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Background The optimal first‐line approach for patients with symptomatic atrial fibrillation (AF) remains unclear. We compared the efficacy and safety of cryoballoon ablation (CBA) and antiarrhythmic drugs (AADs) in the initial management of symptomatic AF. Hypothesis CBA is superior to AAD as initial therapy for symptomatic AF. Methods We searched the EMBASE, PubMed, and Cochrane Library databases for randomized controlled trials (RCTs) that compared CBA with AAD as first‐line treatment for AF from the date of database establishment until March 18, 2021. The risk ratio (RR) with a 95% confidence interval (CI) was used as a measure of treatment effect. Results Three RCTs that enrolled 724 patients in total were included in this meta‐analysis. Majority of the patients were relatively young and had paroxysmal AF. CBA was associated with a significant reduction in the recurrence of atrial arrhythmia compared with AAD therapy, with low heterogeneity (RR, 0.59; 95% CI, 0.49–0.71; p

During 2016-2020, the United States experienced person-to-person hepatitis A outbreaks that are unprecedented in the vaccine era, during which case-fatality ratios reported by some jurisdictions exceeded those historically associated with hepatitis A.To identify factors associated with hepatitis A-related mortality, we performed a matched case-control study (matched on age [±5 years] and county of residence in a 1:4 ratio) using data collected from health department and hospital medical records of outbreak-associated patients in Kentucky, Michigan, and West Virginia. Controls were hepatitis A outbreak-associated patients who did not die. There were 110 cases (mean age 53.6 years) and 414 matched controls (mean age 51.9 years); most cases (68.2%) and controls (63.8%) were male. Significantly (P 0.05) higher odds of mortality were associated with preexisting nonviral liver disease (adjusted odds ratio [aOR], 5.2), history of hepatitis B (aOR, 2.4), diabetes (aOR, 2.2), and cardiovascular disease (aOR, 2.2), as well as initial Model for End-Stage Liver Disease (MELD) score ≥ 30 (aOR, 10.0), aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio2 (aOR, 10.3), and platelet count150,000/μL (aOR, 3.7) among hepatitis A outbreak-associated patients in the independent multivariable conditional logistic regression analyses (each model adjusted for sex).Preexisting liver disease, diabetes, cardiovascular disease, and initial MELD score ≥ 30, AST/ALT ratio ≥ 1, and platelet count150,000/μL among hepatitis A patients were independently associated with higher odds of mortality. Providers should be vigilant for such features and have a low threshold to escalate care and consider consultation for liver transplantation. Our findings support the recommendation of the Advisory Committee on Immunization Practices to vaccinate persons with chronic liver disease, though future recommendations to include adults with diabetes and cardiovascular disease should be considered.

BACKGROUND Congenital fiber-type disproportion (CFTD) is a form of congenital myopathy. CFTD is rare, especially when presenting in patients with critical illnesses. Here, we report a case of CFTD presenting with type II respiratory failure after delivery and provide a review of the literature on CFTD. CASE SUMMARY A 30-year-old woman was admitted to the obstetrics department of our hospital with premature rupture of the fetal membrane and with 7 h of regular contractions. After delivery, the patient experienced a refractory type II respiratory failure. Physical examination along with diagnostic procedures such as electromyography and biopsy confirmed CFTD. Use of invasive ventilator followed by intermittent use of noninvasive ventilator attenuated her symptoms. The patient recovered after ventilator-assisted respiration and was weaned off the noninvasive ventilator on the seventh day postpartum. CONCLUSION Congenital myopathy should be considered a differential diagnosis for type II respiratory failures that cannot be attributed to other diseases.

As an effective anticancer drug, the clinical limitation of doxorubicin (Dox) is the time- and dose-dependent cardiotoxicity. Yes-associated protein 1 (YAP1) interacts with transcription factor TEA domain 1 (TEAD1) and plays an important role in cell proliferation and survival. However, the role of YAP1 in Dox-induced cardiomyopathy has not been reported. In this study, the expression of YAP1 was reduced in clinical human failing hearts with dilated cardiomyopathy and Dox-induced in vivo and in vitro cardiotoxic model. Ectopic expression of Yap1 significantly blocked Dox-induced cardiomyocytes apoptosis in TEAD1 dependent manner. Isorhapontigenin (Isor) is a new derivative of stilbene and responsible for a wide range of biological processes. Here, we found that Isor effectively relieved Dox-induced cardiomyocytes apoptosis in a dose-dependent manner in vitro. Administration with Isor (30 mg/kg/day, intraperitoneally, 3 weeks) significantly protected against Dox-induced cardiotoxicity in mice. Interestingly, Isor increased Dox-caused repression in YAP1 and the expression of its target genes in vivo and in vitro. Knockout or inhibition of Yap1 blocked the protective effects of Isor on Dox-induced cardiotoxicity. In conclusion, YAP1 may be a novel target for Dox-induced cardiotoxicity and Isor might be a new compound to fight against Dox-induced cardiotoxicity by increasing YAP1 expression.

Adipose-derived stem cells (ADSCs) have been documented as possible candidates for skin rejuvenation. However, the effects of ADSC-derived exosomes on photoaged skin remain to be fully elucidated. This study was aimed at determining the antiaging effects of ADSC-derived exosomes on photoaged skin. Human ADSCs were isolated from the adipose tissue of healthy women and cultured in vitro. Then, exosomes were extracted from the cultured ADSCs, purified by ultracentrifugation, and verified by examination of cell morphology using transmission electron microscopy and the identification of specific biomarkers. Meanwhile, the optimal exosome concentration and treatment time were selected. The photoaged skin model was created by subjecting Sprague-Dawley rats to ultraviolet B radiation. Exosomes were injected into the photoaged skin in a single therapeutic dose. The thickness of the epidermis and dermis was observed by HE staining. The relative mRNA expression of type I collagen, type III collagen, and matrix metalloproteinases (MMP-1 and MMP-3) was determined by real-time PCR. In the rat model of photoaged skin, the injected exosomes markedly decreased the epidermal thickness and increased the dermal thickness of the photoaged skin 7 days after treatment. Moreover, the proportion of the stratum corneum of the epidermis was decreased. Furthermore, real-time RT-PCR showed that the mRNA expression of type I collagen was increased and that of type III collagen, MMP-1, and MMP-3 was decreased. Our results demonstrate that ADSC-derived exosome treatment could significantly improve skin photodamage and that ADSC-derived exosomes may be a potential agent for photoaged skin treatment.

Background Since 2016, the United States has experienced person-to-person hepatitis A outbreaks unprecedented in the vaccine era. The proportion of cases hospitalized in these outbreaks exceeds historical national surveillance data. Methods We described the epidemiology, characterized the reported increased morbidity, and identified factors associated with hospitalization during the outbreaks by reviewing a 10% random sample of outbreak-associated hepatitis A cases in Kentucky, Michigan, and West Virginia—3 heavily affected states. We calculated descriptive statistics and conducted age-adjusted log-binomial regression analyses to identify factors associated with hospitalization. Results Participants in the random sample (n = 817) were primarily male (62.5%) with mean age of 39.0 years; 51.8% were hospitalized. Among those with available information, 73.2% reported drug use, 14.0% were experiencing homelessness, 29.7% were currently or recently incarcerated, and 61.6% were epidemiologically linked to a known outbreak-associated case. Residence in Michigan (adjusted risk ratio [aRR] = 1.8), being a man who has sex with men (aRR = 1.5), noninjection drug use (aRR = 1.3), and homelessness (aRR = 1.3) were significantly (P Conclusions Our findings support current Advisory Committee on Immunization Practices recommendations to vaccinate all persons who use drugs, men who have sex with men, and persons experiencing homelessness against hepatitis A.

