ABSTRACT
Aim: Education on insulin self-injection techniques is important for good glycemic control, but its effectiveness in some elderly patients is limited due to loss of cognitive function and impaired activities of daily living. We hypothesized that classification using the Dementia Assessment Sheet for Community-based Integrated Care System 8-items (DASC-8) would help identify elderly patients with diabetes who effectively learn self-injection techniques. Methods: Diabetes patients aged ≥ 65 years who used a self-injection insulin pen were administered the DASC-8 and a questionnaire to evaluate insulin self-injection techniques, and then received technical education. The questionnaire was administered again 4 months later, and patients were classified into the education-effective and education-ineffective groups. The achievement of HbA1c targets defined for each patient according to guidelines based on DASC-8 category was examined over 12 months. Results: 76 Japanese patients (median age 72.0 years and 53.9% female) with DASC-8 categories I (n = 55), II (n = 13), and III (n = 8) were enrolled. In the education-effective group, the percentage of patients in category I was significantly higher than that of patients in category II or III (92.0% to 23.8%, P < 0.001). Category I was independently associated with education effectiveness (odds ratio 14.50, 95% confidence interval: 2.110-100.0, P = 0.007). Category I patients in the education-effective group showed significantly improved achievement of target HbA1c from baseline to the 12th month (from 27.6% to 62.1%, P = 0.008). Conclusions: The DASC-8 was a useful indicator for identifying elderly patients who would benefit from education on self-injection techniques. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-024-00710-z.
ABSTRACT
Most cases of nontuberculous mycobacterial pulmonary disease (NTM-PD) have a progressive clinical course, and initiation of treatment is recommended rather than watchful waiting. The NTM-PD medications are frequently associated with adverse reactions, occasionally serious. Optimization of the methods for monitoring and managing adverse events in NTM-PD treatment is thus an important medical issue. Here we report a first case of postprandial hypoglycemia caused by the combination of clarithromycin (CAM) and rifampicin (RFP) in a patient with NTM-PD. A 73-year-old Japanese woman with NTM-PD was hospitalized for treatment with a combination of oral CAM, RFP, and ethambutol. She took the first doses of antibiotics before breakfast, and 3 h later went into a hypoglycemic state. Postprandial hypoglycemia occurred with high reproducibility and was accompanied by relative insulin excess. Continuous glucose monitoring with or without food and in combination with various patterns of medication revealed that the combination of CAM and RFP specifically induced postprandial hypoglycemia. Shifting the timing of administration of the CAM and RFP combination from morning to before sleep corrected the hypoglycemia and enabled continuation of the antimicrobial treatment. In conclusion, our report suggests the importance of introducing NTM-PD medication under inpatient management in order to closely monitor and early detect postprandial hypoglycemia and other serious adverse events.
ABSTRACT
BACKGROUND: Whether human T-lymphotropic virus type 1 (HTLV-1) carriers can develop sufficient humoral immunity after coronavirus disease 2019 (COVID-19) vaccination is unknown. METHODS: To investigate humoral immunity after COVID-19 vaccination in HTLV-1 carriers, a multicenter, prospective observational cohort study was conducted at five institutions in southwestern Japan, an endemic area for HTLV-1. HTLV-1 carriers and HTLV-1-negative controls were enrolled for this study from January to December 2022. During this period, the third dose of the COVID-19 vaccine was actively administered. HTLV-1 carriers were enrolled during outpatient visits, while HTLV-1-negative controls included health care workers and patients treated by participating institutions for diabetes, hypertension, or dyslipidemia. The main outcome was the effect of HTLV-1 infection on the plasma anti-COVID-19 spike IgG (IgG-S) titers after the third dose, assessed by multivariate linear regression with other clinical factors. RESULTS: We analyzed 181 cases (90 HTLV-1 carriers, 91 HTLV-1-negative controls) after receiving the third dose. HTLV-1 carriers were older (median age 67.0 vs. 45.0 years, p < 0.001) and more frequently had diabetes, hypertension, or dyslipidemia than did HTLV-1-negative controls (60.0% vs. 27.5%, p < 0.001). After the third dose, the IgG-S titers decreased over time in both carriers and controls. Multivariate linear regression in the entire cohort showed that time since the third dose, age, and HTLV-1 infection negatively influenced IgG-S titers. After adjusting for confounders such as age, or presence of diabetes, hypertension, or dyslipidemia between carriers and controls using the overlap weighting propensity score method, and performing weighted regression analysis in the entire cohort, both time since the third dose and HTLV-1 infection negatively influenced IgG-S titers. CONCLUSIONS: The humoral immunity after the third vaccination dose is impaired in HTLV-1 carriers; thus, customized vaccination schedules may be necessary for them.
