Weight, CYP3A5 Genotype, and Voriconazole Co-administration Influence Tacrolimus Initial Dosage in Pediatric Lung Transplantation Recipients with Low Hematocrit based on a Simulation Model.

OBJECTIVE: The method of administering the initial doses of tacrolimus in recipients of pediatric lung transplantation, especially in patients with low hematocrit, is not clear. The present study aims to explore whether weight, CYP3A5 genotype, and voriconazole co-administration influence tacrolimus initial dosage in recipients of pediatric lung transplantation with low hematocrit based on safety and efficacy using a simulation model. METHODS: The present study utilized the tacrolimus population pharmacokinetic model, which was employed in lung transplantation recipients with low hematocrit. RESULTS: For pediatric lung transplantation recipients not carrying CYP3A5*1 and without voriconazole, the recommended tacrolimus doses for weights of 10-13, 13-19, 19-22, 22-35, 35-38, and 38-40 kg are 0.03, 0.04, 0.05, 0.06, 0.07, and 0.08 mg/kg/day, which are split into two doses, respectively. For pediatric lung transplantation recipients carrying CYP3A5*1 and without voriconazole, the recommended tacrolimus doses for weights of 10-18, 18-30, and 30-40 kg are 0.06, 0.08, 0.11 mg/kg/day, which are split into two doses, respectively. For pediatric lung transplantation recipients not carrying CYP3A5*1 and with voriconazole, the recommended tacrolimus doses for weights of 10-20 and 20-40 kg are 0.02 and 0.03 mg/kg/day, which are split into two doses, respectively. For pediatric lung transplantation recipients carrying CYP3A5*1 and with voriconazole, the recommended tacrolimus doses for weights of 10-20, 20-33, and 33-40 kg are 0.03, 0.04, and 0.05 mg/kg/day, which are split into two doses, respectively. CONCLUSION: The present study is the first to recommend the initial dosages of tacrolimus in recipients of pediatric lung transplantation with low hematocrit using a simulation model.

Effects of tacrolimus on proteinuria in Chinese and Indian patients with idiopathic membranous nephropathy: the results of machine learning study.

PURPOSE: The present study aims to explore the effects of tacrolimus on proteinuria in patients with idiopathic membranous nephropathy (IMN) and recommend an appropriate dosage schedule via machine learning method. METHODS: The Emax model was constructed to analyze the effects of tacrolimus on proteinuria in patients with IMN. Data were mined from published literature and machine learning was built up with Emax model, among which the efficacy indicator was proteinuria change rates from baseline. 463 IMN patients were included for modeling, and tacrolimus therapeutic window concentrations were 4-10 ng/ml. RESULTS: In machine learning model, the Emax from tacrolimus effecting proteinuria in IMN patients was -72.7%, the ET50 was 0.43 months, and the time to achieving 25% Emax, 50% Emax, 75% Emax, and 80% (plateau) Emax of tacrolimus on proteinuria in patients with IMN were 0.15, 0.43, 1.29, and 1.72 months, respectively. CONCLUSION: For achieving better therapeutic effects from tacrolimus on proteinuria in patients with IMN, tacrolimus concentration range need to be maintained at 4-10 ng/ml for at least 1.72 months.

Bacterial Cellulose Applied in Wound Dressing Materials: Production and Functional Modification - A Review.

In recent years, the development of new type wound dressings has gradually attracted more attention. Bacterial cellulose (BC) is a natural polymer material with various unique properties, such as ultrafine 3D nanonetwork structure, high water retention capacity, and biocompatibility. These properties allow BC to be used independently or in combination with different components (such as biopolymers and nanoparticles) to achieve diverse effects. This means that BC has great potential as a wound dressing. However, systematic summaries for the production and commercial application of BC-based wound dressings are still lacking. Therefore, this review provides a detailed introduction to the production fermentation process of BC, including various production strains and their biosynthetic mechanisms. Subsequently, with regard to the functional deficiencies of bacterial cellulose as a wound dressing, recent research progress in this area is enumerated. Finally, prospects are discussed for the low-cost production and high-value-added product development of BC-based wound dressings.

Cold-resistant, highly stretchable ionic conductive hydrogels for intelligent motion recognition in winter sports.

