Overlapping risk factors for diabetic ketoacidosis in patients with type 1 diabetes on ipragliflozin: case analysis of spontaneous reports in Japan from a pharmacovigilance safety database.

BACKGROUND: In patients with type 1 diabetes mellitus (T1D), sodium-glucose cotransporter 2 (SGLT2) inhibitors are associated with an increased risk of diabetic ketoacidosis (DKA). Ipragliflozin is an SGLT2 inhibitor approved in Japan in combination with insulin for patients with T1D. RESEARCH DESIGN AND METHODS: Spontaneous safety reports of ipragliflozin adverse drug reactions (ADRs) in patients with T1D were collected during early post-marketing phase vigilance (EPPV; 21 December 2018-20 June 2019). For patients with T1D prescribed ipragliflozin who experienced DKA, we examined DKA event data registered in the manufacturer's safety database (21 December 2018-31 December 2021), including patient background characteristics. RESULTS: During EPPV, there were 189 total events (45 serious) of ADRs, including 32 serious events of ketoacidosis. From 2018 to 2021, the major DKA risk factors were sick days, stopping or inappropriately decreasing insulin, insulin pump trouble, and low carbohydrate diet, with substantial overlap among these factors. CONCLUSIONS: In Japanese patients with T1D using ipragliflozin, DKA events were linked to several overlapping factors, including sick days and reduced dose/interruption of insulin, whether intentional or unexpected. These results highlight the need for improved patient education regarding ipragliflozin use and appropriate self-management of ketosis from an early stage.

Effect of Intradialytic Supine Ergometer Exercise on Hemodialysis Patients with Different Nutritional Status.

OBJECTIVE: It is important for hemodialysis patients to exercise while their nutritional status is being monitored. This study aimed to examine the difference in physical exercise function and the effect of exercise intervention in hemodialysis patients who were divided into two groups (high-nutrition and low-nutrition groups) based on the serum albumin levels. METHOD: A total of 26 outpatients (18 men and 8 women) undergoing hemodialysis (age: 66 ± 10 years) were included in this study. The patients' body composition data (weight, body mass index, percentage of body fat, fat-free mass, and total body water) and physical functions (grip strength, knee extensor strength, open-eyed one-legged standing time, long sitting trunk anteflexion, and 6-minute walking distance [6MWD] test) were measured. The intervention was supine ergometer exercise during hemodialysis, and the patients exercised for 30 minutes during hemodialysis thrice a week. The intervention period was three months. RESULTS: Compared to the high-nutrition group, the low-nutrition group showed a significant decrease in muscle strength. Furthermore, long sitting trunk anteflexion in the high-nutrition group and 6MWD in the low-nutrition group improved significantly after the intervention. CONCLUSION: The result of this study may indicate that 6MD can be improved by exercise during dialysis, regardless of nutritional status. It is said that low nutritional status has a negative impact on survival rate; thus, considering the impact on survival rate, it is hemodialysis patients with a low nutritional status that should be considered to introduce more active exercise during dialysis.

Effects of an additional resistance training intervention in hemodialysis patients performing long-term ergometer exercise during dialysis.

[Purpose] To verify the effect of a 12-week additional resistance training intervention in patients on hemodialysis who had been performing supine ergometer exercises alone during dialysis. [Participants and Methods] Overall, 18 patients undergoing hemodialysis were included. A 12-week intervention with additional resistance training was conducted in hemodialysis patients who had been performing supine ergometer exercise for 30 min during dialysis for over >3 months. Physical function before and after the period of bicycle ergometer exercise alone and before and during the additional intervention was compared. Resistance training consisted of 1-3 sets per day of five different exercises for the large muscle groups of the upper and lower limbs. [Results] The results of the 6-min walk test improved significantly after the additional intervention. The average driving distance in the supine ergometer exercise during the additional intervention was identified as an associated factor. [Conclusion] The addition of the resistance training to long-term supine ergometer exercisers improved walking endurance. When supine ergometer exercise alone does not change physical function, the additional use of resistance training subsequently may have a positive effect on walking endurance.

Plant secondary cell wall proteome analysis with an inducible system for xylem vessel cell differentiation.