Subject(s)
COVID-19 , Diabetes Mellitus , Dyslipidemias , HTLV-I Infections , Human T-lymphotropic virus 1 , Hypertension , Humans , Aged , COVID-19/prevention & control , COVID-19 Vaccines , Immunity, Humoral , Prospective Studies , Vaccination , Immunoglobulin G , Antibodies, ViralABSTRACT
Aims: The longitudinal effect of personality traits on glycemic control is unclear. This prospective observational study explored the relationship between personality traits and glycemic control in patients with uncontrolled diabetes after inpatient diabetes education. Methods: Patients with diabetes mellitus (HbA1c ≥ 7.5%, measured by high-performance liquid chromatography) who received inpatient diabetes education were scored on the Big Five personality traits: neuroticism, extraversion, openness, agreeableness, and conscientiousness. Multiple linear analysis was used to determine whether any personality traits were independently associated with HbA1c on admission and HbA1c change from admission to 1, 3, and 6 months after discharge. Results: One hundred seventeen participants (mean age 60.4 ± 14.5 years; 59.0% male) were enrolled. HbA1c values on admission and 1, 3, and 6 months after discharge were 10.2 ± 2.1%, 8.3 ± 1.4%, 7.6 ± 1.4%, and 7.7 ± 1.5%, respectively. Multiple linear analysis showed that no personality traits were associated with HbA1c on admission. Neuroticism was negatively associated with the HbA1c change from admission to 3 months (ß = -0.192, P = 0.025) and 6 months after discharge (ß = -0.164, P = 0.043). Conclusions: Neuroticism was associated with good long-term glycemic control after inpatient diabetes education.
ABSTRACT
There is no computed tomography (CT)-based numerical index for predicting Cushing's syndrome (CS) in patients with adrenal incidentalomas. We tested the hypothesis that the iliopsoas muscle (Ip-M) to visceral fat (V-fat) ratio (IVR) on CT may predict CS in elderly female patients with adrenal tumors. We examined the V-fat area, subcutaneous fat (S-fat) area, Ip-M area, V-fat/S-fat ratio, and IVR at the third lumbar vertebra (L3) level using abdominal CT in female patients aged ≥50 years with cortisol-producing adrenal tumor diagnosed with CS or non-functioning adrenal tumor (NFT) in the derivation cohort. We performed receiver operating characteristic (ROC) analysis to evaluate the diagnostic value of the V-fat/S-fat ratio and IVR for predicting CS. We assessed the usefulness of the IVR in a separate validation cohort. In the derivation cohort, the IVR was significantly lower in the 9 patients with CS than in the 15 patients with NFT (p < 0.001). In ROC analysis with a cut-off value of 0.067, the IVR showed a sensitivity of 100%, speciï¬city of 80.0%, positive likelihood ratio (PLR) of 5.000, and negative likelihood ratio (NLR) of 0.000. The area under the curve was significantly higher for the IVR than for the V-fat/S-fat ratio (0.933 vs. 0.704, respectively, p = 0.036). In 23 patients in the validation cohort, the IVR demonstrated a PLR of 5.714 and an NLR of 0.327. The novel IVR index, based on single-slice CT at the L3 level, predicted CS in elderly female patients with adrenal tumors.
