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Background Clinical factors affecting renal prognosis in patients with immunoglobulin A nephropathy (IgAN) and low urinary protein excretion (U-Prot) remain unclear. This study evaluated such factors in patients with clinical grade I (CG-I) IgAN with U-Prot Methods This secondary analysis of a previous retrospective study included 394 patients with CG-I IgAN. The primary outcome was the first occurrence of a 1.5-fold increase in serum creatinine levels from baseline. Factors related to renal prognosis were examined using univariate and multivariate Cox regression analyses. CG-I was divided into C-Grade Ia (CG-Ia) (n = 330) with baseline eGFR ≥ 60 ml/min/1.73 m2, and C-Grade Ib (CG-Ib) (n = 64) with baseline eGFR 2. Outcome incidence was compared between conservative and aggressive therapy (corticosteroids and/or tonsillectomy) groups. Results Overall outcome incidence was significantly higher in CG-Ib than in CG-Ia; the cumulative incidence was significantly higher in CG-Ib (hazard ratio, 9.67; 95% confidence interval, 2.90–32.23). Older age, higher IgA levels, eGFR 2, lower eGFR at baseline were independent prognostic factors for CG-I. Older age, lower eGFR, higher IgA levels at baseline, and U-Prot remission at 1-year post-diagnosis were independent prognostic factors for CG-Ib. Aggressive therapy tended to suppress the cumulative outcome incidence compared with conservative therapy in CG-Ib (p = 0.087). Conclusion An eGFR 2 is a significant predictor of renal prognosis in patients with IgAN and U-Prot

BACKGROUND In recent years, many researchers have focused on legacy data utilization, such as pooled analyses that collect and re-analyze data from multiple studies. However, the methodology for the integration of pre-existing databases whose data were collected for different purposes has not been established. Previously, we developed a tool to efficiently generate Study Data Tabulation Model (SDTM) data from hypothetical clinical trial data using the Clinical Data Interchange Standards Consortium (CDISC) SDTM. OBJECTIVE To design a practical model for integrating pre-existing databases using the CDISC SDTM. METHODS Data integration was performed in three phases: i) confirmation of the variables, ii) SDTM mapping, and iii) generation of the SDTM data. In phase 1, the definitions of the variables in detail were confirmed, and the datasets were converted to vertical datasets. In phase 2, the items derived from the SDTM format were set as mapping items. Three types of metadata (domain name, variable name, and test code), based on the CDISC SDTM, were embedded in the REDCap field annotation. In phase 3, the data dictionary, including the SDTM metadata, were output in the Operational Data Model (ODM) format. Finally, the mapped SDTM were generated using REDCap2SDTM v2. RESULTS SDTM data were generated as a comma-separated values file for each of the seven domains defined in the metadata. Twenty-two items were commonly mapped to three databases. Because the SDTM data were set in each database correctly, we were able to integrate three independently pre-existing databases into one database in the CDISC SDTM format. CONCLUSIONS Our project suggests that the CDISC SDTM is useful for integrating multiple pre-existing databases.

Objectives IgA nephropathy (IgAN) is the most common primary chronic glomerulonephritis and a major cause of end-stage kidney disease worldwide. Novel biomarkers, including the aberrantly glycosylated IgA1 and glycan-specific antibodies, could be useful in the diagnosis of IgAN. The aim of this study was to assess the cost analysis of IgAN screening using novel biomarkers in addition to the conventional screening compared with conventional screening alone. Methods To estimate the medical expense of each strategy related to renal disease for 40 years, we developed an analytical decision model. The decision tree started at “40 years of age with first-time hematuria.” It simulated 2 clinical strategies: IgAN screening using the novel biomarkers (group N) and conventional screening (group C). The analysis results were presented as medical expenses from a societal perspective. Discounting was not conducted. Results The expected medical expense per person for 40 years was ¥31.2 million (~$291 000) in group N and ¥33.4 million (~$312 000) in group C; hence, expense in group N was lower by ¥2.2 million (~$21 000). In group N, the expected value of IgAN increased by 5.67% points (N 48.44%, C 42.77%) and that of dialysis introduction decreased by 0.85% points (N 19.06%, C 19.91%). In the sensitivity analysis, expenses could be reduced in almost all cases except when renal biopsy using conventional screening was performed at the rate of 73% or higher. Conclusion Screening for IgAN using novel biomarkers would reduce renal disease–related expenses.

Background Recent clinical reports indicate a correlation between gross hematuria after the coronavirus 2019 (COVID-19) vaccination in patients with glomerulonephritis, especially immunoglobulin A nephropathy (IgAN). Furthermore, healthcare workers in Japan were initially vaccinated with an mRNA vaccine from February 17, 2021, and some of them experienced gross hematuria after receiving the vaccination. Methods We conducted a web-based survey of the councilor members of the Japanese Society of Nephrology (581 members, 382 facilities) to elucidate the relationship between gross hematuria and COVID-19 vaccination. Results In the first survey, 27 cases (female: 22, 81.5%) of gross hematuria were reported after receiving a COVID-19 vaccination. Of them, 19 (70.4%) patients were already diagnosed with IgAN at the occurrence of gross hematuria. Proteinuria appeared in eight of the 14 (57.1%) cases with no proteinuria before vaccination and hematuria in five of the seven (71.4%) cases with no hematuria before vaccination. The second survey revealed that a renal biopsy was performed after vaccination in four cases, all of whom were diagnosed with IgAN. Only one case showed a slightly increased serum creatinine level, and no patients progressed to severe renal dysfunction. Conclusion This study clarified the clinical features of gross hematuria after a COVID-19 vaccination. Because there was no obvious progression to severe renal dysfunction, safety of the COVID-19 vaccination is warranted at least in the protocol of inoculation twice.