Plant cell walls are typically composed of polysaccharide polymers and cell wall proteins (CWPs). CWPs account for approximately 10% of the plant cell wall structure and perform a wide range of functions. Previous studies have identified approximately 1000 CWPs in the model plant Arabidopsis thaliana; however, the analyses mainly targeted primary cell walls, which are generated at cell division. In contrast, little is known about CWPs in secondary cell walls (SCWs), which are rigid and contain the phenolic polymer lignin. Here, we performed a cell wall proteome analysis to obtain novel insights into CWPs in SCWs. To this end, we tested multiple methods for cell wall extraction with cultured Arabidopsis cells carrying the VND7-VP16-GR system, with which cells can be transdifferentiated into xylem-vessel-like cells with lignified SCWs by dexamethasone treatment. We then subjected the protein samples to in-gel trypsin digestion followed by LC-MS/MS analysis. The different extraction methods resulted in the detection of different cell wall fraction proteins (CWFPs). In particular, centrifugation conditions had a strong impact on the extracted CWFP species, resulting in the increased number of identified CWFPs. We successfully identified 896 proteins as CWFPs in total, including proteases, expansins, purple phosphatase, well-known lignin-related enzymes (laccase and peroxidase), and 683 of 896 proteins were newly identified CWFPs. These results demonstrate the usefulness of our CWP analysis method. Further analyses of SCW-related CWPs could be expected to produce information useful for understanding the roles of CWPs in plant cell functions.

Artificial Intelligence in Current Diabetes Management and Prediction.

PURPOSE OF REVIEW: Artificial intelligence (AI) can make advanced inferences based on a large amount of data. The mainstream technologies of the AI boom in 2021 are machine learning (ML) and deep learning, which have made significant progress due to the increase in computational resources accompanied by the dramatic improvement in computer performance. In this review, we introduce AI/ML-based medical devices and prediction models regarding diabetes. RECENT FINDINGS: In the field of diabetes, several AI-/ML-based medical devices and regarding automatic retinal screening, clinical diagnosis support, and patient self-management tool have already been approved by the US Food and Drug Administration. As for new-onset diabetes prediction using ML methods, its performance is not superior to conventional risk stratification models that use statistical approaches so far. Despite the current situation, it is expected that the predictive performance of AI will soon be maximized by a large amount of organized data and abundant computational resources, which will contribute to a dramatic improvement in the accuracy of disease prediction models for diabetes.

Safety of Ipragliflozin in Patients with Type 2 Diabetes Mellitus: Pooled Analysis of Phase II/III/IV Clinical Trials.

INTRODUCTION: Ipragliflozin is a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM). The objective of this pooled analysis was to characterise the safety profile of ipragliflozin based on safety data from published randomised controlled trials. METHODS: Safety data from 12 randomised, phase II/III/IV placebo-controlled, parallel group, comparative studies of ipragliflozin in patients with T2DM were pooled. Treatment-emergent adverse events (TEAEs) were analysed for patients who had received at least one dose of ipragliflozin 50 mg (n = 1209) or placebo (n = 796) in studies lasting for up to 24 weeks. TEAEs of special interest and serious adverse events (SAEs) were assessed, as well as abnormal laboratory test and vital sign measurements. RESULTS: The overall incidences of TEAEs and SAEs between the ipragliflozin and placebo groups were similar, 63.8% vs 59.3% and 2.5% vs 3.3%, respectively. The incidence of TEAEs leading to permanent discontinuation was lower for ipragliflozin (3.6%) than placebo (6.5%). The incidences of TEAEs of special interest including those related to urinary tract infection, cardiovascular events, renal disorder, fracture, malignant tumours and hypoglycaemia were also similar between the groups. Genital infections were more frequent with ipragliflozin (2.4%) than placebo (0.6%), as were pollakiuria/polyuria (6.0% vs 2.0%), volume depletion (4.9% vs 1.8%) and skin/subcutaneous tissue disorders (7.7% vs 4.4%). There were no reported cases of diabetic ketoacidosis, fractures, lower-limb amputation or Fournier's gangrene in ipragliflozin-treated patients across the 12 studies. CONCLUSION: In randomised, placebo-controlled trials of patients with T2DM, ipragliflozin was well tolerated, with a similar overall incidence of TEAEs to placebo. No new safety signals were observed. TRIAL REGISTRATION NUMBERS: NCT01071850, NCT00621868, NCT01057628, NCT01117584, NCT01135433, NCT01225081, NCT01242215, NCT02175784, NCT01505426, NCT02452632, NCT02794792, NCT01316094. FUNDING: Astellas Pharma Inc.