Subject(s)
Adrenal Gland Neoplasms , Cushing Syndrome , Aged , Humans , Female , Cushing Syndrome/diagnostic imaging , Cushing Syndrome/pathology , Adrenal Gland Neoplasms/complications , Adrenal Gland Neoplasms/diagnostic imaging , Adrenal Gland Neoplasms/pathology , Intra-Abdominal Fat/diagnostic imaging , Intra-Abdominal Fat/pathology , Tomography, X-Ray Computed , Hydrocortisone , Muscle, Skeletal/diagnostic imaging , Muscle, Skeletal/pathologyABSTRACT
INTRODUCTION: Endothelial dysfunction is a risk factor for cardiovascular disease in patients with diabetes. We hypothesized that imeglimin, a novel oral hypoglycemic agent, would improve endothelial function. METHODS: In this study, imeglimin was administered to patients with type 2 diabetes and HbA1c ≥ 6.5% who were not receiving insulin therapy. A meal tolerance test (592 kcal, glucose 75.0 g, fat 28.5 g) was performed before and 3 months after administration, and endothelial function, blood glucose, insulin, glucagon, and triglycerides were evaluated. Endothelial function was assessed by flow-mediated dilation (FMD). RESULTS: Twelve patients (50% male) with a median age of 55.5 years old (interquartile range [IQR] 51.3-66.0) were enrolled. Fasting FMD did not differ before or 3 months after imeglimin administration (from 6.1 [3.9-8.5] to 6.6 [3.9-9.0], p = 0.092), but 2 h postprandial FMD was significantly improved 3 months after imeglimin administration (from 2.3 [1.9-3.4] to 2.9 [2.4-4.7], p = 0.013). In terms of the glucose profile, imeglimin administration significantly improved HbA1c (from 7.2 ± 0.6% to 6.9 ± 0.6%, p = 0.007), fasting glucose (from 138 ± 19 mg/dL to 128 ± 20 mg/dL, p = 0.020), and 2 h postprandial glucose (from 251 ± 47 mg/dL to 215 ± 68 mg/dL, p = 0.035). The change in 2 h postprandial FMD between before and 3 months after imeglimin administration (Δ2 h postprandial FMD) was negatively correlated with Δ2 h postprandial glucose (r = - 0.653, p = 0.021) in a univariate correlation coefficient analysis. Both patients with and without decreased postprandial glucose 3 months after imeglimin administration had improved postprandial FMD. CONCLUSION: In this small study, imeglimin administration improved 2 h postprandial FMD. Both glycemic control-dependent and -independent mechanisms might contribute to improved endothelial function. TRIAL REGISTRATION: This research was registered in the University Hospital Medical Information Network (UMIN, UMIN000046311).
ABSTRACT
OBJECTIVE: NF-κB signaling is an important modulator in osteoarthritis (OA), and IκB kinase ε (IKKε) regulates the NF-κB pathway. This study was undertaken to identify the functional involvement of IKKε in the pathogenesis of OA and the effectiveness of IKKε inhibition as a modulatory treatment. METHODS: IKKε expression in normal and OA human knee joints was analyzed immunohistochemically. Gain- or loss-of-function experiments were performed using human chondrocytes. Furthermore, OA was surgically induced in mice, followed by intraarticular injection of BAY-985, an IKKε/TANK-binding kinase 1 inhibitor, into the left knee joint every 5 days for 8 weeks. Mice were subsequently examined for histologic features of cartilage damage and inflammation. RESULTS: IKKε protein expression was increased in human OA cartilage. In vitro, expression levels of OA-related factors were down-regulated following knockdown of IKKε with the use of small interfering RNA in human OA chondrocytes or following treatment with BAY-985. Conversely, IKKε overexpression significantly increased the expression of OA-related catabolic mediators. In Western blot analysis of human chondrocytes, IKKε overexpression increased the phosphorylation of IκBα and p65. In vivo, intraarticular injection of BAY-985 into the knee joints of mice attenuated OA-related cartilage degradation and hyperalgesia via NF-κB signaling. CONCLUSION: These results suggest that IKKε regulates cartilage degradation through a catabolic response mediated by NF-κB signaling, and this could represent a potential target for OA treatment. Furthermore, BAY-985 may serve as a major disease-modifying compound among the drugs developed for OA.
Subject(s)
Cartilage, Articular , Osteoarthritis , Humans , Mice , Animals , NF-kappa B/metabolism , I-kappa B Kinase/metabolism , Disease Models, Animal , Cartilage/metabolism , Osteoarthritis/metabolism , Knee Joint/metabolism , Chondrocytes/metabolism , Cartilage, Articular/metabolismABSTRACT
OBJECTIVE: Konjac is a food mainly consumed in Asian countries with high fiber and low energy. Although glucomannan, a component of konjac, have been used for several clinical studies, there is few reports using konjac itself. This study examined the effects of the active consumption of konjac in patients with type 2 diabetes mellitus (T2DM). METHODS: The study included 26 Japanese patients with T2DM. Participants were recommended to take konjac at least once a day using free konjac products (various noodles, rice, and desserts) and plate konjac for 12 weeks. RESULTS: HbA1c and fasting plasma glucose levels significantly decreased from 8.3 ± 0.9% to 8.0 ± 0.8% and from 173.2 ± 44.4 to 152.8 ± 36.7 mg/dL, respectively. No significant changes were observed in body weight and insulin resistance indices, but the index for insulin secretion significantly increased. Serum high molecular weight adiponectin levels significantly increased. Plasma ghrelin, leptin and glucagon-like peptide-1 levels tended to decrease (p = 0.084), decrease (p = 0.057) and increase (p = 0.071), respectively. Actual konjac intake positively correlated with age (r = 0.61, p = 0.001). Body weight and HbA1c significantly decreased in patients aged ≥50 years than in those aged <50 years, and the changes significantly inversely correlated with age. CONCLUSION: Active consumption of konjac and konjac products seems to be a useful dietary therapy with multifaceted action for T2DM. Further studies with greater sample size and long-term are needed to confirm these findings.