ObjectivesTo visualise the trajectories of pulmonary arterial pressure (PAP) in systemic sclerosis (SSc) and identify the clinical phenotypes for each trajectory, by applying latent trajectory modelling for PAP repeatedly estimated by echocardiography.MethodsThis was a multicentre, retrospective cohort study conducted at four referral hospitals in Kyoto, Japan. Patients with SSc who were treated at study sites between 2008 and 2021 and who had at least three echocardiographic measurements of systolic PAP (sPAP) were included. A group-based trajectory model was applied to the change in sPAP over time, and patients were classified into distinct subgroups that followed similar trajectories. Pulmonary hypertension (PH)-free survival was compared for each trajectory. Multinomial logistic regression analysis was performed for baseline clinical characteristics associated with trajectory assignment.ResultsA total of 236 patients with 1097 sPAP measurements were included. We identified five trajectories: rapid progression (n=9, 3.8%), early elevation (n=30, 12.7%), middle elevation (n=54, 22.9%), late elevation (n=24, 10.2%) and low stable (n=119, 50.4%). The trajectories, in the listed order, showed progressively earlier elevation of sPAP and shorter PH-free survival. In the multinomial logistic regression analysis with the low stable as a reference, cardiac involvement was associated with rapid progression, diffuse cutaneous SSc was associated with early elevation and anti-centromere antibody was associated with middle elevation; older age of onset was associated with all three of these trajectories.ConclusionThe pattern of changes in PAP over time in SSc can be classified into five trajectories with distinctly different clinical characteristics and outcomes.

Background: Tranexamic acid is frequently reported to reduce bleeding-related complications in major surgery and trauma. We aimed to investigate whether tranexamic acid reduced hematoma size after percutaneous kidney biopsy. Methods: We conducted a double-blind, parallel three-group, randomized placebo-controlled trial at a teaching hospital in Japan between January 2016 and July 2018. Adult patients with clinical indication for ultrasound-guided percutaneous biopsy of a native kidney were included. Participants were randomly assigned into three groups: high-dose tranexamic acid (1,000 mg in total), low-dose tranexamic acid (500 mg in total), or placebo (counterpart saline). Intervention drugs were intravenously administered twice, as a bolus just before the biopsy and as a continuous infusion initiated just after the biopsy. Primary outcome was post-biopsy perirenal hematoma size as measured by ultrasound on the morning after the biopsy. Results: We assessed 90 adult patients for study eligibility, of whom 56 were randomly allocated into the three groups: 20 for high-dose tranexamic acid, 19 for low-dose tranexamic acid, and 17 for placebo. The median size of perirenal hematoma was 200 mm2 (interquartile range, 21–650) in the high-dose tranexamic acid group, 52 mm2 (0–139) in the low-dose tranexamic acid group, and 0 mm2 (0–339) in the placebo group (p = 0.048 for high-dose tranexamic acid vs. placebo). Conclusion: In this trial, the median size of post-kidney biopsy hematoma was unexpectedly larger in the high-dose tranexamic acid group than in the placebo group. Although our results do not support the routine use of tranexamic acid in percutaneous kidney biopsy at present, further studies are needed to confirm the results.

Five undescribed norfriedelane triterpenoids, anchietins A-E, along with three known norfriedelane triterpenoids, 21β-hydroxycaloncobalactone, and welwitschiilactones B and C, were isolated from the vine of Anchietia pyrifolia. The compounds were characterized by spectroscopic and crystallographic methods, including 2D NMR spectroscopy and single crystal X-ray crystallography. The isolated compounds were evaluated for the cytotoxic activity against HeLa and HL60 cells and for the inhibitory activity against lipopolysaccharide-induced NO production. Further, inhibitory effects on the inducible nitric oxide synthase mRNA expression levels were also assessed.

Kidney international 102(1), 160-172 (2022). doi:10.1016/j.kint.2022.02.042, Published by Elsevier, New York, NY

Microscopic hematuria is being increasingly recognized as a major indicator of kidney deterioration. Persistent hematuria may better detect estimated glomerular filtration rate (eGFR) deterioration and potential glomerulonephritis. We conducted a retrospective cohort study to investigate the associations between persistent hematuria: the frequency or consistency of positive dipstick hematuria defined by the preceding 3 years urinalyses, and eGFR deterioration over 5 years and abnormal urinalyses suggesting potential glomerulonephritis (hematuria 1+ or higher, 2+ or higher, proteinuria, and hematuria and proteinuria) 5 years later, among adult participants with positive dipstick hematuria at baseline in a large-scale Japanese health checkup setting (n = 2104). There was no significant association between persistent hematuria and eGFR deterioration over 5 years. The higher the frequency of preceding hematuria, the greater the RR of hematuria 5 years later; RRs of hematuria with preceding thrice, twice, or once hematuria were 3.64 [95% CI, 3.11–4.25], 2.97 [95% CI, 2.52–3.51], or 1.91 [95% CI, 1.58–2.30] for “hematuria 1+ or higher,” and 7.13 [95% CI, 5.17–9.83], 4.26 [95% CI, 3.02–6.02], or 2.23 [95% CI, 1.52–3.27] for “hematuria 2+ or higher”. The presence of both hematuria and proteinuria 5 years later was only associated with preceding thrice hematuria (RR: 2.35 [95% CI, 1.37–4.03]). In conclusion, persistent hematuria for 3 years was associated with hematuria and proteinuria that were suggesting glomerulonephritis, but not associated with eGFR deterioration over 5 years. Multiple dipstick urinalyses over years can add some values to detect potential glomerulonephritis as an early sign of chronic kidney diseases.