Effect of two load escalation methods using a supine ergometer on the cardiorespiratory system and lower limb muscle activity.

[Purpose] This study aimed to determine the effects of two load escalation methods, such as pedal weight increasing method and pedal speed raising method using a supine ergometer, on the cardiorespiratory system and lower limb muscle activity. [Participants and Methods] The study included 20 healthy adult males (age: 21 ± 1 years). Two different parameters were modulated during exercise intervention. Pedal load progression was applied in the load group (28.9 N, 72.3 N, 101.3 N), and pedal rate progression was applied in the speed group (60 rpm, 80 rpm, 100 rpm). Each group performed 5 minutes of exercise at their respective level of progression, for a total duration of 15 minutes. [Results] Oxygen consumption, carbon dioxide output, and minute ventilation were significantly increased as exercise intensity increased in both groups. Significant differences in muscle activity were found between the highest exercise intensities (101.3 N and 100 rpm). The activities of the biceps femoris and gastrocnemius were significantly higher with exercise at 100 rpm than at 101.3 N. [Conclusion] Increasing the number of revolutions per minute may significantly increase the activity of the lower limb muscles at comparable exercise intensities, despite the low work load.

Effects of α-tocopherol on bone marrow mesenchymal cells derived from type II diabetes mellitus rats.

It is widely accepted that vitamin E (VE) acts as an antioxidant and is involved in various metabolic systems including the regulation of gene expression and inhibition of cell proliferation. The most predominant isoform of VE in the living body is α-tocopherol. However, the influence of α-tocopherol on bone marrow mesenchymal cells (BMMCs) in a background of type II diabetes mellitus (DM) has not been investigated. The focus of the present study was to clarify the effect of α-tocopherol on BMMCs derived from rats with type II DM and the underlying mechanisms involved. BMMCs were isolated from rats with type II DM. The BMMCs were either untreated or exposed to α-tocopherol at concentrations of 1.0, 10, and 100 µM, and the resulting effects of α-tocopherol on cell proliferation, H2O2 activity, and antioxidant and inflammatory cytokine production were examined. At 100 µM, α-tocopherol had no effect on cell proliferation, but H2O2 activity was significantly increased. At 10 µM, α-tocopherol increased the gene expression of IL-1ß, and markedly promoted that of TNF-α. Expression of catalase in the presence of 100 µM α-tocopherol was lower than for the other concentrations. At a low concentration, α-tocopherol exerted good antioxidant and anti-inflammatory effects on BMMCs. The study suggests that maintaining α-tocopherol at a low concentration might promote the recovery of BMMCs from oxidative stress.

Proteomic analysis of xylem vessel cell differentiation in VND7-inducible tobacco BY-2 cells by two-dimensional gel electrophoresis.

The xylem vessel is an essential structure for water conduction in vascular plants. Xylem vessel cells deposit thick secondary cell walls and undergo programmed cell death, to function as water-conducting elements. Since the discovery of the plant-specific NAC domain-type VASCULAR-RELATED NAC-DOMAIN (VND) transcription factors, which function as master switches of xylem vessel cell differentiation in Arabidopsis, much has been learned about the transcriptional regulatory network of xylem vessel cell differentiation. However, little is known about proteome dynamics during xylem vessel cell differentiation. Here, we performed two-dimensional electrophoresis-based proteomic analysis of xylem vessel cell differentiation using a transgenic tobacco BY-2 cell line carrying the VND7-inducible system (BY-2/35S::VND7-VP16-GR), in which synchronous trans-differentiation into xylem vessel cells can be induced by the application of a glucocorticoid. Of the 47 spots revealed by gel electrophoresis, we successfully identified 40 proteins. Seventeen proteins, including several well-characterized proteins such as a cysteine protease and serine carboxypeptidase (involved in programmed cell death), were upregulated after 24 h of induction. However, previous transcriptomic analysis showed that only eight of these proteins are upregulated at the transcriptional level during xylem vessel cell differentiation in BY-2/35S::VND7-VP16-GR cells. These findings suggest that post-transcriptional regulation strongly affects proteomic dynamics during xylem vessel cell differentiation.