Subject(s)
Amorphophallus , Diabetes Mellitus, Type 2 , Humans , Glycated Hemoglobin , Glycemic Control , Body WeightABSTRACT
BACKGROUND: X-ray images are commonly used to assess the bone destruction of rheumatoid arthritis. The purpose of this study is to propose an automatic-bone-destruction-evaluation system fully utilizing deep neural networks (DNN). This system detects all target joints of the modified Sharp/van der Heijde score (SHS) from a hand X-ray image. It then classifies every target joint as intact (SHS = 0) or non-intact (SHS ≥ 1). METHODS: We used 226 hand X-ray images of 40 rheumatoid arthritis patients. As for detection, we used a DNN model called DeepLabCut. As for classification, we built four classification models that classify the detected joint as intact or non-intact. The first model classifies each joint independently, whereas the second model does it while comparing the same contralateral joint. The third model compares the same joint group (e.g., the proximal interphalangeal joints) of one hand and the fourth model compares the same joint group of both hands. We evaluated DeepLabCut's detection performance and classification models' performances. The classification models' performances were compared to three orthopedic surgeons. RESULTS: Detection rates for all the target joints were 98.0% and 97.3% for erosion and joint space narrowing (JSN). Among the four classification models, the model that compares the same contralateral joint showed the best F-measure (0.70, 0.81) and area under the curve of the precision-recall curve (PR-AUC) (0.73, 0.85) regarding erosion and JSN. As for erosion, the F-measure and PR-AUC of this model were better than the best of the orthopedic surgeons. CONCLUSIONS: The proposed system was useful. All the target joints were detected with high accuracy. The classification model that compared the same contralateral joint showed better performance than the orthopedic surgeons regarding erosion.
Subject(s)
Arthritis, Rheumatoid , Deep Learning , Arthritis, Rheumatoid/diagnostic imaging , Disease Progression , Humans , Joints/diagnostic imaging , Radiography , Severity of Illness IndexABSTRACT
BACKGROUND: Adipose-derived mesenchymal stem cells (ADMSCs) are a promising source of material source for medical regeneration of cartilage. Growth factors, including transforming growth factor-ß (TGFß) subfamily members and bone morphogenetic proteins (BMPs), play important roles in inducing and promoting chondrogenic differentiation of MSCs. However, these exogenous growth factors have some drawbacks related to their cost, biological half-life, and safety for clinical application. Several studies have reported that statins, the competitive inhibitors of 3-hydroxy-2-methylglutaryl coenzyme A (HMG-CoA) reductase, induce the expression of BMP2 in multiple cell types as the pleotropic effects. The objective of this study was to investigate the effects of fluvastatin during chondrogenic differentiation of human ADMSCs (hADMSCs). METHODS: The effects of fluvastatin were analyzed during chondrogenic differentiation of hADMSCs in the pellet culture without exogenous growth factors by qRT-PCR and histology. For functional studies, Noggin, an antagonist of BMPs, mevalonic acid (MVA) and geranylgeranyl pyrophosphate (GGPP), metabolites of the mevalonate pathway, ROCK inhibitor (Y27632), or RAC1 inhibitor (NSC23766) were applied to cells during chondrogenic differentiation. Furthermore, RhoA activity was measured by RhoA pulldown assay during chondrogenic differentiation with or without fluvastatin. Statistically significant differences between groups were determined by Student's t-test or the Tukey-Kramer test. RESULTS: Fluvastatin-treated cells expressed higher levels of BMP2, SOX9, ACAN, and COL2A1 than control cells, and accumulated higher levels of glycosaminoglycans (GAGs). Noggin significantly inhibited the fluvastatin-mediated upregulation of ACAN and COL2A1. Both MVA and GGPP suppressed the effects of fluvastatin on the expressions of BMP2, SOX9, ACAN, and COL2A1. Furthermore, fluvastatin suppressed the RhoA activity, and inhibition of RhoA-ROCK signaling by Y27632 increased the expressions of BMP2, SOX9, ACAN, and COL2A1, as well as fluvastatin. CONCLUSIONS: Our results suggest that fluvastatin promotes chondrogenic differentiation of hADMSCs by inducing endogenous BMP2, and that one of the mechanisms underlying the effects is inhibition of RhoA-ROCK signaling via suppression of GGPP. Fluvastatin is a safe and low-cost compound that holds promise for use in transplantation of hADMSCs for cartilage regeneration.