In septic acute kidney injury (SAKI), the positive feedback between damaged mitochondria and accumulation of reactive oxygen species results in cell and tissue damage through multiple mechanisms. Removing the damaged mitochondria or neutralizing the reactive oxygen species has been considered beneficial to alleviating cell damage. The antioxidant Procyanidin B2 has been reported to inhibits reactive oxygen species and thereby reduces cell injury. However, it is unclear whether this effect is associated with clearance of damaged mitochondria. Here, we evaluated the efficacy of procyanidin B2 on SAKI, and focused on its effects on mitochondrial dynamics and removing damaged mitochondria via mitophagy. The results showed that the renal function, renal tubular cell vacuolization and oxidative stress were decreased in SAKI mice treated with procyanidin B2, moreover, skewed mitochondrial fusion/fission, mitochondrial mediated apoptosis and impaired mitophagy were improved in SAKI mice treated with procyanidin B2. In mechanism, the improvement of procyanidin B2 on mitochondrial dynamics were associated with increased nuclear translocation of the transcription factor, Nrf2. In summary, our findings highlighted that the protective efficacy of procyanidin B2 in reducing cellular damage in SAKI, and mechanisms improving mitochondrial dynamics and quality control at least in part by promoting Nrf2 translocation into the nucleus.

The invasion ability of glioblastoma (GBM) causes tumor cells to infiltrate the surrounding brain parenchyma and leads to poor outcomes. Transient receptor potential vanilloid 4 (TRPV4) exhibits a remarkable role in cancer cell motility, but the contribution of TRPV4 to glioblastoma metastasis is not fully understood. Here, we reported that TRPV4 expression was significantly elevated in malignant glioma compared to normal brain and low-grade glioma, and TRPV4 expression was negatively correlated with the prognosis of glioma patients. Functionally, stimulation of TRPV4 promoted glioblastoma cell migration and invasion, and repression of TRPV4 hindered the migration and invasion of glioblastoma cells in vitro. Molecularly, TRPV4 strongly colocalized and interacted with skeletal protein-F-actin at cellular protrusions, and TRPV4 regulated the formation of invadopodia and filopodia in glioblastoma cells. Furthermore, the Cdc42/N-wasp axis mediated the effect of TRPV4-regulated cellular protrusions and invasion. Foremost, TRPV4 inhibitor treatment or downregulation of TRPV4 significantly reduced the invasion-growth of subcutaneously and intracranially transplanted glioblastoma in mice. In conclusion, the TRPV4/Cdc42/wasp signaling axis regulates cellular protrusion formation in glioblastoma cells and influences the invasion-growth phenotype of glioblastoma in vivo. TRPV4 may serve as a prognostic factor and specific therapeutic target for GBM patients.

Diabetic retinopathy (DR) is a common complication of diabetes and a leading cause of blindness among the working-age population. Diabetic patients often experience functional deficits in dark adaptation, contrast sensitivity, and color perception before any microvascular pathologies on the fundus become detectable. Previous studies showed that the regeneration of 11-cis-retinal and visual pigment is impaired in a type 1 diabetes animal model, which negatively affects visual function at the early stage of DR. Here, Akita mice, type 1 diabetic model, were treated with the visual pigment chromophore, 9-cis-retinal. This treatment rescued a- and b-wave amplitudes of scotopic electroretinography responses, compared with vehicle-treated Akita mice. In addition, the administration of 9-cis-retinal alleviated oxidative stress significantly as shown by reduced 3-nitrotyrosine levels in the retina of Akita mice. Furthermore, the 9-cis-retinal treatment decreased retinal apoptosis as shown by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and DNA fragment enzyme-linked immunosorbent assay. Overall, these findings showed that 9-cis-retinal administration restored visual pigment formation and decreased oxidative stress and retinal degeneration, which resulted in improved visual function in diabetic mice, suggesting that chromophore deficiency plays a causative role in visual defects in early DR.

Purpose: Elevated blood levels of C-reactive protein (CRP) are associated with both type 1 and type 2 diabetes and diabetic complications, such as diabetic retinopathy (DR). However, its pathogenic role in DR remains unknown. The present study aims to investigate the potential role of CRP in DR pathogenesis and explore its underlying mechanism. Materials and methods: Human CRP transgenic (hCRP-Tg) rats were employed for streptozotocin (STZ)-induced diabetic and oxygen-induced retinopathy (OIR) models. The retina function was monitored by electroretinography (ERG) and retinal thickness was measured by optical coherence tomography (OCT). TUNEL and cell death ELISA were performed to measure the apoptosis. Oxidative stress was detected by the measurement of reactive oxygen species (ROS) in cells and 3-Nitrotyrosine staining in tissue sections. Results: In non-diabetic condition, hCRP-Tg with elevated hCRP levels in the retinas demonstrated declined ERG responses and decreased retinal thickness. In STZ-induced diabetic condition, overexpression of hCRP deteriorated retinal neurodegeneration as shown by ERG and apoptosis assays. hCRP also exacerbated retinal leukostasis and acellular capillary formation induced by diabetes. In the OIR model, overexpression of hCRP exacerbated retinal neovascularization (NV). In retinal cell lines, hCRP treatment induced cell death and over-production of ROS. Furthermore, hCRP-induced overexpression of pro-inflammatory, pro-oxidative, and pro-angiogenic factors was associated with up-regulation of CD32 and the NF-κB signaling in the retinas. Conclusions: Elevated hCRP levels play a pathogenic role in DR. Targeting the hCRP-CD32-NF-κB pathway may represent a novel therapeutic strategy for DR.

Diabetes mellitus erectile dysfunction (DMED) is a common complication of diabetes. The level of pigment epithelium-derived factor (PEDF) is significantly upregulated in the serum of individuals with obesity and diabetes. However, whether elevated PEDF levels contribute to DMED remains unknown. This study aimed to investigate the pathogenic role of PEDF and its related mechanism in DMED.We enrolled 65 men, of whom 20 were nondiabetic control participants, 21 participants with diabetes but without erectile dysfunction, and 24 with DMED. The International Index of Erectile Function (IIEF-5) questionnaire was administered to evaluate erectile function. Plasma PEDF in diabetic participants and streptozotocin (STZ)-induced diabetic animals was detected by ELISA. Erectile function was evaluated by measuring the intracavernous pressure (ICP) and the ICP/mean arterial pressure (MAP) ratio in STZ-induced diabetic rats treated with PEDF-neutralising antibody (PEDF-Ab), db/db mice treated with PEDF-Ab, and Pedf knockout mice with STZ-induced diabetes. The overexpression of PEDF was implemented by intraperitoneal injection of recombinant PEDF and intracavernous injection of PEDF-expressing adenovirus. A mechanistic study was performed by immunofluorescence staining, bimolecular fluorescence complementation (BiFC), immunoprecipitation and western blotting.We found that the plasma level of PEDF was significantly higher in participants with DMED compared with diabetic counterparts without erectile dysfunction and nondiabetic controls. Interestingly, PEDF levels were negatively correlated with plasma nitrite/nitrate levels and erectile function in DMED patients and STZ-induced diabetic rats. Furthermore, overexpression of PEDF significantly suppressed ICP and endothelial nitric oxide synthase (eNOS) phosphorylation in control rats. In contrast, the PEDF-Ab and Pedf knockout ameliorated ICP and eNOS phosphorylation in diabetic rats and mice. Mechanistically, PEDF promoted the membrane translocation of Hsp90β and directly bound to the amino acid residues 341-724 of Hsp90β on the endothelial cell surface, subsequently blocking intracellular Hsp90β/Akt/eNOS complex formation and downregulating eNOS phosphorylation.These results indicate that elevated PEDF levels contribute to impaired erectile function by suppressing Hsp90β-mediated eNOS phosphorylation and that PEDF may represent a novel therapeutic target for diabetic erectile dysfunction. Graphical abstract.

