A Chinese patent medicine's long-term efficacy on non-dialysis patients with CKD stages 3-5: a retrospective cohort study.

Background: Chinese patent medicine is commonly used in China as an important treatment mechanism to thwart the progression of chronic kidney disease (CKD) stages 3-5, among which Niaoduqing granules are a representative Chinese patent medicine; however, its long-term efficacy on CKD prognosis remains unclear. Methods: Patients were grouped according to Niaoduqing granule prescription duration (non-Niaoduqing granule (non-NDQ) group vs Niaoduqing granule (NDQ) group). Serum creatinine (SCr) variation was compared using a generalized linear mixed model (GLMM). Multivariate Cox regression models were constructed, adjusting for confounding factors, to explore the risk of composite outcomes (receiving renal replacement therapy (RRT) or having an estimated glomerular filtration rate (eGFR)<5 mL/min/1.73 m2, ≥50% decline in the eGFR from the baseline, and doubling of SCr) in individuals consuming Niaoduqing granules. Results: A total of 1,271 patients were included, with a median follow-up duration of 29.71 (12.10, 56.07) months. The mean SCr Z-scores for the non-NDQ group and NDQ group were -0.175 and 0.153, respectively, at baseline (p = 0.015). The coefficients of the NDQ group from visit 1 to visit 5 were -0.207 (95% CI: -0.346, -0.068, p = 0.004), -0.214 (95% CI: 0.389, -0.039, p = 0.017), -0.324 (95% CI: 0.538, -0.109, p = 0.003), -0.502 (95% CI: 0.761, -0.243, p = 0.000), and -0.252 (95% CI: 0.569, 0.065, p = 0.119), respectively. The survival probability was significantly higher in the NDQ group (p = 0.0039). Taking Niaoduqing granules was a significant protective factor for thwarting disease progression (model 1: HR 0.654 (95% CI 0.489-0.875, p = 0.004); model 2: HR 0.646 (95% CI 0.476, 0.877, p = 0.005); and model 3: HR 0.602 (95% CI 0.442, 0.820, p = 0.001)). Conclusion: The long-term use of Niaoduqing granules improved SCr variation and lowered the risk of CKD progression by 39.8%.

MACE and Hyperthyroidism Treated With Medication, Radioactive Iodine, or Thyroidectomy.

Importance: Excessive thyroid hormones from hyperthyroidism increase cardiovascular risks. Among 3 available treatments for hyperthyroidism, comparisons of long-term outcomes associated with antithyroid drugs (ATDs), radioactive iodine (RAI), and surgery to treat newly diagnosed hyperthyroidism are lacking. Objective: To compare risks of major adverse cardiovascular events (MACE) and all-cause mortality among patients with hyperthyroidism treated with ATDs, RAI, or surgery. Design, Setting, and Participants: This nationwide cohort study used the Taiwan National Health Insurance Research Database. Patients aged 20 years or older with newly diagnosed hyperthyroidism between 2011 and 2020 were enrolled. Treatment groups were determined within 18 months from diagnosis, with follow-up until the development of MACE, death, or the end date of the database, whichever came first. Data were analyzed from October 2022 through December 2023. Exposures: The ATD group received ATDs only. RAI and surgery groups could receive ATDs before treatment. Anyone who underwent thyroid surgery without RAI was classified into the surgery group and vice versa. Main Outcomes and Measures: The primary outcomes included MACE (a composite outcome of acute myocardial infarction, stroke, heart failure, and cardiovascular mortality) and all-cause mortality. Results: Among 114 062 patients with newly diagnosed hyperthyroidism (mean [SD] age, 44.1 [13.6] years; 83 505 female [73.2%]), 107 052 patients (93.9%) received ATDs alone, 1238 patients (1.1%) received RAI, and 5772 patients (5.1%) underwent surgery during a mean (SD) follow-up of 4.4 (2.5) years. Patients undergoing surgery had a significantly lower risk of MACE (hazard ratio [HR] = 0.76; 95% CI, 0.59-0.98; P = .04), all-cause mortality (HR = 0.53; 95% CI, 0.41-0.68; P < .001), heart failure (HR = 0.33; 95% CI, 0.18-0.59; P < .001), and cardiovascular mortality (HR = 0.45; 95% CI, 0.26-0.79; P = .005) compared with patients receiving ATDs. Compared with ATDs, RAI was associated with lower MACE risk (HR = 0.45; 95% CI, 0.22-0.93; P = .03). Risks for acute myocardial infarction and stroke did not significantly differ between treatment groups. Conclusions and Relevance: In this study, surgery was associated with lower long-term risks of MACE and all-cause mortality, while RAI was associated with a lower MACE risk compared with ATDs.

