HIF3A gene disruption causes abnormal alveoli structure and early neonatal death.

Transcriptional response to changes in oxygen concentration is mainly controlled by hypoxia-inducible transcription factors (HIFs). Besides regulation of hypoxia-responsible gene expression, HIF-3α has recently been shown to be involved in lung development and in the metabolic process of fat tissue. However, the precise mechanism for such properties of HIF-3α is still largely unknown. To this end, we generated HIF3A gene-disrupted mice by means of genome editing technology to explore the pleiotropic role of HIF-3α in development and physiology. We obtained adult mice carrying homozygous HIF3A gene mutations with comparable body weight and height to wild-type mice. However, the number of litters and ratio of homozygous mutation carriers born from the mating between homozygous mutant mice was lower than expected due to sporadic deaths on postnatal day 1. HIF3A gene-disrupted mice exhibited abnormal configuration of the lung such as a reduced number of alveoli and thickened alveolar walls. Transcriptome analysis showed, as well as genes associated with lung development, an upregulation of stearoyl-Coenzyme A desaturase 1, a pivotal enzyme for fatty acid metabolism. Analysis of fatty acid composition in the lung employing gas chromatography indicated an elevation in palmitoleic acid and a reduction in oleic acid, suggesting an imbalance in distribution of fatty acid, a constituent of lung surfactant. Accordingly, administration of glucocorticoid injections during pregnancy resulted in a restoration of normal alveolar counts and a decrease in neonatal mortality. In conclusion, these observations provide novel insights into a pivotal role of HIF-3α in the preservation of critically important structure and function of alveoli beyond the regulation of hypoxia-mediated gene expression.

[The Metaverse: A New Frontier for Healthcare].

We discuss leveraging a cutting-edge technology known as the Metaverse to tackle healthcare challenges, with a particular focus on enhancing patient satisfaction and improving working conditions for medical professionals. We plan to achieve this by improving real-digital collaboration and utilizing the advantages of the Metaverse, such as novel communication and experiences and increased work efficiency and quality. This article showcases several concrete examples of Metaverse services in the medical field, as demonstrated by the "Medical Metaverse Joint Research Course" established through a collaboration between IBM and Juntendo University, and also highlights possible future prospects.

Clinical application of artificial intelligence algorithm for prediction of one-year mortality in heart failure patients.

Risk prediction for heart failure (HF) using machine learning methods (MLM) has not yet been established at practical application levels in clinical settings. This study aimed to create a new risk prediction model for HF with a minimum number of predictor variables using MLM. We used two datasets of hospitalized HF patients: retrospective data for creating the model and prospectively registered data for model validation. Critical clinical events (CCEs) were defined as death or LV assist device implantation within 1 year from the discharge date. We randomly divided the retrospective data into training and testing datasets and created a risk prediction model based on the training dataset (MLM-risk model). The prediction model was validated using both the testing dataset and the prospectively registered data. Finally, we compared predictive power with published conventional risk models. In the patients with HF (n = 987), CCEs occurred in 142 patients. In the testing dataset, the substantial predictive power of the MLM-risk model was obtained (AUC = 0.87). We generated the model using 15 variables. Our MLM-risk model showed superior predictive power in the prospective study compared to conventional risk models such as the Seattle Heart Failure Model (c-statistics: 0.86 vs. 0.68, p < 0.05). Notably, the model with an input variable number (n = 5) has comparable predictive power for CCE with the model (variable number = 15). This study developed and validated a model with minimized variables to predict mortality more accurately in patients with HF, using a MLM, than the existing risk scores.

U2AF - Hypoxia-induced fas alternative splicing regulator.

