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The effects of glass bead size in the conical space of flow-through cells on the dissolution profiles were investigated in a USP apparatus 4. Dissolution tests of disintegrating and non-disintegrating tablets in flow-through dissolution systems were performed using semi-high precision glass beads with diameters ranging from 0.5 mm to 1.5 mm. Computational fluid dynamics (CFD) was used to evaluate the effect of shear stress from the dissolution media flow. The use of smaller glass beads in a larger cell resulted in a faster dissolution of the model formulations under certain test conditions. The effect on the dissolution was highly dependent on the size of the beads in the top layer, including those in contact with the tablets. The absence of a bead-size effect on the dissolution of an orodispersible tablet in a small cell can be explained by the floating fragments during the test. CFD analysis showed that smaller bead diameters led to greater shear stress on the tablet, which was correlated with the dissolution rate. Hence, fluid flow through the narrow gaps between the small beads generated strong local flows, causing shear stress. The size of the glass beads used in flow-through cells affects the dissolution rate of tablets by altering the shear stress on the tablets in certain cases (e.g., direct deposition of the formulation on glass beads, large cells, and very low flow rates). Thus, glass bead size must be considered for a robust dissolution test in a flow-through cell system., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

We aimed to clarify the long-term safety and efficacy of rituximab (RTX) as a remission induction therapy following severe relapse in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We retrospectively collected the data of patients with severely relapsed AAV from a Japanese multicentre cohort. The primary exposure was RTX use; the primary outcome was complete remission (CR) proportions at week 24. Baseline characteristics were compared between the RTX and non-RTX groups. We performed multivariate logistic regression analysis and one-to-one propensity score matching analysis as a sensitivity analysis. Totally, 100 patients were enrolled: 52 in the RTX group and 48 in the non-RTX group. Baseline characteristics were comparable between the two groups, except for age, AAV subtype and ANCA serotype. The median age was 71 vs. 75 years, and the PR3-ANCA positivity rate was 44.2% vs. 18.8% in the RTX and non-RTX groups, respectively. No significant difference was observed in CR proportions at week 24 between the two groups (79.2% vs. 68.1%, p = 0.321), with an adjusted odds ratio of 1.27 (95% confidence interval [CI] 0.47-3.51). At week 48, CR proportions were significantly higher in the RTX group (91.7% vs. 64.9%, p = 0.005), with an adjusted odds ratio of 2.95 (95% CI 0.97-9.91). Serious infection rates were lower in the RTX group than in the non-RTX group, with no statistically significant difference. RTX was not superior to conventional immunosuppressive therapies at week 24 but showed significantly favourable results at week 48 for severely relapsed AAV., (© 2024. The Author(s).)

Background: Optimal preoperative biliary drainage for patients with pancreatic cancer before pancreatoduodenectomy remains unclear. This study aimed to investigate the comparison of efficacy and safety between a metallic stent (MS) and a plastic stent (PS)., Methods: Comparative studies on the use of MS and PS for pancreatic cancer before pancreatoduodenectomy were systematically searched using the MEDLINE and Web of Science databases. Pre- and postoperative data also were extracted. Random-effects meta-analyses were performed to compare post-endoscopic retrograde cholangiopancreatography (ERCP) complications as well as intra- and postoperative outcomes between the two arms of the study, and pooled odds ratios (ORs) or mean differences (MDs) were calculated with 95 percent confidence intervals (CIs)., Results: The study analyzed 12 studies involving 683 patients. Insertion of MS was associated with a lower incidence of re-intervention (OR, 0.06; 95% CI 0.03-0.15; P < 0.001), increased post-ERCP adverse events (OR, 2.22; 95% CI 1.13-4.36; P = 0.02), and similar operation time (MD, 18.0 min; 95% CI -29.1 to 65.6 min; P = 0.46), amount of blood loss (MD, 43.0 ml; 95% CI -207.1 to 288.2 ml; P = 0.73), and surgical complication rate (OR, 0.78; 95% CI 0.53-1.15; P = 0.21). The cumulative stent patency rate after 3 months was higher in the MS group than in the PS group (70-100 % vs 30.0-45.0 %)., Conclusion: For biliary drainage in patients with pancreatic cancer during this era of multidisciplinary treatment, MS use might be the first choice because MS provides a more durable biliary drainage and a similar risk of postoperative outcomes compared with PS., (© 2023. Society of Surgical Oncology.)

The use of apex vessels may solve coning problems associated with dissolution testing. However, excessive dissolution acceleration can reduce the discriminatory power. This study aimed to clarify how different apex vessel sizes affect the dissolution behavior of cone-forming formulations. Five apex vessels with different heights, centralities, and compendial vessels were used. The paddle rotation speed at which the coning phenomenon resolved was measured using standard particles of different densities. Three model formulations-USP prednisone tablets, atorvastatin calcium hydrate tablets, and levofloxacin fine granules-were selected, and dissolution tests were conducted at 30-100 revolutions per minute (rpm). Compared to the compendial vessels, the disappearance of standard particles at the apex base at lower paddle speeds in apex vessels was observed. Standard particles tended to remain in the center of the apex vessels and disappear at rotational speeds comparable to those of the compendial vessels. Dissolution increased in an apex height-dependent manner in the model formulations, except for the atorvastatin calcium hydrate tablets at 50 rpm. For levofloxacin fine granules, dissolution was also improved by reducing the paddle agitation speed to 30 rpm in the compendial vessels. Differences in apex centrality by 3 mm did not affect the dissolution rate. Our results indicate that apex vessels with low apex heights have a mount-resolving effect, but the degree of dissolution improvement by avoiding the coning phenomenon depends on the formulation characteristics used in the dissolution tests., (© 2023. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Purpose: The aim of this study was to develop a new workflow for 1.5-T magnetic resonance (MR)-guided on-line adaptive radiation therapy (MRgART) and assess its feasibility in achieving dose constraints., Materials and Methods: We retrospectively evaluated the clinical data of patients who underwent on-line adaptive radiation therapy using a 1.5-T MR linear accelerator (MR-Linac). The workflow in MRgART was established by reviewing the disease site, number of fractions, and re-planning procedures. Five cases of prostate cancer were selected to evaluate the feasibility of the new workflow with respect to achieving dose constraints., Results: Between December 2021 and September 2022, 50 consecutive patients underwent MRgART using a 1.5-T MR-Linac. Of these, 20 had prostate cancer, 10 had hepatocellular carcinoma, 6 had pancreatic cancer, 5 had lymph node oligo-metastasis, 3 had renal cancer, 3 had bone metastasis, 2 had liver metastasis from colon cancer, and 1 had a mediastinal tumor. Among a total of 247 fractions, 235 (95%) were adapt-to-shape (ATS)-based re-planning. The median ATS re-planning time in all 50 cases was 17 min. In the feasibility study, all dose constraint sets were met in all 5 patients by ATS re-planning. Conversely, a total of 14 dose constraints in 5 patients could not be achieved by virtual plan without using adaptive re-planning. These dose constraints included the minimum dose received by the highest irradiated volume of 1 cc in the planning target volume and the maximum dose of the rectal/bladder wall., Conclusion: A new workflow of 1.5-T MRgART was established and found to be feasible. Our evaluation of the dose constraint achievement demonstrated the effectiveness of the workflow., (© 2023. The Author(s).)