Subject(s)
Bone Morphogenetic Protein 2 , Mesenchymal Stem Cells , Bone Morphogenetic Protein 2/genetics , Bone Morphogenetic Protein 2/metabolism , Bone Morphogenetic Protein 2/pharmacology , Cell Differentiation , Cells, Cultured , Chondrogenesis , Fluvastatin/metabolism , Fluvastatin/pharmacology , Humans , Mesenchymal Stem Cells/metabolismABSTRACT
We present a female patient with autonomously functioning thyroid nodule (AFTN) and coexisting follicular thyroid carcinoma (FTC). At age 21, a left thyroid nodule was incidentally detected on computer tomography (CT) scan. At age 33, she had cervical compression and CT showed the left thyroid nodule had increased in size from 13 to 27 mm. Laboratory investigation showed subclinical hyperthyroidism with positive for anti-thyroid peroxidase antibody and normal level of serum thyroglobulin. Repeated fine needle aspiration cytology diagnosed with follicular neoplasm with Hashimoto's thyroiditis. At age 35, she presented with palpitations due to overt hyperthyroidism. The left thyroid nodule increased in diameter to 33 mm, and thyroid scintigraphy showed elevated uptake in the left thyroid nodule, indicating an AFTN. Thyroidectomy was performed, and the left thyroid nodule was pathologically diagnosed with FTC with capsular invasion. In this case, the longitudinal increase in AFTN size suggested FTC and led to thyroidectomy.
ABSTRACT
Homozygous ENPP1 mutations are associated with autosomal recessive hypophosphatemic rickets type 2 (ARHR2), severe ossification of the spinal ligaments, and generalized arterial calcification of infancy type 1. There are a limited number of reports on phenotypes associated with heterozygous ENPP1 mutations. Here, we report a series of three probands and their families with heterozygous and compound heterozygous ENPP1 mutations. The first case (case 1) was a 47-year-old male, diagnosed with early-onset osteoporosis and low-normal serum phosphate levels, which invoked suspicion for hypophosphatemic rickets. The second and third cases were 77- and 54-year-old females who both presented with severe spinal ligament ossification and the presumptive diagnosis of diffuse idiopathic skeletal hyperostosis (DISH). Upon workup, fibroblast growth factor 23 (FGF23) was noted to be relatively high in case 2 and serum phosphorous was low-normal in case 3, and the diagnoses of X-linked hypophosphatemic rickets (XLH) and ARHR2 were considered. Genetic testing for genes related to congenital hypophosphatemic rickets was therefore performed, revealing heterozygous ENPP1 variants in cases 1 and 2 (case 1, c.536A>G, p.Asn179Ser; case 2, c.1352A>G, p.Tyr451Cys) and compound heterozygous ENPP1 variants in case 3 constituting the same variants present in cases 1 and 2 (c.536A>G, p.Asn179Ser and c.1352A>G, p.Tyr451Cys). Several in silico tools predicted the two variants to be pathogeneic, a finding confirmed by in vitro biochemical analysis demonstrating that the p.Asn179Ser and p.Tyr451Cys ENPP1 variants possessed a catalytic velocity of 45% and 30% compared with that of wild-type ENPP1, respectively. Both variants were therefore categorized as pathogenic loss-of-function mutations. Our findings suggest that ENPP1 mutational status should be evaluated in patients presenting with the diagnosis of idiopathic DISH, ossification of the posterior longitudinal ligament (OPLL), and early-onset osteoporosis. © 2022 American Society for Bone and Mineral Research (ASBMR).
Subject(s)
Familial Hypophosphatemic Rickets , Hyperostosis, Diffuse Idiopathic Skeletal , Osteoporosis , Rickets, Hypophosphatemic , Familial Hypophosphatemic Rickets/complications , Familial Hypophosphatemic Rickets/genetics , Female , Fibroblast Growth Factors/genetics , Haploinsufficiency , Humans , Hyperostosis, Diffuse Idiopathic Skeletal/complications , Male , Osteoporosis/complications , Osteoporosis/genetics , Phosphoric Diester Hydrolases/genetics , Pyrophosphatases/genetics , Rickets, Hypophosphatemic/complicationsABSTRACT
AIMS/INTRODUCTION: The Japanese diabetes treatment guidelines do not specify the first choice of hypoglycemic agents, unlike those of Western countries. Furthermore, the current situation in diabetes treatment is that the choice of hypoglycemic agents is determined by each physician. Therefore, we aimed to determine the current situation in Miyazaki Prefecture, Japan, in this context. For this, we carried out a questionnaire survey among physicians twice regarding the target value of glycated hemoglobin and the choice of hypoglycemic agents in various cases. MATERIALS AND METHODS: We administered an unsigned questionnaire to physicians in Miyazaki Prefecture, Japan, in July 2016 and March 2020. We divided responses into those of diabetologists and those of non-diabetologists, and analyzed each response. We then compared the results between both years. RESULTS: In total, 18 diabetologists and 142 non-diabetologists responded in 2016, and 21 diabetologists and 134 non-diabetologists responded in 2020. Many diabetologists chose biguanide as the first-line drug for obese type 2 diabetes patients. In addition, the rate of choice of sodium-glucose cotransporter 2 inhibitor (SGLT2i) among physicians almost increased in 2020. Some non-diabetologists, and even a few diabetologists, inappropriately chose SGLT2i and biguanide for patients with severe renal dysfunction. CONCLUSIONS: Because SGLT2i became available in 2016 and a few years have passed, both diabetologists and non-diabetologists seemed to refrain from prescribing SGLT2i. However, with the emergence of various lines of firm evidence regarding the use of SGLT2i, physicians started to prescribe it. However, some diabetologists and non-diabetologists chose hypoglycemic agents inadequately; therefore, there is a need for novel and precise information.