The Transplantation of 3-Dimensional Spheroids of Adipose-Derived Stem Cells Promotes Achilles Tendon Healing in Rabbits by Enhancing the Proliferation of Tenocytes and Suppressing M1 Macrophages.

BACKGROUND: Tendons have limited regenerative potential, so healing of ruptured tendon tissue requires a prolonged period, and the prognosis is suboptimal. Although stem cell transplantation-based approaches show promise for accelerating tendon repair, the resultant therapeutic efficacy remains unsatisfactory. HYPOTHESIS: The transplantation of stem cells preassembled as 3-dimensional spheroids achieves a superior therapeutic outcome compared with the transplantation of single-cell suspensions. STUDY DESIGN: Controlled laboratory study. METHODS: Adipose-derived stem cells (ADSCs) were assembled as spheroids using a methylcellulose hydrogel system. The secretome of ADSC suspensions or spheroids was collected and utilized to treat tenocytes and macrophages to evaluate their therapeutic potential and investigate the mechanisms underlying their effects. RNA sequencing was performed to investigate the global difference in gene expression between ADSC suspensions and spheroids in an in vitro inflammatory microenvironment. For the in vivo experiment, rabbits that underwent Achilles tendon transection, followed by stump suturing, were randomly assigned to 1 of 3 groups: intratendinous injection of saline, rabbit ADSCs as conventional single-cell suspensions, or preassembled ADSC spheroids. The tendons were harvested for biomechanical testing and histological analysis at 4 weeks postoperatively. RESULTS: Our in vitro results demonstrated that the secretome of ADSCs assembled as spheroids exhibited enhanced modulatory activity in (1) tenocyte proliferation (P = .015) and migration (P = .001) by activating extracellular signal-regulated kinase (ERK) signaling and (2) the suppression of the secretion of interleukin-6 (P = .005) and interleukin-1α (P = .042) by M1 macrophages via the COX-2/PGE2/EP4 signaling axis. Gene expression profiling of cells exposed to an inflammatory milieu revealed significantly enriched terms that were associated with the immune response, cytokines, and tissue remodeling in preassembled ADSC spheroids. Ex vivo fluorescence imaging revealed that the engraftment efficiency of ADSCs in the form of spheroids was higher than that of ADSCs in single-cell suspensions (P = .003). Furthermore, the transplantation of ADSC spheroids showed superior therapeutic effects in promoting the healing of sutured stumps, as evidenced by improvements in the tensile strength (P = .019) and fiber alignment (P < .001) of the repaired tendons. CONCLUSION: The assembly of ADSCs as spheroids significantly advanced their potential to harness tenocytes and macrophages. As a proof of concept, this study clearly demonstrates the effectiveness of using ADSC spheroids to promote tendon regeneration. CLINICAL RELEVANCE: The present study lays a foundation for future clinical applications of stem cell spheroid-based therapy for the management of tendon injuries.

The thermal degradation and soil recovery of thermal treatment of field-weathered decabrominated diphenyl ether-contaminated soil.

