Live tracking of basal stem cells of the epidermis during growth, homeostasis and injury response in zebrafish.

Basal stem cells of the epidermis continuously differentiate into keratinocytes and replenish themselves via self-renewal to maintain skin homeostasis. Numerous studies have attempted to reveal how basal cells undergo differentiation or self-renewal; however, this has been hampered by a lack of robust basal cell markers and analytical platforms that allow single-cell tracking. Here, we report that zebrafish integrin beta 4 is a useful marker for basal cell labelling, irrespective of the body region, stage and regenerative status. We employed Cre-loxP recombination in combination with live cell tracking of single basal clones in the caudal fin and investigated the embryonic origin and behaviour of basal cells during fish growth and homeostasis. Although most basal cells, including those in fins, became quiescent in the adult stage, genetic cell ablation showed that basal cells were reactivated to either self-renew or differentiate, depending on the injured cell type. Our study provides a simple and easy-to-use platform for quantitative in vivo imaging of basal stem cells at wider stages and under various conditions.

A Disintegrin and metalloproteinase carves T cell abnormalities and pathogenesis in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder impacting various organs, notably prevalent in women of reproductive age. This review explores the involvement of a disintegrin and metalloproteinases (ADAMs) in SLE pathogenesis. Despite advancements in understanding SLE through genome and transcriptome studies, the role of ADAMs in post-translational regulations remains insufficiently explored. ADAMs, transmembrane proteins with diverse functions, impact cell adhesion, migration, and inflammation by shedding cell surface proteins, growth factors, and receptors. Notably, ADAM9 is implicated in Th17 cell differentiation, which is crucial in SLE pathology. ADAM10 and ADAM17 play pivotal roles in T-cell biology, influencing immune cell development and differentiation. Elevated soluble ADAM substrates in SLE patients serve as potential biomarkers correlating with disease activity. Targeting ADAMs or their substrates offers promising therapeutic avenues for SLE management and treatment enhancement.

Period prevalence of uveitis in human T-lymphotropic virus 1 carriers versus noncarriers in a highly endemic area: The Nagasaki Islands Study.

The magnitude of the effect of human T-lymphotropic virus 1 (HTLV-1) infection on uveitis remains unclear. We conducted a cross-sectional study in a highly endemic area of HTLV-1 in Japan. The study included 4265 residents (men, 39.2%), mostly middle-aged and older individuals with a mean age of 69.9 years, who participated in our surveys between April 2016 and September 2022. We identified HTLV-1 carriers by screening using chemiluminescent enzyme immunoassays and confirmatory tests, and the proportion of carriers was 16.1%. Participants with uveitis were determined from the medical records of all hospitals and clinics where certified ophthalmologists practiced. We conducted logistic regression analyses in an age- and sex-adjusted model to compute the odds ratio (OR) and 95% confidence interval (CI) of uveitis according to HTLV-1 infection status. Thirty-two (0.8%) participants had uveitis. For HTLV-1 carriers, the age- and sex-adjusted OR (95% CI) of uveitis was 3.27 (1.57-6.72) compared with noncarriers. In conclusion, HTLV-1 infection was associated with a higher risk of uveitis among mostly middle-aged and older Japanese residents in a highly endemic HTLV-1 area. Our findings suggest that physicians who treat HTLV-1 carriers should assess ocular symptoms, and those who diagnose patients with uveitis should consider HTLV-1 infection.

Independent mesenchymal progenitor pools respectively produce and maintain osteogenic and chondrogenic cells in zebrafish.