The splicing machinery heavily contributes to biological complexity and especially to the ability of cells to adapt to altered cellular conditions. Hypoxia also plays a key role in the pathophysiology of many disease states. Recent studies have revealed that tumorigenesis and hypoxia are involved in large-scale alterations in alternative pre-mRNA splicing. Fas pre-mRNA is alternatively spliced by excluding exon 6 to produce soluble Fas (sFas) protein that lacks a transmembrane domain and acts by inhibiting Fas mediated apoptosis. In the present study we show that U2AF is involved in hypoxia dependent anti-apoptotic Fas mRNA isoform formation. Our performed studies show that U2AF-RNA interaction is reduced in hypoxic cells, leading to reduction of Fas and increased sFas mRNAs formation. Efficient U2AF-RNA interactions of both subunits are important for Fas exon 6 inclusion into forming mRNA in normoxic and hypoxic cells.

A Low-Carbohydrate Diet Improves Glucose Metabolism in Lean Insulinopenic Akita Mice Along With Sodium-Glucose Cotransporter 2 Inhibitor.

Objective: A low-carbohydrate diet (LC) can be beneficial to obese subjects with type2 diabetes mellitus (T2DM). Sodium-glucose cotransporter 2 inhibitor (SGLT2i) presents prompt glucose-lowering effects in subjects with T2DM. We investigated how LC and SGLT2i could similarly or differently influence on the metabolic changes, including glucose, lipid, and ketone metabolism in lean insulinopenic Akita mice. We also examined the impacts of the combination. Methods: Male Akita mice were fed ad libitum normal-carbohydrate diet (NC) as a control or low-carbohydrate diet (LC) as an intervention for 8 weeks with or without SGLT2i treatment. Body weight and casual bold glucose levels were monitored during the study, in addition to measuring TG, NEFA, and ketone levels. We quantified gene expressions involved in gluconeogenesis, lipid metabolism and ketogenesis in the liver and the kidney. We also investigated the immunostaining analysis of pancreatic islets to assess the effect of islet protection. Results: Both LC and SGLT2i treatment reduced chronic hyperglycemia. Moreover, the combination therapy additionally ameliorated glycemic levels and preserved the islet morphology in part. LC but not SGLT2i increased body weight accompanied by epididymal fat accumulation. In contrast, SGLT2i, not LC potentiated four-fold ketone production with higher ketogenic gene expression, in comparison with the non-treated Akita mice. Besides, the combination did not enhance further ketone production compared to the SGLT2i alone. Conclusions: Our results indicated that both LC and SGLT2i reduced chronic hyperglycemia, and the combination presented synergistic favorable effects concomitantly with amelioration of islet morphology, while the combination did not enhance further ketosis in Akita mice.

Structure of cortical network activity across natural wake and sleep states in mice.

Cortical neurons fire intermittently and synchronously during non-rapid eye movement sleep (NREMS), in which active and silent periods are referred to as ON and OFF periods, respectively. Neuronal firing rates during ON periods (NREMS-ON-activity) are similar to those of wakefulness (W-activity), raising the possibility that NREMS-ON neuronal-activity is fragmented W-activity. To test this, we investigated the patterning and organization of cortical spike trains and of spike ensembles in neuronal networks using extracellular recordings in mice. Firing rates of neurons during NREMS-ON and W were similar, but showed enhanced bursting in NREMS with no apparent preference in occurrence, relative to the beginning or end of the on-state. Additionally, there was an overall increase in the randomness of occurrence of sequences comprised of multi-neuron ensembles in NREMS recorded from tetrodes. In association with increased burst firing, somatic calcium transients were increased in NREMS. The increased calcium transients associated with bursting during NREM may activate calcium-dependent, cell-signaling pathways for sleep related cellular processes.

Physiological Signature of Memory Age in the Prefrontal-Hippocampal Circuit.

The long-term storage of episodic memory requires communication between prefrontal cortex and hippocampus. However, how consolidation alters dynamic interactions between these regions during subsequent recall remains unexplored. Here we perform simultaneous electrophysiological recordings from anterior cingulate cortex (ACC) and hippocampal CA1 in mice during recall of recent and remote contextual fear memory. We find that, in contrast to recent memory, remote memory recall is accompanied by increased ACC-CA1 synchronization at multiple frequency bands. The augmented ACC-CA1 interaction is associated with strengthened coupling among distally spaced CA1 neurons, suggesting an ACC-driven organization of a sparse code. This robust shift in physiology permits a support vector machine classifier to accurately determine memory age on the basis of the ACC-CA1 synchronization pattern. Our findings reveal that memory consolidation alters the dynamic coupling of the prefrontal-hippocampal circuit and results in a physiological signature of memory age.

