East Asian-specific and cross-ancestry genome-wide meta-analyses provide mechanistic insights into peptic ulcer disease.

Peptic ulcer disease (PUD) refers to acid-induced injury of the digestive tract, occurring mainly in the stomach (gastric ulcer (GU)) or duodenum (duodenal ulcer (DU)). In the present study, we conducted a large-scale, cross-ancestry meta-analysis of PUD combining genome-wide association studies with Japanese and European studies (52,032 cases and 905,344 controls), and discovered 25 new loci highly concordant across ancestries. An examination of GU and DU genetic architecture demonstrated that GUs shared the same risk loci as DUs, although with smaller genetic effect sizes and higher polygenicity than DUs, indicating higher heterogeneity of GUs. Helicobacter pylori (HP)-stratified analysis found an HP-related host genetic locus. Integrative analyses using bulk and single-cell transcriptome profiles highlighted the genetic factors of PUD being enriched in the highly expressed genes in stomach tissues, especially in somatostatin-producing D cells. Our results provide genetic evidence that gastrointestinal cell differentiations and hormone regulations are critical in PUD etiology.

Analysis of Quadriceps Muscle Tightness as a Risk Factor for Osgood-Schlatter Disease: A Prospective Cohort Study.

Background: The prevalence of Osgood-Schlatter disease (OSD) is unknown. Tightness of the quadriceps femoris has been reported to be a risk factor for OSD. Hypothesis: Quadriceps muscle tightness would not contribute to the development of OSD. Study Design: Cohort study; Level of evidence, 2. Methods: We enrolled 150 Japanese male junior high school soccer players (N = 300 knees), with a mean age at first examination of 12.5 years (range, 12-13 years). All players were assessed annually and evaluated for 2 years. Ten players (n = 14 knees) had a history of OSD before the first medical examination. After excluding these 10 players (n = 20 knees), the remaining 140 players (n = 280 knees) were included in this prospective analysis. Age at the time of starting soccer, history of injury (including OSD and time missed), height, weight, annual increase in height, body mass index (BMI), straight-leg raise angle, heel-buttock distance (HBD), and ultrasound images of the tibial tuberosity (maturity and morphology) were compared between players who developed OSD and those who did not. Results: OSD was identified in 8 knees of 6 players, with an incidence of 2.9% of knees (8/280) and 4.3% of players (6/140). Univariate analysis revealed significant differences between the OSD and non-OSD groups regarding BMI (17.1 ± 1 kg/m2 vs 18.5 ± 1.6 kg/m2, respectively; P = .018), HBD (1.5 ± 1.6 cm vs 4.8 ± 4.5 cm; P < .001), and stage of tibial tuberosity maturity (P < .001). The maturity of the tibial tuberosity was the only independent risk factor for the development of OSD in multivariate logistic regression analysis (odds ratio, 9.848 [95% CI, 3.297-29.41]; P < .001). Conclusion: Study findings indicated that quadriceps muscle tightness did not contribute to the development of OSD.

Parameter variation effects on millimeter wave dosimetry based on precise skin thickness in real rats.

This study presents a parametric analysis of the steady-state temperature elevation in rat skin models due to millimeter wave exposure at frequencies from 6-100 GHz. The statistical data of the thickness of skin layers, namely epidermis, dermis, dermal white adipose tissue, and panniculus carnosus, were measured for the first time using the excised tissues of real male Sprague-Dawley rats. Based on the precise structure obtained from the histological analysis of rat skin, we solve the bioheat transfer equation to investigate the effects of changes in parameters, such as body parts and thermal constants, on the absorbed power density and temperature elevation of biological tissues. Owing to the notably thin dermal white adipose tissue layer, the surface temperature elevation in the rat head and dorsal skin at 6-100 GHz is 52.6-32.3% and 83.3-58.8% of the average values of different human skin models, respectively. Our results also reveal that the surface temperature elevation of rat skin may correlate with the tissue thickness and deep blood perfusion rates.