Conductive hydrogels have attracted much attention for their wide application in the field of flexible wearable sensors due to their outstanding flexibility, conductivity and sensing properties. However, the weak mechanical properties, lack of frost resistance and susceptibility to microbial contamination of traditional conductive hydrogels greatly limit their practical application. In this work, multifunctional polyvinyl alcohol (PVA)/carboxymethyl cellulose (CMC)/poly(acrylamide-co-1-vinyl-3-butylimidazolium bromide) (P(AAm-co-VBIMBr)) (PCPAV) ionic conductive hydrogels with high strength and good conductive, transparent, anti-freezing and antibacterial properties were constructed by introducing a network of chemically crosslinked AAm and VBIMBr copolymers into the base material of PVA and CMC by in situ free radical polymerization. Owing to the multiple interactions between the polymers, including covalent crosslinking, multiple hydrogen bonding interactions, and electrostatic interactions, the obtained ionic conductive hydrogels exhibit a high tensile strength (360.6 kPa), a large elongation at break (810.6%), good toughness, and fatigue resistance properties. The introduction of VBIMBr endows the PCPAV hydrogels with excellent transparency (∼92%), a high ionic conductivity (15.2 mS cm-1), antimicrobial activity and good flexibility and conductivity at sub-zero temperatures. Notably, the PCPAV hydrogels exhibit a wide strain range (0-800%), high strain sensitivity (GF = 3.75), fast response, long-term stability, and fantastic durability, which enable them to detect both large joint movements and minute muscle movements. Based on these advantages, it is believed that the PCPAV-based hydrogel sensors would have potential applications in health monitoring, human motion detection, soft robotics, ionic skins, human-machine interfaces, and other flexible electronic devices.

Comparation of the outcomes between ProGlide based post-closure technique and arteriotomy repair for veno-arterial extracorporeal membrane oxygenation decannulation.

PURPOSE: To compare outcomes between post-closure technique based on ProGlide and arteriotomy repair for veno-arterial extracorporeal membrane oxygenation (VA-ECMO) decannulation in this study. MATERIALS AND METHODS: Patients who received VA-ECMO treatment and successfully removed from its support in Changhai Hospital from January 2018 to December 2021 were included in this study. Patients was divided into post-closure group and surgical repair group according to the artery access closure method used. Clinical data of these patients were retrospectively collected and analyzed. RESULTS: A total of 58 patients were eventually enrolled in this study, including 26 (44.83%) patients in post-closure group and 32 (55.17%) patients in surgical repair group. Post-closure group had shorter procedure time, less minor bleeding events, estimated blood loss and packed cells transfused compared with the surgical repair group. The intensive care unit (ICU) length of stay after decannulation and the hospital length of stay after ICU in post-closure group were both shorter than surgical repair group. Nine patients (15.52%) died of multiple system organ failure after decannulation in this cohort and there were no significant differences between two groups. CONCLUSIONS: Our study showed the post-closure technique based on ProGlide for VA-ECMO decannulation is feasible, safe and effective.

A Coordination Polymer for the Fluorescence Turn-On Sensing of Saccharin, 2-Thiazolidinethione-4-carboxylic Acid, and Periodate.

A luminescent 1D coordination polymer (CP) [Zn2L2(H2O)4]·H2O (1, H2L = 1-(4-carboxyphenyl)-1H-pyrazole-3-carboxylic acid) was prepared by a solvothermal method. 1 shows excellent fluorescence properties and has an obvious fluorescence "turn-on" phenomenon for saccharin (SAC), 2-thiazolidinethione-4-carboxylic acid (TTCA), and periodate (IO4-). Between 0 and 60 µM concentration range of SAC, the fluorescence enhancement efficiency (KEC) of 1 reaches 1.00 × 105 M-1 with the limit of detection (LOD) of 90 nM. 1 is the first CP-based sensing material for SAC detection. For TTCA detection, the KEC is 2.73 × 105 M-1 at the 25-80 µM concentration range, and the LOD is 33 nM, the lowest LOD among the sensors that detect TTCA at present. For IO4- ion detection, when the IO4- ion concentration ranges from 0 to 10 µM, the KEC is 2.34 × 105 M-1 and the LOD is as low as 39 nM. In order to better understand the sensing phenomenon, we also discuss in detail the sensing mechanisms for SAC, TTCA, and IO4- ions.