Skeletal tissues including cartilage and bones are characteristic features of vertebrates that are crucial for supporting body morphology and locomotion. Studies mainly in mice have shown that osteoblasts and chondroblasts are supplied from several progenitors like the sclerotome cells in the embryonic stage, osteo-chondroprogenitors in growing long bones, and skeletal stem cells of bone marrow in the postnatal period. However, the exact origins of progenitor cells, their lineage relationships, and their potential to differentiate into osteoblasts and chondroblasts from embryos to adult tissues are not well understood. In this study, we conducted clonal cell tracking in zebrafish and showed that sox9a+ cells are already committed to either chondrogenic or osteogenic fates during embryonic stages and that respective progenies are independently maintained as mesenchymal progenitor pools. Once committed, they never change their lineage identities throughout animal life, even through regeneration. In addition, we further revealed that only osteogenic mesenchymal cells replenish the osteoblast progenitor cells (OPCs), a population of reserved tissue stem cells found to be involved in the de novo production of osteoblasts during regeneration and homeostasis in zebrafish. Thus, our clonal cell tracking study in zebrafish firstly revealed that the mesenchymal progenitor cells that are fated to develop into either chondroblasts or osteoblasts serve as respective tissue stem cells to maintain skeletal tissue homeostasis. Such mesenchymal progenitors dedicated to producing either chondroblasts or osteoblasts would be important targets for skeletal tissue regeneration.

Absence of Glucocorticoids Concomitant With Avacopan and Subsequent Liver Injury in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Avacopan, a C5a receptor (C5aR) inhibitor, has emerged as a novel treatment for antineutrophil cytoplasmic antibody-associated vasculitis (AAV), providing an alternative to glucocorticoids (GCs).1 Despite its promising potential, severe liver dysfunction associated with avacopan has been reported in Japan.2,3.

Glucagon secretion and its association with glycaemic control and ketogenesis during sodium-glucose cotransporter 2 inhibition by ipragliflozin in people with type 1 diabetes: Results from the multicentre, open-label, prospective study.

AIM: Clinical trials showed the efficacy of sodium-glucose cotransporter 2 inhibitors for type 1 diabetes (T1D) by significant reductions in body weight and glycaemic variability, but elevated susceptibility to ketoacidosis via elevated glucagon secretion was a potential concern. The Suglat-AID evaluated glucagon responses and its associations with glycaemic control and ketogenesis before and after T1D treatment with the sodium-glucose cotransporter 2 inhibitor, ipragliflozin. METHODS: Adults with T1D (n = 25) took 50-mg open-labelled ipragliflozin daily as adjunctive to insulin. Laboratory/clinical data including continuous glucose monitoring were collected until 12 weeks after the ipragliflozin initiation. The participants underwent a mixed-meal tolerance test (MMTT) twice [before (first MMTT) and 12 weeks after ipragliflozin treatment (second MMTT)] to evaluate responses of glucose, C-peptide, glucagon and ß-hydroxybutyrate. RESULTS: The area under the curve from fasting (0 min) to 120 min (AUC0-120min) of glucagon in second MMTT were significantly increased by 14% versus first MMTT. The fasting and postprandial ß-hydroxybutyrate levels were significantly elevated in second MMTT versus first MMTT. The positive correlation between postprandial glucagon secretion and glucose excursions observed in first MMTT disappeared in second MMTT, but a negative correlation between fasting glucagon and time below range (glucose, <3.9 mmol/L) appeared in second MMTT. The percentage changes in glucagon levels (fasting and AUC0-120min) from baseline to 12 weeks were significantly correlated with those in ß-hydroxybutyrate levels. CONCLUSIONS: Ipragliflozin treatment for T1D increased postprandial glucagon secretion, which did not exacerbate postprandial hyperglycaemia but might protect against hypoglycaemia, leading to reduced glycaemic variability. The increased glucagon secretion might accelerate ketogenesis when adequate insulin is not supplied.

New onset of isolated adrenocorticotropin deficiency associated with encephalopathy following coronavirus disease 2019 in a healthy elderly man.