Intensity-dependent Temperature Rise Induced by Local Exposure to 26.5 GHz Quasi-Millimeter-Wave in Rat.

BACKGROUND/AIM: The widespread use of fifth-generation 5G millimeter-waves (MMW) generates concern about potential adverse health effects. The latest international guidelines for MMW exposure adopt an absorbed power density (APD) of 200 W/m2 to avoid a local temperature rise of 5°C in human tissues as an operational adverse health effect threshold. However, because APD is estimated by simulations using human tissue models, it is unknown whether a similar value can be confirmed for living tissues. The aim of this study was to investigate the relationship between APD and skin temperature rise in vivo, and to validate the estimated values. MATERIALS AND METHODS: The rat dorsal skin was locally exposed to a 26.5 GHz quasi-MMW (qMMW) for 18 min using a patch antenna. The qMMW exposure intensities estimated by dosimetry were set to 0-500 W/m2 of APD. The temperatures in the dorsal skin and rectum were simultaneously measured during exposure. RESULTS: The qMMW-induced local temperature increase at different sites. The dorsal skin temperature increased by approximately 11.3°C at a maximum intensity of 500 W/m2, but the rectal temperature increased by only 0.6°C, indicating highly localized effects of exposure to rats. A significant correlation was observed between APD and skin temperature rise. The relationship provided a linear regression model, and a temperature rise of less than 5°C was estimated in the skin exposed to 200 W/m2 of APD. CONCLUSION: These results suggest that the operational threshold for the MMW exposure guidelines is valid under the present experimental conditions using rats.

Is legislation to prevent genetic discrimination necessary in Japan? An overview of the current policies and public attitudes.

Genetic discrimination (GD) has not been discussed in East Asia as extensively as in Europe and North America. Influenced by UNESCO's universal declaration in 1997, the Japanese government took a stringent approach toward GD by releasing the Basic Principles on Human Genome Research in 2000. However, Japanese society has mostly been ignoring the prevention of GD for decades, and the principle of prohibiting GD was never adhered to in any of the Japanese laws. We conducted anonymous surveys among the general adult population in 2017 and 2022 to explore their experiences of GD and attitudes toward laws carrying penalties to prevent GD in Japan. In both years, approximately 3% of the respondents had experienced some unfavorable treatment regarding their genetic information. They showed higher recognition of the benefits of using genetic information and lower recognition of concerns about using genetic information and GD in 2022 than in 2017. However, the awareness regarding the need for legislation with penalties on GD had increased over the five-year period. In 2022, the framework of a bill to promote genomic medicine and prevent GD without any relevant penalties was released by the Bipartisan Diet Members Caucus. Considering that the absence of regulations may be a barrier to obtaining genomic medicine, as the initial step toward making the prohibition of GD more effective, legislation that no form of GD will be tolerated may stimulate education and awareness regarding respect for the human genome and its diversity.

Expectations, concerns, and attitudes regarding whole-genome sequencing studies: a survey of cancer patients, families, and the public in Japan.

Whole-genome sequencing (WGS) is being used in research and clinical settings in cancer genomics. Studies show that cancer patients generally have positive attitudes toward tumor profiling tests; however, few works revealed their attitudes toward WGS. This study clarifies the expectations, concerns, and result preferences of cancer patients (CPs), family members (FMs) and general adults (GAs) regarding WGS study in Japan. We conducted an anonymous survey with 1204 CPs, 5958 FMs, and 2915 GAs in 2021. Despite low awareness of the WGS studies, CPs had the highest expectations for it. FMs had a higher level of concern than CPs and GAs; feeling anxious by knowing the results, being treated unfavorably if germline findings were detected. Both the FMs and CPs were highly concerned about the protection of genetic information. CPs preferred results with actionability, however, only half preferred to know germline findings. Given the possibility of detecting variants across multidisciplinary diseases and the long-term continuity of WGS research, a system is needed in which study participants can consult and receive decision-making support at any time according to their needs.

