.016) were associated with RX/R1 resection. Furthermore, in underwater endoscopic mucosal resection cases, the R0 rate was significantly higher for lesions diameter ≤10 mm than >10 mm, and was significantly higher in the 51st-treatment period than in the 1st-50th period. Conventional endoscopic mucosal resection and underwater endoscopic mucosal resection cases showed no significant difference in resection depth and muscularis mucosa containing rate. CONCLUSIONS: Underwater endoscopic mucosal resection may be more acceptable than conventional endoscopic mucosal resection for superficial non-ampullary duodenal epithelial tumours ≤ 10 mm. A steep early learning curve may be acquired for underwater endoscopic mucosal resection. Large multicentre prospective studies need to be conducted to confirm the effectiveness of underwater endoscopic mucosal resection.

Unilateral lymphadenitis caused by community-associated methicillin-resistant Staphylococcus aureus ST834 strain.

Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is a global concern, primarily as a cause of skin and soft tissue infections, particularly in young people. Here, we describe a case of unilateral multiple lymphadenitis caused by the CA-MRSA sequence type (ST) 834 strain. A previously healthy 15-year-old girl was referred to our hospital with fever and swollen lymph nodes in the right axillary, cubital, and groin regions. Imaging examinations revealed enlargement of the lymph nodes in these areas but no swelling in any other lymph nodes. The patient had self-destructive lymph nodes in her groin. MRSA was detected in all swollen lymph node samples. Antimicrobial susceptibility tests showed that MRSA was susceptible to clindamycin and levofloxacin, leading to the suspicion of CA-MRSA. Genetic analysis revealed that all strains were ST834 and carried the staphylococcal cassette chromosome mec IV and the toxic shock syndrome toxin-1 gene but not the Panton-Valentine leukocidin gene. The patient was treated with linezolid followed by oral clindamycin. This was a rare case of unilateral multiple lymphadenitis caused by ST834 CA-MRSA. Although ST834 strains are rarely reported, lymphadenitis has been frequently reported and is considered more likely to cause lymphadenitis than other CA-MRSA strains.

Underwater clip closure method for mucosal defects after duodenal endoscopic submucosal dissection (with video).

Conventional clip closure of mucosal defects after duodenal endoscopic submucosal dissection decreases the incidence of delayed adverse events, but may result in incomplete closure, depending on size or location. This study aimed to assess the effectiveness of the underwater clip closure method for complete duodenal defect closure without the difficulties associated with conventional closure methods. We investigated 19 patients with 20 lesions who underwent endoscopic submucosal dissection of the duodenum and subsequent mucosal defect closure in underwater conditions at our facility between February 2021 and January 2022. The success rate of the underwater clip closure method was defined as the complete endoscopic closure of the mucosal defect; a success rate of 100% was achieved. The median resected specimen size was 34.3 mm, the median procedure time for mucosal defect closure was 14 min, and the median number of clips used per patient was 12. No delayed adverse events were observed. The underwater clip closure method is a feasible option for complete closure of mucosal defects, regardless of the size or location of a duodenal endoscopic submucosal dissection.

Sample size calculation in clinical trials with two co-primary endpoints including overdispersed count and continuous outcomes.

Count outcomes are collected in clinical trials for new drug development in several therapeutic areas and the event rate is commonly used as a single primary endpoint. Count outcomes that are greater than the mean value are termed overdispersion; thus, count outcomes are assumed to have a negative binomial distribution. However, in clinical trials for treating asthma and chronic obstructive pulmonary disease (COPD), a regulatory agency has suggested that a continuous endpoint related to lung function must be evaluated as a primary endpoint in addition to the event rate. The two co-primary endpoints that need to be evaluated include overdispersed count and continuous outcomes. Some researchers have proposed sample size calculation methods in the context of co-primary endpoints for various outcome types. However, methodologies for sample size calculation in trials with two co-primary endpoints, including overdispersed count and continuous outcomes, required when planning clinical trials for treating asthma and COPD, remain to be proposed. In this study, we aimed to develop a hypothesis-testing method and a corresponding sample size calculation method with two co-primary endpoints including overdispersed count and continuous outcomes. In a simulation, we demonstrated that the proposed sample size calculation method has adequate power accuracy. In addition, we illustrated an application of the proposed sample size calculation method to a placebo-controlled Phase 3 trial for patients with COPD.