Unusual manifestations of giant cell arteritis and granulomatosis with polyangiitis.

Giant cell arteritis (GCA) is a type of large vessel vasculitis, and it involves the aorta, large vessels and terminal branches of the external carotid artery, especially the temporal artery. Temporal artery biopsy is a simple tool for the diagnosis of vasculitis, however, the histopathological findings do not always differentiate between the small-vessel vasculitis and GCA. We report the case of 72-year-old male who initially had a clinical diagnosis of GCA, then in the course of treatment, diagnostic histopathological approach revealed the necrotizing vasculitis with bronchocentric granulomatosis in the inflammatory nodule of the lung. The manifestations of patients with systemic vasculitis represent the disorders of multiple organ systems thus are diverse and may vary through the course of the disease. Presentation of unexpected features such as insufficient response to antibiotics, sinusitis, runny nose, discomfort of frontal region or pachymeningitis which anticipates re-evaluation of systemic vasculitis that may lead us to an appropriate diagnosis and the treatment.

Impacts of Diabetes and an SGLT2 Inhibitor on the Glomerular Number and Volume in db/db Mice, as Estimated by Synchrotron Radiation Micro-CT at SPring-8.

BACKGROUND: Recent large-scale clinical studies demonstrate that sodium-glucose cotransporter 2 (SGLT2) inhibitors protect the diabetic kidney. However, clinical and animal studies have not shown the changes of the total glomeruli in the whole kidney treated with SGLT2 inhibitors. METHODS: We performed computed tomography (CT) imaging on mice using synchrotron radiation to investigate the impact of luseogliflozin, a SGLT2 inhibitor, on the number and volume of glomeruli in the whole kidney. FINDINGS: We did not observe a significant difference in the total glomerular number (Nglom) among mice. Luseogliflozin redistributed the number of glomeruli in different regions, accompanied by the normalization of diabetes-augmented renal volume (Vkidney). Diabetic db/db mice had a larger glomerular volume in the mid-cortex than did control db/m mice, and luseogliflozin increased the glomerular volume in all renal cortical zones of the whole kidney in db/db mice. According to the multivariate regression analysis, hemoglobin A1c level was the most relevant determinant of Vkidney, not Nglom or mean glomerular volume (Vglom), indicating that hyperglycemia induced renal (tubular) hypertrophy, but not glomerular enlargement. Luseogliflozin increased hypoxia in the juxtamedullary region, sustained upregulated renal renin expression and plasma renin activity, and failed to decrease albuminuria by downregulating megalin in db/db mice. INTERPRETATION: Based on our findings, SGLT2 inhibitors may alter glomerular distribution and size in addition to their glucose-lowering effects, presumably by affecting oxygen metabolism and humoral factors. FUND: Funding for this research was provided by The Japan Society for the Promotion of Science, the Japan Diabetes Foundation, and Asahikawa Medical University.

Takayasu's arteritis associated with eosinophilic gastroenteritis, possibly via the overactivation of Th17.

BACKGROUND: Takayasu's arteritis (TA) is a large-vessel vasculitis pathologically characterized by granulomatous necrotizing vasculitis with giant cells. Although the cause of TA is still unclear, genetic factors as well as immunological abnormalities, particularly the overactivation of Th1 and Th-17, are considered to play important roles in the pathogenesis of this disease. Eosinophilic gastroenteritis (EGE) is a type of refractory inflammation in which numerous eosinophils infiltrate the inflammatory area. It is known that the overactivation of Th2 is associated with the pathogenesis of EGE, although the cause of EGE is still unclear. The immunological abnormalities in TA are therefore thought to be different from those in EGE. To date, no cases of complication of TA and EGE have been reported. CASE PRESENTATIONS: An 18 year-old female was diagnosed with EGE and treated with prednisolone. At 6 months after completion of the treatment, the patient experienced chest pain, and was diagnosed with TA. TH1 and TH17 immunity are thought to be involved with TA, while TH2 are considered to be involved with EGE. In this case, the expression of IL-17 mRNA in the colon mucosa greatly decreased after prednisolone treatment for EGE. CONCLUSIONS: This is the first report of TA complicated with EGE, and the overactivation of TH17 is considered to be associated with the pathogenesis of these two diseases.