The pentameric hydrocoel lobes organize adult pentameral structures in a sea cucumber, Apostichopus japonicus.

Despite being one of the bilaterians, the body plan of echinoderms shifts from bilateral symmetry to five-fold radial, or pentaradial symmetry during embryogenesis or their metamorphosis. While the clarification of the developmental mechanism behind this transition will be a basis for understanding their unique body plan evolution, it is still poorly understood. With this regard, the hydrocoel, a mesodermal coelom formed on the left side of bilateral larva, would be a clue for understanding the mechanism as it is the first pentaradial structure that appears before metamorphosis and develops into the water vascular system of adults. By analyzing the development of a sea cucumber, Apostichopus japonicus, we found that the hydrocoel expresses genes related in muscle and neural formation such as myosin heavy chain, tropomyosin, soxC, and elav, implying that cells of the hydrocoel contributes to muscle and neural structures in the adult. Furthermore, ablation of one of the hydrocoel lobes led to incomplete development of adult pentameral structures. The ablation of primary hydrocoel lobes resulted in the reduction in tentacles and the ablation of secondary hydrocoel lobes resulted in the reduction in water vascular canals and nerve cords. Our findings suggest that the hydrocoel lobes may serve as a potential organizing center for establishing the pentaradial body plan in echinoderms.

Age-related differences in glenohumeral internal rotation deficit, humeral retrotorsion angle, and posterior shoulder tightness in baseball players.

BACKGROUND: Glenohumeral internal rotation deficit is generally recognized as a risk factor for throwing disability in baseball players. However, the pathology, timing of onset, role in the onset of humeral retrotorsion angle (HTA) and soft tissue extensibility (STE), and the relationship with age remain unclear. Therefore, the purpose of this cross-sectional study was to investigate age-related glenohumeral internal rotation deficit, HTA, and STE in Japanese baseball players and determine whether these factors correlate with throwing disability. METHODS: Participants were 172 male baseball players divided into a symptomatic group (n = 68) and an asymptomatic group (n = 104). The mean age at examination was 15.4 ± 3.2 (range, 8-22) years. Measurement items were range of motion of bilateral internal and external rotation at 90° abduction (2ndIR and 2ndER, respectively), bilateral HTA, and posterior shoulder muscle elasticity. Correlations of age, symptom, and dominance with these measurements were investigated, and significant bilateral differences in HTA and STE by age and symptom were analyzed. RESULTS: HTA and 2ndER of the dominant side were significantly greater than those of the nondominant side in those over the age of 13 years in both the asymptomatic and symptomatic groups. In contrast, 2ndIR of the dominant side was significantly smaller than that of the nondominant side in those over the age of 13 years in both the asymptomatic and symptomatic groups. The difference in HTA between the dominant and nondominant sides increased and then plateaued at 12° after the age of 16 years. STE was observed only in the symptomatic group, and the value of STE was significantly greater in players aged >16 years compared with that in players aged <12 years (P = .001). Muscle elasticity did not differ significantly between sides and showed no correlation with STE. CONCLUSIONS: The difference in HTA between the dominant and nondominant sides increased with age until 16 years old regardless of symptoms. STE in the dominant side was observed only in symptomatic baseball players after the age of 13 years and increased with age, plateauing around the age of 16 years. Posterior shoulder muscle elasticity was not indicated as a cause of STE.

Local Injection of Hydroxyapatite Electret Ameliorated Infarct Size After Myocardial Infarction.