Affinity Purification and Characterization of Functional Tubulin from Cell Suspension Cultures of Arabidopsis and Tobacco.

Microtubules assemble into several distinct arrays that play important roles in cell division and cell morphogenesis. To decipher the mechanisms that regulate the dynamics and organization of this versatile cytoskeletal component, it is essential to establish in vitro assays that use functional tubulin. Although plant tubulin has been purified previously from protoplasts by reversible taxol-induced polymerization, a simple and efficient purification method has yet to be developed. Here, we used a Tumor Overexpressed Gene (TOG) column, in which the tubulin-binding domains of a yeast (Saccharomyces cerevisiae) TOG homolog are immobilized on resin, to isolate functional plant tubulin. We found that several hundred micrograms of pure tubulin can readily be purified from cell suspension cultures of tobacco (Nicotiana tabacum) and Arabidopsis (Arabidopsis thaliana). The tubulin purified by the TOG column showed high assembly competence, partly because of low levels of polymerization-inhibitory phosphorylation of α-tubulin. Compared with porcine brain tubulin, Arabidopsis tubulin is highly dynamic in vitro at both the plus and minus ends, exhibiting faster shrinkage rates and more frequent catastrophe events, and exhibits frequent spontaneous nucleation. Furthermore, our study shows that an internal histidine tag in α-tubulin can be used to prepare particular isotypes and specifically engineered versions of α-tubulin. In contrast to previous studies of plant tubulin, our mass spectrometry and immunoblot analyses failed to detect posttranslational modification of the isolated Arabidopsis tubulin or detected only low levels of posttranslational modification. This novel technology can be used to prepare assembly-competent, highly dynamic pure tubulin from plant cell cultures.

High Glucose Concentrations Suppress the Proliferation of Human Periodontal Ligament Stem Cells and Their Differentiation Into Osteoblasts.

BACKGROUND: Diabetes mellitus (DM) is a major risk factor for periodontal disease and affects various cellular functions. Periodontal ligament stem cells (PDLSCs) play an important role in periodontal tissue regeneration; however, the effect of hyperglycemia on PDLSCs is unclear. The aim of this study is to investigate whether hyperglycemia affects periodontal tissue regeneration, using human PDLSCs and high-glucose medium as a model of DM. METHODS: PDLSCs were obtained from healthy adult human mandibular third molars. Cell proliferation, osteoblastic differentiation, and proinflammatory cytokine expression were investigated by culturing PDLSCs in media supplemented with four different glucose concentrations representative of control patients (5.5 mM), patients with postprandial or controlled DM (8.0 mM), and patients with uncontrolled DM (12.0 and 24.0 mM). The molecular effects of hyperglycemia on PDLSC physiology were examined with a focus on the nuclear factor (NF)-(κB signaling pathway. The involvement of NF-κB was investigated with a specific NF-κB inhibitor in PDLSCs under hyperglycemic conditions. RESULTS: High glucose levels inhibited PDLSC proliferation and differentiation into osteoblasts but induced NF-κB activation and subsequent interleukin (IL)-6 and IL-8 expression. Treatment with an NF-κB inhibitor rescued the defects in cell proliferation and osteoblastic differentiation and inhibited the IL-6 expression caused by the high-glucose environment. CONCLUSION: The results of this study demonstrate that hyperglycemia inhibits human PDLSC proliferation and osteoblastic differentiation.

Validity of body impedance analysis for evaluating body composition in patients undergoing long-term hemodialysis.