Characteristics of Gastric Mucosa-Associated Microbiota in Patients with Early Gastric Cancer After Successful Helicobacter pylori Eradication.

BACKGROUND: Helicobacter pylori (H. pylori) is widely recognized as a definite carcinogen in gastric cancer (GC). Although H. pylori eradication reduces the risk of GC, GC recurrence has been detected even after successful H. pylori eradication. Recently, the analysis of gut microbiota was reported. AIMS: This study aimed to evaluate the correlation between gastric mucosa-associated microbiota (G-MAM) and early gastric cancer (EGC) after successful H. pylori eradication. METHODS: In this pilot study, G-MAM were collected during the esophagogastroduodenoscopy of 17 patients, receiving H. pylori eradication therapy at least 5 years ago. The patients were divided into those with EGC (the EGC group, 8 patients) and those without EGC (the NGC group, 9 patients). Microbial samples in the greater curvature of the pyloric site were obtained using an endoscopic cytology brush, and the G-MAM profiles of each sample were analyzed using 16S rRNA V3-V4 gene sequencing. RESULTS: Between the two groups, there was no significant difference in the median age, sex, median period after successful eradication of H. pylori, the α diversity, and the average abundance at the phylum level. At the genus level, the average abundance of Unclassified Oxalobacteraceae, Capnocytophaga, and Haemophilus was significantly lower in the EGC group than in the NGC group (0.89 vs. 0.14%, P < 0.01, 0.28 vs. 0.00%, P < 0.01 and 5.84 vs. 2.16%, P = 0.034, respectively). CONCLUSIONS: We demonstrated alternations in the profiles of G-MAM between the two groups. Our results suggest that G-MAM may influence carcinogenesis after successful H. pylori eradication.

Factors determining the resection ability of snares in cold snare polypectomy: Construction of an ex vivo model for accurately evaluating resection ability.

OBJECTIVES: Cold snare polypectomy (CSP)-dedicated snares (DSs) may have a higher resection ability than conventional snares. However, a model that can accurately and objectively evaluate and compare the resection ability of each snare has yet to be determined, and characteristics of snare parts that increase resection ability remain unknown. Therefore, we elucidated DSs' resection ability and all characteristics of the parts required for acquiring high resection ability. METHODS: An ex vivo model for evaluating resection ability was generated using human colons obtained from forensic autopsy specimens. The force required to resect a 15 mm wide human colonic mucosa (FRR) was measured using this model; if the FRR is small, the resection ability is high. Next, after measuring the stiffness of each snare part, the correlation between the stiffness and resection ability was analyzed. RESULTS: The force required to resect using SnareMaster Plus, Micro-Tech Cold Snare, Captivator Cold, Exacto Cold Snare, or Captivator II was 13.6 ± 1.0, 12.5 ± 1.2, 7.4 ± 1.2, 6.5 ± 1.0, and 28.7 ± 3.7 N, respectively. All DSs had significantly lower FRR than the conventional snare (Captivator II) and had higher resection ability (P < 0.001). A negative correlation was found between FRR and sheath or wire spindle stiffness, with correlation coefficients of 0.72 (P = 0.042) or 0.94 (P < 0.001), respectively. Moreover, 1 × 7 type wire rings had significantly higher friction coefficients than 1 × 3 type wire rings (P < 0.002). CONCLUSION: Sheath and wire spindle stiffness should be increased to increase resection ability; 1 × 7 type wire rings may be suitable for CSP-snare parts.

Higher Viral Stability and Ethanol Resistance of Avian Influenza A(H5N1) Virus on Human Skin.

Evaluating the stability of highly pathogenic avian influenza viruses on human skin and measuring the effectiveness of disinfectants are crucial for preventing contact disease transmission. We constructed an evaluation model using autopsy skin samples and evaluated factors that affect the stability and disinfectant effectiveness for various subtypes. The survival time of the avian influenza A(H5N1) virus on plastic surfaces was ≈26 hours and on skin surfaces ≈4.5 hours, >2.5-fold longer than other subtypes. The effectiveness of a relatively low ethanol concentration (32%-36% wt/wt) against the H5N1 subtype was substantially reduced compared with other subtypes. Moreover, recombinant viruses with the neuraminidase gene of H5N1 survived longer on plastic and skin surfaces than other recombinant viruses and were resistant to ethanol. Our results imply that the H5N1 subtype poses a higher contact transmission risk because of its higher stability and ethanol resistance, which might depend on the neuraminidase protein.