Background: Previous studies showed that hydroxyapatite electret (HAE) accelerates the regeneration of vascular endothelial cells and angiogenesis. This study investigated the effects of HAE in myocardial infarction (MI) model mice. Methods and Results: MI was induced in mice by ligating the left anterior descending artery. Immediately after ligation, HAE, non-polarized hydroxyapatite (HAN), or water (control) was injected into the infarct border myocardium. Functional and histological analyses were performed 2 weeks later. Echocardiography revealed that HAE injection preserved left ventricular systolic function and the wall thickness of the scar, whereas HAN-injected mice had impaired cardiac function and thinning of the wall, similar to control mice. Histological assessment showed that HAE injection significantly attenuated the length of the scar lesion. There was significant accumulation of CD31-positive cells and increased expression of vascular endothelial growth factor (Vegf), intercellular adhesion molecule-1 (Icam1), vascular cell adhesion molecule-1 (Vcam1), hypoxia-inducible factor-1α (Hif1a), and C-X-C motif chemokine ligand 12 (Cxcl12) genes in the infarct border zone of HAE-injected mice. These effects were not induced by HAN injection. Anti-VEGFR2 antibody canceled the beneficial effect of HAE. In vitro experiments in a human cardiovascular endothelial cell line showed that HAE dose-dependently increased VEGFA expression. Conclusions: Local injection of HAE attenuated infarct size and improved cardiac function after MI, probably due to angiogenesis. The electric charge of HAE may stimulate angiogenesis via HIF1α-CXCL12/VEGF signaling.

Cause-specific mortality rates in patients with diabetes according to comorbid macro- and microvascular complications: BioBank Japan Cohort.

Objective: This study aimed to compare cause-specific mortality rates in patients with type 2 diabetes with and without various vascular complications. Methods: In Japanese hospitals, we followed up 30 834 patients with a mean age of 64.4 (standard deviation [SD]: 11.1) years. Patients were followed up from 2003 to 2007 for a median of 7.5 (interquartile range: 6.1-9.7) years. We calculated cause-specific mortality rates (number of deaths/1000 person-years) and confounder-adjusted hazard ratios in patients with macrovascular disease and in those with diabetic nephropathy, neuropathy and retinopathy, allowing for overlap of complications. Results: All-cause mortality rate was highest (51.4) in the nephropathy group, followed by the macrovascular disease group (45.2), the neuropathy group (39.5), the retinopathy group (38.7) and the nonvascular complication group (18.1). In the nephropathy group, morality rates of ischaemic heart, cerebrovascular, and infectious diseases and cancer were also highest among the groups. However, the cancer mortality rate was similar among the vascular complication groups. Relative to the nonvascular complication group, covariate-adjusted hazard ratios for ischaemic heart and cerebrovascular disease mortality were triple to quadruple in the macro- and microvascular complication groups. All-cause mortality rates rose exponentially according to age. Conclusion: Highest risks of all-cause, cancer, and ischaemic heart, infectious, and cerebrovascular disease mortality were determined in Japanese patients with diabetic nephropathy. Although cancer is the primary cause of death in Japanese patients with diabetes, cancer mortality rates are similar among those with and without vascular complications.

The conditional deletion of steroidogenic factor 1 (Nr5a1) in Sox9-Cre mice compromises testis differentiation.

Steroidogenic factor 1 (NR5A1) is essential for gonadal development. To study the importance of NR5A1 during early gonadal sex differentiation, we generated Sox9-Cre-Nr5a1 conditional knockout (cKO) mice: Sox9-Cre;Nr5a1flox/flox and Sox9-Cre;Nr5a1flox/- mice. Double-immunostaining for NR5A1 and AMH revealed silenced NR5A1 in Sertoli cells and reduced AMH+ cells in the gonads of XY Sox9-Cre-Nr5a1 cKO mice between embryonic days 12.5 (E12.5) and E14.5. Double-immunostaining for SOX9 and FOXL2 further indicated an early block in Sertoli cells and ectopic granulosa cell differentiation. The number of cells expressing the Leydig cell marker 3ßHSD obviously reduced in the gonads of XY Sox9-Cre;Nr5a1flox/- but not Sox9-Cre;Nr5a1flox/flox mice at E15.5. The presence of STRA8+ cells indicated that germ cells entered meiosis in the gonads of XY Sox9-Cre-Nr5a1 cKO mice. The results of qRT-PCR revealed remarkably reduced and elevated levels of testis and ovary markers, respectively, in the gonads of XY Sox9-Cre-Nr5a1 cKO mice at E12.5‒E13.5. These data suggested that the loss of Nr5a1 abrogates the testicular pathway and induces the ectopic ovarian pathway, resulting in postnatal partial/complete male-to-female gonadal sex reversal. Our findings provide evidence for the critical role of NR5A1 in murine gonadal sex determination in vivo.

