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Objectives Pediatric Reference Intervals in China (PRINCE) is a nationwide initiative that aims to establish and validate harmonized reference intervals (RIs) for Chinese children and adolescents, in which 15,150 healthy volunteers aged up to 20 years were recruited from 11 centers to establish RIs and 7,557 children and adolescents were enrolled from 21 centers to validate RIs. Methods The complete blood cell counts (CBC) of venous whole blood were measured by hematology analyzers through Sysmex systems in different centers. Age- and sex-specific RIs were calculated according to the guidelines. Results Unlike adults with certain levels of analyte concentrations, hematological parameters of children changed through growth and development. Red blood cell counts, hemoglobin, and hematocrit increased with age, and revealed higher concentrations in boys than girls after puberty. White blood cell counts and platelet counts showed significant higher levels than adults before 2 years of age, and then gradually decreased without distinct sex differences. In addition, lymphocyte counts decreased with age while neutrophil counts showed an opposite trend. The lower and upper limits of pediatric RIs of CBC were different from those of adults. Conclusions The validation of RIs indicated that the PRINCE study provided a version of RIs suitable for most of regions in China. This first harmonized pediatric RIs of CBC across China provided a robust database to understand the dynamic changes of hematologic parameters from birth to adolescence, and will contribute to clinical diagnosis and prognosis evaluation for pediatric patients as well.

Background Osteoarthritis (OA) is a leading cause of disability and a source of societal costs among older adults, especially with an increasingly obese population. However, very few published studies have investigated the burden of knee and hip OA due to a high body mass index (BMI). Therefore, this study aimed to systematically summarize the trends of knee and hip OA due to a high BMI in China and the USA between 1990 and 2019. Methods Data from the Global Burden of Disease Study 2019 were used to estimate the age-standardized prevalence, disability-adjusted life years (DALYs) rates of knee and hip OA, and the burden of knee and hip OA due to a high BMI by sex. Joinpoint regression analysis was used to determine the temporal trend changes in the related DALYs rates of knee and hip OA. Results The trends in the DALYs rates of knee OA due to a high BMI have shown a steady and large increase in China, while the trends first showed an increase followed by a large decrease near 2001-2005 and finally a steady increase in the USA. The trends in the DALYs rates of hip OA due to a high BMI have shown a steady and large increase in both men and women in China and the USA from 1990 to 2019. For the comparison by age categories from 30 to 34 years to 90–94 years in 2019, the age-standardized DALYs rates due to a high BMI first increased and then decreased after 60–64 years and 70-74 years in both men and women from China and the USA for knee OA, respectively. For hip OA, the age-standardized DALYs rates first increased and then decreased after 70–74 years in both men and women from China and the USA. Conclusions The burden of knee and hip OA due to a high BMI is substantially increasing in China and the USA in recent years. Researchers and health policy makers should assess the changing patterns of high BMI on the burden of OA and devise corresponding weight-control strategies.

Immunosuppression of unknown aetiology is a hallmark feature of glioblastoma and is characterized by decreased CD4 T-cell counts and downregulation of major histocompatibility complex class II expression on peripheral blood monocytes in patients. This immunosuppression is a critical barrier to the successful development of immunotherapies for glioblastoma. We recapitulated the immunosuppression observed in glioblastoma patients in the C57BL/6 mouse and investigated the aetiology of low CD4 T-cell counts. We determined that thymic involution was a hallmark feature of immunosuppression in three distinct models of brain cancer, including mice harbouring GL261 glioma, B16 melanoma, and in a spontaneous model of diffuse intrinsic pontine glioma. In addition to thymic involution, we determined that tumour growth in the brain induced significant splenic involution, reductions in peripheral T cells, reduced MHC II expression on blood leucocytes, and a modest increase in bone marrow resident CD4 T cells. Using parabiosis we report that thymic involution, declines in peripheral T-cell counts, and reduced major histocompatibility complex class II expression levels were mediated through circulating blood-derived factors. Conversely, T-cell sequestration in the bone marrow was not governed through circulating factors. Serum isolated from glioma-bearing mice potently inhibited proliferation and functions of T cells both in vitro and in vivo. Interestingly, the factor responsible for immunosuppression in serum is non-steroidal and of high molecular weight. Through further analysis of neurological disease models, we determined that the immunosuppression was not unique to cancer itself, but rather occurs in response to brain injury. Non-cancerous acute neurological insults also induced significant thymic involution and rendered serum immunosuppressive. Both thymic involution and serum-derived immunosuppression were reversible upon clearance of brain insults. These findings demonstrate that brain cancers cause multifaceted immunosuppression and pinpoint circulating factors as a target of intervention to restore immunity.