Extracellular vesicle-encapsulated miR-30e suppresses cholangiocarcinoma cell invasion and migration via inhibiting epithelial-mesenchymal transition.

Early-staged cholangiocarcinoma (CCA) is difficult to diagnose due to its high potential for invasion and metastasis. Epithelial-mesenchymal transition (EMT) is induced by transforming growth factor-ß (TGF-ß) in a process thought to be important for invasion and metastasis in several cancers, including CCA. Although microRNAs (miRNAs) have been implicated in the pathogenesis of several malignancies, their roles to CCA are not clearly understood. Some miRNAs were reported to be included in extracellular vesicles (EVs) and transferred from their donor cells to other cells, modulating recipient cell behaviors. In this study, the involvement and functional roles of EV-contained miRNAs during EMT in human CCA were determined. Expression profiling identified a subset of miRNAs that were reduced by TGF-ß in CCA cells. Among these, miR-30e was highly downregulated by TGF-ß and predicted to target Snail, which is an EMT-inducible transcription factor. MiR-30e overexpression suppressed cell invasion and migration via inhibiting EMT, whereas miR-30e inhibition promoted EMT, cell invasion and migration. Moreover, miR-30e was enriched in EVs derived from CCA cells after miR-30e overexpression, and miR-30e intercellular transfer through EVs suppressed EMT, cell invasion and migration in recipient CCA cells. Together, our results suggest that EV-mediated miR-30e transfer could inhibit EMT via directly targeting Snail, which subsequently suppresses CCA cell invasion and migration. These findings provide several new insights into regulatory mechanisms of tumor invasion and metastasis in human CCA.

Expression of transcription factors in MEN1-associated pancreatic neuroendocrine tumors.

MEN1-associated pancreatic neuroendocrine tumors (pNETs) may potentially express distinct hormones, but the mechanism has not been elucidated. Transcription factors such as MafA and Pdx1 have been identified to lead to beta cell differentiation, while Arx and Brn4 to alpha cell differentiation in developing pancreas. We hypothesized those transcription factors are important to produce specific hormones in pNETs, similarly to developing pancreas, and examined the expression of transcription factors in a case of MEN1 who showed immunohistological coexistence of several hormone-producing pNETs including insulinoma. A 70-year-old woman was found to manifest hypoglycemia with non-suppressed insulinemia and hypercalcemia with elevated PTH level. She was diagnosed as MEN1 based on the manifestation of primary hyperparathyroidism, pituitary adenoma and insulinoma, with genetic variation of MEN1 gene. She had pylorus-preserving pancreaticoduodenectomy because CT scan and SACI test indicated that insulinoma was localized in the head of the pancreas. Histopathological finding was MEN1-associated NET, G1. Interestingly, immunohistological examination of the resected pancreas revealed that two insulinomas, a glucagon-positive NET and a multiple hormone-positive NET coexisted. Hence, we examined the expression of transcription factors immunohistochemically to elucidate the role of the transcription factors in MEN1-associated hormone-producing pNETs. We observed homogeneous expressions of MafA and Pdx1 in insulinomas and Arx in glucagon-positive NET, respectively. Moreover, multiple hormone-positive NETs expressed several transcription factors heterogeneously. Collectively, our results suggested that transcription factors could play important roles in the production of specific hormones in MEN1-associated pNETs, similar to islet differentiation. LEARNING POINTS: To date, it has been shown that different hormone-producing tumors coexist in MEN1-associated pNETs; however, the underlying mechanism of the hormone production in MEN1-associated pNETs has not been well elucidated.Although this case presented symptomatic hypoglycemia, several hormone-producing pNETs other than insulinoma also coexisted in the pancreas.Immunohistochemical analysis showed MafA and Pdx1 expressions distinctly in insulinoma, and Arx expression particularly in a glucagon-positive NET, while a multiple hormone-positive NET expressed MafA, Pdx1 and Arx.Collectively, clinicians should consider that several hormone-producing pNETs may coexist in a MEN1 case and examine both endocrinological and histopathological analysis of pNETs, regardless of whether symptoms related to the excess of hormones are observed or not.