Background Novel criteria for the remission of Immunoglobulin A nephropathy (IgAN) based on an opinion survey of Japanese nephrologists and literature review were proposed in 2013. This single-center, longitudinal retrospective cohort study was conducted to validate this criteria. Methods Present study included the IgAN patients diagnosed between 2001 and 2005 in the Juntendo University Hospital. Remission of hematuria was defined as three consecutive dipstick test results of ( −) to ( ±) or a red blood cell count 2/year) and a decrease in the eGFR of 30% from baseline eGFR as the secondary outcome, respectively. Results A total of 74 patients (male: 47.3%, median age: 30 years) were included and were followed for a median of 86.5 months. During the period, forty-one patients achieved neither remission of proteinuria nor hematuria (NR). Twelve patients met the primary study outcome. A survival analysis revealed that the NR had the worst prognosis and the steepest slope of eGFR decline. Conclusion Although further validation in a large cohort is necessary, these novel remission criteria for IgAN patients appear to predict the renal prognosis.

Pinellia tuber (PTE, 半夏, 大半夏, 掌葉半夏, 天南星, 水半夏, 半夏瀉心湯, 半夏厚朴湯, 六君子湯) is derived from the tuber of Pinellia ternata Breitenbach (Araceae), which is a crude drug used in traditional Japanese Kampo medicine for the purpose of antiemesis and expectoration. Since the separation of ephedrine from PTE in 1978, it has been listed as a PTE component in textbooks and internet information. Therefore, there are harmful effects on appropriate use in clinical practice because PTE is dealt with as a crude drug for doping target, and traditional Japanese Kampo medicine containing PTE must be carefully administered to the elderly. However, since the 1978 published report, there has not been any report on the isolation of ephedrine from PTE and the interpretation of biosynthesis remains questionable. In the present study, we analyzed the PTE samples in market distribution products by LC-TOF/MS. From the analysis of the result of ephedrine’s m/z 148.113 [M + H-H2O]+, PTE was not detected (n = 55, detection limit: 0.5 ppb). Additionally, the tuber of P. tripartite (PTR, 大半夏), the tuber of P. pedatisecta (PPE, 掌葉半夏), Arisaema Tuber (ART, 天南星), and the tuber of Typhonium flagelliforme (TFI, 水半夏) that have a similar description to PTE were also not detected. Moreover, the genetic analysis of experimental samples showed that PTE is derived from P. ternata. Furthermore, our attempt to isolate ephedrine from PTE based on the past literature was unsuccessful. These results suggest that PTE in market distribution products may not contain ephedrine as a component.

BackgroundDepressive disorders in University students have risen dramatically in the past few decades to the extent that students’ mental health has become a current global public health priority. Obtaining information from University students about their mental health is challenging because of potential embarrassment of disclosing one’s concerns and fear of stigmatization. Self-rated health might be a good solution to evaluate mental health state by a simple and neutral indicator. The aim of the study is to investigate the association between depressive symptoms and self-rated health by sex among University students in France and Japan.MethodsA cross-sectional study was conducted by using two large cohorts of students aged ≥18 years (n = 5655 in Bordeaux, France andn = 17,148 in Kyoto, Japan). Depressive symptoms (PHQ-2 scale), Likert scale of self-rated health, socio-demographic characteristics and health habits were collected through self-administered questionnaires. Multivariate logistic regression models were performed to describe the association between depressive symptoms and other variables including self-rated health, stratified by sex.ResultsA high score of PHQ-2 (high depressive symptoms) was associated with poor self-rated health in both cohorts independently of all other variables (OR 2.82, 95%CI 1.99–4.01 in France, OR 7.10, 95%CI 5.76–8.74 in Japan). Although the prevalence of depressive symptoms between sexes was different in French students (males 15.4%, females 25.0%,p p = 0.466), who reported less depressive symptoms than French students. The association between depressive symptoms and poor self-rated health was greater in Japanese females (OR 12.40, 95%CI 7.74–20.00) than in males (OR 6.30, 95%CI 4.99–7.95), whereas the strength of the association was almost similar in French students (OR 2.17, 95%CI 0.86–5.47 in males, OR 2.98, 95%CI 2.03–4.38 in females).ConclusionsDepressive symptoms were associated with self-rated health among University students in both countries with slightly differences in sex. Self-rated health would be a simple, reliable and universal indicator for healthcare professionals and University staff to identify students at risk of depression.