Coronavirus disease 2019 (COVID-19) due to a severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection can include various systemic organ disorders including endocrinopathies and neurological manifestations. We report the case of a 65-year-old Japanese man who developed isolated adrenocorticotropic hormone (ACTH) deficiency and encephalopathy following SARS-CoV-2 infection. Two weeks after his COVID-19 diagnosis, he was emergently admitted to our hospital because of subacute-onset delirium. On admission, he presented hyponatremia (128 mEq/L) and secondary adrenal insufficiency (ACTH <1.5 pg/mL, cortisol 0.53 µg/dL). Brain imaging and laboratory examinations including SARS-CoV-2 polymerase chain reaction testing in the cerebrospinal fluid revealed no abnormalities. His consciousness level worsened despite the amelioration of hyponatremia by intravenous hydrocortisone (100 mg/day), but his neurological presentations completely resolved after three consecutive days of high-dose (400 mg/day) hydrocortisone. His encephalopathy did not deteriorate during hydrocortisone tapering. He continued 15 mg/day hydrocortisone after discharge. His encephalopathy might have developed via a disturbance of the autoimmune system, or a metabolic effect associated with adrenal insufficiency, although the time lag between the hyponatremia's improvement and the patient's neurological response to the steroid was incompatible with common cases of delirium concurrent with adrenal insufficiency. At 13 months after his hospitalization, the patient's neurological symptoms have not recurred and he has no endocrinological dysfunctions other than the remaining ACTH deficiency. A thorough consideration of the immunological and metabolic characteristics of SARS-CoV-2 is advisable when clinicians treat patients during and even after their COVID-19 disease period.

Association of denosumab with serum cytokines, chemokines, and bone-related factors in patients with rheumatoid arthritis: A post hoc analysis of a multicentre, open-label, randomised, parallel-group study.

OBJECTIVES: To clarify changes in serum cytokines, chemokines, and bone-related factors during denosumab treatment in rheumatoid arthritis (RA) patients. METHODS: This was a post hoc analysis of a multicentre, open-label, randomised, parallel-group study. Patients were randomly assigned to continue treatment with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) plus receive treatment with denosumab (csDMARDs plus denosumab group) or to continue treatment with csDMARD therapy alone for 12 months. Serum biomarker levels were measured at baseline and at 6 and 12 months. RESULTS: Baseline and 6-month data from the csDMARDs plus denosumab (n = 22) and csDMARD therapy alone (n = 22) groups were analysed. Statistically significant changes from baseline were seen: Dickkopf-related protein 1 decreased at 6 and 12 months (both groups); osteopontin decreased at 6 months in the csDMARDs plus denosumab group; osteopontin and soluble CD40 ligand increased at 6 and 12 months in the csDMARD therapy alone group; osteocalcin decreased at 6 and 12 months, epidermal growth factor decreased at 12 months, and macrophage-derived chemokine decreased at 6 months in the csDMARDs plus denosumab group; and interferon gamma-induced protein-10 increased at 12 months in the csDMARD therapy alone group. CONCLUSIONS: Denosumab may inhibit bone destruction by suppressing bone-related factors/chemokines.

Influences of advanced age in rheumatoid arthritis: A multicentre ultrasonography cohort study.

OBJECTIVES: We aimed to evaluate the effects of age on clinical characteristics and outcomes in biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD)-naïve patients with rheumatoid arthritis (RA). METHODS: We analysed the cases of 234 Japanese b/tsDMARD-naïve RA patients who underwent b/tsDMARD treatment in a multicentre ultrasound prospective observational cohort. We compared the clinical characteristics at baseline and outcomes at 12 months between those aged ≥60 years and those <60 years. RESULTS: Compared to the <60-year-old group (n = 78), the ≥60-year-old group (n = 156) had higher inflammatory marker values and ultrasound combined scores, especially wrist joints, at baseline. Age at baseline positively correlated significantly with the ultrasound scores at baseline; however, age was not a significant variable by the multiple regression analysis. The patients treated with different MOAs in the ≥60-year-old group had comparable outcomes and multiple regression analysis revealed that mechanism of action (MOA) was not a significant contributor to the Clinical Disease Activity Index at 12 months. CONCLUSIONS: RA patients with advanced age demonstrated distinctive clinical characteristics. The MOAs were not associated with clinical outcomes and ultrasound outcomes in RA patients with advanced age.

Biomarkers and Signaling Pathways Implicated in the Pathogenesis of Idiopathic Multicentric Castleman Disease/Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis, Renal Insufficiency, and Organomegaly (TAFRO) Syndrome.