Serum lncRNA THRIL predicts benign and malignant pulmonary nodules and promotes the progression of pulmonary malignancies.

BACKGROUND: This project aimed to research the significance of THRIL in the diagnosis of benign and malignant solitary pulmonary nodules (SPNs) and to investigate the role of THRIL/miR-99a in malignant SPNs. METHODS: The study groups consisted of 169 patients with SPN and 74 healthy subjects. The differences in THRIL levels were compared between the two groups and the healthy group. The receiver operating characteristic curve (ROC) was utilized to analyze the THRIL's significance in detecting benign and malignant SPN. Pearson correlation and binary regression coefficients represented the association between THRIL and SPN. CCK-8 assay, Transwell assay, and flow cytometry were utilized to detect the regulatory effect of THRIL silencing. The interaction between THRIL, miR-99a, and IGF1R was confirmed by the double luciferase reporter gene. RESULTS: There were differences in THRIL expression in the healthy group, benign SPN group, and malignant SPN group. High accuracy of THRIL in the diagnosis of benign SPN and malignant SPN was observed. THRIL was associated with the development of SPN. The expression of THRIL was upregulated and miR-99a was downregulated in lung cancer cells. The double luciferase report experiment confirmed the connections between THRIL/miR-99a/IGF1R. Silencing THRIL could suppress cell proliferation, migration, and invasion and promote cell apoptosis by binding miR-99a. CONCLUSION: The detection of THRIL in serum is useful for the assessment of malignant SPN. THRIL can regulate the expression of IGF1R through miR-99a, thereby promoting the growth of lung cancer cells and inhibiting apoptosis.

Liuwei Dihuang Decoction Drug-containing Serum Attenuates Transforming Growth Factor-ß1-induced Epithelial-mesenchymal Transition in HK-2 Cells by Inhibiting NF-κB/Snail Signaling Pathway.

OBJECTIVES: The nuclear factor-κB (NF-κB) signaling pathway plays an important role in regulating tubular epithelial-mesenchymal transition (EMT), an indispensable cellular programme for driving organ fibrosis and tumor progression. Liuwei Dihuang Decoction (LWD) is an effective Chinese formula for treating chronic renal failure. METHODS: First, by using morphological examination, immunofluorescence staining assay, RTqPCR, and Western blot analysis, in vitro experiments were designed to analyze NF-κB and EMT markers (including Snail, α-SMA, and E-cadherin) in transforming growth factor-ß1 (TGF-ß1) induced renal tubular epithelial cells (HK-2) and to detect the expression levels of LWD-CS cotreatment. Then, the recombinant lentiviral vector was overexpressed and knocked down by NF- κB and transfected into HK-2 cells. Cells were treated with TGF-ß1 (10 ng/ml) with blank serum or LWD-containing serum, respectively, and the expression of these molecules in the NF-κB/Snail signaling pathway was further evaluated. RESULTS: Our results confirmed that TGF-ß1 could induce EMT, nuclear translocation of NF-κB p65, and activate the NF-κB/Snail signaling pathway in HK-2 cells. Furthermore, NF-κB knocked-down dramatically increases the TGF-ß1-induced mRNA and protein expression level of E-cadherin and reduces the level of Snail and α-SMA; this is reversed by NF-κB overexpression. LWD can decrease the EMT levels through the NF-κB/Snail signaling activation in TGF-ß1-induced EMT of HK-2 cells. CONCLUSION: The present study provides evidence suggesting a novel mechanism that LWD exerts anti-fibrosis effects through inhibiting activation of the NF-κB/Snail signaling pathway and consequently downregulating the TGF-ß1-induced EMT in renal tubular epithelial cells.

Strategies to Attenuate Myocardial Infarction and No-Reflow Through Preservation of Vascular Integrity by Pigment Epithelium-Derived Factor.