Background This study aimed to construct prognostic model by screening prognostic miRNA signature of bladder cancer. Methods The miRNA expression profile data of bladder cancer (BC) in The Cancer Genome Atlas (TCGA) were obtained and randomly divided into the training set and the validation set. Differentially expressed miRNAs (DEMs) between BC and normal control samples in the training set were firstly identified, and DEMs related to prognosis were screened by Cox Regression analysis. Then, the MiR Score system was constructed using X-Tile based cutoff points and verified in the validation set. The prognostic clinical factors are selected out by univariate and multivariate Cox Regression analysis. Finally, the mRNAs related to prognosis were screened and the biological pathway analysis was carried out. Results We identified the 7-miRNA signature was significantly associated with the patient’s Overall Survival (OS). A prognostic model was constructed based on the prognostic 7-miRNA signature, and possessed a relative satisfying predicted ability both in the training set and validation set. In addition, univariate and multivariate Cox Regression analysis showed that age, lymphovascular invasion and MiR Score were considered as independent prognostic factors in BC patients. Furthermore, based on MiR Score prognostic model, several differentially expressed genes (DEGs), such as WISP3 and UNC5C, as well as their related biological pathway(s), including cell–cell adhesion and neuroactive ligand-receptor interaction, were considered to be related to BC prognosis. Conclusion The prognostic model which was constructed based on the prognostic 7-miRNA signature presented a high predictive ability for BC.

Doxorubicin (Dox) is an effective chemotherapy drug against a wide range of cancers, including both hematological and solid tumors. However, the serious cardiotoxic effect restricted its clinical application. We previously have illuminated the protective role of canonical Wnt/β-catenin signaling in Dox-induced cardiotoxicity. Secreted frizzled-related protein 1 (sFRP1) is one of the endogenous inhibitors of both canonical and noncanonical Wnt signaling. In this study, we investigated the relationship between sFRP1 and noncanonical Wnt/PCP-JNK (Wnt/planar cell polarity-c-Jun N-terminal kinase) pathway in Dox-induced cardiotoxicity in vitro and in vivo. We showed that treatment of H9c2 cardiac myoblasts with Dox (1 μM) time-dependently suppressed cell viability accompanied by significantly decreased sFRP1 protein level and increased Wnt/PCP-JNK signaling. Pretreatment with SP600125, the Wnt/PCP-JNK signaling inhibitor, attenuated Dox-induced apoptosis of H9c2 cells. Overexpression of sFRP1 protected H9c2 cells from Dox-induced apoptosis by inhibiting the Wnt/PCP-JNK pathway. After intraperitoneal injection of a cumulative dose of 15 mg/kg Dox, rats displayed significant cardiac dysfunction; their heart showed inhibited Wnt/β-catenin signaling and activated Wnt/PCP-JNK signaling. These results suggest that sFRP1 may be a novel target for Dox-induced cardiotoxicity.

Background. Critical patients with the coronavirus disease 2019 (COVID-19), even those whose nucleic acid test results had turned negative and those receiving maximal medical support, have been noted to progress to irreversible fatal respiratory failure. Lung transplantation (LT) as the sole therapy for end-stage pulmonary fibrosis related to acute respiratory distress syndrome has been considered as the ultimate rescue therapy for these patients. Methods. From February 10 to March 10, 2020, three male patients were urgently assessed and listed for transplantation. After conducting a full ethical review and after obtaining assent from the family of the patients, we performed three LT procedures for COVID-19 patients with illness durations of more than one month and extremely high sequential organ failure assessment scores. Results. Two of the three recipients survived post-LT and started participating in a rehabilitation program. Pearls of the LT team collaboration and perioperative logistics were summarized and continually improved. The pathological results of the explanted lungs were concordant with the critical clinical manifestation, and provided insight towards better understanding of the disease. Government health affair systems, virology detection tools, and modern communication technology all play key roles towards the survival of the patients and their rehabilitation. Conclusions. LT can be performed in end-stage patients with respiratory failure due to COVID-19-related pulmonary fibrosis. If confirmed positive-turned-negative virology status without organ dysfunction that could contraindicate LT, LT provided the final option for these patients to avoid certain death, with proper protection of transplant surgeons and medical staffs. By ensuring instant seamless care for both patients and medical teams, the goal of reducing the mortality rate and salvaging the lives of patients with COVID-19 can be attained.

Previous studies by us and others demonstrated that activation of Wnt/β-catenin signaling plays a pathogenic role in chronic kidney diseases (CKD). Wnt co-receptor LRP5 variants are reported to associate with autosomal dominant polycystic kidney disease; but their exact roles in this disease and renal fibrosis have not been explored. Here, we observed the upregulation of LRP5 in the renal tubules of both type 1 and type 2 diabetic models and of an obstructive nephropathy model. In the obstructed kidneys, Lrp5 knockout significantly ameliorated tubulointerstitial fibrosis and tubular injury without changing Wnt/β-catenin signaling. Instead, decreased levels of TGF-β1 and TGF-β receptors (TβRs) were detected in Lrp5 knockout kidneys, followed by attenuated activation and nuclear translocation of Smad2/3 in the renal tubules, suggesting a regulatory effect of LRP5 on TGF-β/Smad signaling. In consistent with this hypothesis, LRP5 overexpression resulted in enhanced TGF-β/Smad signaling activation in renal tubule epithelial cells. Furthermore, LRP5 was co-immunoprecipitated with TβRI and TβRII, and its extracellular domain was essential for interacting with TβRs and for its pro-fibrotic activity. In addition to stabilizing TβRs, LRP5 increased the basal membrane presentation and TGF-β1-induced internalization of these receptors. Notably, TGF-β1 also induced LRP5 internalization. These findings indicate that LRP5 promotes tubulointerstitial fibrosis, at least partially, via direct modulation of TGF-β/Smad signaling, a novel, Wnt-independent function.

Kallistatin is an inhibitor of tissue kallikrein and also inhibits the Wnt pathway. Its role in diabetic nephropathy (DN) is uncertain. Here we reported that serum kallistatin levels were significantly increased in diabetic patients with DN compared to those in diabetic patients without DN and healthy controls, and positively correlated with urinary albumin excretion. In addition, renal kallistatin levels were significantly upregulated in mouse models of type 1 (Akita, OVE26) and type 2 diabetes (db/db). To unveil the effects of kallistatin on DN and its underlying mechanism, we crossed transgenic mice overexpressing kallistatin with OVE26 mice (KS‐tg/OVE). Kallistatin overexpression exacerbated albuminuria, renal fibrosis, inflammation, and oxidative stress in diabetes. Kallikrein activity was inhibited while the renin‐angiotensin system (RAS) upregulated in the kidney of KS‐tg/OVE mice compared to WT/OVE mice, suggesting a disturbed balance between the RAS and kallikrein‐kinin systems. As shown by immunostaining of endothelial makers, renal vascular densities were decreased accompanied by increased HIF‐1α and erythropoietin levels in the kidneys of KS‐tg/OVE mice. Taken together, high levels of kallistatin exacerbate DN at least partly by inducing RAS overactivation and hypoxia. The present study demonstrated a positive correlation between kallistatin levels and DN, suggesting a potential biomarker for prognosis of DN.