Contains fulltext : 225968.pdf (Publisher’s version ) (Closed access) Immunosuppression in IgA nephropathy (IgAN) should be reserved for patients at high-risk of disease progression, which KDIGO guidelines determine based solely on proteinuria 1g or more/day. To investigate if treatment decisions can be more accurately accomplished using individualized risk from the International IgAN Prediction Tool, we simulated allocation of a hypothetical immunosuppression therapy in an international cohort of adults with IgAN. Two decision rules for treatment were applied based on proteinuria of 1g or more/day or predicted risk from the Prediction Tool above a threshold probability. An appropriate decision was defined as immunosuppression allocated to patients experiencing the primary outcome (50% decline in eGFR or ESKD) and withheld otherwise. The net benefit and net reduction in treatment are the proportion of patients appropriately allocated to receive or withhold immunosuppression, adjusted for the harm from inappropriate decisions, calculated for all threshold probabilities from 0-100%. Of 3299 patients followed for 5.1 years, 522 (15.8%) experienced the primary outcome. Treatment allocation based solely on proteinuria of 1g or more/day had a negative net benefit (was harmful) because immunosuppression was increasingly allocated to patients without progressive disease. Compared to using proteinuria, treatment allocation using the Prediction Tool had a larger net benefit up to 23.4% (95% confidence interval 21.5-25.2%) and a larger net reduction in treatment up to 35.1% (32.3-37.8%). Thus, allocation of immunosuppression to high-risk patients with IgAN can be substantially improved using the Prediction Tool compared to using proteinuria.

Background and Aims A relative reduction in proteinuria has been proposed as a surrogate outcome for therapeutic trials in IgA nephropathy. It is currently unknown how long a reduction in proteinuria needs to be maintained in order to mitigate the long-term risk of disease progression. To address this knowledge gap we sought to quantify the association between duration of proteinuria remission and the risk of disease progression in IgA nephropathy. Method In this retrospective multi-ethnic international cohort of adult patients with biopsy-proven IgA nephropathy, we defined proteinuria remission based on three criteria: (i) peak proteinuria on/after biopsy ≥1g/day; (ii) an absolute reduction in proteinuria to Results A total of 1864 patients met criteria for remission, which occurred a median of 8.3 months after biopsy (IQR 3.6-22). They had a median age of 36.8 (IQR 29.4-46.6) years and a median eGFR of 78 (IQR 55-104) mL/min/1.73m2. Median proteinuria was 1.54 (IQR 1.09-2.4) g/day at the time of biopsy and 0.55 (IQR 0.33-0.76) g/day at the time of entering remission. During a median follow-up of 3.9 years, 274 patients (14.7%) experienced the primary outcome. The relationship between duration of proteinuria remission and the primary outcome was non-linear (Figure). Each 3 months in sustained remission up to 51 months was associated with an additional 9% reduction in the risk of disease progression (hazard ratio 0.91, 95% confidence interval 0.89-0.93). In contrast, each additional 3 months in remission beyond 51 months was associated with a smaller non-significant risk reduction (hazard ratio 0.99, 95% confidence interval 0.96-1.03). These finding were robust to multivariable adjustment and were consistent across subgroups based on the MEST histology score, and whether or not the remission occurred while on renin-angiotensin-aldosterone-system blockade or after immunosuppression treatment. Results were similar when relapse was defined as either a 50% or 100% increase in proteinuria from the nadir value after remission to an absolute value of ≥1g/day. Conclusion We observed a strong non-linear dose-response relationship between the duration of proteinuria remission and the risk of disease progression in patients with IgA nephropathy. The ability to quantitate the renal survival benefit related to the duration of remission is an important advance for patients and their physicians. Rather than there being a minimum duration of proteinuria remission in IgA nephropathy, our results demonstrate that even short durations in remission, or small increases in remission duration, are both associated with significant reductions in the risk of disease progression. For future therapeutic trials in IgA nephropathy using proteinuria as a surrogate outcome, our findings illustrate the need to consider the duration of proteinuria reduction, in addition to the magnitude of proteinuria reduction, when evaluating the anticipated treatment effect on long-term clinical endpoints.

Background and Aims IgA nephropathy (IgAN) is the most common primary chronic glomerulonephritis and a major cause of end-stage kidney disease worldwide. Recently, novel biomarkers including aberrantly glycosylated IgA1 and the glycan-specific antibodies can be measured and will predict the IgAN. However, little is known about the cost-effectiveness of this screening method from the societal perspective. This is the cost analysis of additional novel biomarkers to the conventional IgAN screening strategy. Method Cost analysis was carried out to compare the two diagnostic strategies with or without biomarkers. We developed an analytical decision model to estimate the lifetime medical expense of each strategy. The decision tree was started at forty years old with first time hematuria, and simulated the clinical strategy after the screening using the novel biomarkers (Group N: N), and conventional strategy (Group C: C). The result of the analysis is presented as the lifetime medical expenses from societal perspective. Discount was not considered. Results Lifetime medical expenses per person during forty years were calculated as 31.6 million JPY (≈287,270 USD) for using the novel biomarkers, 33.9 million JPY (≈307,903 USD) for conventional strategy. They were lower by 2.3 million JPY (≈20,633 USD) in Group N. Moreover, by using the novel biomarkers, the expected value of IgAN led to increase by 5.67 percent points (N: 48.44%, C: 42.77%), and the expected value of the dialysis led to decrease by 0.85 percent points (N: 19.91%, C: 19.06%). One-way sensitive analysis showed that the prevalence of IgAN was the most influential variable. In the sensitivity analysis, the rate of tonsillectomy with steroid pulse therapy and achieved clinical remission was higher, the expected lifetime expenses were reduced by 3.3 million JPY (≈30,355 USD) and the expected value of the dialysis led to decrease by 1.76 percent points (N: 11.80%, C: 13.56%). Conclusion Screening for IgAN using novel biomarkers is expected to reduce the lifetime medical expenses.