The phenomenon of no-reflow seriously limits the therapeutic value of coronary recanalization and leads to poor prognosis. Recent studies have demonstrated the potential role of pigment epithelium-derived factor (PEDF) in stabilizing endothelial cell junction, reducing vascular permeability and maintaining a quiescent vasculature. In this study, intramyocardial gene delivery was performed 5 days before the acute myocardial infarction/recanalization experiment in male rats. Positron emission tomography perfusion imaging with 13N-NH3 indicated PEDF to promote microvascular reperfusion significantly 4 h postcoronary occlusion. PEDF was observed to maintain the stability of endothelial adherens junctions (AJs), thus preventing the occurrence of no-reflow. PEDF reduced the hypoxia-induced vascular endothelial (VE)-cadherin endocytosis through PEDF/LR/Src/VE-cadherin S665 axis in vitro, which was remarkably observed to maintain endothelial AJs. Generally, PEDF might function as a relevant target for therapeutic vasculoprotection by way of regulating the phosphorylation level of VE-cadherin according to our data, thus being crucial for preventing no-reflow.

User capabilities in eyes-free spatial target acquisition in immersive virtual reality environments.

In immersive virtual reality (VR) environments, users rely on the vision channel to search for objects. Such eyes-engaged interactive techniques may significantly degrade the interaction efficiency and user experience, particularly when users have to turn their head frequently to search for a target object in the limited field of view (FOV) of a head-mounted display (HMD). In this study, we systematically investigated user capabilities in eyes-free spatial target acquisition considering different horizontal angles, vertical angles, distances from the user's body, and body sides. Our results show that high acquisition accuracy and low task load are achieved for target locations at front and middle horizontal angles as well as those at middle vertical angles. Meanwhile, a trade-off cannot be achieved between the acquisition accuracy and the task load for target locations at long distances from the user's body. In addition, the acquisition accuracy and task load for the target locations vary with the body side. Our research findings can provide a deeper understanding of user capability in eyes-free target acquisition and offer concrete design guidelines for appropriate target arrangement for eyes-free target acquisition in immersive VR environments.

Response Gene to Complement-32 Promotes the Imbalance of Treg/Th17 in Patients with Dilated Cardiomyopathy.

BACKGROUND/AIMS: The imbalance of Treg/Th17 cells plays important role in the pathogenesis of dilated cardiomyopathy (DCM). Response gene to complement (RGC)-32 is a cell cycle regulator that plays an important role in cell proliferation. We evaluated whether the upregulation of RGC-32 was implicated in the homeostasis of Treg/Th17 cells in DCM. METHODS: The levels of plasma RGC-32, IL-17 and TGF-ß1, and the frequencies of circulating CD4+ RGC-32+ T cells, Th17 and Treg cells in patients with DCM were determined by Cytokine-specific sandwich ELISA and the flow cytometer (FCM), respectively. RESULTS: A significant elevation of plasma RGC-32 in patients with DCM compared with healthy control (HC) subjects was observed. This upregulation was associated with an increase in frequency of Th17 and a decrease in frequency of Treg cells. To further assessed the role of RGC-32, we investigated the effects of RGC-32 up- or down-regulation on frequencies of Th17 and Treg cells in peripheral blood mononuclear cells (PBMCs) from subjects. Importantly, overexpression of RGC-32 was accompanied by an augmentation of Th17 and a reduction of Treg expression. CONCLUSION: In summary, our study demonstrated the up-regulation of RGC-32 contributed to the imbalance of Treg/Th17 cells in patients with DCM.

Bamboo leaf extract ameliorates cardiac fibrosis possibly via alleviating inflammation, oxidative stress and apoptosis.