The purpose of this study was to investigate the protective role of peroxisome proliferator–activated receptor α (PPARα) against diabetic keratopathy and corneal neuropathy. Corneal samples were obtained from human donors with and without diabetes. Streptozotocin-induced diabetic rats and mice were orally treated with PPARα agonist fenofibrate. As shown by immunohistochemistry and Western blotting, PPARα was downregulated in the corneas of humans with diabetes and diabetic rats. Immunostaining of β-III tubulin demonstrated that corneal nerve fiber metrics were decreased significantly in diabetic rats and mice, which were partially prevented by fenofibrate treatment. As evaluated using a Cochet-Bonnet aesthesiometer, corneal sensitivity was significantly decreased in diabetic mice, which was prevented by fenofibrate. PPARα−/− mice displayed progressive decreases in the corneal nerve fiber density. Consistently, corneal sensitivity was decreased in PPARα−/− mice relative to wild-type mice by 21 months of age. Diabetic mice showed increased incidence of spontaneous corneal epithelial lesion, which was prevented by fenofibrate while exacerbated by PPARα knockout. Western blot analysis revealed significantly altered neurotrophic factor levels in diabetic rat corneas, which were partially restored by fenofibrate treatment. These results indicate that PPARα protects the corneal nerve from degeneration induced by diabetes, and PPARα agonists have therapeutic potential in the treatment of diabetic keratopathy.

The recommended standard treatment for giant bullae is surgical bullectomy. However, with a relatively high risk for perioperative morbidity and mortality, it is unsuitable for some patients. Recently, bronchoscopic bullectomy with one-way valves has shown efficacy and safety in some cases. Locating the giant bulla and confirming the negative collateral ventilation are essential for the bronchoscopic bullectomy with valves. Here, we report a case with a giant bulla using the Chartis System to correct the previous mislocation by the high-resolution computed tomography (HRCT), thus helping to achieve a great efficacy in the bronchoscopic bullectomy with valves. Our case suggests that bronchoscopic bullectomy with valves could be an effective and safe choice. Chartis system can be helpful in determining the location of a bulla when difficulty is encountered using HRCT.

Peroxisome proliferator-activated receptor alpha (PPARα) is expressed in retinal Müller cells, endothelial cells, and in retinal pigment epithelium, and agonism of PPARα with genetic or pharmacological tools ameliorates inflammation, vascular leakage, neurodegeneration, and neovascularization associated with retinal diseases in animal models. As such, PPARα is a promising drug target for diabetic retinopathy and age-related macular degeneration. Herein, we report proof-of-concept in vivo efficacy in an STZ-induced vascular leakage model (rat) and preliminary pharmacokinetic assessment of a first-generation lead 4a (A91). Additionally, we present the design, synthesis, and evaluation of second-generation analogs, which led to the discovery of 4u and related compounds that reach cellular potencies 2,700-fold selectivity for PPARα over other PPAR isoforms. These studies identify a pipeline of candidates positioned for detailed PK/PD and pre-clinical evaluation.

Background: Little is known about the pathophysiological diversity of myocardial injury in type 2 diabetes mellitus (T2DM), but analyzing these differences is important for the accurate diagnosis and precise treatment of diabetic cardiomyopathy. This study aimed to elucidate the key cardiac pathophysiological differences in myocardial injury between obese and non-obese T2DM from mice to humans. Methods: Obese and non-obese T2DM mouse models were successfully constructed and observed until systolic dysfunction occurred. Changes in cardiac structure, function, energy metabolism and oxidative stress were assessed by biochemical and pathological tests, echocardiography, free fatty acids (FFAs) uptake fluorescence imaging, transmission electron microscopy, etc. Key molecule changes were screened and verified by RNA sequencing, quantitative real-time polymerase chain reaction and western blotting. Further, 28 human heart samples of healthy population and T2DM patients were collected to observe the cardiac remodeling, energy metabolism and oxidative stress adaptations as measured by pathological and immunohistochemistry tests. Results: Obese T2DM mice exhibited more severe cardiac structure remodeling and earlier systolic dysfunction than non-obese mice. Moreover, obese T2DM mice exhibited severe and persistent myocardial lipotoxicity, mainly manifested by increased FFAs uptake, accumulation of lipid droplets and glycogen, accompanied by continuous activation of the peroxisome proliferator activated receptor alpha (PPARα) pathway and phosphorylated glycogen synthase kinase 3 beta (p-GSK-3β), and sustained inhibition of glucose transport protein 4 (GLUT4) and adipose triglyceride lipase (ATGL), whereas non-obese mice showed no myocardial lipotoxicity characteristics at systolic dysfunction stage, accompanied by the restored PPARα pathway and GLUT4, sustained inhibition of p-GSK-3β and activation of ATGL. Additionally, both obese and non-obese T2DM mice showed significant accumulation of reactive oxygen species (ROS) when systolic dysfunction occurred, but the NF-E2-related factor 2 (Nrf2) pathway was significantly activated in obese mice, while was significantly inhibited in non-obese mice. Furthermore, the key differences found in animals were reliably verified in human samples. Conclusion: Myocardial injury in obese and non-obese T2DM may represent two different types of complications. Obese T2DM individuals, compared to non-obese individuals, are more prone to develop cardiac systolic dysfunction due to severe and persistent myocardial lipotoxicity. Additionally, anti-oxidative dysfunction may be a key factor leading to myocardial injury in non-obese T2DM.

Background Platelet-rich plasma (PRP) improves the healing of refractory wounds, and its application is receiving more attention in the field of wound repair. However, when a patient's condition is very poor, it may be difficult to provide whole blood to harvest autologous PRP. Methods We evaluated the efficacy and safety of allogeneic PRP in the field of chronic refractory wound repair. Sixty patients (39 males and 21 females, 57 ± 10 y old) with chronic wounds were enrolled in this prospective, randomized, single-center study during January 2014 to January 2018. Their wounds were treated by standard care. The patients with chronic refractory wounds were divided into allogeneic PRP treatment and control groups on the basis of the presence or absence of allogeneic PRP in wounds after debridement, respectively. Allogeneic PRP was prepared by collecting whole blood from healthy individuals and two-step centrifugation. Clinical effects were evaluated by visually observing wound conditions and objectively assessing wound surfaces. Results After 30 d of treatment, the allogeneic PRP-treated group showed bright red granulation that bled easily with reduced inflammatory exudation. No rejection reactions were observed. The rate of chronic wound healing was much faster in the allogeneic PRP-treated group than that in the control group. Conclusions The present study shows that combined treatment of chronic wounds by standard care and allogeneic PRP significantly shortens healing time, suggesting that allogeneic PRP is an effective, safe adjuvant treatment for chronic wounds.

