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Background It has been reported that the composition of human gut microbiota changes with age; however, few studies have used molecular techniques to investigate the long-term, sequential changes in gut microbiota composition. In this study, we investigated the sequential changes in gut microbiota composition in newborn to centenarian Japanese subjects. Results Fecal samples from 367 healthy Japanese subjects between the ages of 0 and 104 years were analyzed by high-throughput sequencing of amplicons derived from the V3-V4 region of the 16S rRNA gene. Analysis based on bacterial co-abundance groups (CAGs) defined by Kendall correlations between genera revealed that certain transition types of microbiota were enriched in infants, adults, elderly individuals and both infant and elderly subjects. More positive correlations between the relative abundances of genera were observed in the elderly-associated CAGs compared with the infant- and adult-associated CAGs. Hierarchical Ward’s linkage clustering based on the abundance of genera indicated five clusters, with median (interquartile range) ages of 3 (0–35), 33 (24–45), 42 (32–62), 77 (36–84) and 94 (86–98) years. Subjects were predominantly clustered with their matched age; however, some of them fell into mismatched age clusters. Furthermore, clustering based on the proportion of transporters predicted by phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) showed that subjects were divided into two age-related groups, the adult-enriched and infant/elderly-enriched clusters. Notably, all the drug transporters based on Kyoto Encyclopedia of Genes and Genomes (KEGG) Orthology groups were found in the infant/elderly-enriched cluster. Conclusion Our results indicate some patterns and transition points in the compositional changes in gut microbiota with age. In addition, the transporter property prediction results suggest that nutrients in the gut might play an important role in changing the gut microbiota composition with age.

To determine the parameters of the anterior segment of eyes that are significantly associated with the refractive error in healthy young Japanese university students. This was a cross-sectional observational study of 229 healthy Japanese university students (men: women,147:82) whose age ranged between 20 to 29 years. Univariate and multivariate linear regression analyses were performed to identify the factors that were significantly correlated with the refractive error. The independent variables included age, sex, axial length, anterior chamber depth, corneal diameter, curvature of anterior surface of cornea, and central corneal thickness. The mean refractive error (spherical equivalent) was −4.1 ± 2.7 diopters (D) with a range of −12.5 to +0.5 D, and the mean axial length was 25.4 ± 1.3 mm with a range of 22.4 to 29.0 mm. Pearson univariate correlation analysis found that the refractive error was significantly and negatively correlated with the axial length (R = −0.82, P  < 0.001), deeper anterior chamber (R = −0.30, P  < 0.001), and larger corneal diameter (R = −0.21, P  = 0.001). Multiple regression analysis showed that the refractive error was significantly associated with a longer axial length ( P  < 0.001), a deeper anterior chamber ( P  < 0.001), and a flatter corneal curvature ( P  < 0.001).The biometric values of the anterior segment of the eyes should make the eye more hyperopic which would reduce the myopia-inducing lengthening of the axial length.

We previously developed an amphipathic arginine-rich peptide, A2-17, which has high ability to directly penetrate across cell membranes. To understand the mechanism of the efficient cell-penetrating ability of the A2-17 peptide, we designed three structural isomers of A2-17 having different values of the hydrophobic moment and compared their membrane interaction and direct cell penetration. Confocal fluorescence microscopy revealed that cell penetration efficiency of peptides tends to increase with their hydrophobic moment, in which A2-17 L14R/R15L, an A2-17 isomer with the highest hydrophobic moment, predominantly remains on plasma cell membranes. Consistently, Trp fluorescence analysis indicated the deepest insertion of A2-17 L14R/R15L into lipid membranes among all A2-17 isomers. Electrophysiological analysis showed that the duration and charge flux of peptide-induced pores in lipid membranes were prominent for A2-17 L14R/R15L, indicating the formation of stable membrane pores. Indeed, the A2-17 L14R/R15L peptide exhibited the strongest membrane damage to CHO-K1 cells. Atomic force microscopy quantitatively defined the peptide-induced membrane perturbation as the decrease in the stiffness of lipid vesicles, which was correlated with the hydrophobic moment of all A2-17 isomers. These results indicate that optimal membrane perturbation by amphipathic A2-17 peptide is critical for its efficient penetration into cells without inducing stabilized membrane pores.