Subject(s)
Diabetes Mellitus, Type 2 , Sodium-Glucose Transporter 2 Inhibitors , Biguanides/therapeutic use , Diabetes Mellitus, Type 2/chemically induced , Diabetes Mellitus, Type 2/drug therapy , Humans , Hypoglycemic Agents/adverse effects , Japan/epidemiology , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Surveys and QuestionnairesABSTRACT
Osteoarthritis (OA), the most prevalent joint disease, is characterized by the progressive loss of articular cartilage. Autophagy, a lysosomal degradation pathway, maintains cellular homeostasis, and autophagic dysfunction in chondrocytes is a hallmark of OA pathogenesis. However, the cause of autophagic dysfunction in OA chondrocytes remains incompletely understood. Recent studies have reported that decidual protein induced by progesterone (C10orf10/DEPP) positively regulates autophagic functions. In this study, we found that DEPP was involved in mitochondrial autophagic functions of chondrocytes, as well as in OA pathogenesis. DEPP expression decreased in human OA chondrocytes in the absence or presence of pro-inflammatory cytokines, and was induced by starvation, hydrogen peroxide (H2 O2 ), and hypoxia (cobalt chloride). For functional studies, DEPP knockdown decreased autophagic flux induced by H2 O2 , whereas DEPP overexpression increased autophagic flux and maintained cell viability following H2 O2 treatment. DEPP was downregulated by knockdown of forkhead box class O (FOXO) transcription factors and modulated the autophagic function regulated by FOXO3. In an OA mouse model by destabilization of the medial meniscus, DEPP-knockout mice exacerbated the progression of cartilage degradation with TUNEL-positive cells, and chondrocytes isolated from knockout mice were decreased autophagic flux and increased cell death following H2 O2 treatment. Subcellular fractionation analysis revealed that mitochondria-located DEPP activated mitochondrial autophagy via BCL2 interacting protein 3. Taken together, our data demonstrate that DEPP is a major stress-inducible gene involved in the activation of mitochondrial autophagy in chondrocytes, and maintains chondrocyte viability during OA pathogenesis. DEPP represents a potential therapeutic target for enhancing autophagy in patients with OA.
Subject(s)
Autophagy/physiology , Cell Survival/physiology , Chondrocytes/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Mitochondria/metabolism , Osteoarthritis/metabolism , Aged , Aged, 80 and over , Animals , Cartilage, Articular/metabolism , Cartilage, Articular/pathology , Cell Death/physiology , Chondrocytes/pathology , Female , Forkhead Box Protein O3/metabolism , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Mitochondria/pathology , Osteoarthritis/pathologyABSTRACT
G protein-coupled receptor kinase 5 (GRK5) regulates inflammatory responses via the nuclear factor-kappa B (NF-κB) pathway. This study investigated the functional involvement of GRK5 in the pathogenesis of inflammatory arthritis. Immunohistochemically, rheumatoid arthritis (RA) synovium had a significantly higher proportion of GRK5-positive cells in the synovial lining layer than healthy control synovium. Gene expression and NF-κB activation in lipopolysaccharide-stimulated human SW982 synovial cells were significantly suppressed by silencing of the GRK5 gene. Similarly, GRK5 kinase activity inhibition in human primary RA synovial cells attenuated gene expressions of inflammatory factors. In a murine model of collagen antibody-induced arthritis, arthritis scores and serum IL6 production of GRK5 knockout (GRK5-/-) mice were significantly lower than those of wild-type mice. Histologically, the degree of synovitis and cartilage degeneration in GRK5-/- mice was significantly lower than in wild-type mice. In in vitro analyses using activated murine macrophages and fibroblast-like synoviocytes, gene expression of inflammatory factors and p65 nuclear translocation were significantly lower in GRK5-/- mice compared to wild-type mice. In conclusion, our results suggested that GRK5 is deeply involved in the pathogenesis of inflammatory arthritis, therefore, GRK5 inhibition could be a potential therapeutic target for types of inflammatory arthritis such as RA.