Background: During the coronavirus disease-2019 (COVID-19) pandemic, there was a lack of access to outpatient facilities for other diseases. Conversely, few studies have reported changes in clinical features of idiopathic nephrotic syndrome (INS) in children before and after the COVID-19 pandemic., Methods: Thirty-two children with primary INS, who were admitted to four Showa University-affiliated hospitals between January 2017 and December 2022, were enrolled in this retrospective study. Children were divided according to the onset of INS into a post-COVID-19 group (onset in 2020-2022, n = 25) and a pre-COVID-19 group (onset in 2017-2019, n = 32). We compared the clinical characteristics and features of initial INS between two groups., Results: In the post-COVID-19 group, these patients had interval between noticing symptoms of INS, such as edema and INS diagnosis was significantly longer (7 days versus 3.5 days; p = 0.0047), and had significantly raised serum LDL cholesterol levels at the time of INS diagnosis than in the pre-COVID-19 group (314 mg/dL versus 260 mg/dL; p = 0.028). Likewise, steroid-resistant nephrotic syndrome was significantly more common in the post-COVID-19 group [32% (n = 8) versus 6% (n = 2); p = 0.016]. A correlation analysis revealed a moderate positive correlation between the interval from symptom to diagnosis and LDL cholesterol (r = 0.460015, p = 0.0003)., Conclusions: Children with INS after the COVID-19 pandemic showed a longer time between noticing symptoms of INS and diagnosis, increased serum LDL cholesterol and more steroid resistance than before the pandemic., (© 2023. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Ascending inflammation from the vagina is a major cause of preterm birth. Currently, this condition-especially when uncontrolled-has no effective treatment. Human amniotic fluid stem cells (hAFSCs) are mesenchymal stem cells known to exert potent anti-inflammatory effects in animal models of perinatal diseases, such as periventricular leukomalacia, myelomeningocele, and neonatal sepsis. However, hAFSC therapy for inflammation-induced preterm birth has not been tested. In order to determine the therapeutic effect of hAFSC transplantation, we employed a preterm mouse model of ascending infection; this model was constructed by administering lipopolysaccharide to pregnant mice. We investigated the preterm birth rate and evaluated the inflammation of tissues, which is related to progressive infections, such as those involving the cervix, placenta, and lavage cells, using real-time qPCR. Further, we tracked the fluorescence of fluorescently labeled hAFSCs using an in vivo imaging system, and hAFSC aggregation was evaluated using immunohistochemistry analysis. We also investigated the presence of multiple types of peritoneal macrophages via flow cytometry analysis. Finally, we performed sphere culturing and co-culturing to determine the therapeutic effects of hAFSCs, such as their anti-inflammatory effects and their potential to alter macrophage polarization. We found that hAFSC administration to the peritoneal cavity significantly reduced inflammation-induced preterm birth in the mouse model. The treatment also significantly suppressed inflammation of the placenta and cervix. Transplanted hAFSCs may have aggregated with peritoneal macrophages, switching them from an inflammatory to an anti-inflammatory type. This property has been reported in vivo previously, but here, we examined the effect in vitro. Our findings support the hypothesis that hAFSCs suppress inflammation and reduce preterm birth by switching macrophage polarity. This study is the first to demonstrate that hAFSCs are effective in the treatment and prevention of inflammation-induced preterm birth., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: The best strategy for durable left atrial posterior wall isolation (PWI) after completion of pulmonary vein isolation (PVI) is not yet determined. This study aimed to examine the differences in the durability of PWI based on the isolation process and the predictors of the reconduction of PWI., Methods: Among the 221 patients (mean age, 65 ± 11 years) with consecutive non-paroxysmal atrial fibrillation (AF) who completed PVI and PWI, 50 patients undergoing repeat AF ablation were enrolled and divided into the following groups based on how PWI was achieved at the initial procedure: by only the first line on the roof and floor line (group A), by additional gap ablation to the first line or second liner ablation next to the first line (group B), and by adjunct ablation inside the PW revealing the earliest activation (group C)., Results: Reconduction of PWI occurred in 24 of the 50 patients (48%). The durability of PWI in groups A, B, and C was 81% (17 of 21 patients), 75% (6 of 8 patients), and 14% (3 of 21 patients), respectively (p < 0.01). In a multivariate analysis, the ablation inside the PW for PWI was the independent predictor of the reconduction of PWI (p < 0.001)., Conclusion: PWI achieved by the ablation inside the PW resulted in a high rate of reconduction. It may be necessary to aim to achieve the PWI without ablating the inside of the PW to prevent reconduction., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Hematuria is the essential symptom of IgA nephropathy that has been suggested to be associated with long-term renal prognosis, Tonsillectomy and steroid pulse therapy (TSP), which is widely practiced in Japan, is effective for achieving hematuria remission. However, some cases are refractory to TSP, and additional steroid pulse therapy (SP) administered to these cases to achieve remission of hematuria. Nonetheless, the clinical significance of additional SP is unknown., Methods: In this retrospective study, we enrolled 99 patients from Okubo Hospital whose hematuria persisted following TSP. Patients were divided into the hematuria remission and non-remission groups. A multivariate regression analysis was performed on the factors that contributed to hematuria remission., Results: Following TSP, 103 of 403 patients (32.3%) did not achieve hematuria remission. Additional SP were performed in 99 of these patients, and remission of hematuria was achieved in 57 (57.6%). Patients with a greater degree of improvement in hematuria with TSP were significantly more likely to have remission of hematuria with additional SP (p = 0.0084*). Even in the hematuria non-remission group, both hematuria and proteinuria improved after additional SP., Conclusion: In IgA nephropathy, additional SP could induce hematuria remission and reduce proteinuria., (© 2022. The Author(s), under exclusive licence to The Japanese Society of Nephrology.)

Purpose: Various biofeedback stimulation techniques of managing sleep bruxism (SB) have recently emerged; however, the effect of successive application of vibratory feedback stimulation has not been clarified. This study elucidated the effect of vibration feedback stimulation via an oral appliance (OA) on SB when vibration feedback was applied for 4 weeks., Methods: This was a prospective, single-arm, open-label, intervention study. Ten participants diagnosed with "definite" SB wore a specially designed OA for 45 nights in a home-setting. A force-based SB detection system, including a pressure-sensitive piezoelectric film placed internally in the OA, triggered a vibrator attached to the OA. Vibratory stimulation was withheld during the first 2-week adaptation period (1st-15th nights), applied during the 4-week stimulation period (16th-43rd nights), and again withheld during the post-stimulation period (44th and 45th nights). The number and duration of SB episodes/hour of sleep were calculated based on masseter electromyographic activity recorded with in-home portable polysomnography and compared between the 15th and 45th nights (without stimulation) and the 17th and 43rd nights (with stimulation)., Results: The number and duration of SB episodes significantly decreased after vibratory stimulation (15th vs. 17th nights: p = 0.012 and p = 0.012, respectively), then significantly increased upon cessation of vibratory stimulation after the stimulation period (43rd vs. 45th nights: p = 0.023 and p = 0.023, respectively)., Conclusion: Contingent vibratory stimulation through an OA may suppress SB-related masticatory muscle activity continuously for 4 weeks and may be an effective alternative for the management of SB., Trial Registration: https://jrct.niph.go.jp/ ; trial registration number: jRCTs032190225., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction and Hypothesis: The aim was to compare pelvic floor muscle (PFM) elasticity between interstitial cystitis/bladder pain syndrome (IC/BPS) patients and healthy women using real-time tissue elastography., Methods: The subjects were 17 IC/BPS female patients (IC/BPS group; age 34-84 years), 10 healthy middle-aged women (middle-aged group; 50-80 years), and 17 healthy young adult women (young group; 23-37 years). The target sites of elastography were the striated urethral sphincter (SUS) and adipose tissue as the reference site; muscle elasticity was calculated as the strain ratio (SR) of the SUS to the reference site. Evaluations were performed at rest and during PFM contraction. The IC/BPS group completed lower urinary tract symptom and pain questionnaires. SUS SR was compared among the three groups. SUS SR at rest and during PFM contraction was compared among the three groups with the t-test and the Wilcoxon test. Associations between questionnaire results and SUS SR were evaluated by correlation analysis., Results: There was no significant difference in age between the IC/BPS and middle-aged groups, but the young group was significantly younger than the other groups (p < 0.001). SUS SR at rest was significantly higher in the IC/BPS group than in the middle-aged (p = 0.014) and young groups (p = 0.002). Furthermore, in the IC/BPS group, there was no significant difference in SUS SR between at rest and during PFM contraction. SUS SR was not significantly correlated with questionnaire results for lower urinary tract symptoms., Conclusions: SUS SR at rest was significantly higher in the IC/BPS group than in the young and middle-aged groups., (© 2021. The International Urogynecological Association.)

