A Pragmatic Method to Integrate Data From Preexisting Cohort Studies Using the Clinical Data Interchange Standards Consortium (CDISC) Study Data Tabulation Model: Case Study.

Background: In recent years, many researchers have focused on the use of legacy data, such as pooled analyses that collect and reanalyze data from multiple studies. However, the methodology for the integration of preexisting 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: This study aimed to design a practical model for integrating preexisting databases using the CDISC SDTM. Methods: Data integration was performed in three phases: (1) the confirmation of the variables, (2) SDTM mapping, and (3) the generation of the SDTM data. In phase 1, the definitions of the variables in detail were confirmed, and the data sets were converted to a vertical structure. 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 Research Electronic Data Capture (REDCap) field annotation. In phase 3, the data dictionary, including the SDTM metadata, was outputted in the Operational Data Model (ODM) format. Finally, the mapped SDTM data were generated using REDCap2SDTM version 2. Results: SDTM data were generated as a comma-separated values file for each of the 7 domains defined in the metadata. A total of 17 items were commonly mapped to 3 databases. Because the SDTM data were set in each database correctly, we were able to integrate 3 independently preexisting databases into 1 database in the CDISC SDTM format. Conclusions: Our project suggests that the CDISC SDTM is useful for integrating multiple preexisting databases.

A Pragmatic Method to Integrate Data from Pre-existing Cohort Studies using the Clinical Data Interchange Standards Consortium (CDISC) Study Data Tabulation Model: Practical use of REDCap2SDTM.

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.

BMP4-SMAD1/5/9-RUNX2 pathway activation inhibits neurogenesis and oligodendrogenesis in Alzheimer's patients' iPSCs in senescence-related conditions.

In addition to increasing ß-amyloid plaque deposition and tau tangle formation, inhibition of neurogenesis has recently been observed in Alzheimer's disease (AD). This study generated a cellular model that recapitulated neurogenesis defects observed in patients with AD, using induced pluripotent stem cell lines derived from sporadic and familial AD (AD iPSCs). AD iPSCs exhibited impaired neuron and oligodendrocyte generation when expression of several senescence markers was induced. Compound screening using these cellular models identified three drugs able to restore neurogenesis, and extensive morphological quantification revealed cell-line- and drug-type-dependent neuronal generation. We also found involvement of elevated Sma- and Mad-related protein 1/5/9 (SMAD1/5/9) phosphorylation and greater Runt-related transcription factor 2 (RUNX2) expression in neurogenesis defects in AD. Moreover, BMP4 was elevated in AD iPSC medium during neural differentiation and cerebrospinal fluid of patients with AD, suggesting a BMP4-SMAD1/5/9-RUNX2 signaling pathway contribution to neurogenesis defects in AD under senescence-related conditions.

Association between 3-Year Repetitive Isolated Hematuria and eGFR Deterioration in an Apparently Healthy Population: A Retrospective Cohort Study.

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.

Identification of High-Risk Groups in Urinalysis: Lessons from the Longitudinal Analysis of Annual Check-Ups.

BACKGROUND: For effective screening in urinalysis, information on high-risk groups is needed; however, there is a lack of evidence in young adults in particular. The aim of this study was to provide information on urinalysis in young adults and to identify high-risk groups of urinalyses using multi-year data obtained from annual large-scale check-ups. METHOD: We used annual health check-up data collected from 2011 to 2016 at Kyoto University in Japan. Eligible participants were those aged 18-39 years who underwent annual health check-ups for four consecutive years between 2011 and 2016. We conducted descriptive analyses and calculated the risk ratios (RRs) for urinary abnormalities in the fourth year of urinalysis. RESULTS: In total, 13,640 participants (10,877 men, 79.7%) met the eligibility criteria. The mean prevalence rates of proteinuria, haematuria and glucosuria were 1.61% (men: 1.63%; women: 1.53%), 1.48% (men: 0.53%; women: 5.22%) and 0.46% (men: 0.52%; women: 0.25%), respectively. Participants with urinary abnormalities at least once in the initial 3 years had a higher risk of urinary abnormalities in the fourth year than participants with no abnormal findings in the initial 3 years; the risk ratios (RRs) of proteinuria, haematuria and glucosuria were 3.5 (95% confidence interval (CI) = 3.2-3.7), 12.2 (95% CI = 11.7-12.7) and 42.6 (95% CI = 37.7-48.1), respectively. The RRs of all urinary abnormalities in the fourth year increased as the frequency of urinary abnormalities over the preceding 3 years increased. In haematuria, differences of the RR were observed between men and women. CONCLUSION: We clarified the prevalence of urinary abnormalities in young adults and high-risk groups of urinary abnormalities. Our findings support the need for multi-year annual urinalysis.