Steroid pulse therapy with tonsillectomy is known as a major treatment for IgA nephropathy (IgAN). However, its protocol was different among institutions and the effects of varying the number of steroid pulses remain unclear. From a total of 1,174 IgAN patients in a multicenter retrospective cohort analysis in Japan, 195 patients were treated by tonsillectomy combined with corticosteroid. They were divided into four groups based on the number of administered steroid pulses from 0 to three (TSP0-3), and remission of urinary abnormalities and renal survival until 1.5-fold increase in serum creatinine level from baseline were analyzed among the four groups and between TSP1 and TSP3. Among the four groups, renal function was relatively good when the estimated glomerular filtration rate was approximately 80–90 mL/min/1.73m2 and proteinuria was relatively mild (

Genus Dendrobium (Orchidaceae) contains numerous species. Phylogenetic analyses based on morphological characteristics and DNA sequences indicated that this genus is divided into two major groups: Asian and Australasian clades. On the other hand, little is known about the phytochemical differences and similarities among the species in each clade. In this study, we selected 18 Dendrobium species (11 from the Asian clade and 7 from the Australasian clade) and constructed HPLC profiles, arrays composed of relative intensity of the chromatographic peaks. Next, orthogonal partial least square discriminant analysis (OPLS-DA) was applied to the profile matrix to classify Dendrobium species into the Asian and Australasian clades in order to identify the peaks that significantly contribute to the class separation. In the end, two phenanthrenes, 4,9-dimethoxyphenanthrene-2,5-diol 1 and 1,5-dimethoxyphenanthrene-2,7-diol 2, which contributed to the class separation, were isolated from the HPLC peaks. The existence of 2 was limited to the genetically related Australasian species.

Two new Erythrina alkaloid glycosides, 1 and 2, and three new diarylpropanoid glycosides 12–14 together with nine known compounds were isolated from the MeOH extracts of the seeds of Erythrina velutina. The structures and absolute configurations of these new compounds were elucidated through comprehensive spectroscopic analyses as well as experimental and calculated ECD data. The inhibitory potency of these compounds against nitric oxide production in LPS-induced RAW 264.7 cells and the cytotoxicity of these compounds against the HeLa and HL-60 human cancer cell lines were also discussed.

From the bark of Ladenbergia hexandra Klotzsch, ten triterpenoid glycosides were isolated along with five known compounds, and their structures were determined based on extensive NMR and mass spectroscopic, GC and HPLC analyses. Some triterpenoid glycosides contained 6-deoxy-D-allose or D-allose as a sugar moiety. The absolute stereochemical assignment of the sugars was determined by comparison with synthetic samples, as well as by GC and HPLC analysis.

Importance Immunoglobulin A nephropathy is a major cause of end-stage renal disease worldwide; previous methods of medical management, including use of renin-angiotensin system inhibitors and corticosteroids, remain unproven in clinical trials. Objective To investigate the possible association between tonsillectomy and outcomes in patients with IgA nephropathy. Design, Setting, and Participants This cohort study included 1065 patients with IgA nephropathy enrolled between 2002 and 2004 and divided into 2 groups, those who underwent tonsillectomy and those who did not. Initial treatments (renin-angiotensin system inhibitors or corticosteroids) within 1 year after renal biopsy were also evaluated. A 1:1 propensity score matching was performed to account for between-group differences and 153 matched pairs were obtained. Follow-up concluded January 31, 2014. Analysis was conducted between September 11, 2017, and July 31, 2018. Exposure Tonsillectomy. Main Outcomes and Measures The primary outcome was the first occurrence of a 1.5-fold increase in serum creatinine level from baseline or dialysis initiation. Secondary outcomes included additional therapy with renin-angiotensin system inhibitors or corticosteroids initiated 1 year after renal biopsy and adverse events. Results In 1065 patients (49.8% women; median [interquartile range] age, 35 [25-52] years), the mean (SD) estimated glomerular filtration rate was 76.6 (28.9) mL/min/1.73 m2and the median (interquartile range) proteinuria was 0.68 (0.29-1.30) g per day. In all, 252 patients (23.7%) underwent tonsillectomy within 1 year after renal biopsy and 813 patients (76.3%) did not undergo tonsillectomy. The primary outcome was reached by 129 patients (12.1%) during a median (interquartile range) follow-up of 5.8 (1.9-8.5) years. In matching analysis, tonsillectomy was associated with primary outcome reduction (hazard ratio, 0.34; 95% CI, 0.13-0.77;P = .009). In subgroup analyses, benefit associated with tonsillectomy was not modified by baseline characteristic differences. Those undergoing tonsillectomy required fewer additional therapies 1 year following renal biopsy (adjusted hazard ratio, 0.37; 95% CI, 0.20-0.63;P Conclusions and Relevance This study found that tonsillectomy was associated with a lower risk of renal outcomes in patients with IgA nephropathy. The potential role of tonsillectomy should be considered for preventing end-stage renal disease in patients with IgA nephropathy.