[Purpose] This study assessed changes in body composition before and after dialysis in chronic hemodialysis patients and determined the relationships between various body composition parameters and blood lipid levels in these patients. [Subjects] The cross-sectional study included 19 dialysis outpatients (17 men and 2 women, aged 35-82 years). [Methods] Body mass index, body weight, percent body fat, and percent skeletal muscle were measured before and after dialysis by using body impedance analysis. Blood lipid levels were obtained from patients' clinical records. The body composition parameters before and after dialysis were compared using paired t-tests. Spearman's rank correlation coefficients were calculated to determine relationships between the body composition parameters, before and after dialysis, and the blood lipid levels. [Results] All body composition parameters differed significantly before and after dialysis. High-density lipoprotein cholesterol level significantly correlated with all the body composition parameters, whereas total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels significantly correlated with some of these parameters. The correlation coefficients revealed no major differences in the relationships between blood lipid parameters and body compositions before and after dialysis. [Conclusion] Our findings suggest that body composition parameters, whether measured before or after dialysis, can be used to evaluate obesity in longitudinal studies.

Smoking as a confounding factor on the influence of cold therapy on the vascular endothelium function of young men.

[Purpose] This study was designed to determine whether smoking affects endothelium function after cold therapy in young men. [Subjects] The final cohort included 27 healthy men (age, 20-21 years). Because an impact on vascular endothelium function was anticipated to be caused by smoking, the study enrolled 14 participants in a smoking group and 13 in a non-smoking group. [Methods] Vascular endothelial function was assessed by determining the reactive hyperemia index (RHI), using finger-tonometry. RHI was measured twice, at rest (baseline) and after a cold stimulus. The forearm was cooled with an ice bag for 10 min as the cold stimulus. Comparisons between the RHI at baseline and after cold treatment, and between the smoking and non-smoking groups, were performed using the paired and unpaired t-tests, respectively. [Results] There was a significant difference in baseline RHI values between the smoking and non-smoking groups, but there was no significant difference between the baseline and post-treatment RHI values in either group. [Conclusion] These results suggest that cigarette smoking damages the endothelial cells in young men with a short history of smoking. However, cold therapy did not have a significant impact on the RHI in either group.

Vasodilator effects of flunarizine on retinal blood vessels in anesthetized rats.

The aim of this study was to investigate the effects of intravenous administration of flunarizine on the diameter of retinal blood vessels and blood pressure in anesthetized rats and to compare the effects of this antagonist with those of nicardipine and nifedipine. Retinal vascular images were captured with a fundus camera system for small animals and the diameter of retinal blood vessels contained in the images was measured using image-processing softwares on a personal computer. Blood pressure was continuously measured. Flunarizine [1-30 microg/kg, intravenously (i.v.)] dose-dependently increased the diameter of retinal blood vessels without significantly changing systemic blood pressure. Nicardipine (1-30 microg/kg, i.v.) increased the retinal blood vessel diameter but decreased blood pressure in a dose-dependent manner. Nifedipine (10-100 microg/kg, i.v.) failed to dilate the retinal blood vessels, although it produced comparable depressor responses as those to nicardipine. These results suggest that flunarizine selectively acts on the retinal blood vessels rather than on the peripheral resistance vessels. Flunarizine could therefore be considered as a candidate for therapeutic drugs to treat diseases associated with disorders of retinal circulation without severe cardiovascular side-effects.

Vasodilator effects of ibudilast on retinal blood vessels in anesthetized rats.

Ibudilast (3-isobutyryl-2-isopropylpyrazolo[1,5-alpha]pyridine) is clinically used as a cerebral vasodilator in Japan. However, the effects of ibudilast on retinal blood vessels have not been fully examined. The aim of this study, therefore, was to examine the effects of ibudilast on retinal blood vessels in rats in vivo. Male Wistar rats (8 to 10 weeks old) were anesthetized with thiobutabarbital (120 mg/kg, intraperitoneally (i.p.)). Retinal vascular images were captured with a fundus camera system for small animals, and the diameter of retinal blood vessels was measured. Ibudilast (0.1 and 1 mg/kg, intravenously (i.v.)) elicited a sustained increase in the diameter of retinal blood vessels and heart rate without altering systemic blood pressure. The effects of ibudilast were significantly reduced by treatment with the nonselective cyclooxygenase inhibitor indomethacin (5 mg/kg, i.p.). These results suggest that ibudilast dilates retinal blood vessels through cyclooxygenase-dependent mechanisms in rats in vivo.