Cost Analysis of Screening for IgA Nephropathy Using Novel Biomarkers.

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.

The association between depressive symptoms and self-rated health among university students: a cross-sectional study in France and Japan.

BACKGROUND: Depressive 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. METHODS: A cross-sectional study was conducted by using two large cohorts of students aged ≥18 years (n = 5655 in Bordeaux, France and n = 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. RESULTS: A 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 < 0.001), it was similar in Japanese students (males 3.5%, females 3.3%, 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). CONCLUSIONS: Depressive 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.

Unusual Proliferative Glomerulonephritis in a Patient Diagnosed to Have Hypoparathyroidism, Sensorineural Deafness, and Renal Dysplasia (HDR) Syndrome with a Novel Mutation in the GATA3 Gene.

Hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome is a rare autosomal dominant disease caused by GATA3 mutations. Although several cases with variable renal features have been reported, the presence of histological changes within the glomeruli in adult patients is unclear. We herein report an adult case of HDR syndrome with a novel p.C288W (TGC>TGG) missense mutation in GATA3. His renal histology showed a membranoproliferative glomerulonephritis-like glomerular lesion. Additional renal histological analyses of HDR syndrome patients will be needed to clarify the role of GATA3 in both the developing and adult kidney.

Hematopoietic Stem Cell Transplantation Nephropathy Associated with Chronic Graft-versus-Host Disease without Extrarenal Involvement.

A 30-year-old woman with myelodysplastic syndrome underwent allogeneic hematopoietic stem cell transplantation (HSCT) derived from her HLA-matched sister six years previously. She received preconditioning total body irradiation with renal shielding and was subsequently administered cyclosporin A (CyA) as prophylaxis against graft-versus-host disease (GVHD). Four months after HSCT, asymptomatic proteinuria and glomerular hematuria developed during CyA tapering without obvious extrarenal involvements of GVHD, and persisted for six years. A renal biopsy revealed endothelial injury in the glomeruli, and the deposition of C4d was detected diffusely on glomerular capillaries and focally on peritubular capillaries, suggesting that nephropathy involved antibody- or complement-associated immune reactions.

The COUP-TFII/Neuropilin-2 is a molecular switch steering diencephalon-derived GABAergic neurons in the developing mouse brain.

The preoptic area (POa) of the rostral diencephalon supplies the neocortex and the amygdala with GABAergic neurons in the developing mouse brain. However, the molecular mechanisms that determine the pathway and destinations of POa-derived neurons have not yet been identified. Here we show that Chicken ovalbumin upstream promoter transcription factor II (COUP-TFII)-induced expression of Neuropilin-2 (Nrp2) and its down-regulation control the destination of POa-derived GABAergic neurons. Initially, a majority of the POa-derived migrating neurons express COUP-TFII and form a caudal migratory stream toward the caudal subpallium. When a subpopulation of cells steers toward the neocortex, they exhibit decreased expression of COUP-TFII and Nrp2. The present findings show that suppression of COUP-TFII/Nrp2 changed the destination of the cells into the neocortex, whereas overexpression of COUP-TFII/Nrp2 caused cells to end up in the medial part of the amygdala. Taken together, these results reveal that COUP-TFII/Nrp2 is a molecular switch determining the pathway and destination of migrating GABAergic neurons born in the POa.