Previous studies have shown that inflammatory process contributes to the pathogenesis of cardiac damage induced by diabetes mellitus. However, the underlying mechanisms and strategies to alleviate inflammatory injury in the diabetic heart are not fully elucidated. In this study, we investigated the potential role and related mechanism of bamboo leaf extract (BLE) on diabetes-induced cardiac fibrosis in rats. Diabetes was induced by streptozocin (STZ) in rats, blood glucose and glycosylated hemoglobin A1c (HbAlc) were measured. Super oxide dismutase (SOD) activity and malondialdehyde (MDA) level in rat heart homogenates were tested using special kits. Cardiac function was evaluated by echocardiography, and myocardial histology was detected by hematoxylin eosin (HE) staining and Masson's trichrome staining. Furthermore, expression of transforming growth factor-ß1 (TGF-ß1), interleukin 6 (IL-6) and Cleaved-cysteinyl aspartate-specific proteinase-3 (Cleaved-caspase-3), and the activity of nuclear factor κB (NF-κB) were examined by western blot analysis. From the data, we found that the BLE treatment inhibits oxidative stress and improved cardiac function in STZ-induced diabetic rats. BLE treatment significantly ameliorated diabetes-induced myocardial morphological changes and cardiac inflammation. Moreover, the protein levels of TGF-ß1, IL-6,Cleaved-caspase-3 and the nuclear transcription of NF-κB in the hearts were markedly reduced in diabetic rats result from BLE treatment. In conclusion, this study suggested that BLE ameliorates cardiac fibrosis in streptozotocin-induced diabetic rats, and this protective effect possibly through inhibiting inflammation, oxidative stress and apoptosis. BLE might serve as a potential therapeutic target for the treatment of the cardiac fibrosis in diabetic patients.

A novel modified physiologically relevant model for cardiac angiogenesis.

Angiogenesis assays are important tools for studying both the mechanisms of cardiac angiogenesis and the potential development of therapeutic strategies to ischemic heart diseases. Currently, various assays have been used to quantitate cardiac tubule formation, yet no consensus has been reached regarding a suitable assay for evaluating the efficacy of angiogenic stimulants or inhibitors. Most in vivo angiogenesis assays are complex and difficult to interpret, whereas traditional in vitro angiogenesis models measure only one aspect of this process. To bridge the gap between in vivo and in vitro angiogenesis assays, here, we have developed a novel modified cardiac explants matrigel assay. We observed the morphology of vascular sprouts formed in three forms of cardiac angiogenesis assays then used quantitative image analyses to further compare the morphological features of vascular sprouts formed in two cardiac explants angiogenesis assays. Vascular sprouts formed in the fibronectin group were less and short, whereas those formed in the matrigel group were significantly longer, consisting of more area and branch points. Moreover, we found the benefits of this matrigel model by observing the ability of cardiac explants to form vascular sprouts under normoxia or hypoxia condition in the presence of angiogenic stimulant and inhibitor, VEGF and PEDF. In summary, the above analyses revealed that the morphology of vascular sprouts formed in this model appears more representative of myocardial capillary formation in vivo, and this accessible, reliable angiogenic assay is a more physiologically relevant assay which allows further assessment of pharmacologic compounds on cardiac angiogenesis.

Pigment epithelium-derived factor attenuates myocardial fibrosis via inhibiting Endothelial-to-Mesenchymal Transition in rats with acute myocardial infarction.

Endothelial mesenchymal transition (EndMT) plays a critical role in the pathogenesis and progression of interstitial and perivascular fibrosis after acute myocardial infarction (AMI). Pigment epithelium-derived factor (PEDF) is shown to be a new therapeutic target owing to its protective role in cardiovascular disease. In this study, we tested the hypothesis that PEDF is an endogenous inhibitor of EndMT and represented a novel mechanism for its protective effects against overactive cardiac fibrosis after AMI. Masson's trichrome (MTC) staining and picrosirius red staining revealed decreased interstitial and perivascular fibrosis in rats overexpressing PEDF. The protective effect of PEDF against EndMT was confirmed by co-labeling of cells with the myofibroblast and endothelial cell markers. In the endothelial cells of microvessels in the ischemic myocardium, the inhibitory effect of PEDF against nuclear translocation of ß-catenin was observed through confocal microscopic imaging. The correlation between antifibrotic effect of PEDF and inactivation of ß-catenin was confirmed by co-transfecting cells with lentivirus carrying PEDF or PEDF RNAi and plasmids harboring ß-catenin siRNA(r) or constitutive activation of mutant ß-catenin. Taken together, these results establish a novel finding that PEDF could inhibit EndMT related cardiac fibrosis after AMI by a mechanism dependent on disruption of ß-catenin activation and translocation.

PEDF and PEDF-derived peptide 44mer inhibit oxygen-glucose deprivation-induced oxidative stress through upregulating PPARγ via PEDF-R in H9c2 cells.