Idiopathic multicentric Castleman disease (iMCD) and TAFRO syndrome present a variety of symptoms thought to be caused by excessive inflammatory cytokines and chemokines, but the underlying mechanisms are unknown. iMCD is broadly classified into two types: iMCD-NOS and iMCD-TAFRO, which have distinct laboratory findings, pathological features, and responses to treatments. It is thought that iMCD-NOS, particularly the IPL type, responds favorably to IL-6 inhibitors due to its IL-6-centric profile. iMCD-TAFRO frequently progresses acutely and seriously, similar to TAFRO syndrome. Elevated levels of cytokines, including IL-1ß, TNF-α, IL-10, and IL-23, as well as chemokines like CXCL13 and CXCL-10 (especially in iMCD-TAFRO), SAA, and VEGF, have been linked to the disease's pathology. Recent research has identified key signaling pathways including PI3K/Akt/mTOR and JAK-STAT3, as well as those regulated by type I IFN, as crucial in iMCD-TAFRO. These results suggest that dominant pathways may vary between subtypes. Further research into the peripheral blood and lymph nodes is required to determine the disease spectrum of iMCD-NOS/iMCD-TAFRO/TAFRO syndrome.

Anti-centromere antibody positivity is an independent variable associated with salivary gland ultrasonography score in Sjögren's syndrome.

Sjögren's syndrome (SS) is an autoimmune disease characterized by periductal lymphocytic infiltration of the salivary and lacrimal glands. SS also exhibits extra-glandular manifestations and specific autoantibodies. Salivary gland ultrasonography (SGUS) is a common procedure used to assess the severity of glandular involvement. However, the association between SGUS and extra-glandular lesions remains poorly understood. This study aimed to identify clinical indices, including disease activity, associated with glandular involvement using SGUS in patients with SS. We included 115 patients with SS and 90 without SS. Patients with SS had significantly higher ultrasonography (US) score than patients without SS. Multivariate analysis revealed focus score, Saxon test positivity, and anti-centromere antibody (ACA) positivity as independent variables associated with the US score in patients with SS. In addition, these results were similar to those obtained in patients with primary SS. Patients with SS and ACA positivity had higher US score and an increased prevalence of hyperechoic bands in the parotid glands and submandibular glands. In conclusion, this study indicated that ACA positivity is associated with the US score in patients with SS. These results suggest that US findings in patients with ACA positivity might show specific changes in the salivary glands, especially fibrosis.

Correction: Arimori et al. Association between Lifestyle Factors and Weight Gain among University Students in Japan during COVID-19 Mild Lockdown: A Quantitative Study. Healthcare 2023, 11, 2630.

In our published publication [...].

TERT promoter mutations increase tumor aggressiveness by altering TERT mRNA splicing in papillary thyroid carcinoma.

CONTEXT: Telomerase reverse transcriptase promoter (TERT-p) mutations, which upregulate TERT expression, are strongly associated with tumor aggressiveness and worse prognosis in papillary thyroid carcinomas (PTCs). TERT expression is also observed in a proportion of PTCs without TERT-p mutations, but such tumors show less aggressiveness and better prognosis compared with TERT-p mutation-positive tumors. OBJECTIVE: TERT has multiple splicing variants whose relationships with the TERT-p status and clinicopathological characteristics remain poorly understood. We examined the relationship between the TERT-p mutational status, the TERT splicing pattern, and clinicopathological features. METHODS: We investigated the expression of two major variants, α deletion (dA) and ß deletion (dB), in a series of 207 PTCs operated between November 2001 and March 2020 in Nagasaki University Hospital and Kuma Hospital. RESULTS: The TERT-p mutations were found in 33 cases, and among 174 mutation-negative cases, 24 showed TERT expression. All cases were classified into three groups: the TERT-p mutation-negative/expression-negative group (mut-/exp-), the TERT-p mutation-negative/expression-positive group (mut-/exp+), and the TERT-p mutation-positive group (mut+/exp+). The +A + B/dB ratio in mut+/exp + was significantly higher than that in mut-/exp + PTCs. Analysis with clinicopathological data revealed that +A + B expression was associated with higher PTC aggressiveness, whereas dB expression counteracted this effect. Functional in vitro study demonstrated that dB strongly inhibited cell growth, migration, and clonogenicity, suggesting its tumor suppressive role. CONCLUSION: These results provide evidence that the TERT-p mutations alter the expression of different TERT splice variants, which, in turn, associates with different tumor aggressiveness.