Dipeptidyl peptidase-4 inhibitor treatment induces a greater increase in plasma levels of bioactive GIP than GLP-1 in non-diabetic subjects.

OBJECTIVE: Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) possess multiple bioactive isoforms that are rendered non-insulinotropic by the enzyme dipeptidyl peptidase-4 (DPP-4). Recently, some ELISA kits have been developed to specifically measure "active" GIP and GLP-1, but it is unclear if these kits can accurately quantify all bioactive forms. Therefore, it remains uncertain to what extent treatment with a DPP-4 inhibitor boosts levels of biologically active GIP and GLP-1. Thus, we evaluated our novel receptor-mediated incretin bioassays in comparison to commercially available ELISA kits using plasma samples from healthy subjects before and after DPP-4 inhibitor administration. METHODS: We utilized cell lines stably co-transfected with human GIP or GLP-1 receptors and a cAMP-inducible luciferase expression construct for the bioassays and commercially available ELISA kits. Assays were tested with synthetic GIP and GLP-1 receptor agonists and plasma samples collected from subjects during a 75 g oral glucose tolerance test (OGTT) performed before or following 3-day administration of a DPP-4 inhibitor. RESULTS: A GIP isoform GIP(1-30)NH2 increased luciferase activity similarly to GIP(1-42) in the GIP bioassay but was not detectable by either a total or active GIP ELISA kit. During an OGTT, total GIP levels measured by ELISA rapidly increased from 0 min to 15 min, subsequently reaching a peak of 59.2 ± 8.3 pmol/l at 120 min. In contrast, active GIP levels measured by the bioassay peaked at 15 min (43.4 ± 6.4 pmol/l) and then progressively diminished at all subsequent time points. Strikingly, at 15 min, active GIP levels as determined by the bioassay reached levels approximately 20-fold higher after the DPP-4 inhibitor treatment, while total and active GIP levels determined by ELISA were increased just 1.5 and 2.1-fold, respectively. In the absence of DPP-4 inhibition, total GLP-1 levels measured by ELISA gradually increased up to 90 min, reaching 23.5 ± 2.4 pmol/l, and active GLP-1 levels determined by the bioassay did not show any apparent peak. Following administration of a DPP-4 inhibitor there was an observable peak of active GLP-1 levels as determined by the bioassay at 15 min after oral glucose load, reaching 11.0 ± 0.62 pmol/l, 1.4-fold greater than levels obtained without DPP-4 inhibitor treatment. In contrast, total GLP-1 levels determined by ELISA were decreased after DPP-4 inhibitor treatment. CONCLUSION: Our results using bioassays indicate that there is a greater increase in plasma levels of bioactive GIP than GLP-1 in subjects treated with DPP-4 inhibitors, which may be unappreciated using conventional ELISAs.

Sodium-Glucose Cotransporter 2 Inhibitor and a Low Carbohydrate Diet Affect Gluconeogenesis and Glycogen Content Differently in the Kidney and the Liver of Non-Diabetic Mice.