Background: Because patients on maintenance hemodialysis (HD) have an impaired immune response to pathogens, they are at higher risk of severe coronavirus disease 2019 (COVID-19). However, data on antibody production among HD patients with COVID-19 is scarce. Thus, we performed a retrospective cohort study evaluating severe acute respiratory syndrome coronavirus two antibody (SARS-CoV-2) production within 1 month after COVID-19 onset in hospitalized patients on HD., Methods: SARS-CoV-2-specific immunoglobulin (Ig) G levels were quantified using an iFlash 3000 Chemiluminescence Immunoassay analyzer (Shenzhen YHLO Biotech Co., Ltd.) to detect IgG antibodies specific for the S1 subunit of the spike protein (IgG-S1). Propensity score matching was used to balance covariate distribution in HD and non-HD patients. From April 2020 to February 2021, antibody testing was performed on 161 hospitalized patients with symptomatic COVID-19. Of them, 34 HD patients were matched to 68 non-HD patients., Results: After propensity score matching, the median levels of IgG-S1 in the HD patients at 7-13 days after symptom onset were significantly lower than in non-HD patients, especially in those with severe disease. Among all patients, those with severe disease produced lower levels of IgG-S1 at 7-13 days compared with non-severe patients., Conclusion: COVID-19 patients with severe disease, especially those undergoing HD, had lower IgG-S1 production in the second week of the disease. Thus, the increased risk of severe COVID-19 in HD patients may be, in part, due to a slow and reduced antibody response., (© 2021. Japanese Society of Nephrology.)

Protein structures fluctuate in solution; therefore, proteins have multiple stable structures that are slightly different from each other. In this study, we determined the crystal structure of hen egg lysozyme refolded after denaturation at acidic pH (rHEL) and found a structure different from native HEL (nHEL). The different local conformations of the peptide bond between Asp101 and Gly102 found in the crystal structure was supported by the NMR results for nHEL and rHEL. The NMR experiments also showed shifts in the heteronuclear single quantum coherence signals derived from Thr43 and Asp52. The chemical shift change of Asp52 could be explained by the crystal structure of rHEL, showing the conformational change of Tyr53, whose phenol ring directly lies on the main chain of Asp52. The catalytic activity of rHEL was similar to that of nHEL, indicating that the conformational change had little effect on activity. In contrast, conformational changes could be detected by the binding of monoclonal antibodies against HEL. Using multiple methods, we successfully detected the unusual structure of HEL, which might be another stable structure of HEL in solution., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We showed an association between serum concentrations of vitamin D and bone health among community-dwelling adults in Japan after adjustment for confounding factors, with 730 participants in a city, with concentrations of 25(OH) vitamin D, and with parameters of quantitative ultrasound., Purpose: The primary objective of this study was to examine the correlation between serum 25-hydroxyvitamin D (25(OH)D) concentration and bone indicators as measured by quantitative ultrasound in middle-aged and older Japanese adults living in low-latitude seaside areas during summer and autumn., Methods: We conducted a cross-sectional study, the Unzen study, on community-dwelling Japanese adults who participated to periodic health examinations between 2011 and 2013 (during the months of May to November)., Results: A total of 301 men (mean (SD) age, 67.9 (8.2) years; range, 50-92 years) and 429 women (mean (SD) age, 67.9 (7.7); range, 50-89 years) participated in this study. Serum 25(OH)D levels and quantitative ultrasound parameters (broadband ultrasound (BUA), speed of sound (SOS), and stiffness index of the calcaneus were measured for the participants. We excluded two men and 28 women from the 730 participants because they were on medication for osteoporosis. So, 299 men and 401 women were included in the final data analysis. The prevalence of vitamin D insufficiency (< 30 ng/ml) was very high: 71.9% in men and 95.5% in women. In women, the log(25(OH)D) positively and significantly correlated with SOS (p = 0.011) and stiffness index (p = 0.028) but not with BUA (p = 0.176). In men, the log(25(OH)D) did not correlate with the BUA, SOS, or stiffness index (p = 0.218, 0.420, and 0.262, respectively)., Conclusions: Serum 25(OH)D levels were associated with SOS or stiffness index in women but not in men., (© 2021. International Osteoporosis Foundation and National Osteoporosis Foundation.)

Background: Serum adiponectin circulates in three multimeric isoforms: high-molecular-weight (HMW), middle-molecular-weight (MMW), and low-molecular-weight (LMW) isoforms. Potential change in the circulating adiponectin levels in patients with nephrotic syndrome (NS) remain unknown. This study aimed to assess the levels of total adiponectin and the distribution of its isoforms in pediatric patients with NS., Methods: We sequentially measured total adiponectin and each adiponectin isoform levels at the onset of NS, initial remission, and during the remission period of the disease in 31 NS patients. We also calculated the ratios of HMW (%HMW), MMW (%MMW), and LMW (%LMW) to total adiponectin incuding 51 control subjects., Results: The median of total serum adiponectin levels in patients were 36.7, 36.7, and 20.2 μg/mL at the onset, at initial remission, and during the remission period of NS, respectively. These values were significantly higher than those in control subjects. The median values of %HMW, %MMW, and %LMW values were 56.9/27.0/14.1 at the onset, 62.0/21.8/13.4 at the initial remission, and 58.1/21.7/17.5 at during the remission period of NS, respectively. Compared with control subjects, %HMW at initial remission and %MMW at the onset were high, and the %LMW values at the onset and at initial remission were low., Conclusions: In patients with NS, total serum adiponectin levels increase at the onset of the disease, and the ratio of adiponectin isoforms changes during the course of the disease. Further studies are needed to delineate the mechanisms between proteinuria and adiponectin isoforms change., (© 2021. The Author(s).)

This study investigated how air bubbles in media affect tablet dissolution in a flow-through cell system (USP 4) using disintegrating (USP prednisone) and non-disintegrating (USP salicylic acid) tablets. Cell hydrodynamics were studied using particle image velocimetry (PIV) and computational fluid dynamics (CFD). The PIV analysis showed periodic changes in the local flow corresponding to the discharge and suction of the pump cycles. The absence of prior deaeration induced small air bubbles in the media and lower maximum flow during the cycle, explaining the slower dissolution of the USP salicylic acid tablets. Bubbles, occurring during the USP prednisone tablets study, induced the transition of floating disintegrated particles towards the cell outlet, whereas the particles precipitated to form a white layer on the glass beads used in the study with prior deaeration. CFD analysis showed local flow variation in multiple positions of small (ID 12 mm) and large (ID 22.6 mm) cells, explaining the different rates of dissolution of prednisone tablet particles depending on their distribution. These results emphasize the importance of prior deaeration in dissolution studies using a flow-through system. Bubbles in the flow-through cell system affected tablet dissolution by reducing the area in contact with the media (wettability), lowering the maximum instantaneous flow (pressure buffering), and altering the position of disintegrated particles in the cell., (© 2021. American Association of Pharmaceutical Scientists.)

Background: Despite the increasing number of laparoscopic liver resection (LLR) procedures, postoperative bile leakage (POBL) remains a major complication. We occasionally experienced intraoperative bile leakage (IOBL) during LLR and managed it within the restrictions of laparoscopic surgery. However, there have been no reports about IOBL in LLR. We therefore investigated the impact of IOBL on postoperative outcomes and its predictive factors., Methods: We reviewed 137 patients who underwent LLR from April 2016 to March 2019 at our institute and assigned them to IOBL-positive or IOBL-negative groups. We compared clinicopathological characteristics and perioperative outcomes. Patients were further divided into four groups according to IOBL pattern, and the frequency of POBL in each was calculated. Predictors of IOBL were identified using multivariate logistic regression analysis., Results: There were 30 and 107 patients in the IOBL-positive and IOBL-negative groups, respectively. In the IOBL-positive group, operative time and postoperative hospital stays were significantly longer (P < 0.001). The frequency of POBL was significantly higher in the IOBL-positive group (P = 0.006). The IOBL-positive group was divided into two subgroups: IOBL from the transected parenchyma (IOBL-TP, n = 18) and from the main Glissonean pedicle (IOBL-mGP, n = 12). The IOBL-negative group was divided into two subgroups: bile staining in the mGP (BS-mGP, n = 9) and no change (NC, n = 98). POBL occurred in 11% (n = 2/18) of patients with IOBL-TP, 25% (n = 3/12) of those with IOBL-mGP, 11% (n = 1/9) of those with BS-mGP, and 1% (n = 1/98) of those with NC. Age, diabetes mellitus, indocyanine green retention rate, and Glissonean approach were predictors of IOBL (P < 0.05)., Conclusions: IOBL was relatively common during LLR and resulted in a higher incidence of POBL. Depending on the predictive factors, IOBL must be promptly identified and appropriately managed.