Bifidobacterium longum subsp. longum represents one of the most prevalent bifidobacterial species in the infant, adult and elderly (human) gut. In the current study, we performed a comparative genome analysis involving 145 B. longum representatives, including 113 B. longum subsp. longum strains obtained from healthy Japanese subjects aged between 0 and 98 years. Although MCL clustering did not reveal any correlation between isolated strains and subject age, certain characteristics appear to be more prevalent among strains corresponding to specific host ages, such as genes involved in carbohydrate metabolism and environmental response. Remarkably, a substantial number of strains appeared to have been transmitted across family members, a phenomenon that was shown not to be confined to mother-infant pairs. This suggests that the ubiquitous distribution of B. longum subsp. longum across the human lifespan is at least partly due to extensive transmission between relatives. Our findings form a foundation for future research aimed at unraveling the mechanisms that allow B. longum strains to successfully transfer between human hosts, where they then colonize and persist in the gut environment throughout the host’s lifespan.

Since 2015, hydroxychloroquine (HCQ) has been widely used as a standard treatment for systemic lupus erythematosus (SLE) and cutaneous lupus erythematosus (CLE) under the national health insurance system in Japan. However, the status of routine ophthalmological screening for retinopathy, which is a notable safety concern of HCQ, remains unclear. In this retrospective study using the nationwide health insurance claims database, we aimed to investigate the status of ophthalmological screening in routine clinical practice in Japan. A total of 2567 patients with SLE or CLE were included in the analysis. The proportion of ophthalmology visits was 88.0% at the initiation of HCQ prescription, decreased to 76.3% after one year, and then remained constant. Moreover, only 50% of the patients underwent spectral-domain optical coherence tomography (SD-OCT) and automated visual field (VF) tests, which are useful for the early detection of HCQ retinopathy-related changes. Importantly, the proportion of ophthalmology visits remained consistently high among patients who visited an ophthalmologist in the previous year, ranging from 77.3% to 90.2%. These findings highlight the need to improve screening adherence and promote regular ophthalmological evaluations, particularly for patients without prior ophthalmology visits, to enhance the early detection of HCQ retinopathy.

Previous studies have shown that Japanese people exhibit a higher abundance of Bifidobacterium compared to people from other countries. Among the possible factors affecting the gut microbiota composition, an association of functional lactase gene variants with a higher abundance of Bifidobacterium in the gut has been proposed in some reports. However, no Japanese subjects were included in these studies. In this study, we investigated the possible contribution of functional lactase loci to the high abundance of Bifidobacterium in Japanese populations. Based on a data analysis assessing 1,068 healthy Japanese adults, a number of subjects is at least seven times greater than that reported in available online data. all subjects possessed CC genotype at rs4988235 and the GG at rs182549, which are associated with low lactase activity. We observed a positive correlation between dairy product intake and Bifidobacterium abundance in the gut. Considering previous reports, which revealed that four additional functional lactase loci, rs145946881, rs41380347, rs41525747 and rs869051967 (ss820486563), are also associated with low lactase activity in Japanese people, our findings imply the possible contribution of host genetic variation-associated low lactase activity to the high abundance of Bifidobacterium in the Japanese population.

We aimed to examine the usefulness of cystoscopic findings to guide mesh tension adjustment during laparoscopic sacrocolpopexy (LSC) to promote better repair of pelvic organ prolapse (POP) and prevent de novo stress urinary incontinence (SUI). In this technique, the bladder wall was observed using a cystoscope when various traction pressures were applied by pulling the mesh arm with forceps before fixation to the promontory during LSC. Adjustment was performed on 20 patients, and postoperative outcomes of POP repair and development of de novo SUI were evaluated. When excessive traction was applied on the mesh arm, a bladder neck opening and a cord-like elevation in the center of the trigone and posterior wall were observed in all cases. The tension was gradually loosened, and precisely when the above-mentioned cystoscopic finding (“Central Road”) disappeared, an anatomically appropriate elevation of the vaginal apex was achieved; the mesh arm was fixed to the promontory. At 6 months after LSC, anterior wall recurrences were diagnosed in four patients (beyond the hymen in one) with few symptoms, while no occurrence of de novo SUI. Cystoscopic findings during mesh tension adjustment in LSC could be useful in achieving improved POP repair.