Subject(s)
Arthritis, Experimental/prevention & control , G-Protein-Coupled Receptor Kinase 5/genetics , Gene Silencing , Synovitis/prevention & control , Animals , Arthritis, Experimental/metabolism , Case-Control Studies , Disease Models, Animal , Humans , Inflammation Mediators/metabolism , Mice , NF-kappa B/metabolism , RNA, Small Interfering/genetics , Synovitis/metabolismABSTRACT
We report a case of a 47-year-old woman with hypercalcemia 6 months after discontinuation of denosumab. She underwent right mastectomy for breast cancer and had received aromatase inhibitor and denosumab therapy for 5 years. Thirst, appetite loss, and bilateral ankle pain began few months after cessation of denosumab. She was admitted to the hospital for hypercalcemia and hyperthyroidism 6 months after the last dose of denosumab. Laboratory investigations revealed hypercalcemia, normophosphatemia, normal renal function, and elevated levels of fibroblast growth factor 23 (FGF-23). Serum tartrate-resistant acid phosphatase 5b and urine N-terminal cross-linked telopeptide of type I collagen were both elevated, and bone scintigraphy revealed increase of whole bone uptake. Radiological examinations showed no recurrence of breast cancer or tumors that secrete intact PTH or FGF-23. Hypercalcemia, which lasted for 1 month, was refractory to discontinuation of the aromatase inhibitor, normalization of thyroid hormone levels, saline hydration, and calcitonin administration, but was effectively treated with zoledronic acid. Abnormal uptake on bone scintigraphy and ankle pain both resolved a few months after treatment, and hypercalcemia has not recurred in the ensuing 2 years. In conclusion, we found elevated levels of circulating FGF-23 with hypercalcemia following the discontinuation of denosumab. FGF-23 might be a surrogate marker for massive bone resorption triggered by discontinuation of long-term denosumab treatment.
Subject(s)
Aromatase Inhibitors/therapeutic use , Bone Density Conservation Agents/therapeutic use , Bone Neoplasms/prevention & control , Bone Resorption/blood , Breast Neoplasms/drug therapy , Denosumab/therapeutic use , Deprescriptions , Hypercalcemia/blood , Ankle , Anorexia/etiology , Anorexia/physiopathology , Antithyroid Agents/therapeutic use , Arthralgia/etiology , Arthralgia/physiopathology , Bone Neoplasms/secondary , Bone Resorption/drug therapy , Bone Resorption/etiology , Bone Resorption/physiopathology , Collagen Type I/urine , Female , Fibroblast Growth Factor-23 , Fibroblast Growth Factors/blood , Graves Disease/diagnosis , Graves Disease/drug therapy , Humans , Hypercalcemia/drug therapy , Hypercalcemia/etiology , Hypercalcemia/physiopathology , Methimazole/therapeutic use , Middle Aged , Parathyroid Hormone/blood , Peptides/urine , Potassium Iodide/therapeutic use , Radionuclide Imaging , Tartrate-Resistant Acid Phosphatase/blood , Thirst , Zoledronic Acid/therapeutic useABSTRACT
OBJECTIVE: NF-κB-dependent signaling is an important modulator in osteoarthritis (OA), and G protein-coupled receptor kinase 5 (GRK5) regulates the NF-κB pathway. This study was undertaken to investigate the functional involvement of GRK5 in OA pathogenesis. METHODS: GRK5 expression in normal and OA human knee joints was analyzed immunohistochemically. Gain- or loss-of-function experiments were performed using human and mouse chondrocytes. OA was induced in GRK5-knockout mice by destabilization of the medial meniscus, and histologic examination was performed. OA was also induced in wild-type mice, which were then treated with an intraarticular injection of amlexanox, a selective GRK5 inhibitor, every 5 days for 8 weeks. RESULTS: GRK5 protein expression was increased in human OA cartilage. In vitro, expression levels of OA-related factors and NF-κB transcriptional activation were down-regulated by suppression of the GRK5 gene in human OA chondrocytes (3.49-fold decrease in IL6 [P < 0.01], 2.43-fold decrease in MMP13 [P < 0.01], and 2.66-fold decrease in ADAMTS4 [P < 0.01]). Conversely, GRK5 overexpression significantly increased the expression of OA-related catabolic mediators and NF-κB transcriptional activation. On Western blot analysis, GRK5 deletion reduced IκBα phosphorylation (up to 4.4-fold decrease [P < 0.05]) and decreased p65 nuclear translocation (up to 6.4-fold decrease [P < 0.01]) in mouse chondrocytes. In vivo, both GRK5 deletion and intraarticular amlexanox protected mouse cartilage against OA. CONCLUSION: Our results suggest that GRK5 regulates cartilage degradation through a catabolic response mediated by NF-κB signaling, and is a potential target for OA treatment. Furthermore, amlexanox may be a major compound in relevant drugs.