Background: Patients with diabetes mellitus and severe proteinuria present with poor renal prognoses, despite improvements in diabetes and kidney disease therapies. In this study, we designed a low-density lipoprotein (LDL)-cholesterol apheresis treatment for patients with diabetic nephropathy (DN)/diabetic kidney disease and severe proteinuria. This was a multicenter prospective LICENSE study to confirm the impact of LDL apheresis on proteinuria that exhibited hyporesponsiveness to treatment. In addition, we sought to determine the efficacy and safety of LDL apheresis by comparing the outcomes to those of historical controls in patients with diabetes, refractory hypercholesterolemia, and severe proteinuria., Methods: This was a prospective, multicenter study, including 40 patients with diabetes, severe proteinuria, and dyslipidemia. LDL apheresis was performed 6-12 times over a 12-week period. The primary endpoint was the proportion of patients with a decrease in proteinuria excretion of at least 30% in the 6 months after starting therapy. The secondary endpoints included serum creatinine levels and laboratory variables, which were evaluated 4, 6, 12, 18, and 24 months after therapy initiation., Results: LDL apheresis was performed on 40 registered patients with diabetes. The proportion of cases in which proteinuria decreased by 30% or more after 6 months of LDL apheresis was 25%, which was similar to that of historical controls. The overall survival and end-stage kidney disease-free survival rates were significantly higher in the LICENSE group compared to those in historical controls., Conclusion: Our results suggest that LDL apheresis may be effective and safe for patients with diabetes, proteinuria, and dyslipidemia., Trial Registration: Trial registration number: jRCTs042180076.

Background: Bone quality is as important as bone mineral density in terms of bone strength. Bone turnover markers (BTMs) are clinical indicators of bone quality. In implant dentistry, bone quality is considered equivalent to bone density on radiographic assessments. The purpose of this study was to determine whether the BTM values are reflected in jawbone condition by evaluating the relationship at baseline and during follow-up in patients with prosthodontic implants. Computed tomography (CT) scans were obtained and BTM (osteocalcin, bone-specific alkaline phosphatase, pyridinoline cross-linked carboxyterminal telopeptide of type I collagen, and crosslinked N-telopeptide of type I collagen) levels in blood samples were measured in partially edentulous eighteen patients before implant surgery. During the follow-up observation after implant surgery, marginal bone loss (MBL) was measured on dental radiography. We investigated the relationship between the presence of BTM abnormalities and radiographic bone density., Results: More women than men had abnormal BTM values. Bone turnover was accelerated in the group of women with abnormal BTM values. The density of cancellous bone at the implant placement site was significantly lower in the patients with abnormally high BTM values than in their counterparts with BTM values in the normal range., Conclusions: Female patients who undergo implant treatments may have reduced bone quality; evaluations of bone strength will require assessments of both BTMs and the density of cancellous bone.

Background: Laparoscopic hepatectomy has rapidly evolved and has become a viable alternative to open hepatectomy. However, the dissection of liver parenchyma via the laparoscopic caudal approach (parenchymal transection from the caudal to cranial direction under a laparoscopic caudal view) has several limitations. To avoid these limitations in anatomical hepatectomy along the hepatic vein with the caudal approach, it is important to recognize the "tenting sign of the hepatic vein," which helps to identify the running of the main trunk of the hepatic vein., Technical Presentation: In the bifurcation of the hepatic vein, there is a possibility of splitting of the hepatic vein branch or disorientation between the main trunk and branch. Therefore, it is vital that when the branch is pulled, the main trunk of the hepatic vein appears to be toward the direction of the branch. As a result, the main trunk appears in the direction from the original route to the pseudo route. In the caudal approach, this phenomenon is called "tenting sign of the hepatic vein." Therefore, liver dissection should be performed in the contralateral and cranial sides of the main trunk, with the "tenting sign of the hepatic vein" in mind. This report describes specific cases of the "tenting sign of the hepatic vein.", Conclusion: The "tenting sign of the hepatic vein" from the caudal approach is essential knowledge for safe and reliable anatomical laparoscopic hepatectomy and can lead to expansion of indications in the future.

The relationship between the geometric particle size distribution (GPSD) and the aerodynamic particle size distribution (APSD) of commercial solution and suspension metered-dose inhaler (MDI) formulations was assessed to clarify the use of GPSD to estimate the APSD. The size distribution of particles discharged from four suspension and four solution MDIs was measured using the Inas®100 light-scattering spectrometer and a Next Generation Impactor. The conversion factor was calculated by measuring the GPSD and APSD of MDIs. The morphology and physical properties of MDIs were studied using scanning electron microscopy (SEM) and differential scanning calorimetry (DSC). Six of the eight MDIs showed similar conversion factor profiles, irrespective of their composition and formulation types. Applying the conversion factor obtained from one of the six MDIs resulted in a particle size distribution comparable to each APSD except for some formulations. The two other solution MDIs, which contained citric acid, had much higher and variable conversion factors. SEM images and DSC scans of the solids obtained by nebulization of the solutions containing beclomethasone and/or citric acid showed the formation of a paste-like amorphous solid. These results indicated that APSD of solution and suspension MDIs that form rigid particles may be estimated by using the conversion factor and GPSD. Contrarily, the estimation is more difficult in formulations that tend to lose the particle structure during the measurement.

Background: Urinary tract infections caused by extended-spectrum beta-lactamase-producing bacteria are increasing worldwide. At our hospital, the number of pediatric patients hospitalized because of an upper urinary tract infection has dramatically increased since 2016. In total, 60.5% of urinary tract infections are caused by extended-spectrum beta-lactamase-producing Escherichia coli. Such a high prevalence of extended-spectrum beta-lactamase-producing E. coli has not been detected previously in Japan. Therefore, we evaluated the clinical and bacteriologic characteristics and efficacy of antibiotics against upper urinary tract infections caused by E. coli in children., Methods: This retrospective study surveyed 152 patients who were hospitalized in the pediatric department of Shimane Prefectural Central Hospital because of upper urinary tract infections caused by E. coli. Medical records were reviewed to examine patient characteristics. O antigens, antibiotic susceptibility, gene typing, and pulse-field gel electrophoresis were studied at the Shimane Prefectural Institute of Public Health and Environmental Science., Results: Urine sample analyses showed extended-spectrum beta-lactamase types such as CTX-M-9 and plural virulence genes. We changed the primary antibiotic treatment to flomoxef or cefmetazole to treat upper urinary tract infections caused by Gram-negative bacilli. After changing treatment, the time to fever alleviation was significantly shortened., Conclusion: Extended-spectrum beta-lactamase-producing E. coli should be suspected in community-acquired upper urinary tract infections. Therefore, when treating patients, it is necessary to focus on antibiotic susceptibility and the prevalence of extended-spectrum beta-lactamase-producing bacteria found in each area. Flomoxef and cefmetazole are useful primary treatments for upper urinary tract infections caused by extended-spectrum beta-lactamase-producing E. coli.

Background: Laparoscopic repeat liver resection (LRLR) still represents a challenge for surgeons especially in case with previous open liver surgery. The aim of the study is to perform a systematic review of the current literature to investigate the feasibility of LRLR after open liver resection (OLR) for liver diseases., Methods: A computerized search was performed for all English language studies evaluating LRLR. A meta-analysis was performed to evaluate the short-term outcomes in comparative studies between LRLR with previous laparoscopic liver resection (LLR) and OLR., Results: From the initial 55 manuscripts, 8 studies including 3 comparative studies between LRLR after OLR and LLR were investigated. There was a total of 108 patients. Considering initial surgery, the extent of initial liver resection was major liver resection in 20% of patients in whom it was reported. In all the patients, the most frequent primary histology was hepatocellular carcinoma, followed by colorectal liver metastasis. A half of reported patients had severe adhesions at the time of LRLR. The median operative time for LRLR was ranged from 120 to 413 min and the median blood loss ranged from 100 to 400 mL. There were 11% of the patients conversions to open surgery, hand-assisted laparoscopic surgery, or tumor ablation. The overall postoperative morbidity was 15% of all the patients, and there was no postoperative mortality. The median postoperative hospital stay was ranged from 3.5 to 10 days. The meta-analysis shows that LRLR after OLR is associated with a longer operative time and a more important blood loss compared to LRLR after LLR. However, no difference between LRLR after OLR and LLR was shown as far as hospital stay and morbidity rate are concerned., Conclusions: LRLR after OLR has been described in eight articles with favorable short-term outcomes in highly selected patients.