A Randomized Controlled Trial on the Effect of Luseogliflozin on Bone Microarchitecture Evaluated Using HR-pQCT in Elderly Type 2 Diabetes.

INTRODUCTION: Bone fragility is a critical issue in the treatment of elderly people with type 2 diabetes (T2D). In the Canagliflozin Cardiovascular Assessment Study, the subjects with T2D who were treated with canagliflozin showed a significant increase in fracture events compared to a placebo group as early as 12 weeks post-initiation. In addition, it has been unclear whether sodium-glucose co-transporter 2 (SGLT2) inhibitors promote bone fragility. We used high-resolution peripheral quantitative computed tomography (HR-pQCT) to prospectively evaluate the short-term effect of the SGLT2 inhibitor luseogliflozin on bone strength and microarchitecture in elderly people with T2D. METHODS: This was a single-center, randomized, open-label, active-controlled pilot trial for ≥ 60-year-old Japanese individuals with T2D without osteoporosis. A total of 22 subjects (seven women and 15 men) were randomly assigned to a Lusefi group (added luseogliflozin 2.5 mg) or a control group (added metformin 500 mg) and treated for 48 weeks. We used the second-generation HR-pQCT (Xtreme CT II®, Scanco Medical, Brüttisellen, Switzerland) before and 48 weeks after the treatment to evaluate the subjects' bone microarchitecture and estimate their bone strength. RESULTS: Twenty subjects (Lusefi group, n = 9; control group, n = 11) completed the study, with no fracture events. As the primary outcome, the 48-week changes in the bone strength (stiffness and failure load) estimated by micro-finite element analysis were not significantly different between the groups. As the secondary outcome, the changes in all of the cortical/trabecular microarchitectural parameters at the radius and tibia from baseline to 48 weeks were not significantly different between the groups. CONCLUSIONS: In the pilot trial, we observed no negative effect of 48-week luseogliflozin treatment on bone microarchitecture or bone strength in elderly people with T2D. TRIAL REGISTRATION: UMIN-CTR no. 000036202 and jRCT 071180061.

Improved Hearing Impairment of Granulomatosis with Polyangiitis Treated with Rituximab and Avacopan without Glucocorticoids.

A 78-year-old woman with a history of intractable otitis media presented with a fever, hearing impairment, thigh pain, and a skin rash. She had renal dysfunction, positive myeloperoxidase-antineutrophil cytoplasmic autoantibody, otitis media, and multiple nodules in both lungs. She was diagnosed with granulomatosis with polyangiitis, crescentic glomerulonephritis, and interstitial nephritis, which was confirmed in a kidney biopsy specimen. Induction therapy with rituximab and avacopan without glucocorticoids promptly resolved her fever and thigh pain and improved her auditory acuity and nodule in the right lung. The patient experienced no adverse effects with rituximab or avacopan.

Fatal Systemic Capillary Leak Syndrome in a Patient with a COVID-19 Infection.

A 29-year-old Japanese woman was admitted to our hospital with a fever, cardiogenic shock, and cardiac arrest. Laboratory data indicated multiple organ failure in addition to hemoconcentration, hypoalbuminemia, and myocardial damage. The coronary angiography findings were normal, and fulminant myocarditis was suspected. Venoarterial peripheral extracorporeal membrane oxygenation and an Impella CP left ventricular assist device were initiated, along with the administration of positive inotropic agents. However, hypovolemic shock and hypoalbuminemia progressed along with severe anemia, and the patient died 18 hours after admission. The patient was diagnosed with systemic capillary leak syndrome associated with coronavirus disease 2019.