BackgroundInfection and rejection are the two most common complications after lung transplantation (LT) and are associated with increased morbidity and mortality. The differential diagnosis of infection and rejection is sometimes difficult due to similar clinical manifestations. However, few studies have investigated the airway microbiota between lung transplant recipients (LTRs) with infection and rejection. ResultsA total of 181 sputum samples (event-free, n=47; infection, n=103; rejection, n=31) were collected from 59 LTRs. A distinct airway microbiota was observed among clinically stable (or event-free) recipients and those with infection or acute rejection after LT. Alpha and beta diversity were significantly different between event-free and rejection recipients and between infection and rejection recipients. Ten differential genera were identified by linear discriminant analysis effect size (LEfSe), with Corynebacterium, unclassified Enterococcaceae and unclassified Lactobacillales enriched in recipients with infection, and Rothia, Granulicatella, Neisseria, Actinomyces, Leptotrichia, Lactobacillus and unclassified Aerococcaceae more abundant in LTRs with acute rejection. Random forest analyses indicated that the combination of the 10 microbiota constituents and procalcitonin (PCT) and T-lymphocyte levels showed AUCs of 0.894, 0.955 and 0.913 to differentiate between event-free and infection, event-free and rejection, and infection and rejection recipients, respectively. ConclusionsOur study is the first to compare the airway microbiota between LTRs with infection and acute rejection. The airway microbiota, especially combined with PCT and T-lymphocyte levels, showed satisfactory predictive efficiency in discriminating among clinically stable recipients and those with infection and acute rejection, suggesting that the airway microbiota was an indicator to differentiate between infection and acute rejection after LT.

Subretinal fibrosis is a key pathological feature in neovascular age-related macular degeneration (nAMD). Previously, we identified soluble very low-density lipoprotein receptor (sVLDLR) as an endogenous Wnt signaling inhibitor. This study investigates whether sVLDLR plays an anti-fibrogenic role in nAMD models, including Vldlr-/- mice and laser-induced choroidal neovascularization (CNV). We found that fibrosis factors including P-Smad2/3, α-SMA, and CTGF were upregulated in the subretinal area of Vldlr-/- mice and the laser-induced CNV model. The antibody blocking Wnt co-receptor LRP6 significantly attenuated the overexpression of fibrotic factors in these two models. Moreover, there was a significant reduction of sVLDLR in the interphotoreceptor matrix (IPM) in the laser-induced CNV model. A transgenic strain (sVLDLR-Tg) with sVLDLR overexpression in the IPM was generated. Overexpression of sVLDLR ameliorated the profibrotic changes in the subretinal area of the laser-induced CNV model. In addition, Wnt and TGF-β signaling synergistically promoted fibrogenesis in human primary retinal pigment epithelium (RPE) cells. CRISPR/Cas9-mediated LRP6 gene knockout (KO) attenuated this synergistic effect. The disruption of VLDLR expression promoted, while the overexpression of sVLDLR inhibited TGF-β-induced fibrosis. These findings suggest that overactivated Wnt signaling enhances the TGF-β pathway in subretinal fibrosis. sVLDLR confers an antifibrotic effect, at least partially, through the inhibition of Wnt signaling and thus, has therapeutic potential for fibrosis.

Common upper limb peripheral artery diseases (PADs) are atherosclerosis, embolic diseases, and systemic diseases, which are often asymptomatic, and the narrowed arteries (stenosis) will gradually reduce blood flow in the right or left upper limbs. Upper extremity vascular disease (UEVD) and atherosclerosis are high-risk PADs for patients with Type 2 diabetes or with both diabetes and end-stage renal disease. For early UEVD detection, a fingertip-based, toe-based, or wrist-based photoplethysmography (PPG) tool is a simple and noninvasive measurement system for vital sign monitoring and healthcare applications. Based on time-domain PPG analysis, a Duffing–Holmes system with a master system and a slave system is used to extract self-synchronization dynamic errors, which can track the differences in PPG morphology (in amplitudes (systolic peak) and time delay (systolic peak to diastolic peak)) between healthy subjects and PAD patients. In the preliminary analysis, the self-synchronization dynamic errors can be used to evaluate risk levels based on the reflection index (RI), which includes normal condition, lower PAD, and higher PAD. Then, a one-dimensional convolutional neural network is established as a multilayer classifier for automatic UEVD screening. The experimental results indicated that the self-synchronization dynamic errors have a positive correlation with the RI (R2 = 0.6694). The K-fold cross-validation is used to verify the performance of the proposed classifier with recall (%), precision (%), accuracy (%), and F1 score.

Kallistatin or kallikrein-binding protein (KBP) has been reported to regulate angiogenesis, inflammation and tumor progression. Autoimmune uveitis is a common, sight-threatening inflammatory intraocular disease. However, the roles of kallistatin in autoimmunity and autoreactive T cells are poorly investigated. Compared to non-uveitis controls, we found that plasma levels of kallistatin were significantly upregulated in patients with Vogt-Koyanagi-Harada (VKH) disease, one of the non-infectious uveitis. Using an experimental autoimmune uveitis (EAU) model induced by human interphotoreceptor retinoid-binding protein peptide 651-670 (hIRBP651-670), we examined the effects of kallistatin on the pathogenesis of autoimmune diseases. Compared to wild type (WT) mice, kallistatin transgenic (KS) mice developed severe uveitis with dominant Th17 infiltrates in the eye. In addition, the proliferative antigen-specific T cells isolated from KS EAU mice produced increased levels of IL-17A, but not IFN-γ or IL-10 cytokines. Moreover, splenic CD4+ T cells from naïve KS mice expressed higher levels of Il17a mRNA compared to WT naïve mice. Under Th17 polarization conditions, KS mice exhibited enhanced differentiation of naïve CD4+ T cells into Th17 cells compared to WT controls. Together, our results indicate that kallistatin promotes Th17 differentiation and is a key regulator of aggravating autoinflammation in EAU. Targeting kallistatin might be a potential to treat autoimmune disease.

Pathologies of the central nervous system (CNS) white matter often result in permanent functional deficits because mature mammalian projection neurons fail to regenerate long-distance axons after injury. A major barrier to axonal regenerative research is that the CNS axons that regenerate in response to experimental treatments stall growth before reaching their post-synaptic targets. Here, we test the hypothesis that premature, de novo, myelination of regenerating axons stalls their growth, even after bypassing the glial scar. To test this hypothesis, first, we used single cell RNA-seq (scRNA-seq) and immunohistological analysis to investigate whether post-injury born oligodendrocytes integrate into the glial scar after optic nerve injury. Then, we used a multiple sclerosis model of demyelination concurrently with the stimulation of axon regeneration by Pten knockdown (KD) in projection neurons after optic nerve injury. We found that post-injury born oligodendrocytes integrate into the glial scar, where they are susceptible to the demyelination treatment, which prevented premature myelination, and thereby enhanced Pten KD-stimulated axon regeneration. We also present a website for comparing the gene expression of scRNA-seq-profiled optic nerve oligodendrocytes under physiological and pathophysiological conditions.SIGNIFICANCE STATEMENTMyelin debris from degenerating axons along with reactive astrocytes in the glial scar inhibit CNS axon regeneration. However, even with the recently developed experimental approaches which activate axons to regenerate passed the glial scar, almost all axons still stall growth before reaching their post-synaptic targets. Here, we show that post-injury born oligodendrocytes integrate into the glial scar, and that other than myelin debris, live oligodendrocytes prematurely myelinating the regenerating axons inhibit growth, even if the axons have already regenerated passed the glial scar.