Background: The combination of major hepatectomy and pancreatoduodenectomy (PD), that is, a hepatopancreatoduodenectomy (HPD), is the only curative treatment for bile duct cancer with extensive horizontal tumor spread invading both the hepatic hilum and the intrapancreatic bile duct. However, this aggressive procedure remains controversial with regard to the balance between the survival benefit and high risk of mortality and morbidity, especially the risk for postoperative hepatic failure and postoperative pancreatic fistula. Here, we describe the efficacy of a novel modified technique of HPD with delayed division of the pancreatic parenchyma for hilar cholangiocarcinoma, and focus on the surgical technique and the short-term outcomes, with a representative case., Technical Presentation: This new surgical technique involves dissection of the pancreatic parenchyma and relevant mesoduodenum at the final step after dissecting the required parts on the inferior side and superior side of the tumor, enabling excision of the resected specimen. This technique described herein can prevent saponification of the resected surface of the pancreas by dissecting the pancreatic parenchyma toward the latter half of the surgical procedure as much as possible. The results suggest that there may also be a relationship between this technique and the prevention of postoperative pancreatic fistula., Conclusion: This new surgical technique of HPD may be able to prevent postoperative pancreatic fistula by performing intraoperative dissection of the pancreatic parenchyma as late as possible, which in turn, may improve the safety of HPD.

P2X purinergic receptors are ATP-driven ionic channels expressed as trimers and showing various functions. A subtype, the P2X4 receptor present on microglial cells is highly involved in neuropathic pain. In this study, in order to prepare antibodies recognizing the native structure of rat P2X4 (rP2X4) receptor, we immunized mice with rP2X4's head domain (rHD, Gln111-Val167), which possesses an intact structure stabilized by S-S bond formation (Igawa and Abe et al. FEBS Lett. 2015), as an antigen. We generated five monoclonal antibodies with the ability to recognize the native structure of its head domain, stabilized by S-S bond formation. Site-directed mutagenesis revealed that Asn127 and Asp131 of the rHD, in which combination of these amino acid residues is only conserved in P2X4 receptor among P2X family, were closely involved in the interaction between rHD and these antibodies. We also demonstrated the antibodies obtained here could detect rP2X4 receptor expressed in 1321N1 human astrocytoma cells.

Purpose: Although sleep bruxism (SB) is one of the most important clinical problems in dental practice, there is no definitive method for controlling it. This pilot study evaluated the effects of contingent vibratory feedback stimuli using an occlusal splint for inhibition of sleep bruxism., Methods: Thirteen subjects with clinically diagnosed SB participated after providing an informed consent. Portable polysomnographic recordings were conducted in the subjects' home environment to make a definitive SB diagnosis and to evaluate the effects of the vibratory stimuli on SB. A force-based bruxism detection system, which used a pressure-sensitive piezoelectric film embedded in the occlusal splint, was utilized to trigger vibration feedback stimuli, which was scheduled to be applied intermittently for 30 min, at 30-min intervals., Results: The number of SB episodes (times/hour), the total SB duration (seconds/hour), the mean duration of SB episodes (seconds/episode), and the micro-arousal index (times/hour) were scored for each time period (with and without vibration). The effects of the vibration on these scores were tested (paired t test; p < 0.05). The number of SB episodes tended to decrease with the vibration stimuli, and the decrease in the total SB duration was statistically significant (14.3 ± 9.5 vs. 26.0 ± 20.0, p = 0.03). No substantial change was found in terms of the micro-arousal index., Conclusions: These study results suggested that the SB inhibitory system employing a vibratory stimulus might be able to suppress the total SB duration without disturbing sleep.

Alport syndrome (AS) is a progressive hereditary renal disease that is characterized by sensorineural hearing loss and ocular abnormalities. It is divided into three modes of inheritance, namely, X-linked Alport syndrome (XLAS), autosomal recessive AS (ARAS), and autosomal dominant AS (ADAS). XLAS is caused by pathogenic variants in COL4A5, while ADAS and ARAS are caused by those in COL4A3/COL4A4. Diagnosis is conventionally made pathologically, but recent advances in comprehensive genetic analysis have enabled genetic testing to be performed for the diagnosis of AS as first-line diagnosis. Because of these advances, substantial information about the genetics of AS has been obtained and the genetic background of this disease has been revealed, including genotype-phenotype correlations and mechanisms of onset in some male XLAS cases that lead to milder phenotypes of late-onset end-stage renal disease (ESRD). There is currently no radical therapy for AS and treatment is only performed to delay progression to ESRD using nephron-protective drugs. Angiotensin-converting enzyme inhibitors can remarkably delay the development of ESRD. Recently, some new drugs for this disease have entered clinical trials or been developed in laboratories. In this article, we review the diagnostic strategy, genotype-phenotype correlation, mechanisms of onset of milder phenotypes, and treatment of AS, among others.

Adult wound healing can result in fibrotic scarring (FS) characterized by excess expression of myofibroblasts and increased type I/type III collagen expression. In contrast, fetal wound healing results in complete regeneration without FS, and the mechanism remains unclear. Amniotic fluid cells could contribute to scar-free wound healing, but the effects of human amniotic fluid cells are not well characterized. Here, we determined the effect of human amniotic fluid stem cells (hAFS) on FS during wound healing. Human amniotic fluid was obtained by amniocentesis at 15-17 weeks of gestation. CD117-positive cells were isolated and defined as hAFS. hAFS (1 × 10 6 ) suspended in PBS or cell-free PBS were injected around wounds created in the dorsal region of BALB/c mice. Wound size was macroscopically measured, and re-epithelialization in the epidermis, granulation tissue area in the dermis and collagen contents in the regenerated wound were histologically analyzed. The ability of hAFS to engraft in the wound was assessed by tracking hAFS labeled with PKH-26. hAFS fulfilled the minimal criteria for mesenchymal stem cells. hAFS injection into the wound accelerated wound closure via enhancement of re-epithelialization with less FS. The process was characterized by lower numbers of myofibroblasts and higher expression of type III collagen. Finally, transplanted hAFS were clearly observed in the dermis until day 7 implying that hAFS worked in a paracrine manner. hAFS can function in a paracrine manner to accelerate cutaneous wound healing, producing less FS, a process resembling fetal wound healing.

Oral squamous cell carcinoma (OSCC) is the most common malignant tumor in the head and neck region. The aim of this study was to identify the key molecules and to elucidate the molecular mechanisms of OSCC carcinogenesis through a microarray analysis of RNA extracted from normal epithelium, dysplasia, and squamous cell carcinoma components. Out of molecules that showed changes in gene expression in the microarray analysis, we focused on Sulfite oxidase (SUOX), which correlated significantly with carcinogenic process and exhibited a stepwise decrease in expression. The expression of SUOX was evaluated in detail at the protein level using samples from 58 patients with cancer of the tongue, and correlating clinicopathological factors were also comprehensively examined. SUOX expression declined significantly from normal epithelium to dysplasia to squamous cell carcinoma components in line with carcinogenic process. With regard to squamous cell carcinoma, SUOX expression was significantly lower when T classification was high. Our findings indicated that SUOX is negatively associated with the progression and proliferation of tongue cancer, and suggest that SUOX may be a key molecule in tongue tumors.

Insulinoma-associated protein 1 (INSM1) is an important biomarker of Achaete-scute homolog-like 1-driven pathways. For diagnosis of pancreatic neuroendocrine tumors (PanNET), chromogranin A (CGA), synaptophysin (SYP), and neural cell adhesion molecule (NCAM) were also considered as potential biomarkers. However, it is often difficult to diagnose it immunohistochemically. Hence, we examined the expression pattern of INSM1 in pancreatic solid tumors. We detected INSM1, CGA, SYP, and NCAM immunohistochemically, in 27 cases of NET [pure type: 25 cases, mixed adenoneuroendocrine carcinoma (MANEC): 2 cases]. We included 5 cases of solid-pseudopapillary neoplasm (SPN), 7 cases of acinar cell carcinoma (ACC), and 15 cases of pancreatic ductal adenocarcinoma (PDAC) as the control group. Nuclear expression of INSM1 was found in all PanNET pure type cases. However, expression of INSM1 was negative in PDAC, ACC, and SPN in all cases, whereas faint expression was seen in the cytoplasm from SPN. MANEC comprises of two components: neuroendocrine carcinoma and adenocarcinoma components. The NET component was positive for INSM1 expression, whereas the PDAC component does not express INSM1, which aids in distinguishing these components. Our results suggest that INSM1 is a useful immunohistochemical marker for diagnosing pancreatic neuroendocrine tumor.