A low carbohydrate diet (LCHD) as well as sodium glucose cotransporter 2 inhibitors (SGLT2i) may reduce glucose utilization and improve metabolic disorders. However, it is not clear how different or similar the effects of LCHD and SGLT2i are on metabolic parameters such as insulin sensitivity, fat accumulation, and especially gluconeogenesis in the kidney and the liver. We conducted an 8-week study using non-diabetic mice, which were fed ad-libitum with LCHD or a normal carbohydrate diet (NCHD) and treated with/without the SGLT-2 inhibitor, ipragliflozin. We compared metabolic parameters, gene expression for transcripts related to glucose and fat metabolism, and glycogen content in the kidney and the liver among the groups. SGLT2i but not LCHD improved glucose excursion after an oral glucose load compared to NCHD, although all groups presented comparable non-fasted glycemia. Both the LCHD and SGLT2i treatments increased calorie-intake, whereas only the LCHD increased body weight compared to the NCHD, epididimal fat mass and developed insulin resistance. Gene expression of certain gluconeogenic enzymes was simultaneously upregulated in the kidney of SGLT2i treated group, as well as in the liver of the LCHD treated group. The SGLT2i treated groups showed markedly lower glycogen content in the liver, but induced glycogen accumulation in the kidney. We conclude that LCHD induces deleterious metabolic changes in the non-diabetic mice. Our results suggest that SGLT2i induced gluconeogenesis mainly in the kidney, whereas for LCHD it was predominantly in the liver.

Alternative form of glucose-dependent insulinotropic polypepide and its physiology.

Glucose-dependent insulinotropic polypepide (GIP) was first extracted from porcine gut mucosa and identified as "incretin" decades ago. Though early studies have shown the possible GIP isoforms by gel filtration profiles from porcine or human intestinal extracts analyzed by radioimmunoassay (RIA), GIP is currently believed to consist of 42 amino acids (GIP1-42), which are released from gut K-cells and promote postprandial insulin release. In fact, GIP1-42 is usually processed from proGIP by the action of prohormone convertase (PC) 1/3 in the gut. GIP expression is occasionally found in the intestinal glucagon-like peptide-1-secreting cells, suggesting gene expression of both GIP and proglucagon can co-exist in identical cells. However, GIP1-42 immunoreactivity is rarely found in α-cells or other pancreatic endocrine cells of wild-type mammals. Interestingly, we found that short-form GIP1-30 is expressed in and released from pancreatic α-cells and a subset of enteroendocrine cells through proGIP processing by PC2. GIP1-30 is also insulinotropic and modulates glucose-stimulated insulin secretion in a paracrine manner. It is also suggested that short-form GIP1-30 possibly plays a crucial role for the islet development. It has not been well elucidated whether expression of GIP1-30 is modulated in the diabetic status, and whether GIP1-30 might have therapeutic potentials. Our preliminary data suggest that short-form GIP1-30 might play important roles in glucose metabolism.

High glucose induces platelet-derived growth factor-C via carbohydrate response element-binding protein in glomerular mesangial cells.

Persistent high concentration of glucose causes cellular stress and damage in diabetes via derangement of gene expressions. We previously reported high glucose activates hypoxia-inducible factor-1αand downstream gene expression in mesangial cells, leading to an extracellular matrix expansion in the glomeruli. A glucose-responsive transcription factor carbohydrate response element-binding protein (ChREBP) is a key mediator for such perturbation of gene regulation. To provide insight into glucose-mediated gene regulation in mesangial cells, we performed chromatin immunoprecipitation followed byDNAmicroarray analysis and identified platelet-derived growth factor-C (PDGF-C) as a novel target gene of ChREBP In streptozotocin-induced diabetic mice, glomerular cells showed a significant increase inPDGF-C expression; the ratio ofPDGF-C-positive cells to the total number glomerular cells demonstrated more than threefold increase when compared with control animals. In cultured human mesangial cells, high glucose enhanced expression ofPDGF-C protein by 1.9-fold. Knock-down of ChREBPabrogated this induction response. UpregulatedPDGF-C contributed to the production of typeIVand typeVIcollagen, possibly via an autocrine mechanism. Interestingly, urinaryPDGF-C levels in diabetic model mice were significantly elevated in a fashion similar to urinary albumin. Taken together, we hypothesize that a high glucose-mediated induction ofPDGF-C via ChREBPin mesangial cells contributes to the development of glomerular mesangial expansion in diabetes, which may provide a platform for novel predictive and therapeutic strategies for diabetic nephropathy.