Inflammation, vascular smooth muscle cell apoptosis and oxidative stress are believed to play important roles in abdominal aortic aneurysm (AAA) pathogenesis. Human kallistatin (KAL; gene SERPINA4) is a serine proteinase inhibitor previously shown to inhibit inflammation, apoptosis and oxidative stress. The aim of this study was to investigate the role of KAL in AAA through studies in experimental mouse models and patients. Serum KAL concentration was negatively associated with the diagnosis and growth of human AAA. Transgenic overexpression of the human KAL gene (KS-Tg) or administration of recombinant human KAL (rhKAL) inhibited AAA in the calcium phosphate (CaPO4) and subcutaneous angiotensin II (AngII) infusion mouse models. Upregulation of KAL in both models resulted in reduction in the severity of aortic elastin degradation, reduced markers of oxidative stress and less vascular smooth muscle apoptosis within the aorta. Administration of rhKAL to vascular smooth muscle cells incubated in the presence of AngII or in human AAA thrombus-conditioned media reduced apoptosis and downregulated markers of oxidative stress. These effects of KAL were associated with upregulation of Sirtuin 1 activity within the aortas of both KS-Tg mice and rodents receiving rhKAL. These results suggest KAL-Sirtuin 1 signalling limits aortic wall remodelling and aneurysm development through reductions in oxidative stress and vascular smooth muscle cell apoptosis. Upregulating KAL may be a novel therapeutic strategy for AAA.

Breast tumor ranks fourth among various cancers in terms of mortality rate in Taiwan, and it is also the most commonly prevalent cancer in females. Early detection of any malignant lesions can increase the survival rate and also decline the mortality rate through current advanced medical therapies. Acoustic radiation force impulse (ARFI) is a new imaging technique for distinguishing breast lesions in the early stage based on localized tissue displacement, which is quantitated by virtual touch tissue imaging (VTI). Digital ARFI-VTI is an initial breast imaging modality and appears to be more effective in women aged >30 years. Therefore, image enhancement process is a key technique to enhance a low-contrast image in a region of interest (ROI) for visualizing texture details and morphological features. In this study, two-dimensional (2D) fractional-order convolution, as a 2D sliding filter window (eight filters are selected), is applied to enhance ARFI-VTI images for an accurate extrapolation of lesions in an ROI. Then, the maximum pooling is performed to reduce the dimensions of the feature patterns from 32×32 to 16×16 size. A multilayer machine vision classifier, as a generalized regression neural network (GRNN), is then used to screen subjects with benign or malignant tumors. With a 10fold cross-validation, promising results such as mean recall (%), mean precision (%), mean accuracy (%), and mean F1 score of 92.92±3.43%, 80.42±6.45%, 87.78±2.17%, and 0.8615±0.0495, respectively, are achieved for quantifying the performance of the proposed classifier. Breast tumors visualized on ARFI-VTI images can be useful as digitalized images for rapid screening of malignant from benign lesions by the proposed machine vision classifier.

Lung diseases can result in acute breathing problems and prevent the human body from acquiring enough oxygen. These diseases, such as pneumonia (P), pleural effusion (Ef), lung cancer, pneumothorax (Pt), pulmonary fibrosis (F), infiltration (In) and emphysema (E), adversely affect airways, alveoli, blood vessels, pleura and other parts of the respiratory system. The death rates of P and lung cancer are higher than those of other typical lung diseases. In visualization examination, chest radiography, such as anterior-posterior or lateral image viewing, is a straightforward approach used by clinicians/radiologists to diagnose and locate possible lung abnormalities rapidly. However, a chest X-ray image of patients may show multiple abnormalities associated with coexisting conditions, such as P, E, F, Pt, atelectasis, lung cancer or surgical interventions, which further complicate diagnosis. In addition, poor-quality X-ray images and manual inspection have limitations in digital image-automated classification. Hence, this study intends to propose a multilayer machine vision classifier to automatically identify the possible class of lung diseases within a bounding region of interest (ROI) on a chest X-ray image. For digital image texture analysis, a two-dimensional (2D) fractional-order convolution (FOC) operation with a fractional-order parameter, $v =0.3-0.5$ , is used to enhance the symptomatic feature and remove unwanted noises. Then, maximum pooling is performed to reduce the dimensions of feature patterns and accelerate complex computations. A multilayer machine vision classifier with radial Bayesian network and gray relational analysis is used to screen subjects with typical lung diseases. Anterior-posterior chest X-ray images from the NIH chest X-ray database (NIH Clinical Center) are enrolled. For digital chest X-ray images, with $K$ -fold cross-validation, the proposed multilayer machine vision classifier is applied to facilitate the diagnosis of typical lung diseases on specific bounding ROIs, as promising results with mean recall (%), mean precision (%), mean accuracy (%) and mean F1 score of 98.68%, 82.42%, 83.57% and 0.8981, respectively, for assessing the performance of proposed multilayer classifier for rapidly screening lung lesions on digital chest X-ray images.

Chest X-ray (CXR) images are usually used to identify the causes of patients’ symptoms, including the classes of lung or heart disorders. In visualization examination, CXR imaging in anterior–posterior (A–P) views is a preliminary screening method used by clinicians or radiologists to diagnose possible lung abnormalities, such as pneumothorax (Pt), emphysema (E), infiltration (In), lung cancer (M), pneumonia (P), pulmonary fibrosis (F), and pleural effusion (Ef). However, the identification of the causes of multiple abnormalities associated with coexisting conditions presents a challenge. In ruling out a suspected lung disease, the signs and symptoms of physical conditions need to be identified to arrive at a definitive diagnosis. In addition, low contrast CXR images and manual inspection restrict automated screening applications. Hence, this study aims to propose an iterated function system (IFS) and a multilayer fractional-order machine learning classifier to rapidly screen the possible classes of lung diseases within regions of interest on CXR images and to improve screening accuracy. For digital image processes, a two-dimensional (2D) fractional-order convolution is used to enhance symptomatic features. The IFS with nonlinear interpolation functions is then used to reconstruct the 2D feature patterns. These reconstructed patterns are self-affine in the same class and thus help distinguish normal subjects from those with lung diseases. The accuracy rate is thus improved. Pooling is performed to reduce the dimensions of the feature patterns and speed up complex computations. A gray relational analysis-based classifier is used to identify the possible classes of the signs and symptoms of lung diseases. For digital CXR images in A-P view, the proposed multilayer machine learning classifier with k-fold cross-validation presents promising results in screening lung diseases and improving screening accuracy rate relative to traditional methods. The proposed classifier is evaluated in terms of recall (99.6%), precision (87.78%), accuracy (88.88%), and F1 score (0.9334).

Breast cancer is the most common cancer among women in Taiwan, and the number of breast cancer cases reported annually continues to increase. In 2018, breast cancer ranked fourth in terms of mortality. Early stages (stages 0–2) of malignant breast lesions can be diagnosed during regular screening, and early treatment via advanced medical therapies increases survival rates. Ultrasound imaging, including acoustic radiation force impulse (ARFI) imaging, is the first-line examination technique used to locate breast lesion tissue, which can then be quantitated by virtual touch tissue imaging (VTI). ARFI-VTI elastography is a breast imaging modality that creates two-dimensional (2D) images to visualize the texture details, elasticity, and morphological features of a region of interest (ROI). The 2D Harris corner convolution is applied during digital imaging to remove speckle noise and enhance the ARFI-VTI images for extrapolation of lesion tissue in a ROI. Then, 2D Harris corner convolution, maximum pooling, and random decision forests (RDF) are integrated into a machine vision classifier to screen subjects with benign or malignant tumors. A total of 320 ARFI-VTI images were collected for experiments. In training stages, 122 images were randomly selected to train the RDF-based classifiers and the remaining images were randomly selected for performance evaluation via cross-validation in recalling stages. In a 10-fold cross-validation, promising results with mean sensitivity, mean specificity, and mean accuracy of 86.02%, 87.63%, and 86.97%, respectively, are achieved for quantifying the performance of the proposed classifier. Breast tumors visualized on ARFI-VTI images can be used for rapid screening of malignant or benign lesions by using the proposed machine vision classifier.