Exercise-associated Hyponatremia Developing Immediately after a Musical Stage Performance in a Healthy Actress.

Exercise-associated hyponatremia (EAH) is a life-threatening dilutional hyponatremia that typically occurs during or immediately after exercise in endurance athletes. A 49-year-old actress experienced dizziness 15 min after a 2-h stage performance while drinking several bottles of water. Thirty minutes later, the patient fell unconscious and was hospitalized. On admission, she showed dilutional hyponatremia (117 mmol/L) with extremely elevated arginine vasopressin (11.3 pg/mL). After initial treatment with 3% saline, her sodium levels immediately increased, and she recovered consciousness without developing subsequent osmotic demyelination syndrome. This case emphasizes the need for caution against excessive fluid intake during and/or after exercise to avoid EAH, even in non-athletes.

Diagnostic challenges of the idiopathic plasmacytic lymphadenopathy (IPL) subtype of idiopathic multicentric Castleman disease (iMCD): Factors to differentiate from IgG4-related disease.

AIMS AND METHODS: Idiopathic multicentric Castleman disease (iMCD) is currently considered to be classified into three clinical subtypes, including idiopathic plasmacytic lymphadenopathy (IPL), thrombocytopaenia, anasarca, fever, reticulin fibrosis/renal dysfunction, organomegaly (TAFRO) and not otherwise specified (NOS). Among the three, iMCD-IPL closely mimics IgG4-related disease (IgG4-RD). In diagnosing IgG4-RD, it is sometimes challenging to distinguish iMCD-IPL patients that also meet the histological diagnostic criteria for IgG4-RD. In this study, we focused on the number of IgG4-positive cells in the lymph nodes and analysed the relationship with laboratory findings to distinguish iMCD-IPL from IgG4-RD. Thirty-nine patients with iMCD-IPL and 22 patients with IgG4-RD were included. RESULTS: Among the cases considered to be iMCD-IPL, 33.3% (13/39) cases also met the histological diagnostic criteria for IgG4-RD and serum IgG4 levels were not different between the two groups. However, the serum IgG4/IgG ratio was significantly higher in IgG4-RD, with a cut-off value of 19.0%. Additionally, a significant positive correlation between serum IgG levels and the number of IgG4-positive cells was observed in iMCD-IPL (p=0.001). The serum IgG cut-off value for distinguishing iMCD-IPL meeting histological criteria for IgG4-RD from other iMCD-IPL was 5381 mg/dL. CONCLUSIONS: iMCD-IPL cases with high serum IgG levels (>5000 mg/dL) were likely to meet the diagnostic criteria for IgG4-RD because of the numerous IgG4-positive cells observed. A combination of clinical presentations, laboratory values including the serum IgG4/IgG ratios and histological analysis is crucial for diagnosis of IgG4-RD and iMCD-IPL.

The double shared epitope: Its impact on clinical features and ultrasound findings in rheumatoid arthritis.

OBJECTIVES: The link between the HLA-DRB1 locus and the risk of rheumatoid arthritis (RA) shown in genome-wide association studies strengthens the shared epitope (SE) hypothesis. We aimed to assess the impact of the double dose of the SE (double SE) on RA and explore its clinical associations, including the response to abatacept. METHODS: We evaluated RA patients treated with csDMARDs or abatacept for HLA-DRB1 typing, clinical characteristics at baseline, and disease activity and ultrasound findings over 12 months. RESULTS: Patients with the double SE (n = 12) had significantly higher anti-citrullinated protein antibody (ACPA) titers, higher total grayscale (GS) score, and power Doppler (PD) score at baseline than patients without the double SE. Patients with the double SE exhibited reduced rates of SDAI remission and pronounced improvements in multiple disease activity between baseline and 12 months, including SDAI, CDAI, total GS score, and total PD score. When focusing on abatacept-treated patients, the decreases in SDAI, CDAI, and total PD score between baseline and 12 months were significantly larger in patients with the double SE. CONCLUSIONS: Patients with the double SE exhibited distinct characteristics, increased disease activity, and improved response to abatacept treatment.