A rare case of hyperostosis frontalis interna in an 86-year-old Japanese female cadaver.

Hyperostosis frontalis interna (HFI) is a condition characterized by abnormal bone outgrowth on the inner surface of the frontal bone. Most HFI cases occur in post-menopausal elderly women. The pathology of HFI development is uncertain. The estimated incidence of HFI ranges from 5 to 12% in Western countries, but few cases have been reported in the Japanese population. Here, we report a case of HFI in an 86-year-old Japanese female cadaver. Macroscopically, the internal surface of the frontal bone exhibited bilateral nodular protrusion with sparing of the midline, while the external surface was normal. According to the morphological classification of HFI proposed by Hershkovitz et al. this case belongs to type D, the most severe type. Using computed tomography (CT), we defined five layers, designated as I-V from the inner to the outer layer, in the nodular region of HFI; however, the normal frontal bone is composed of three layers. Histological results demonstrated that layers I, III, and V consisted of the cortical bone, and layers II and IV consisted of the trabecular bone. We also observed increases in the numbers of lamellar bone and blood vessels on the dural side of layer I, indicating increased vascularization and active osteogenesis. These results indicate that layer II represents a new diploe within the inner table, which split into layers I and III, suggesting that diploization within the inner table by activated remodeling may be involved in the development of hyperostosis in this case.

All-cause and cardiovascular disease mortality in underweight patients with diabetic nephropathy: BioBank Japan cohort.

We aimed to determine mortality risk in underweight patients with diabetic nephropathy for microalbuminuria or macroalbuminuria. We analyzed mortality and death-cause data from BioBank Japan, with baseline years 2003-2007. We analyzed mortality rates from all causes and ischemic heart disease, according to body mass index (<18.5, 18.5-21.9, 22-24.9 and ≥25 kg/m2 ). The mean (standard deviation) of patient age, body mass index, and glycated hemoglobin at enrollment was 61.6 years (11.7 years), 25.0 kg/m2 (4.4 kg/m2 ) and 7.7% (1.5%), respectively. Hazard ratios of all-cause and ischemic heart disease mortality were highest (1.79 [P = 0.0001] and 2.95 [P = 0.027], respectively) in patients with body mass index <18.5 kg/m2 , as compared with body mass index 22-24.9 kg/m2 . All-cause mortality risk for body mass index <18.5 kg/m2 was similar to that for current smokers (hazard ratio 1.70, P < 0.0001). Underweight could be a predictor of mortality risk in patients with diabetic nephropathy for microalbuminuria or macroalbuminuria.

Cardiomyocyte uptake mechanism of a hydroxyapatite nanoparticle mediated gene delivery system.

Gene therapy has been explored as a future alternative for treating heart disease. Among several gene delivery systems aimed at penetrating specific target cells, we focused on safe and non-viral gene delivery materials with a high transfection efficiency. Although various techniques have been developed, the mechanisms underlying the cellular uptake of gene delivery materials have not yet been sufficiently studied in cardiomyocytes. The aim of this study was to determine how hydroxyapatite (HAp) nanoparticles contribute to the delivery of plasmid DNA (pDNA) into cardiomyocytes. We fabricated HAp nanoparticles using the water-in-oil (W/O) emulsion method and used these nanoparticles as the delivery vector for transfecting cardiomyocyte-derived HL-1 cells. HAp exhibited particles on the nanoscale and with a low cytotoxicity in HL-1 cells. The transfection assay performed with several endocytosis inhibitors suggested that the HAp/pDNA complexes were internalized by HL-1 cells through macropinocytosis. Furthermore, this HL-1 cell uptake was generated in response to HAp stimulation. Thus, HAp is a positive regulator of macropinocytosis in HL-1 cells and a good system for gene delivery in cardiomyocytes.