A farm at Taoyuan in Taiwan was highly contaminated with decabrominated diphenyl ether (BDE-209), a widely used commercial brominated flame retardant and persistent in the environment, more than 10 years. Since crops are able to absorb and accumulate BDE-209 from soils in our previous research, posing a hazardous risk for humans, it is essential to develop a practical method of soil treatment. Thermal treatment was studied among different approaches. In our previous study (Ko et al., 2022), we found that heating to 450 °C for 30 min achieved a complete removal of BDE-209 in soil. However, the high temperature significantly decreased the original soil organic matter (SOM) from 2.47% to 0.27%, altering the soil texture, damaging microbial biomass, and thus affecting the revegetation after the thermal treatment. Sugarcane bagasse, a common agricultural residue, served as an amendment to restore soil fertility. Current results indicate that 2.5% bagasse can improve the SOM in soil by up to 2.73% and restore its bacterial composition, making the plant growth conditions similar to those of the untreated contaminated soil. In light of the high removal efficiency provided by the 450°C-thermal treatment and the high recovery efficiency of sugarcane bagasse, the strategy presented in this study serves to be a promising method for sustainable remediation.

Injection of hybrid 3D spheroids composed of podocytes, mesenchymal stem cells, and vascular endothelial cells into the renal cortex improves kidney function and replenishes glomerular podocytes.

Podocytes are highly differentiated epithelial cells that are crucial for maintaining the glomerular filtration barrier in the kidney. Podocyte injury followed by depletion is the major cause of pathological progression of kidney diseases. Although cell therapy has been considered a promising alternative approach to kidney transplantation for the treatment of kidney injury, the resultant therapeutic efficacy in terms of improved renal function is limited, possibly owing to significant loss of engrafted cells. Herein, hybrid three-dimensional (3D) cell spheroids composed of podocytes, mesenchymal stem cells, and vascular endothelial cells were designed to mimic the glomerular microenvironment and as a cell delivery vehicle to replenish the podocyte population by cell transplantation. After creating a native glomerulus-like condition, the expression of multiple genes encoding growth factors and basement membrane factors that are strongly associated with podocyte maturation and functionality was significantly enhanced. Our in vivo results demonstrated that intrarenal transplantation of podocytes in the form of hybrid 3D cell spheroids improved engraftment efficiency and replenished glomerular podocytes. Moreover, the proteinuria of the experimental mice with hypertensive nephropathy was effectively reduced. These data clearly demonstrated the potential of hybrid 3D cell spheroids for repairing injured kidneys.

Transplantation of 3D MSC/HUVEC spheroids with neuroprotective and proangiogenic potentials ameliorates ischemic stroke brain injury.

Ischemic stroke, and the consequent brain cell death, is a common cause of death and disability worldwide. Current treatments that primarily aim to relieve symptoms are relatively inefficient in achieving brain tissue regeneration and functional recovery, and thus novel therapeutic options are urgently needed. Although cell-based therapies have shown promise for treating the infarcted brain, a recurring challenge is the inadequate retention and engraftment of transplanted cells at the target tissue, thereby limiting the ultimate therapeutic efficacy. Here, we show that transplantation of preassembled three-dimensional (3D) spheroids of mesenchymal stem cells (MSCs) and vascular endothelial cells (ECs) results in significantly improved cell retention and survival compared with conventional mixed-cell suspensions. The transplanted 3D spheroids exhibit notable neuroprotective, proneurogenic, proangiogenic and anti-scarring potential as evidenced by clear extracellular matrix structure formation and paracrine factor expression and secretion; this ultimately results in increased structural and motor function recovery in the brain of an ischemic stroke mouse model. Therefore, transplantation of MSCs and ECs using the 3D cell spheroid configuration not only reduces cell loss during cell harvesting/administration but also enhances the resultant therapeutic benefit, thus providing important proof-of-concept for future clinical translation.

Prenatal diagnosis of harlequin ichthyosis by ultrasonography: a case report.