Aim Stress during the perinatal period may result in failure to thrive in the newborn. A possible preventive effect of two kampo formulae, saikokaryukotsuboreito (SRB) and hachimijiogan (HJG) on the incidence of hind-leg paraparesis and mortality in newborns, including that due to maternal cannibalism, were examined in neurotoxin-treated rats. Methods Female Wistar/ST rats treated with SRB or HJG during pregnancy and the lactation period were separated from their pups for 6 h daily and then reunited. The pups were treated daily with a neurotoxin, l-β- N -oxalyl-α,β-diaminopropionic acid (l-β-ODAP), to cause neurolathyrism-like symptoms, a motor defect leading to hind-leg paraparesis. Results Although SRB and HJG treatment in mother rats did not affect the incidence of motor defect (paraparesis) in the pups, pup mortality was greatly and significantly decreased during the treatment period in the SRB group but not in the HJG group. Conclusion SRB treatment in mother rats is effective in decreasing pup mortality mainly due to cannibalism, thus suggesting its potential for anxiety disorder during the perinatal period in humans.

Background As a counter-cluster measure to prevent the spread of the infectious novel coronavirus disease (COVID-19), an efficient system for health observation outside the hospital is urgently required. Personal health records (PHRs) are suitable for the daily management of physical conditions. Importantly, there are no major differences between the items collected by daily health observation via PHR and the observation of items related to COVID-19. Until now, observations related to COVID-19 have been performed exclusively based on disease-specific items. Therefore, we hypothesize that PHRs would be suitable as a symptom-tracking tool for COVID-19. To this end, we integrated health observation items specific to COVID-19 with an existing PHR-based app. Objective This study is conducted as a proof-of-concept study in a real-world setting to develop a PHR-based COVID-19 symptom-tracking app and to demonstrate the practical use of health observations for COVID-19 using a smartphone or tablet app integrated with PHRs. Methods We applied the PHR-based health observation app within an active epidemiological investigation conducted by Wakayama City Public Health Center. At the public health center, a list is made of individuals who have been in close contact with known infected cases (health observers). Email addresses are used by the app when a health observer sends data to the public health center. Each health observer downloads the app and installs it on their smartphone. Self-observed health data are entered daily into the app. These data are then sent via the app by email at a designated time. Localized epidemiological officers can visualize the collected data using a spreadsheet macro and, thus, monitor the health condition of all health observers. Results We used the app as part of an active epidemiological investigation executed at a public health center. During the investigation, 72 close contacts were discovered. Among them, 57 had adopted the use of the health observation app. Before the introduction of the app, all health observers would have been interviewed by telephone, a slow process that took four epidemiological officers more than 2 hours. After the introduction of the app, a single epidemiological officer can carry out health observations. The app was distributed for free beginning in early March, and by mid-May, it had been used by more than 20,280 users and 400 facilities and organizations across Japan. Currently, health observation of COVID-19 is socially recognized and has become one of the requirements for resuming social activities. Conclusions Health observation by PHRs for the purpose of improving health management can also be effectively applied as a measure against large-scale infectious diseases. Individual habits of improving awareness of personal health and the use of PHRs for daily health management are powerful armaments against the rapid spread of infectious diseases. Ultimately, similar actions may help to prevent the spread of COVID-19.

The ASTRO-H mission was designed and developed through an international collaboration of JAXA, NASA, ESA, and the CSA. It was successfully launched on February 17, 2016, and then named Hitomi. During the in-orbit verification phase, the on-board observational instruments functioned as expected. The intricate coolant and refrigeration systems for soft X-ray spectrometer (SXS, a quantum micro-calorimeter) and soft X-ray imager (SXI, an X-ray CCD) also functioned as expected. However, on March 26, 2016, operations were prematurely terminated by a series of abnormal events and mishaps triggered by the attitude control system. These errors led to a fatal event: the loss of the solar panels on the Hitomi mission. The X-ray Astronomy Recovery Mission (or, XARM) is proposed to regain the key scientific advances anticipated by the international collaboration behind Hitomi. XARM will recover this science in the shortest time possible by focusing on one of the main science goals of Hitomi,“Resolving astrophysical problems by precise high-resolution X-ray spectroscopy”.1 This decision was reached after evaluating the performance of the instruments aboard Hitomi and the mission’s initial scientific results, and considering the landscape of planned international X-ray astrophysics missions in 2020’s and 2030’s. Hitomi opened the door to high-resolution spectroscopy in the X-ray universe. It revealed a number of discrepancies between new observational results and prior theoretical predictions. Yet, the resolution pioneered by Hitomi is also the key to answering these and other fundamental questions. The high spectral resolution realized by XARM will not offer mere refinements; rather, it will enable qualitative leaps in astrophysics and plasma physics. XARM has therefore been given a broad scientific charge: “Revealing material circulation and energy transfer in cosmic plasmas and elucidating evolution of cosmic structures and objects”. To fulfill this charge, four categories of science objectives that were defined for Hitomi will also be pursued by XARM; these include (1) Structure formation of the Universe and evolution of clusters of galaxies; (2) Circulation history of baryonic matters in the Universe; (3) Transport and circulation of energy in the Universe; (4) New science with unprecedented high resolution X-ray spectroscopy. In order to achieve these scientific objectives, XARM will carry a 6 × 6 pixelized X-ray micro-calorimeter on the focal plane of an X-ray mirror assembly, and an aligned X-ray CCD camera covering the same energy band and a wider field of view. This paper introduces the science objectives, mission concept, and observing plan of XARM.