Role of IGFBP7 in Diabetic Nephropathy: TGF-ß1 Induces IGFBP7 via Smad2/4 in Human Renal Proximal Tubular Epithelial Cells.

Tubular injury is one of the important determinants of progressive renal failure in diabetic nephropathy (DN), and TGF-ß1 has been implicated in the pathogenesis of tubulointerstitial disease that characterizes proteinuric renal disease. The aim of this study was to identify novel therapeutic target molecules that play a role in the tubule damage of DN. We used an LC-MS/MS-based proteomic technique and human renal proximal epithelial cells (HRPTECs). Urine samples from Japanese patients with type 2 diabetes (n = 46) were used to quantify the candidate protein. Several proteins in HRPTECs in cultured media were observed to be driven by TGF-ß1, one of which was 33-kDa IGFBP7, which is a member of IGFBP family. TGF-ß1 up-regulated the expressions of IGFBP7 mRNA and protein in a dose- and time-dependent fashion via Smad2 and 4, but not MAPK pathways in HRPTECs. In addition, the knockdown of IGFBP7 restored the TGF-ß1-induced epithelial to mesenchymal transition (EMT). In the immunohistochemical analysis, IGFBP7 was localized to the cytoplasm of tubular cells but not that of glomerular cells in diabetic kidney. Urinary IGFBP7 levels were significantly higher in the patients with macroalbuminuria and were correlated with age (r = 0.308, p = 0.037), eGFR (r = -0.376, p = 0.01), urinary ß2-microglobulin (r = 0.385, p = 0.008), and urinary N-acetyl-beta-D-glucosaminidase (NAG) (r = 0.502, p = 0.000). A multivariate regression analysis identified urinary NAG and age as determinants associated with urinary IGFBP7 levels. In conclusion, our data suggest that TGF-ß1 enhances IGFBP7 via Smad2/4 pathways, and that IGFBP7 might be involved in the TGF-ß1-induced tubular injury in DN.

One-year maintenance with routine assessment of patient index data 3-based remission may inhibit radiographic progression in patients with rheumatoid arthritis treated with routine clinical therapy: A retrospective comparison of radiographic outcome and its prognostic factors between maintained remissions with patient-reported outcome index and physician-oriented disease activity indices.

OBJECTIVES: We investigated whether the maintenance of routine assessment of patient index data 3 (RAPID3) remission for one year (RAPID3-MR) may predict good radiographic outcomes. We also compared radiographic progression to prognostic factors among patients with RAPID3-MR, with the maintenance of clinical disease activity index remission for one year (CDAI-MR) or with the maintenance of 28 joint count disease activity score remission for one year (DAS28-MR). METHODS: Of 1220 patients with available clinical data, 92 with RAPID3-MR, 80 with RAPID3-NMR (not satisfying RAPID3-MR), 45 with CDAI-MR, and 75 with DAS28-MR were retrospectively investigated. CDAI and DAS28 for clinical outcomes and the modified total Sharp score (mTSS) for radiographic joint damage were investigated for at least one year. RESULTS: RAPID3, CDAI, DAS28, and their categories remained unchanged or significantly improved in RAPID3-MR patients but significantly deteriorated in RAPID3-NMR patients. The mean annual ΔmTSS was significantly lower in RAPID3-MR patients (0.12 ± 0.55) than in RAPID3-NMR patients (0.54 ± 1.27) (p = 0.025). There was no significant difference among RAPID3-MR patients, CDAI-MR patients (0.06 ± 0.85), and DAS28-MR patients (0.11 ± 0.89). The baseline mTSS (p = 0.038) and monotherapy with nonbiological disease-modifying antirheumatic drugs (p = 0.033) were good prognostic factors in RAPID3-MR patients. CONCLUSIONS: One-year RAPID3 remission maintenance may predict good radiographic outcomes.