Subject(s)
Cartilage, Articular/metabolism , Chondrocytes/metabolism , G-Protein-Coupled Receptor Kinase 5/metabolism , Knee Joint/metabolism , NF-kappa B/metabolism , Osteoarthritis, Knee/metabolism , Signal Transduction/physiology , Adolescent , Adult , Aged , Aged, 80 and over , Aminopyridines/pharmacology , Animals , Cartilage, Articular/pathology , Chondrocytes/drug effects , Chondrocytes/pathology , Enzyme Inhibitors/pharmacology , Female , G-Protein-Coupled Receptor Kinase 5/antagonists & inhibitors , G-Protein-Coupled Receptor Kinase 5/genetics , Gene Expression Regulation , Humans , Knee Joint/pathology , Male , Mice , Mice, Knockout , Middle Aged , NF-KappaB Inhibitor alpha/metabolism , Osteoarthritis, Knee/pathology , Phosphorylation , RNA, Small Interfering , Signal Transduction/drug effects , Young AdultABSTRACT
SUMMARY: We report the case of a 48-year-old man with thyroid storm associated with fulminant hepatitis and elevated levels of soluble interleukin-2 receptor (sIL-2R). Fatigue, low-grade fever, shortness of breath, and weight loss developed over several months. The patient was admitted to the hospital because of tachycardia-induced heart failure and liver dysfunction. Graves' disease with heart failure was diagnosed. He was treated with methimazole, inorganic iodide, and a ß-blocker. On the day after admission, he became unconscious with a high fever and was transferred to the intensive care unit. Cardiogenic shock with atrial flutter was treated with intra-aortic balloon pumping and cardioversion. Hyperthyroidism decreased over 10 days, but hepatic failure developed. He was diagnosed with thyroid storm accompanied by fulminant hepatitis. Laboratory investigations revealed elevated levels of sIL-2R (9770 U/mL). The fulminant hepatitis was refractory to plasma exchange and plasma filtration with dialysis, and no donors for liver transplantation were available. He died of hemoperitoneum and gastrointestinal hemorrhage due to fulminant hepatitis 62 days after admission. Elevated circulating levels of sIL-2R might be a marker of poor prognosis in thyroid storm with fulminant hepatitis. LEARNING POINTS: The prognosis of thyroid storm when fulminant hepatitis occurs is poor. Liver transplantation is the preferred treatment for fulminant hepatitis induced by thyroid storm refractory to plasma exchange. Elevated levels of soluble interleukin-2 receptor might be a marker of poor prognosis in patients with thyroid storm.
ABSTRACT
We report a case of rapid pleural effusion after discontinuation of lenvatinib. A 73-year-old woman was diagnosed with poorly differentiated thyroid cancer with right pleural metastasis. Weekly paclitaxel treatment was performed for 18 weeks, but it was not effective. Oral administration of lenvatinib, a multi-target tyrosine kinase inhibitor, reduced the size of cervical and thoracic tumors and lowered serum thyroglobulin levels. Lenvatinib was discontinued on day 28 because of Grade 2 thrombocytopenia and Grade 3 petechiae. Seven days after discontinuation of lenvatinib, the patient was hospitalized because of dyspnea and right pleural effusion. Pleural effusion rapidly improved with drainage and re-initiation of lenvatinib and did not recur. Anorexia caused by lenvatinib led to undernutrition, which resulted in death 13 months after initiation of lenvatinib. Autopsy revealed extensive necrosis with primary and metastatic lesions, suggesting that the patient responded to lenvatinib. Physicians should be aware of the possibility of flare-up in patients with thyroid cancer treated with lenvatinib. Learning points: Autopsy findings revealed that lenvatinib was efficacious in treating poorly differentiated thyroid cancer without primary lesion resection. Flare-up phenomenon may occur in thyroid cancer treated with lenvatinib. Attention should be paid to flare-up phenomenon within a few days of discontinuing lenvatinib.