Background: The sufficiency of screw anchoring is a critical factor for achieving successful spinal fusion; however, no reliable method for predicting pedicle screw fixation has been established. Recently, Hounsfield units (HU) obtained from computed tomography (CT) was developed as a new reliable tool to determine the bone quality. The purpose of the present study was to demonstrate the utility of regional HU measurement of the screw trajectory to predict the primary and long-term fixation strength of pedicle screws., Method: The insertional torque of pedicle screws using the cortical bone trajectory technique was measured intraoperatively in 92 consecutive patients who underwent single-level posterior lumbar interbody fusion. The cylindrical area of each screw was plotted on the preoperative CT image by precisely confirming the screw position, and the screw trajectory was measured in HU. First, three parameters: the bone mineral density (BMD) of the femoral neck and lumbar vertebrae, and regional HU values of the screw trajectory, were correlated with the insertional torque and compared among three groups. Next, pedicle screw loosening was evaluated by postoperative CT obtained 12 months after surgery, and clinical and imaging data were analyzed to assess whether regional HU values could be used as a predictor of screw loosening., Results: Regional HU values of the screw trajectory (r = 0.75, p < 0.001) had stronger correlation with the insertional torque than the femoral BMD (r = 0.59, p < 0.001) and lumbar BMD (r = 0.55, p < 0.001). The incidence of screw loosening was 4.6% (16/351). Multivariate logistic regression analysis revealed that regional HU value (odds ratio = 0.70; 95% confidence interval = 0.56-0.84; p = 0.018) was an independent risk factor significantly affected screw loosening., Conclusions: Regional HU values of the screw trajectory could be a strong predictor of both primary and long-term screw fixation in vivo.

Diterpenoid alkaloids with remarkable chemical properties and biological activities are frequently found in plants of the genera Aconitum, Delphinium, and Garrya. Accordingly, several diterpenoid alkaloid constituents of Aconitum and Delphinium plants as well as their derivatives exhibited cytotoxic activity against lung, prostate, nasopharyngeal, and vincristine-resistant nasopharyngeal cancer cell lines. Four new C 19 -diterpenoid alkaloids, 14-anisoyllasianine (1), 14-anisoyl-N-deethylaconine (2), N-deethylaljesaconitine A (3), and N-deethylnevadensine (4), together with 17 known C 19 - and C 20 -diterpenoid alkaloids, were isolated in a phytochemical investigation of rhizoma of Aconitum japonicum THUNB. subsp. subcuneatum (NAKAI) KADOTA. Their structures were elucidated by extensive spectroscopic methods including NMR (1D and 2D), IR, and MS (HRMS). Eight known diterpenoid alkaloids, lipoaconitine, lipomesaconitine, aconine, nevadenine, talatisamine, nevadensine, ryosenamine, and dehydrolucidusculine, were isolated the first time from A. japonicum subsp. subcuneatum. Three of the new C 19 -diterpenoid alkaloids (1, 3, 4) and six of the known diterpenoid alkaloids were evaluated for cytotoxic activity against five human tumor cell lines.

The two hemispheres of the human brain differ functionally and structurally. Despite over a century of research, the extent to which brain asymmetry is influenced by sex, handedness, age, and genetic factors is still controversial. Here we present the largest ever analysis of subcortical brain asymmetries, in a harmonized multi-site study using meta-analysis methods. Volumetric asymmetry of seven subcortical structures was assessed in 15,847 MRI scans from 52 datasets worldwide. There were sex differences in the asymmetry of the globus pallidus and putamen. Heritability estimates, derived from 1170 subjects belonging to 71 extended pedigrees, revealed that additive genetic factors influenced the asymmetry of these two structures and that of the hippocampus and thalamus. Handedness had no detectable effect on subcortical asymmetries, even in this unprecedented sample size, but the asymmetry of the putamen varied with age. Genetic drivers of asymmetry in the hippocampus, thalamus and basal ganglia may affect variability in human cognition, including susceptibility to psychiatric disorders.

Background: Septal penetration causes collimator-dependent differences in the heart-to-mediastinum (H/M) ratio in 123 I-metaiodobenzylguanidine (MIBG) cardiac imaging. We investigated generally applicable methods to correct such differences., Methods and Results: Four hours after 123 I-MIBG injection, 40 patients underwent anterior chest imaging successively with medium-energy (ME) and various non-ME collimators. The H/M ratios obtained with the non-ME collimators before and after 123 I-dual-window penetration correction were compared with the ME-derived standard values to determine patient-based conversion equations for empiric and combined corrections, respectively. A 123 I point source was imaged with various collimators, and the central ratio, the ratio of count in a small central region of interest to count in a large one, was calculated. The method of predicting the conversion equations from the central ratios was determined. Correction using the patient-based conversion equations removed systematic underestimation of the H/M ratios obtained with the non-ME collimators, and combined correction depressed residual random errors to some degree. Point-source-based equations yielded results comparable to the patient-based equations., Conclusions: Empiric and combined corrections effectively reduce collimator-dependent differences in the H/M ratio. The conversion equations can be predicted from simple point-source imaging, which would allow to apply these corrections to data obtained with various collimators.

Background: The dicarbonyl methylglyoxal reacts primarily with arginine residues to form advanced glycation end products, including Nδ-(5-hydro-5-methyl-4 -imidazolone-2-yl)-ornithine (MG-H1), which are risk factors for not only diabetic complications but also lifestyle-related disease including renal dysfunction. However, the data on serum level and clinical significance of this substance in chronic kidney disease are limited., Methods: Serum levels of MG-H1 and Nε-(carboxymethyl) lysine (CML) in 50 patients with renal dysfunction were measured by liquid chromatography/triple-quadruple mass spectrometry., Results: The median serum MG-H1 levels in patients with estimated glomerular filtration rate (eGFR) of ≥30, 15-30, and <15 ml/min/1.73 m 2 was 4.16, 12.58, and 14.66 mmol/mol Lys, respectively (p > 0.05). On the other hand, MG-H1 levels in patients with HbA1c of <6 and ≥6 % was 12.85 and 10.45 mmol/mol Lys, respectively, the difference between which is not significant. In logistic regression analysis, decreased renal function (eGFR <15 ml/min/1.73 m 2 ) significantly associated with high serum levels of MG-H1 [odds ratio: 9.39 (95 % confidence interval 1.528-57.76), p = 0.015; Spearman rank correlation: MG-H1 vs. eGFR, r = -0.691, p < 0.01]. In contrast, the serum level of CML did not correlate with eGFR, but correlated with systolic blood pressure [odds ratio 16.17 (95 % confidence interval 1.973-132.5), p = 0.010; Spearman rank correlation coefficient: CML vs. eGFR, r = 0.454, p < 0.01]., Conclusion: These results showed that the serum concentration of MG-H1 was strongly related to renal function rather than to DM.

Glycyrrhiza uralensis roots used in this study were produced using novel cultivation systems, including artificial hydroponics and artificial hydroponic-field hybrid cultivation. The equivalency between G. uralensis root extracts produced by hydroponics and/or hybrid cultivation and a commercial Glycyrrhiza crude drug were evaluated for both safety and efficacy, and there were no significant differences in terms of mutagenicity on the Ames tests. The levels of cadmium and mercury in both hydroponic roots and crude drugs were less than the limit of quantitation. Arsenic levels were lower in all hydroponic roots than in the crude drug, whereas mean lead levels in the crude drug were not significantly different from those in the hydroponically cultivated G. uralensis roots. Both hydroponic and hybrid-cultivated root extracts showed antiallergic activities against contact hypersensitivity that were similar to those of the crude drug extracts. These study results suggest that hydroponic and hybrid-cultivated roots are equivalent in safety and efficacy to those of commercial crude drugs. Further studies are necessary before the roots are applicable as replacements for the currently available commercial crude drugs produced from wild plant resources.