Time-Transient Effects of Silver and Copper in the Porous Titanium Dioxide Layer on Antibacterial Properties.

Recently, silver (Ag) and copper (Cu) have been incorporated into a titanium (Ti) surface to realize their antibacterial property. This study investigated both the durability of the antibacterial effect and the surface change of the Ag- and Cu-incorporated porous titanium dioxide (TiO2) layer. Ag- and Cu-incorporated TiO2 layers were formed by micro-arc oxidation (MAO) treatment using the electrolyte with Ag and Cu ions. Ag- and Cu-incorporated specimens were incubated in saline during a period of 0-28 days. The changes in both the concentrations and chemical states of the Ag and Cu were characterized using X-ray photoelectron spectroscopy (XPS). The durability of the antibacterial effects against Escherichia coli (E. coli) were evaluated by the international organization for standardization (ISO) method. As a result, the Ag- and Cu-incorporated porous TiO2 layers were formed on a Ti surface by MAO. The chemical state of Ag changed from Ag2O to metallic Ag, whilst that of Cu did not change by incubation in saline for up to 28 days. Cu existed as a stable Cu2O compound in the TiO2 layer during the 28 days of incubation in saline. The concentrations of Ag and Cu were dramatically decreased by incubation for up to 7 days, and remained a slight amount until 28 days. The antibacterial effect of Ag-incorporated specimens diminished, and that of Cu was maintained even after incubation in saline. Our study suggests the importance of the time-transient effects of Ag and Cu on develop their antibacterial effects.

Investigation of antibacterial effect of copper introduced titanium surface by electrochemical treatment against facultative anaerobic bacteria.

This study investigated the efficacy of copper (Cu) as an antibacterial element incorporated on titanium (Ti) surface by electrochemical treatment. Cu was incorporated onto Ti surface by micro-arc oxidation (MAO). A small amount of Cu was incorporated into the oxide layer and was found to be in oxidized states. Cu-incorporated samples exhibited no-harmful effect on the proliferation of osteoblastlike cells. Moreover, the difference in antibacterial property between fresh and incubated samples was evaluated using gram-positive and gram-negative facultative anaerobic bacteria. The specific antibacterial property of Cu incorporated into the Ti surface were confirmed. The antibacterial property prolonged upon immersion in physiological saline for 28 days. In other words, MAO-treated Ti containing Cu in this study is expected to achieve long-term antibacterial property in practical usage.

An oriented hydroxyapatite film with arrayed plate-like particles enhance chondrogenic differentiation of ATDC5 cells.

Osteochondral defects of articular cartilage cannot regenerate spontaneously. For its surgical treatment, advancements in cartilage tissue engineering have particularly focused on subchondral bone lesions that tend to delay healing. Therefore, it is important to understand interactions between subchondral bone and chondrocytes. This study aimed to investigate the behavior of chondrogenic ATDC5 cells on oriented hydroxyapatite (HAp) films that mimic bone surfaces. HAp nanoparticles prepared herein were needle like and plate like. HAp films were formed through self-organization of the nanoparticles and had 2D structures regularly arrayed with the particles. Both films prominently comprised a-plane orientation surfaces but differed in the degree of hydrophilicity because of the patterns of particle self-assembly. ATDC5 cells cultured on the HAp film with plate-like particles could adhered in a shorter period but could not spread. The adhesive force of cells was weaker with the hydrophilic surface than with other surfaces, as determined using a trypsin-based cell detachment assay. In addition, ATDC5 cells displayed enhanced proliferation and chondrogenic differentiation. Our results suggest that the oriented HAp film formed using plate-like particles provided chondrogenic cells with a desired scaffold as that of subchondral bone to increase cell proliferation and differentiation.