Pigment epithelial-derived factor (PEDF) is a glycoprotein with broad biological activities including inhibiting oxygen-glucose deprivation(OGD)-induced cardiomyocytes apoptosis through its anti-oxidative properties. PEDF derived peptide-44mer shows similar cytoprotective effect to PEDF. However, the molecular mechanisms mediating cardiomyocytes apoptosis have not been fully established. Here we found that PEDF and 44mer decreased the content of ROS. This content was abolished by either PEDF-R small interfering RNA (siRNA) or PPARγ antagonist. The level of Lysophosphatidic acid (LPA) and phospholipase A2 (PLA2) was observed as drawn from the ELISA assays. PEDF and 44mer sequentially induced PPARγ expression was observed both in qPCR and Western blot assays. The level of LPA and PLA2 and PPARγ expression increased by PEDF and 44mer was significantly attenuated by PEDF-R siRNA. However, PEDF and 44mer inhibited the H9c2 cells and cultured neonatal rat myocardial cells apoptosis rate. On the other hand, TUNEL assay and cleavage of procaspase-3 showed that PEDF-R siRNA or PPARγ antagonist increased the apoptosis again. We conclude that under OGD condition, PEDF and 44mer reduce H9c2 cells apoptosis and inhibit OGD-induced oxidative stress via its receptor PEDF-R and the PPARγ signaling pathway.

PEDF and 34-mer inhibit angiogenesis in the heart by inducing tip cells apoptosis via up-regulating PPAR-γ to increase surface FasL.

Pigment epithelial-derived factor (PEDF) is a potent anti-angiogenic factor whose effects are partially mediated through the induction of endothelial cell apoptosis. However, the underlying mechanism for PEDF and the functional PEDF peptides 34-mer and 44-mer to inhibit angiogenesis in the heart has not been fully established. In the present study, by constructing adult Sprague-Dawley rat models of acute myocardial infarction (AMI) and in vitro myocardial angiogenesis, we showed that PEDF and 34-mer markedly inhibits angiogenesis by selectively inducing tip cells apoptosis rather than quiescent cells. Peptide 44-mer on the other hand exhibits no such effects. Next, we identified Fas death pathway as essential downstream regulators of PEDF and 34-mer activities in inhibiting angiogenesis. By using peroxisome proliferator-activated receptor γ (PPAR-γ) siRNA and PPAR-γ inhibitor, GW9662, we found the effects of PEDF and 34-mer were extensively blocked. These data suggest that PEDF and 34-mer inhibit angiogenesis via inducing tip cells apoptosis at least by means of up-regulating PPAR-γ to increase surface FasL in the ischemic heart, which might be a novel mechanism to understanding cardiac angiogenesis after AMI.

Defibrillation threshold varies during different stages of ventricular fibrillation in canine hearts.

BACKGROUND: Recent studies have shown that short duration ventricular fibrillation (SDVF) and long duration ventricular fibrillation (LDVF) are maintained by different mechanisms. The objective of this study is to evaluate how the defibrillation threshold (DFT) varies over the duration of fibrillation since the mechanism of VF maintenance changes as VF progresses. METHODS: Twelve canines were randomly divided into two groups (Group A and B, n=6 each). DFTs were measured three times in each group: SDVF (20s), LDVF (3min in Group A and 7min in Group B) and the first episode of refibrillation after successful defibrillation for LDVF. Two 64-electrode baskets used to globally map the endocardium were deployed into the left ventricle and right ventricle, respectively. RESULTS: LDVF-DFT in Group A was significantly higher than that of Group B (628±98V vs 313±81V, P<0.001). In Group B, the DFT of refibrillation was significantly increased compared with the LDVF-DFT (570±199V vs 313±81V, P=0.035) but did not differ from the DFT of refibrillation in Group A (570±199V vs 638±116V, P=0.39). Highly synchronised activation patterns on the left ventricular endocardium were observed between 3 and 7min of LDVF in Group B but not within 3min-LDVF in Group A or during refibrillation in each group. CONCLUSIONS: DFT varied during different stages of VF. The highly synchronised activation patterns exhibiting after 3min VF might contribute to the decreased LDVF-DFT.