Apolipoprotein E (APOE) ε4 allele and education have been reported to affect the cognitive function in young-old adults. However, the effects and interactions of the ε4 allele and education on cognitive function in very old age, particularly in centenarians, are not well known. We studied 542 Japanese centenarians. Using the data in total of 452 participants (74 men and 378 women, mean age 103.6 ± 3.2 years) who were genotyped and assessed cognitive function with the Mini-Mental States Examination (MMSE), we examined the effects and interactions of the ε4 allele and education on the MMSE score. First, we coded education as three levels: low, middle, and high based on the formal educational levels (analysis 1). Second, to clarify the modifying effect of education, we adopted a new coding for education into two levels, considering a periodical background (around 1900) of gender differences in educational attainments (analysis 2). In analysis 1, the main effects of the ε4 allele and education on the MMSE score were significant after adjusting for age. Further, there was a significant three-way interaction effect between the ε4 allele, education, and gender on the MMSE. Analysis 2 showed that the modifying effect of the ε4 allele by education was observed only in women with the ε4 allele. These findings suggest that both the APOE ε4 allele and education appear to be associated with cognitive function even in centenarians, but the interaction between the ε4 allele and education might depend on gender in this cohort., Competing Interests: Compliance with ethical standards For participation in any of the studies, written informed consent was obtained either from the participants or by proxy when individuals lacked the capacity to consent. TCS and JSS were approved by the Ethical Committee of the Keio University School of Medicine and Tokyo Metropolitan Institute of Gerontology.

Glycation of amino acid residues in proteins leads to the eventual formation of advanced glycation end products (AGEs). AGE formation significantly influences human health and the aging process. AGE accumulation rates may be slowed by modifications to lifestyle or by pharmacological strategies. But the use of therapeutic drugs is not an appropriate means of controlling AGEs within the general population. However, phytochemical constituents in plant-based foods exhibit anti-glycation activities and may be more appropriate for general consumption. Among these phytochemicals are iridoids. The anti-AGE potential of iridoids has been demonstrated in vitro and in vivo, while also revealing possible mechanisms of action. Inclusion of iridoid food sources in the diet may be a useful component of strategies intended to mitigate AGE accumulation within the body.

To investigate various risk factors of cognitive decline in the very old, we studied 494 subjects over 85 years old without diagnosis of dementia at baseline from the Tokyo Oldest Old Survey on Total Health, an ongoing, community-based cohort in Japan. Cognitive function was assessed at baseline and at 3-year follow-up using Mini-Mental State Examination (MMSE). Plasma samples were assayed for levels of cytomegalovirus (CMV) immunoglobulin G (IgG) antibodies, tumor necrosis factor-alpha, interleukin-6, and blood chemistry. Carotid artery plaques were measured using an ultrasonography. In the cross-sectional analyses using Tobit regression, individuals with high carotid artery plaque score (≥5.0) had MMSE scores that were 1.08 points lower compared to those with no plaque (95 % confidence interval (CI) -1.95 to -0.20; p = 0.016), adjusted for age, sex, and education. Individuals with CMV IgG titers in the highest quartile had MMSE scores that were 1.47 points lower compared to individuals in the lowest quartile (95 % CI -2.44 to -0.50; p = 0.003). CMV and carotid atherosclerosis showed evidence of an interaction, where the association between CMV and MMSE was present only in subjects with carotid artery plaque. In the longitudinal analyses using linear regression, carotid atherosclerosis, smoking, low grip strength, and poor activities of daily living (ADL) status were associated with faster cognitive decline, adjusted for age, sex, education, and baseline cognitive function. Our findings suggest that carotid atherosclerosis is consistently associated with low cognitive function in the very old and modifies the association between latent CMV infection and cognition., Competing Interests: Compliance with ethical standard Conflict of interest Dr. Arai received research grant from DAIICHI SANKYO COMPANY, LIMITED and Takeda Pharmaceutical Company Limited. Dr. Hirose received research grant from MSD K.K. All other authors have nothing to disclose. Sponsor’s role The funding agencies had no direct role in the design or conduct of the study; the collection, management, analyses, or interpretation of the data; or the preparation or approval of the manuscript. Funded by the Grant-in-Aid for Scientific Research (B) (No. 21390245), (C) (No 20590706, 21590775) from Japan Society for the Promotion of Science, the medical-welfare-food-agriculture collaborating consortium project from Japan Ministry of Agriculture, Forestry and Fisheries, by the grant from Novartis Foundation for Gerontological Research, by the grant from Foundation for Total Health Promotion, and by the Chiyoda Mutual Life Foundation.

Background: The cortical bone trajectory (CBT) has attracted attention as a new minimally invasive technique for lumbar instrumentation by minimizing soft-tissue dissection. Biomechanical studies have demonstrated the superior fixation capacity of CBT; however, there is little consensus on the selection of screw size, and no biomechanical study has elucidated the most suitable screw size for CBT. The purpose of the present study was to evaluate the effect of screw size on fixation strength and to clarify the ideal size for optimal fixation using CBT., Method: A total of 720 analyses on CBT screws with various diameters (4.5-6.5 mm) and lengths (25-40 mm) in simulations of 20 different lumbar vertebrae (mean age: 62.1 ± 20.0 years, 8 males and 12 females) were performed using a finite element method. First, the fixation strength of a single screw was evaluated by measuring the axial pullout strength. Next, the vertebral fixation strength of a paired-screw construct was examined by applying forces simulating flexion, extension, lateral bending, and axial rotation to the vertebra. Lastly, the equivalent stress value of the bone-screw interface was calculated., Results: Larger-diameter screws increased the pullout strength and vertebral fixation strength and decreased the equivalent stress around the screws; however, there were no statistically significant differences between 5.5-mm and 6.5-mm screws. The screw diameter was a factor more strongly affecting the fixation strength of CBT than the screw fit within the pedicle (%fill). Longer screws significantly increased the pullout strength and vertebral fixation strength in axial rotation. The amount of screw length within the vertebral body (%length) was more important than the actual screw length, contributing to the vertebral fixation strength and distribution of stress loaded to the vertebra., Conclusions: The fixation strength of CBT screws varied depending on screw size. The ideal screw size for CBT is a diameter larger than 5.5 mm and length longer than 35 mm, and the screw should be placed sufficiently deep into the vertebral body.

Background: Although incisional hernia (IH) is a common complication of abdominal surgery, the incidence rate and risk factors are not well known. The objectives of this study are to determine the incidence rate of IH following colorectal cancer surgery and to describe the associated risk factors., Methods: Between 2005 and 2010, patients who underwent surgery to treat colorectal cancer were examined. The diagnosis of IH was performed by CT scan, and the visceral fat area (VFA) and subcutaneous fat area (SFA) at the level of the umbilicus were calculated using a 3D-image analysis system. Survival analysis was used to assess the incidence and risk factors of IH., Results: A total of 626 patients (326 open, 300 laparoscopic) were included in this study, with median follow-up of 54 (range 2-97) months. Forty patients were diagnosed with postoperative IH, and the cumulative, 5-year incidence of IH was 7.3 %. Univariate analysis revealed that age, body mass index, waist circumference, hip circumference, open laparotomy, wound infection, VFA, and SFA were significantly associated with incidence of IH. Multivariate analysis revealed that age [hazard ratio (HR) 1.043 (1.005-1.083), p = 0.027], open laparotomy [HR 4.410 (1.018-19.095), p = 0.047], and SFA [HR 1.013 (1.004-1.022), p = 0.005] were significant risk factors for developing IH., Conclusions: Higher age and SFA, along with open surgery, are risk factors for developing IH.

Background: This study evaluated our new strategy for treating suspected T2 gallbladder carcinoma (GBC) using a laparoscopic approach., Methods: We examined 19 patients with suspected T2 GBC who were treated laparoscopically (LS group) between December 2007 and December 2013; these patients were compared with 14 patients who underwent open surgery (OS group). Laparoscopic staging was initially performed to exclude factors making the patients ineligible for curative resection. Intraoperative pathological examination of the surgical margin of the cystic duct was performed prior to laparoscopic gallbladder bed resection, and pathological examination was again performed to confirm the presence of carcinoma and the depth of tumor invasion. Surgery was completed when the pathological findings indicated that the patient was cancer free. Lymph node dissection was performed according to the depth of tumor invasion., Results: None of the patients required conversion to laparotomy. For three patients with benign lesions, only gallbladder bed resection was required. Additional regional lymph node dissection was performed in 16 patients in the LS group. The mean operative time (309 vs. 324 min, p = 0.755) and mean number of dissected lymph nodes (12.6 vs. 10.2, p = 0.361) were not significantly different between the LS and OS groups. The intraoperative blood loss was significantly lower (104 vs. 584 mL, p = 0.002) and the postoperative hospital stay was significantly shorter (9.1 vs. 21.6 days, p = 0.002) for LS patients than for those in the OS group. In the LS group, one patient developed postoperative pneumonia, but all patients survived without recurrence after a mean follow-up of 37 months., Conclusion: Our strategy for suspected T2 gallbladder GBC is safe and useful, avoids unnecessary procedures, and is associated with similar oncologic outcomes as the open method.