Autosomal recessive congenital ichthyosis is a genetically and phenotypically heterogeneous group of skin disorders, including harlequin ichthyosis (HI), lamellar ichthyosis, and bullous congenital ichthyosiform erythroderma. HI is the most phenotypically severe autosomal recessive congenital ichthyosis associated with the mutation of the adenosine triphosphate-binding cassette subfamily A member 12 (ABCA12) gene. The clinical manifestations include generalized hyperkeratotic plaques and deep fissures, ectropion, eclabium, and contractures. However, the severe HI may easily be misdiagnosed as epidermolysis bullosa or syndromic ichthyosis. Meanwhile, no consensus exists about the best used in clinical trials or clinical practice when more elaborate scoring systems have been proposed to evaluate skin xerosis, palmoplantar keratoderma, and disease extension an accurate prenatal diagnosis is necessary. Until the ABCA12 gene was identified as the pathogenic gene, prenatal diagnosis of HI had been performed by the invasive techniques of fetal skin biopsy. Now, advances in ultrasound technology and fetal DNA-based analysis have replaced it. The mortality rate is markedly high and prompt; prenatal diagnosis of neonate HI is critical for appropriate perinatal and postnatal management. It is also essential to prepare parents for future pregnancies and reduce the family's physical and mental distress and financial burden. This report presents a rare case of harlequin ichthyosis diagnosed by the ultrasound and discusses the significance of prenatal ultrasound diagnosis and molecular diagnosis in the prenatal diagnosis of HI.

Efficacy of high intensity focused ultrasound treatment for cystic adenomyosis: a report of four cases.

BACKGROUND: Cystic adenomyosis is a particular type of adenomyosis, High intensity focused ultrasound (HIFU), as a non-invasive method, has also been used to treat adenomyosis. The purpose of this study was to investigate the efficacy, safety, and feasibility of HIFU for the treatment of cystic adenomyosis. METHODS: Diagnosis of cystic adenomyosis was obtained through trans-vaginal ultrasound and magnetic resonance imaging (MRI). Ultrasound-guided HIFU ablation was performed under conscious sedation. The patients were evaluated by the comparison of pre-HIFU and post-HIFU imaging, as well as the Uterine Fibroid Symptom and Quality of Life (UFS-QOL) questionnaire subscales, consisting of Symptom Severity Score (SSS) and Heath Related Quality of Life (HRQL). RESULTS: HIFU was effective in treating cystic adenomyosis. No complications were observed in the four patients who were successfully treated with HIFU. Compared to preoperative symptoms and patient satisfaction, symptoms at the first follow-up observed significant improvements, with no dysmenorrhea and high health-related quality of life. During the outpatient follow-up of one month, three months, and six months postoperation, the four patients were still without dysmenorrhea and were highly satisfied with the HIFU ablation. CONCLUSIONS: HIFU, as a non-invasive treatment, supplies a safe and effective possibility for the treatment of cystic adenomyosis.

Enhancement of Subcutaneously Transplanted ß Cell Survival Using 3D Stem Cell Spheroids with Proangiogenic and Prosurvival Potential.

Islet transplantation has been demonstrated to be a promising therapy for type 1 diabetes mellitus. Although it is a minimally invasive operating procedure and provides easy access for graft monitoring, subcutaneous transplantation of the islet only has limited therapeutic outcomes, owing to the poor capacity of skin tissue to foster revascularization in a short period. Herein, 3D cell spheroids of clinically accessible umbilical cord blood mesenchymal stem cells and human umbilical vein endothelial cells are formed and employed for codelivery with ß cells subcutaneously. The 3D stem cell spheroids, which can secrete multiple proangiogenic and prosurvival growth factors, induce robust angiogenesis and prevent ß cell graft death, as indicated by the results of in vivo bioluminescent tracking and histological analysis. These experimental data highlight the efficacy of the 3D stem cell spheroids that are fabricated using translationally applicable cell types in promoting the survival and function of subcutaneously transplanted ß cells.

3D Spheroids of Umbilical Cord Blood MSC-Derived Schwann Cells Promote Peripheral Nerve Regeneration.

Schwann cells (SCs) are promising candidates for cell therapy due to their ability to promote peripheral nerve regeneration. However, SC-based therapies are hindered by the lack of a clinically renewable source of SCs. In this study, using a well-defined non-genetic approach, umbilical cord blood mesenchymal stem cells (cbMSCs), a clinically applicable cell type, were phenotypically, epigenetically, and functionally converted into SC-like cells (SCLCs) that stimulated effective sprouting of neuritic processes from neuronal cells. To further enhance their therapeutic capability, the cbMSC-derived SCLCs were assembled into three-dimensional (3D) cell spheroids by using a methylcellulose hydrogel system. The cell-cell and cell-extracellular matrix interactions were well-preserved within the formed 3D SCLC spheroids, and marked increases in neurotrophic, proangiogenic and anti-apoptotic factors were detected compared with cells that were harvested using conventional trypsin-based methods, demonstrating the superior advantage of SCLCs assembled into 3D spheroids. Transplantation of 3D SCLC spheroids into crush-injured rat sciatic nerves effectively promoted the recovery of motor function and enhanced nerve structure regeneration. In summary, by simply assembling cells into a 3D-spheroid conformation, the therapeutic potential of SCLCs derived from clinically available cbMSCs for promoting nerve regeneration was enhanced significantly. Thus, these cells hold great potential for translation to clinical applications for treating peripheral nerve injury.