Supplemental Digital Content is available in the text, Background: Lung transplantation (LT) has been demonstrated as the only effective therapy for patients with end-stage lung diseases. Increasing listed lung transplant candidates and expanding volumes of lung transplant centers across China require well-organized programs and registry data collection based on the large population. This study aimed to summarize and analyze the data of LT development in China. Methods: We retrospectively collected and analyzed data from the China Lung Transplantation Registry (CLuTR). Key data were reported from the registry with transplant types, indications, donor and recipient characteristics, outcomes and survival. The survival Grade 0), renal insufficiency (estimated glomerular filtration rate

Peripheral arterial disease (PAD) is highly prevalent in haemodialysis (HD) patients with type 2 diabetes. Atherosclerosis may occur in both lower and upper peripheral arteries, causing progressive dialysis access stenosis in HD patients. To assess the risk of PAD, non-invasive bilateral photoplethysmography (PPG) can be used to obtain continuous variations in blood flow volume in in vivo examinations. The authors propose an astable multivibrator to model the peripheral circulation system and to produce PPG oscillation with time constants, duty ratio (rising time), and amplitude ratio of systolic and diastolic pressures. Then, the bilateral differences in the time constant and duty ratio are used to separate the normal condition from PAD. The machine learning decision-making process utilises a screening method to automatically detect subjects with and without the risk of PAD. The radial-based function is employed to parameterise the similarity and dissimilarity levels using probability values. Colour relation analysis incorporates the probability values into the perceptual colour relationships for PAD screening. The experimental results indicate that in comparison with bilateral timing parameters, degree of stenosis, and resistive index, the proposed screening method is efficient in preventing complications of PAD and is easily implemented in an embedded system.

Intra-tumor heterogeneity (ITH) is one of the most important causes of therapy resistance, which eventually leads to the poor outcomes observed in patients with glioma. Mutant-allele tumor heterogeneity (MATH) values are based on whole-exon sequencing and precisely reflect genetic ITH. However, the significance of MATH values in predicting glioma recurrence remains unclear. Information of patients with glioma was obtained from The Cancer Genome Atlas database. The present study calculated the MATH value for each patient, analyzed the distributions of MATH values in different subtypes and investigated the rates of clinical recurrence in patients with different MATH values. Gene enrichment and Cox regression analyses were performed to determine which factors influenced recurrence. A nomogram table was established to predict 1-, 2- and 5-year recurrence probabilities. MATH values were increased in patients with glioma with the wild-type isocitrate dehydrogenase (NADP(+)) (IDH)1/2 (IDH-wt) gene (P=0.001) and glioblastoma (GBM; P=0.001). MATH values were negatively associated with the 2- and 5-year recurrence-free survival (RFS) rates in patients with glioma, particularly in the IDH1/2-wt and GBM cohorts (P=0.001 and P=0.017, respectively). Furthermore, glioma cases with different MATH levels had distinct patterns of gene mutation frequencies and gene expression enrichment. Finally, a nomogram table that contained MATH values could be used to accurately predict the probabilities of the 1-, 2- and 5-year RFS of patients with glioma. In conclusion, the MATH value of a patient may be an independent predictor that influences glioma recurrence. The nomogram model presented in the current study was an appropriate method to predict 1-, 2- and 5-year RFS probabilities in patients with glioma.

Deficiency of endothelial progenitor cells, including endothelial colony-forming cells (ECFCs) and circulating angiogenic cells (CACs), plays an important role in retinal vascular degeneration in diabetic retinopathy (DR). Fenofibrate, an agonist of peroxisome proliferator–activated receptor α (PPARα), has shown therapeutic effects on DR in both patients and diabetic animal models. However, the function of PPARα in ECFC/CACs has not been defined. In this study, we determined the regulation of ECFC/CAC by PPARα. As shown by flow cytometry and Seahorse analysis, ECFC/CAC numbers and mitochondrial function were decreased in the bone marrow, circulation, and retina of db/db mice, correlating with PPARα downregulation. Activation of PPARα by fenofibrate normalized ECFC/CAC numbers and mitochondrial function in diabetes. In contrast, PPARα knockout exacerbated ECFC/CAC number decreases and mitochondrial dysfunction in diabetic mice. Primary ECFCs from PPARα−/− mice displayed impaired proliferation, migration, and tube formation. Furthermore, PPARα−/− ECFCs showed reduced mitochondrial oxidation and glycolysis compared with wild type, correlating with decreases of Akt phosphorylation and expression of its downstream genes regulating ECFC fate and metabolism. These findings suggest that PPARα is an endogenous regulator of ECFC/CAC metabolism and cell fate. Diabetes-induced downregulation of PPARα contributes to ECFC/CAC deficiency and retinal vascular degeneration in DR.

Background Hepatitis B virus (HBV) can transmit through needle sharing. The national HBV infection prevalence in persons who inject drugs remains ill-defined. We estimated the prevalence of total HBV core antibody (anti-HBc) positivity, indicating a previous or ongoing HBV infection, among adults aged 20–59 years with an injection drug use (IDU) history. We compared select characteristics by anti-HBc status. Methods Using 2001–2016 National Health and Nutrition Examination Survey data, we calculated the anti-HBc positivity prevalence among adults with IDU histories and among the general US population. For adults with IDU histories, we compared sex, age group, birth cohort, race/ethnicity, health insurance coverage, and hepatitis A immunity by anti-HBc status. Using marginal structural models, we calculated model-adjusted prevalence rates and ratios to determine the characteristics associated with anti-HBc positivity among adults with IDU histories. Results From 2001–2016, the anti-HBc positivity prevalence was 19.7% (95% confidence interval [CI] 16.0–24.0%) among those with IDU histories, compared with 4.6% (95% CI 4.3–5.0%) in the general population. The HBV surface antigen positivity prevalence was 0.4% (95% CI 0.3–0.5%) in the general population. Among adults with IDU histories, 19.8% reported prior-year IDU and 28.5% had a hepatitis A immunity. Conclusions One-fifth of adults with IDU histories had a previous or ongoing HBV infection: a rate over 4 times higher than the prevalence in the general population. One-fifth of adults with IDU histories reported prior-year use. Programs promoting safe IDU practices, drug treatment, and hepatitis A and B vaccinations should be key components of viral hepatitis prevention.