Background: Whether to perform a renal biopsy for isolated hematuria remains a matter of controversy. We performed renal biopsy in hematuria without overt proteinuria patients and reported the proportion of glomerulonephritis, pathological activities, and statistical analysis of indicators associated with glomerulonephritis., Methods: Among 203 patients who underwent renal biopsy in Okubo Hospital, Japan, between January 2008 and October 2013, we identified 56 patients who fulfilled the criteria: (1) urine dipstick examination shows equal to or greater than ± blood on three or more visits, (2) proteinuria <0.3 g/day (g/g Cr), (3) eGFR ≧60 ml/min/1.73 m(2), and (4) no current medication for renal disease. We investigated biopsy findings and compared the clinical indicators in the IgA nephropathy (IgAN) and non-IgAN group., Results: The pathological diagnosis was IgAN in 35 cases (62 %), thin basement membrane disease (TBMD) in 7 (13 %), minor glomerular abnormality (MGA) in 6 (11 %), glomerular basement membrane (GBM) abnormality in 5 (9 %), and others in 3 (5 %). The histological grade of IgAN was I in 90 % and II in 10; 31 % of patients had some crescentic lesions. Comparisons between the IgAN and non-IgAN group revealed significant differences in age of onset (26 ± 13 vs. 34 ± 17 years, p = 0.04), serum IgA (340 ± 114 vs. 220 ± 101 mg/dl, p < 0.01), proteinuria (0.08 [0-0.25] vs. 0 [0-0.23] g/day [g/gCr], p < 0.01), and the presence of poikilocytes (40 vs. 10 %, p = 0.02)., Conclusions: The proportion of IgAN in hematuria without overt proteinuria was high and the pathological activities were variable. Patients with hematuria without overt proteinuria should continue their medical follow-up and the best timing of biopsy may be controversial for these patients who have multiple risk factors of IgAN.

Background: The safety and feasibility of hepatectomy for hepatocellular carcinoma (HCC) in the elderly population have not been defined to date., Methods: A single-center, retrospective cohort study was conducted with 104 patients who underwent hepatectomy for HCC from 2005 to 2010. The patients were divided into two groups, the elderly group (age, ≥75 years; n = 22) and the nonelderly group (age, <75 years; n = 82), for comparison of short- and long-term outcomes., Results: More patients were categorized as preoperative Eastern Cooperative Oncology Group (ECOG) performance status 1 in the elderly group (32 %) than in the nonelderly group (6 %) (P = 0.003). Complications with a Clavien-Dindo classification of grade 3a or higher were more frequently observed in the elderly group (41 %) than in the nonelderly group (17 %) (P = 0.006). Multivariate logistic regression showed ECOG performance status 1 as the only independent predictor of complications classified as Clavien-Dindo grade 3a or higher. The in-hospital mortality rates were similar between the two groups (P = 0.20). During a median follow-up period of 47 months, the unadjusted 5-year recurrence-free survival rates were similar in the elderly (25 %) and nonelderly (33 %) groups (P = 0.80). Multiple tumors and high alpha-fetoprotein levels emerged as independent negative indicators of recurrence-free survival using multivariate Cox analyses. The adjusted risk for recurrence was not elevated in the elderly group (hazard ratio [HR], 0.92; 95 % confidence interval [CI] 0.50-1.68; P = 0.78)., Conclusions: Despite the more frequent occurrence of complications with a Clavien-Dindo grade of 3a or higher among the elderly patients undergoing hepatectomy for HCC, their mortality and recurrence rates were comparable with those of the nonelderly patients. Therefore, age alone is not a determinant of surgical candidacy for HCC.

Background: Although cryoablation (Cryo) has been advocated as an effective locoregional therapy for hepatocellular carcinoma (HCC), few studies have compared the outcomes with those of radiofrequency ablation (RFA) and microwave coagulation therapy (MCT)., Methods: Consecutive patients with primary HCCs of <5 cm received Cryo or RFA/MCT between 1998 and 2011 and were monitored for local recurrence (defined as a recurrent tumor at or in direct contact with the ablated area) and overall complication rates., Results: The median tumor size was 2.5 cm in the Cryo group (n = 55) and 1.9 cm in the RFA/MCT group (n = 64; P < 0.001), but other patient characteristics were similar. Multivariate Cox regression analysis revealed Cryo as the only independent factor for improved 2-year local recurrence-free survival, with a hazard ratio (HR) of 0.3 (95 % confidence interval, 0.1-0.9; P = 0.02). Tumor diameter was a negative indicator of local recurrence-free survival (HR, 2.0; 95 % confidence interval, 1.1-3.5; P = 0.02). Subgroup analysis of patients with tumors of >2 cm demonstrated significantly better local recurrence rates in the Cryo group compared with the RFA/MCT group (21 vs. 56 % at 2 years; P = 0.006). Overall complication rates and incidences of Clavien-Dindo classification grade ≥ III were identical (both P = 1.00). No in-hospital mortality occurred., Conclusions: Appropriate use of Cryo, as shown in this series, is safe and provides significantly improved local control for the treatment of primary HCCs of >2 cm compared with RFA/MCT.

Although amorphous silica nanoparticles are widely used in the production of food products (e.g., as anticaking agents), there is little information available about their absorption and biological effects after oral exposure. Here, we examined the in vitro intestinal absorption and in vivo biological effects in mice of orally administered amorphous silica particles with diameters of 70, 300, and 1,000 nm (nSP70, mSP300, and mSP1000, respectively) and of nSP70 that had been surface-modified with carboxyl or amine groups (nSP70-C and nSP70-N, respectively). Analysis of intestinal absorption by means of the everted gut sac method combined with an inductively coupled plasma optical emission spectrometer showed that the intestinal absorption of nSP70-C was significantly greater than that of nSP70. The absorption of nSP70-N tended to be greater than that of nSP70; however, the results were not statistically significant. Our results indicate that silica nanoparticles can be absorbed through the intestine and that particle diameter and surface properties are major determinants of the degree of absorption. We also examined the biological effects of the silica particles after 28-day oral exposure in mice. Hematological, histopathological, and biochemical analyses showed no significant differences between control mice and mice treated with the silica particles, suggesting that the silica nanoparticles evaluated in this study are safe for use in food production.

The aim of this study was to investigate the effect of Morinda citrifolia fruit on blood fluidity. M. citrifolia fruit extract (MCF-ext) was investigated for its influence on blood aggregation and fibrinolysis. MCF-ext inhibited polybrene-induced erythrocyte aggregation and thrombin activity. The fibrinolytic activity of MCF-ext, in the euglobulin lysis time test and fibrin plate assay, is reported here for the first time. One of the active compounds was an iridoid glycoside, asperulosidic acid. The results indicated that MCF-ext is a potentially useful health food which is capable of improving blood flow and preventing lifestyle-related diseases.

Background: Septal penetration causes underestimation of the heart-to-mediastinum (H/M) ratio in cardiac (123)I-metaiodobenzylguanidine (MIBG) imaging with a low-energy high-resolution (LEHR) collimator. We aimed to improve the method of estimating the H/M ratios using the LEHR collimator., Methods and Results: 4 hours after (123)I-MIBG injection, 40 patients were imaged successively with the medium-energy (ME) and LEHR collimators using gamma cameras having 3/8-inch crystals. Severe underestimation of the H/M ratios was observed with the LEHR collimator when compared to the ME collimator. Narrowing the energy window width did not reduce the underestimation. Application of (123)I-dual-window (IDW) correction using a narrow or wide subwindow reduced the underestimation substantially but not entirely. The H/M ratios estimated from the LEHR images with or without IDW correction were corrected based on their correlations with the ratios estimated from the ME images. This empiric correction removed systematic underestimation, and residual errors were reduced when the H/M ratios after IDW correction were converted using the empiric equation. The conversion equation was successfully applied to the correction of the H/M ratios determined in another 40 patients using a 5/8-inch crystal., Conclusions: In estimating the H/M ratios using an LEHR collimator, empiric correction combined with IDW correction improves concordance with ME-based values in comparison with empiric correction alone.