Size control of nanoparticles in nanotechnology-based drug products is crucial for their successful development, since the in vivo pharmacokinetics of nanoparticles are size-dependent. In this study, we evaluated the use of atomic force microscopy (AFM) for imaging and size measurement of nanoparticles in aqueous medium. The height sizes of rigid polystyrene nanoparticles and soft liposomes were measured by AFM and were compared with the hydrodynamic sizes measured by dynamic light scattering (DLS). The lipid compositions of the studied liposomes were similar to those of commercial products. AFM proved to be a viable method for obtaining images of both polystyrene nanoparticles and liposomes in aqueous medium. For the polystyrene nanoparticles, the average height size observed by AFM was similar to the average number-weighted diameter obtained by DLS, indicating the usefulness of AFM for measuring the sizes of nanoparticles in aqueous medium. For the liposomes, the height sizes obtained by AFM differed depending upon the procedures of immobilizing the liposomes onto a solid substrate. In addition, the resultant average height sizes of the liposomes were smaller than those obtained by DLS. This knowledge will help the correct use of AFM as a powerful tool for imaging and size measurement of nanotechnology-based drug products for clinical use.

In electroretinographic (ERG) recordings of zebrafish, the light stimulus is usually delivered by a fiber optic cable. The purpose of this study was to determine whether the angle of incidence of the stimulus light from the fiber optic cable will affect the amplitudes and implicit times of the ERGs of zebrafish larvae. The larvae were positioned on their side with the right eye pointed upward. The light stimuli were delivered by a fiber optic cable from three directions of the larvae: frontal 0° (F0°), dorsal 30°(D30°), and ventral 30°(V30°). Photopic ERGs were recorded from 16 larvae at age 5–6 days post-fertilization. Our results showed that the mean amplitude of the b-wave elicited at D30° and V30° stimulation was significantly smaller than that elicited at F0° stimulation ( P  = 0.014 and P  = 0.019, respectively). In addition, the mean amplitude of the d-wave elicited at D30° and V30° stimulation was significantly smaller than that elicited at F0° stimulation ( P  < 0.0001 and P  = 0.015, respectively). However, the difference between the b-wave amplitudes elicited at D30° and V30° stimuli were not significant ( P  = 0.98), and the d-wave amplitudes were also not significantly different ( P  = 0.20). The average b-wave amplitudes elicited at D30° stimulation was 84.6 ± 15.7% and V30° stimulation was 84.8 ± 17.4% relative to that of F0° stimulation. The average d-wave amplitudes elicited by D30° stimulation was 85.5 ± 15.2% and by V30° stimulation was 79.0 ± 11.0% relative to that of F0° stimulation. The differences in the implicit times of the b- and d-wave elicited by the different directions of stimulation were not significant (P  = 0.52 and P  = 0.14, respectively). We conclude that the amplitude of the photopic ERGs is affected by the angle of the incident light. Thus, it would be better to use ganzfeld stimuli to elicit maximum b- and d-wave amplitudes of the photopic ERGs of zebrafish larvae.

PurposeThe study reports a case with metastatic cutaneous malignant melanoma that developed Vogt–Koyanagi–Harada-like uveitis during pembrolizumab treatment. The uveitis improved by discontinuation of pembrolizumab and use of oral and topical steroids. Full-field flicker ERGs were used to monitor the retinal function before and after the steroid treatments.Case reportA 68-year-old women presented with blurred vision in both eyes 3 months after beginning pembrolizumab adjuvant therapy for a malignant melanoma on the lower thigh. Optical coherence tomography showed a serous retinal detachment (SRD) in the right eye and marked choroidal thickening in both eyes. Fluorescein angiography showed spotted hyperfluorescence in the right eye and leakage of fluorescein from both optic disks. Indocyanine green angiography showed dark hypofluorescent spots in both eyes. She was diagnosed with Vogt–Koyanagi–Harada-like uveitis induced by pembrolizumab and discontinued the pembrolizumab. She was then treated with oral prednisolone and topical betamethasone. One week later, the symptoms were improved, and 1 month later the choroidal thickening in both eyes and the SRD of the right eye were not present. The implicit time of the full-field flicker ERGs recorded by RETeval system was significantly delayed at the initial examination but improved within a few weeks after the steroid replacement treatment.ConclusionOur case with Vogt–Koyanagi–Harada-like uveitis induced by pembrolizumab had a reduction in the degree of uveitis after discontinuation of the pembrolizumab and use of oral prednisolone and topical betamethasone. Flicker ERGs were helpful in monitoring the retinal function before and after the steroid treatment.