Background The accumulation of M1-polarized macrophages and excessive inflammation are important in the pathogenesis of diabetic foot ulcer (DFU). However, the underlying mechanism of DFU pathogenesis and the crucial regulators of DFU are less well known. Our previous study reported that kallikrein-binding protein (KBP), an angiogenesis inhibitor, was significantly upregulated in diabetic patients compared to its levels in controls. The effects of KBP on monocyte chemotaxis and macrophage M1 polarization were elucidated in this study. Methods Plasma KBP levels and monocyte counts were assessed by ELISA and flow cytometry. Wound closure rates in different groups were monitored daily. The phenotype and recruitment of macrophages were measured by real-time PCR, western blot and immunofluorescence assays. The expression of Notch and NF-κB signalling pathway members was determined by the methods mentioned above. ChIP and dual-luciferase reporter gene assays were employed to explore the binding and transcriptional regulation of Hes1 and iNOS. Results We found that plasma KBP levels and circulating monocytes were elevated in diabetic patients compared to those in nondiabetic controls, and both were higher in diabetic patients with DFU than in diabetic patients without DFU. KBP delayed wound healing in normal mice; correspondingly, KBP-neutralizing antibody ameliorated delayed wound healing in diabetic mice. Circulating monocytes and macrophage infiltration in the wound were upregulated in KBP-TG mice compared to those in control mice. KBP promoted the recruitment and M1 polarization of macrophages. Mechanistically, KBP upregulated iNOS by activating the Notch1/RBP-Jκ/Hes1 signalling pathway. Hes1 downregulated CYLD, a negative regulator of NF-κB signalling, and then activated the IKK/IκBα/NF-κB signalling pathway. Conclusions Our findings demonstrate that KBP is the key regulator of excessive inflammation in DFUs and provide a novel target for DFU therapy. Electronic supplementary material The online version of this article (10.1186/s12964-019-0376-9) contains supplementary material, which is available to authorized users.

OBJECTIVELaminoplasty has been used in recent years as an alternative approach to laminectomy for preventing spinal deformity after resection of intramedullary spinal cord tumors (IMSCTs). However, controversies exist with regard to its real role in maintaining postoperative spinal alignment. The purpose of this study was to examine the incidence of progressive spinal deformity in patients who underwent laminoplasty for resection of IMSCT and identify risk factors for progressive spinal deformity.METHODSData from IMSCT patients who had undergone laminoplasty at Beijing Tsinghua Changgung Hospital between January 2014 and December 2016 were retrospectively reviewed. Univariate tests and multivariate logistic regression analysis were used to assess the statistical relationship between postoperative spinal deformity and radiographic, clinical, and surgical variables.RESULTSOne hundred five patients (mean age 37.0 ± 14.5 years) met the criteria for inclusion in the study. Gross-total resection (> 95%) was obtained in 79 cases (75.2%). Twenty-seven (25.7%) of the 105 patients were found to have spinal deformity preoperatively, and 10 (9.5%) new cases of postoperative progressive deformity were detected. The mean duration of follow-up was 27.6 months (SD 14.5 months, median 26.3 months, range 6.2–40.7 months). At last follow-up, the median functional scores of the patients who did develop progressive spinal deformity were worse than those of the patients who did not (modified McCormick Scale: 3 vs 2, and p = 0.04). In the univariate analysis, age (p = 0.01), preoperative spinal deformity (p < 0.01), extent of tumor involvement (p < 0.01), extent of abnormal tumor signal (p = 0.02), and extent of laminoplasty (p < 0.01) were identified as factors associated with postoperative progressive spinal deformity. However, in subsequent multivariate logistic regression analysis, only age ≤ 25 years and preoperative spinal deformity emerged as independent risk factors (p < 0.05), increasing the odds of postoperative progressive deformity by 4.1- and 12.4-fold, respectively (p < 0.05).CONCLUSIONSProgressive spinal deformity was identified in 25.7% patients who had undergone laminoplasty for IMSCT resection and was related to decreased functional status. Younger age (≤ 25 years) and preoperative spinal deformity increased the risk of postoperative progressive spinal deformity. The risk of postoperative deformity warrants serious reconsideration of providing concurrent fusion during IMSCT resection or close follow-up after laminoplasty.

Stem cells present in urine possess regenerative capacity to repair kidney injury. However, the unique characteristics of urinary stem cells (USC) from patients with diabetic nephropathy (d-USC) are unknown. The goal of this study was to investigate stemness properties in cell phenotype and regenerative potential of d-USC, compared to USC from healthy individuals. Methods: Thirty-six urine samples collected from patients (n=12, age range 60-75 years) with diabetic nephropathy (stages 3-4 stage chronic kidney disease [CKD]) were compared with 30 urine samples from healthy age-matched donors (n=10, age range 60-74 years). Results: There were approximately six times as many cells in urine samples from patients with diabetic nephropathy, including twice as many USC clones as healthy donors. However, approximately 70% of d-USC had weaker regenerative capacity as assessed by cell proliferation, less secretion of paracrine factors, weaker telomerase activity, and lower renal tubular epithelial differentiation potential compared to healthy controls. In addition, the levels of inflammatory factors (IL-1β and Cx43) and apoptotic markers (Caspase-3, and TUNEL) were significantly increased in d-USC compared to USC (p

Background: Mycoplasma is an opportunistic pathogen causing both urogenital and extragenital infections. The lack of cell wall renders Mycoplasma difficult to culture and identify with ordinary methods. Next-generation sequencing (NGS) is a new technology helping a lot in the diagnosis of infective diseases. In this case, NGS played a key role in the diagnosis of Mycoplasma infection. Case presentation: A mid-aged man suffering from renal cyst underwent cyst incision followed by invasive treatments to eliminate hematoma caused by renal artery hemorrhage. After the cyst incision operation, the patient had a persistent high temperature. The persistent increase of blood neutrophile granulocyte count and C-reaction protein suggested an unresolved infection. The empirically chosen anti-infective agents were meropenem and linezolid since the ordinary bacterial cultures of surgical site drainage and blood yielded a negative result. At postoperation day (POD) 17, NGS result of his drainage clearly indicated the pathogen was Mycoplasma hominis. At POD 24, the drug sensitivity test showed resistance to quinolones, clarithromycin and erythromycin, but intermediate to azithromycin. Since then, the antimicrobial agents were changed into azithromycin and kept unchanged until the patient was fully recovered and discharged at POD 39. Conclusion: When the ordinary laboratory diagnostic methods failed, NGS diagnosis could reduce the hospitalization expenses and shorten the lengths of hospital stay.

High aggressiveness is a hallmark of glioblastoma and predicts poor prognosis of patients with glioblastoma. The expression level of sortilin has been preliminarily reported to be elevated in high-grade glioma; however, the potential significance of sortilin in glioblastoma progression has not been elucidated. In this study, we investigated the oncogenic effect of sortilin in glioblastoma. Increased levels of sortilin were noted in the mesenchymal subtype of glioblastoma and highly aggressive subtypes of glioblastoma tissues and cell lines. In addition, high levels of sortilin predicted poor prognoses in patients with glioblastoma. Sortilin knockdown or inhibition with AF38469 (an orally bioavailable inhibitor of sortilin) significantly suppressed migration and invasion by inhibiting EMT-like mesenchymal transition in glioblastoma cells. Furthermore, we proved that sortilin promoted cell invasion mainly via Glycogen synthase kinase 3 beta (GSK-3β)/β-catenin/Twist-induced EMT-like mesenchymal transition in glioblastoma. Taken together, our results demonstrate a critical role of sortilin in glioblastoma invasion and EMT-like mesenchymal transition, indicating that sortilin contributes to glioblastoma progression. These data also highlight the dramatic antitumor effects of AF38469 in glioblastoma, suggesting that AF38469 is a potentially powerful antitumor agent for sortilin-overexpressing human glioblastoma.