Reoperation after mitral valve repair in viewpoints of kidney injury as well as hemolytic anemia.

A 70-year-old woman developed anemia and kidney injury 10 months after mitral valve (MV) repair. Serological findings and Doppler echocardiography suggested hemolytic anemia due to mitral regurgitation jet collision with an annuloplasty ring (MRCR). Since kidney injury persisted even without exacerbation of anemia over 10 months, we performed an MV replacement. The anemia improved rapidly after the surgery; however, the renal function remained chronic kidney disease (CKD) after reoperation. Kidney injury was thought to be due to iron deposition and decreased renal perfusion that caused tubular injury. A comprehensive literature review shows that hemolysis due to MRCR in the early postoperative phase (within 3 postoperative months) can be often ameliorated with endothelialization without the need for reoperation; however, hemolysis in the late postoperative phase can persist even for a long period without reoperation. Chronic hemolysis can lead to kidney injury and progress to CKD even without clinical evidence of exacerbation of anemia. Therefore, in cases of late postoperative phase hemolysis, reoperation should be considered for better management of kidney injury and hemolytic anemia.

A new spiroindene pigment from the medicinal fungus Phellinus ribis.

A new spiroindene pigment, phelliribsin A, was isolated from the medicinal fungus Phellinus ribis, and its structure was determined by two dimensional (2D)-NMR methods. Phelliribsin A is an unprecedented spiroindene compound, and was found to have cytotoxic activity against PC12 cells at a concentration of 30 µM.

Association of a novel in-frame deletion mutation of the MYH9 gene with end-stage renal failure: case report and review of the literature.

MYH9 disorders are autosomal dominant diseases characterized by giant platelets, thrombocytopenia, and granulocyte inclusion bodies. These diseases are caused by mutations in the MYH9 gene that encodes nonmuscle myosin heavy chain IIA. We describe the case of a 27-year-old male who presented with macrothrombocytopenia and leukocyte inclusion bodies. Chronic kidney disease, probably due to progressive glomerulosclerosis, and high-tone sensorineural deafness were evident. Although deterioration of renal function necessitated renal replacement therapy in the form of peritoneal dialysis, we reconsidered the etiology of the kidney disease due to the patient's clinical history. We identified an in-frame deletion mutation in exon 24 of the MYH9 gene that resulted in the removal of 21 nucleotides. The patient was diagnosed with an MYH9 disorder. We report this novel abnormality of the nucleotide sequence and compare it with previous cases and their associated phenotypes.

A Japanese Family Suffering from Familial Juvenile Hyperuricemic Nephropathy due to a Rare Mutation of the Uromodulin Gene.

We report the case of a Japanese family suffering from familial juvenile hyperuricemic nephropathy (FJHN) due to a rare missense mutation of the uromodulin (UMOD) gene. An 18-year-old male presented with gout, hyperuricemia, and stage 3 chronic kidney disease. Mostly, FJHN is caused by a mutation altering the cystine residue of UMOD/Tamm-Horsfall protein. However, in the present case, a T688C mutation was identified in exon 4, resulting in amino acid substitution with arginine replacing tryptophan at position 230 (Trp230Arg). This mutation was also found in his brother and father with the same phenotype, indicating autosomal dominant inheritance. The affected amino acid was conserved in 200 healthy Japanese controls. Therefore, mutation T688C most likely causes rare structural and/or functional abnormalities in UMOD/Tamm-Horsfall protein.

Peritoneal mesothelial cells as a target of local aldosterone action: upregulation of connective tissue growth factor expression via serum- and glucocorticoid-inducible protein kinase 1.