Micro-CT imaging analysis for the effect of celecoxib, a cyclooxygenase-2 inhibitor, on inflammatory bone destruction in adjuvant arthritis rats.

Cyclooxygenase (COX)-2 is known to play an important role in the differentiation and maturation of osteoclasts. However, the role of COX-1 in bone metabolism has not been well explored. In this study, the bone-conserving effects of COX-2-specific (celecoxib), COX-nonselective (loxoprofen), and COX-1-specific agents (SC-58560) were compared using an adjuvant-induced arthritis (AIA) rat model. Arthritis was induced by injecting 50 microl liquid paraffin containing 1 mg Mycobacterium butyricum into the left footpad of Lewis rats. Drugs were given orally twice daily for 10 days beginning 15 days after adjuvant injection. Celecoxib was administered at the rate of 3 mg/kg per day, loxoprofen at 3 mg/kg per day, and SC-58560 at 10 mg/kg per day. The therapeutic effects on 3-D architectural bone changes in the arthritic condition, e.g., the bone volume/total tissue volume ratio and the amount of trabecular bone pattern factor, were determined by analyzing the hindpaw calcaneus of AIA rats using microcomputed tomography (micro-CT). In addition, dual-energy X-ray absorptiometry 2-D bone analysis was performed to compare with micro-CT analysis. AIA rats are prone to substantial bone erosion, which allows for significant changes in the 3-D architectural index. This inflammatory bone destruction was suppressed potently by celecoxib, only moderately by loxoprofen, and not at all by SC-58560. These data suggest that COX-2 plays an important role in the inflammatory bone destruction that occurs with rheumatoid arthritis. The results also suggest that COX-2 is more effective than COX-1 at suppressing the destruction of bone associated with arthritis.

A method for the low-level (ng/g) determination of perfluorooctanoate in carpet by LC-MS-MS using matrix extracted standards.

Fluorotelomer-based acrylic polymers are applied to the surface of carpet to impart oil, stain, and water repellence properties. Concerns that fluorotelomer-based polymers are a possible source of "low level" exposure to humans, coupled with their widespread use have prompted the need to develop a method to detect and measure perfluorooctanoate (PFO) in carpet. A liquid chromatography tandem mass spectrometry method for the determination of PFO in carpet using a dual labeled 13C-perfluoroctanoic acid (13C-PFOA) internal standard is successfully developed and validated. Levels of PFO are determined using a gradient, reversed-phase high-performance liquid chromatography (HPLC) method with acetic acid acidified water-methanol, separated on a 50 mm Phenomenex Synergi Polar RP column. Ions monitored are 413 (parent) and 369 (daughter) for PFO and 415 (parent) and 370 (daughter) for dual labeled 13C-PFOA internal standard. Accuracy and precision over three days for 5 to 900 ng/g PFO in carpet ranged from 2.4% to 7.6% and 3.7% to 14.1%, respectively. Overall extraction efficiency for samples (n=30) fortified with 13C-PFOA at 20 ng/g and perfluorooctanoic acid (PFOA) at 5, 50, and 500 ng/g is 98.9%+/-8.1%. Specificity of the method was evaluated with two different carpet samples.

FDG PET and PET/CT monitoring of autoimmune pancreatitis associated with extrapancreatic autoimmune disease.

We report a series of FDG PET findings of a 69-year-old male patient with autoimmune pancreatitis (AIP) associated with extrapancreatic disease. The first FDG PET revealed diffuse uptake of FDG in AIP and retroperitoneal fibrosis (RF). The second FDG PET after cessation of steroid treatment indicated subsiding of disease activity in AIP, continuous disease activity in RF, and new extrapancreatic lesions, including enlargement of a right salivary gland, nephritis, and lymphadenopathy. The last FDG PET under steroid treatment revealed reduced FDG uptake in the above abnormal FDG uptake lesions. A series of these FDG PET findings suggest the usefulness of FDG PET for the diagnosis and monitoring of AIP associated with extrapancreatic autoimmune diseases.