Genus Dendrobium (Orchidaceae) contains numerous species. Phylogenetic analyses based on morphological characteristics and DNA sequences indicated that this genus is divided into two major groups: Asian and Australasian clades. On the other hand, little is known about the phytochemical differences and similarities among the species in each clade. In this study, we selected 18 Dendrobium species (11 from the Asian clade and 7 from the Australasian clade) and constructed HPLC profiles, arrays composed of relative intensity of the chromatographic peaks. Next, orthogonal partial least square discriminant analysis (OPLS-DA) was applied to the profile matrix to classify Dendrobium species into the Asian and Australasian clades in order to identify the peaks that significantly contribute to the class separation. In the end, two phenanthrenes, 4,9-dimethoxyphenanthrene-2,5-diol 1 and 1,5-dimethoxyphenanthrene-2,7-diol 2, which contributed to the class separation, were isolated from the HPLC peaks. The existence of 2 was limited to the genetically related Australasian species.

Dysifragilone A, a sesquiterpene aminoquinone based on a rearranged avarone skeleton, has been previously isolated and identified from the South China Sea sponge Dysidea fragilis. In the present study, anti‑inflammatory activity and the underlying molecular mechanism of dysifragilone A were studied using the classical inflammation model of lipopolysaccharide (LPS)‑activated RAW264.7 macrophage cells and an MTT assay, Griess method, ELISA and western blotting were used. The results revealed that dysifragilone A significantly reduced the release of inflammatory mediators and inflammatory cytokines in activated RAW264.7 cells, including nitric oxide (NO), prostaglandin E2,(PGE2) and interleukin‑6 (IL‑6). The protein expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase‑2 (COX‑2), and the enzymatic activity of iNOS and COX‑2 were also inhibited by dysifragilone A in a dose dependent manner. Further mechanistic investigations suggested that the anti‑inflammatory activity of dysifragilone A results from the suppression of p38 mitogen‑activated protein kinase (MAPK) activation in LPS‑activated macrophages; however, this was not associated with inhibition of the extracellular signal‑regulated kinase (ERK) or c‑Jun N‑terminal kinase (JNK) signaling pathways. Therefore, dysifragilone A and similar compounds may be anti‑inflammatories that have potential to be used in the clinic.

Glycyrrhiza (the roots and rhizomes of licorice) has been used worldwide as both an herbal nutraceutical and herbal medicine. In addition, it is well known that Glycyrrhiza contains various compounds with biological effects, such as anti-viral, anti-inflammatory, immunoregulatory, anti-tumor and neuroprotective effects. Among the various compounds in Glycyrrhiza, the active compounds that show biological activity are thought to include glycyrrhizin, glycyrrhetinic acid, glabridin, licochalcones and liquiritin. In the present study, we investigated the biological effects of three of these compounds (glycyrrhizin, liquiritin and isoliquiritin) on B65 neuroblastoma cells derived from serotonergic neurons. Among these three compounds, only liquiritin enhanced the proliferation of B65 neuroblastoma cells. In contrast, both glycyrrhizin and isoliquiritin, particularly at high concentrations had cytotoxic effects. Cells were treated with various cytotoxic agents and liquiritin could ameliorate the cytotoxicity induced by menadione sodium bisulfate in a dose-dependent manner. We also examined the effect of liquiritin on cell survival by evaluating the expression levels of phospho-p44/42 mitogen-activated protein kinase, cyclin-related proteins and glucose-6-phosphate dehydrogenase, which produces nicotinamide adenine dinucleotide phosphate. Under treatment with liquiritin, the protein expression level of glucose-6-phosphate dehydrogenase increased in a dose-dependent manner. In contrast, the protein expression level of cyclin-related proteins did not change at all under treatment with liquiritin. These results suggest that liquiritin, which is contained in Glycyrrhiza, may enhance cell survival by increasing the protein expression level of glucose-6 phosphate dehydrogenase.

Ambuic acid is an organic acid isolated from the solid culture of Pestalotiopsis neglecta, which is an endophytic fungus that widely exists in many species of plants. Ambuic acid has been reported to exert antimicrobial activity against Gram-positive bacterium. The aim of the present study was to investigate the inhibitory effect of ambuic acid on lipopolysaccharide (LPS)-induced inflammation in RAW264.7 macrophages. The results demonstrated that ambuic acid significantly suppressed the overproduction of nitric oxide (NO) and prostaglandin E2 (PGE2) in a dose-dependent manner. Furthermore, ambuic acid also inhibited the release of the proinflammatory cytokine interleukin-6 (IL-6) however, no inhibition of the release of tumor necrosis factor-α (TNF-α) was observed. Further investigations indicated that ambuic acid downregulated the LPS-induced high expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins, as well as inhibited the enzymatic activity of iNOS and COX-2. In addition, ambuic acid suppressed the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK 1/2) and c-Jun N-terminal kinase (JNK) induced by LPS. However, ambuic acid did not inhibit the phosphorylation of p38 mitogen-activated protein kinase (MAPK), the degradation of IκB-α protein or the nuclear translocation of nuclear transcription factor-κB (NF-κB) p65 subunit. These results suggested that ambuic acid may exert anti-inflammatory action by blocking the activation of the ERK/JNK MAPK signaling pathway, without the involvement of the p38 MAPK or NF-κB signaling pathways.