BACKGROUND/AIMS: Peritoneal fibrosis can lead to the discontinuation of continuous ambulatory peritoneal dialysis. The present study investigated the direct effect of aldosterone, which influences tissue fibrosis, and its cellular mechanism using cultured rat peritoneal mesothelial cells (RPMCs). MATERIALS AND METHODS: The expression of aldosterone synthase (CYP11B2), mineralocorticoid receptors, 11beta-hydroxysteroid dehydrogenase 2, serum- and glucocorticoid-inducible protein kinase 1 (SGK1) and connective tissue growth factor (CTGF) was evaluated using reverse transcriptase-polymerase chain reaction and Western blot. The ability of RPMCs to produce aldosterone was examined by enzyme immunoassay. Small interfering RNA of SGK1 was transfected to determine the role of SGK1. RESULTS: CYP11B2, mineralocorticoid receptors and 11beta-hydroxysteroid dehydrogenase 2 were expressed in RPMCs. The release of aldosterone from RPMCs into the culture medium was confirmed. Stimulation of RPMCs with the addition of aldosterone significantly increased SGK1 expression and phosphorylation and CTGF upregulation, and these effects were completely inhibited by the mineralocorticoid receptor antagonist spironolactone. SGK1 gene silencing abrogated aldosterone-induced CTGF expression. CONCLUSION: The local aldosterone system exists and acts directly as a profibrotic factor in the peritoneal mesothelium.

Expression of Sema3D in subsets of neurons in the developing dorsal root ganglia of the rat.

We investigated the expression of the semaphorin family member, Sema3D, in the developing dorsal root ganglia of the rat. Sema3D expression was observed in a subpopulation of dorsal root ganglion (DRG) neurons. The expression peaked at E15 and thereafter it declined. The change in Sema3D expression between E13 and E20 was analyzed by comparison to the expression of TrkA, TrkC and Neuropilin-1 by in situ hybridization. The expression pattern of Sema3D in DRG was similar to that of TrkC and was different from that of TrkA or Neuropilin-1. Double immunohistochemical analysis revealed that Sema3D expression was confined to neurons that expressed TrkC and Runx3, which mediate proprioception, but not to nociceptive neurons that express TrkA. Functionally distinct DRG neurons have different projection patterns in the spinal cord, therefore, Sema3D may regulate the axonal navigation of the large diameter DRG neurons.

Identification and tissue-specific expression of a novel isoform of Semaphorin 3D.

BACKGROUND: Semaphorins are a family of secreted and membrane-associated proteins involved in axon guidance in the developing brain as well as morphogenesis in various organs. There has been no report on the expression of different transcripts of the genes encoding Class 3 Semaphorins with different protein structures. METHODS: Molecular cloning of rat Semaphorin 3D gene and the expression analysis at gene and protein levels were performed. RESULTS: We have isolated two cDNAs encoding rat Sema 3D, a Class 3 Semaphorin. One clone is predicted to encode a protein with a structure common to Class 3 Semaphorins. The other clone encodes a novel isoform of Sema 3D lacking half of the C2-type Ig domain and the entire basic region; this isoform is predicted to have a different structure from Class 3 Semaphorins. Analysis of protein expression using a cell culture system revealed that this splice variant isoform is not secreted into the media, whereas the classical Class 3 isoform is a secreted protein. The expression of each isoform shows tissue-specificity. GENERAL SIGNIFICANCE: Our present findings suggest that gene regulation, via an alternative splicing mechanism, affects not only the tissue-specificity of Sema 3D expression, but also the distance over which it can act.

SUMO-1 immunoreactivity co-localizes with phospho-Tau in APP transgenic mice but not in mutant Tau transgenic mice.

Sumoylation is a post-translational modification process that is supposed to be implicated in the pathogenesis of several neurodegenerative diseases. Recently, the microtubule-associated protein Tau was identified as a target for sumoylation in the analysis of the transfected cells. We investigated the localization of SUMO-1 protein in APP transgenic mice and mutant Tau transgenic mice, and found that SUMO-1 immunoreactivity was co-localized with phosphorylated Tau aggregates in amyloid plaques of APP transgenic mice. By contrast, no SUMO-1 immunoreactivity was observed in phosphorylated Tau aggregates of mutant Tau transgenic mice. The contribution of sumoylation to the neurodegeneration in Alzheimer's disease will be further elucidated via the analysis of APP transgenics.