Investigation of transfusion associated hepatitis C virus infection in Taiwan, 2015-2018.

Continuous strengthening of the safety of blood products to reduce the risk of transfusion-transmitted HCV in recipients is an important issue of Taiwanese government concern. Since 2013, highly sensitivity serology and NAT assays were simultaneously used for blood donation screening to shorten the window period of HIV, HBV and HCV infections. 15 cases of suspected transfusion-transmitted HCV infection were analyzed in 2015-2018. No HCV nucleic acid was detected among a total 91 bags of donated blood. Eleven cases among the 15 suspected recipients were positive for HCV nucleic acid, and 9 recipients had genotype results. Of these 9 recipients, five for genotype 1b (5/9, 55.6%), three for genotype 2a (3/9, 33.3%) and one for genotype 2b (1/9, 11.1%). We will continuously monitor the blood safety of recipients. There have been no confirmed cases of acute hepatitis C (AHC) infection due to transfusions of HCV contaminated blood product in 2015-2018 in Taiwan.

Mercury (II) impairs nucleotide excision repair (NER) in zebrafish (Danio rerio) embryos by targeting primarily at the stage of DNA incision.

Mercuric ion (Hg2+) is the most prevalent form of inorganic Hg found in polluted aquatic environment. As inhibition of DNA damage repair has been proposed as one of the mechanisms of Hg2+-induced genotoxicity in aquatic animals and mammalian cells, this study explored the susceptibility of different stages of nucleotide excision repair (NER) in zebrafish (Danio rerio) embryos to Hg2+ using UV-damaged DNA as the repair substrate. Exposure of embryos at 1h post fertilization (hpf) to HgCl2 at 0.1-2.5µM for 9h caused a concentration-dependent inhibition of NER capacity monitored by a transcription-based DNA repair assay. The extracts of embryos exposed to 2.5µM Hg2+ almost failed to up-regulate UV-suppressed marker cDNA transcription. No inhibition of ATP production was observed in all Hg2+-exposed embryos. Hg2+ exposure imposed either weak inhibitory or stimulating effects on the gene expression of NER factors, while band shift assay showed the inhibition of photolesion binding activities to about 40% of control in embryos treated with 1-2.5µM HgCl2. The damage incision stage of NER in zebrafish embryos was found to be more sensitive to Hg2+ than photolesion binding capacity due to the complete loss of damage incision activity in the extracts of embryos exposed to 1-2.5µM Hg2+. NER-related DNA incision was induced in UV-irradiated embryos based on the production of short DNA fragments matching the sizes of excision products generated by eukaryotic NER. Pre-exposure of embryos to Hg2+ at 0.1-2.5µM all suppressed DNA incision/excision in UV-irradiated embryos, reflecting a high sensitivity of DNA damage incision/excision to Hg2+. Our results showed the potential of Hg2+ at environmental relevant levels to disturb NER in zebrafish embryos by targeting primarily at the stage of DNA incision/excision.

Role of medial abrasion phenomenon in the pathogenesis of knee osteoarthritis.