Background The primary abnormal manifestation in immunoglobulin A nephropathy (IgAN) is recurring bouts of hematuria with or without proteinuria. Although immunohistochemical analysis of renal biopsy tissue remains the gold standard not only for diagnosis but also for evaluating the activity of IgAN, new sensitive and reasonably specific noninvasive tests are emerging to guide therapeutic strategy applicable to all stages of IgAN. The present study examined serum levels of galactose-deficient IgA1 (Gd-IgA1) and its immune complex (IgA/IgG-IC) as noninvasive markers for the disease activity. Methods We enrolled 50 IgAN patients (male 40 %, median age 37 years) showing complete or partial clinical remission after steroid pulse therapy with tonsillectomy (TSP) whose clinical data and serum could be followed up for 3–5 years. Results Cross-sectional analysis revealed that the degree of hematuria and proteinuria were significantly associated with levels of Gd-IgA1 and levels of IgA/IgG-IC. Longitudinal analysis further showed that from the group of 44 patients with heavy hematuria before TSP, 31 patients showed complete disappearance of hematuria (group A), but the remaining patients did not (group B). Although the levels of Gd-IgA1 and IgA/IgG-IC in the two groups before TSP were similar, percentage decrease of Gd-IgA1 and IgA/IgG-IC levels in group A was significantly higher than in group B. Conclusion Disease activity of IgAN assessed by hematuria and proteinuria correlated with serum levels and changes of Gd-IgA1 and IgA/IgG-IC. These new noninvasive disease activity markers can be useful for future activity scoring system and guiding therapeutic approaches.

Five new furanocassane-type diterpenoids, sucupiranins M–Q (1–5) were isolated from the seeds of Bowdichia virgilioides. Their structures and stereo chemistries were elucidated on the basis of spectroscopic analyses including HRESIMS, 2D NMR (1H-1H COSY, HSQC, HMBC, and NOESY), and ECD spectra.

A compound library, which consists of 75 natural β-carboline-type or canthinone-type alkaloids from Simaroubaceae plants and their chemical synthetic analogues, was screened for the anti-inflammatory activity by inhibition of the overproduction of inflammatory mediator nitric oxide (NO) in lipopolysaccharide (LPS)-activated RAW 264.7 macrophage cells. Six compounds, namely, benzalharman (23), kumujian (27), 1-ethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (37), 1-acetophenone-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (42), cathin-6-one (46), and 9-methoxy-cathin-6-one (57), exhibited significant inhibitory activity on the overproduction of NO with good dose dependency. Further investigation demonstrated that all of the six compounds down-regulated the high expression of inducible nitric oxide synthase (iNOS) protein. Among them, two canthinone-type alkaloids (46 and 57) potently down-regulated cyclooxygenase-2 (COX-2) protein expression in a dose-dependent manner and also inhibited the overproduction of inflammatory mediator prostaglandin E2 (PGE2). However, the β-carboline-type alkaloids (23, 27, 37, and 42) exhibited no obvious inhibition on the overproduction of PGE2 and the expression of COX-2 protein. The results suggested that β-carboline-type alkaloids and canthinone-type alkaloids may exert an anti-inflammatory effect through different mechanism.

Summary Clostridium scindens biotransforms primary bile acids into secondary bile acids, and is correlated with inhibition of Clostridium difficile growth in vivo. The aim of the current study was to determine how C. scindens regulates C. difficile growth in vitro and if these interactions might relate to the regulation of gut microbiome structure in vivo. The bile acid 7α-dehydroxylating gut bacteria, C. scindens and C. sordellii, were found to secrete the tryptophan-derived antibiotics, 1-acetyl-β-carboline and turbomycin A, respectively. Both antibiotics inhibited growth of C. difficile and other gut bacteria. The secondary bile acids, deoxycholic acid and lithocholic acid, but not cholic acid, enhanced the inhibitory activity of these antibiotics. These antibiotics appear to inhibit cell division of C. difficile. The results help explain how endogenously synthesized antibiotics and secondary bile acids may regulate C. difficile growth and the structure of the gut microbiome in health and disease.

We investigated the anti-obesity effect of the aerial part of Artemisia scoparia Waldst. et Kit. (Compositae). An 80 % aqueous EtOH extract of the aerial part inhibited triglyceride (TG) accumulation and the nitric oxide (NO) production activity. A new chromane derivative was isolated from the aerial part of A. scoparia Waldst. et Kit. along with 18 known compounds. The structure of the new chromane, scopariachromane (1), was elucidated by spectroscopic analyses. The inhibitory effects of the compounds on TG accumulation activity were examined. Among these, cirsiliol (11) inhibited TG accumulation in 3T3-L1 preadipocytes. Jaceosidin (12) inhibited NO production in a murine macrophage-like cell line (RAW 264.7). These results indicate that the 80 % aqueous EtOH extract and compounds isolated from the aerial part of A. scoparia Waldst. et Kit. may improve obesity-related insulin resistance.