Osteoarthritis of the knee affects a large population worldwide and is associated with an extremely high economic burden largely attributable to the effects of disability, comorbid disease, and the expense of treatment. Since the initiating events that result in the cartilage degradation are poorly understood, there has been very limited success in demonstrating disease modification in clinical trials of potential therapies. Medial plica related medial abrasion phenomenon has recently been identified to have close relationship with medial compartment osteoarthritis. We hypothesized that this abrasion phenomenon will elicit lifelong interplay between pathologic medial plica and the facing medial femoral condyle and might play a role in the pathogenesis of knee osteoarthritis by both physical and chemical effects. After evaluating current evidence, we designed a study to prove that the concentrations of total protein, cartilage degrading related cytokines (tumor necrosis factor-α and interleukin-1ß) and enzyme (matrix metalloproteinase-3) are higher in the medial compartment of the knee having the phenomenon of medial abrasion. The accumulating data and findings about medial abrasion phenomenon might be important for the understanding of the pathogenesis or progression of this common disease. We hope that our hypothesis will stimulate further studies verifying if medial abrasion phenomenon plays more roles in the pathogenesis of knee osteoarthritis. Further clinical observations for its appropriate treatment based on this hypothesis are also mandatory for the benefits of patients.

Antitumor activity of acriflavine in lung adenocarcinoma cell line A549.

UNLABELLED: Aim/Materials and Methods: In order to develop better drugs against non-small cell lung cancer (NSCLC), we screened a variety of compounds and treated the human lung adenocarcinoma cell line A549 with different drug concentrations. We then examined the cell viability using the MTT assay. RESULTS: Data show that a new candidate drug, acriflavine (ACF), suppresses the viability of A549 cells in a concentration- and time-dependent manner. Flow cytometry analysis revealed that ACF significantly caused cell growth arrest in the G2/M phase on A549 cells. Moreover, ACF decreased Bcl-2 expression and increased Bax expression. The content of cleaved poly(ADP-ribose)polymerase-1 (PARP-1) and caspase-3 are significantly increased. These findings suggest that ACF is cytotoxic against A549 cells and suppresses A549 cells growth through the caspase-3 activation pathway. In the in vivo test, nude mice bearing A549 cells xenografts by intravenous injection were randomly assigned into two groups: control and experimental group. Treatment was initiated 10 days after implantation and intraperitoneal injection of 0.9% normal saline or 2 mg/kg of ACF was continued daily for five weeks. ACF treatment significantly decreased tumor size and tumor spots on lung surface of tumor-bearing mice. CONCLUSION: ACF can inhibit cell growth in A549 cells. Our results may assist on the delineation of the mechanism(s) leading to NSCLC cell growth inhibition and provide a new antitumor strategy against NSCLC.

Higher expression of whole blood microRNA-21 in patients with ankylosing spondylitis associated with programmed cell death 4 mRNA expression and collagen cross-linked C-telopeptide concentration.

OBJECTIVE: Bone loss is a recognized feature of ankylosing spondylitis (AS). The binding of microRNA-21 (miR-21) to programmed cell death 4 (PDCD4) could inhibit the expression of PDCD4 and further induce the activation of osteoclasts. In the present study, we compared the difference in miR-21 expression between patients with AS and healthy controls, and evaluated the relationships of miR-21, PDCD4 mRNA, and bone erosion in patients with AS. The influences of nonsteroidal antiinflammatory drugs (NSAID) and disease-modifying antirheumatic drugs (DMARD) on the expressions of miR-21 and PDCD4 mRNA in patients with AS were also assessed. METHODS: Whole blood miR-21 and PDCD4 mRNA expression were evaluated by quantitative real-time PCR among 122 patients with AS and 122 healthy controls. The serum level of collagen cross-linked C-telopeptide (CTX) was measured using ELISA. RESULTS: When compared to controls, patients with AS had significantly higher levels of miR-21, PDCD4 mRNA, and CTX. MiR-21 expression was negatively correlated with PDCD4 mRNA expression in patients with AS who were taking neither NSAID nor DMARD. Interestingly, significantly positive correlations between miR-21 expression with PDCD4 mRNA expression (r = 0.33, p = 0.01) and CTX level (r = 0.44, p < 0.01) were observed in patients with AS who were taking sulfasalazine. Positive correlations of miR-21 and CTX level were also observed in AS patients with disease duration < 7.0 years (r = 0.36, p = 0.004) and active disease (r = 0.42, p = 0.001). CONCLUSION: The expression of miR-21 might have a role in the development of AS.