Background: Most of the previous studies on nursing practice environment and job burnout employed conventional analyses ignoring the impact of unit-level data clusters. This study addressed this gap by examining the effects of the nursing practice environments on dimensions of occupational burnout among a sample of Chinese nurses using multilevel logistic regression models and demonstrating the superiority of employing multilevel models over conventional models within this context. Methods: A proportionate stratified sampling method was applied in this cross-sectional study that invited 1,300 registered nurses (RNs) from nine clinical units of a large, academic hospital in urban China to complete the questionnaire. Nurse-reported information was obtained using the Practice Environment Scale of the Nursing Work Index (PES-NWI) and the Maslach Burnout Inventory (MBI). Findings: A total of 1,178 valid questionnaires were returned for a response rate of 90.62%. RNs generally perceived their nursing practice environment as favorable as measured by the PES-NWI. Approximately 40% of the respondents reported experiencing emotional exhaustion and depersonalization. The multivariate models indicated that nurse burnout was significantly associated with nurse participation in hospital affairs, nursing foundations for quality of care, and adequate staffing. In addition, our results illustrated the advantage of multilevel modeling over the conventional modeling for handling hierarchical data in terms of the accuracy of the estimates and the goodness-of-fit of the model. Conclusions/Application to Practice: These findings underscore the importance of measures aimed at enhancing nursing practice environments to prevent RNs from experiencing feelings of burnout and of considering multilevel analysis in future nursing research.

Monocrotaline (MCT)-induced pulmonary artery hypertension (PAH) has been reported to cause right heart failure (RHF). Moreover, Right heart diseases have been determined to cause ventricular arrhythmia (VA). So we can conclude that MCT-induced PAH increases the incidence of VA. In addition, Previous studies have determined the benefits of Dapagliflozin (DA) on the cardiac system, but the responses of MCT-induced RHF to DA are not fully reported. So the present study sought to evaluate the effects of DA on the MCT-induced PAH. A dose intraperitoneal injection of MCT (60 mg/kg) was carried out to induce a rat model with PAH. DA (60 mg/l) was administered for 4 weeks following MCT injection. Echocardiography, body weight, blood pressure, blood glucose, electrophysiological study, and Western blot were performed. Four weeks after the MCT injection, MCT-treated rats decreased body weight, blood glucose and blood pressure. In addition, MCT caused the formation of PAH and RHF. Moreover, MCT-induced PAH rats increased the incidence of VA, prolonged action potential duration (APD), and shortened effective refractory period (ERP). Additionally, PAH rats significantly prevented the activated expressions of Ion channel proteins such as potassium channel (Kv1.5, Kv2.1, Kv4.2, Kv4.3) and L-type Ca channel (Cav1.2). As we expected, these changes above in PAH rats were reversed when DA was administered. Mechanistically, DA significantly reduced the levels of toll-like receptor (TLR4), the nuclear factor kappa B (NF-κB) in MCT-treated rats. In conclusion, these findings determine that DA reduces the vulnerability of VA in PAH rats through the TLR4/NF-κB signaling pathway.

With the increasing attention to the relationship between male reproductive system diseases and microcirculation disorders, pancreatic kininogenase, a drug to improve microcirculation, is becoming a focus in the studies of the treatment of male reproductive diseases. It is reported recently that pancreatic kininogenase has a similar effect to type-5 phosphodiesterase inhibitors and may become a new drug for the treatment of ED. This article mainly discusses the possible action mechanisms of pancreatic kininogenase from the aspects of kallikrein-kinin system and pancreatic kininogenase promoting semen liquefaction and improving sperm quality and erectile function.

To investigate the clinical characteristics, diagnosis, treatment and etiology of persistent Müllerian duct syndrome (PMDS).A 3-year-old boy was diagnosed with PMDS according to the clinical manifestations and the results of ultrasonography, laboratory examinations and earlier surgical examination. We performed genetic tests for the patient and his family members, removed the infantile uterus by laparoscopic wedge hysterectomy, biopsied and descended the bilateral testes, and ligated the bilateral internal rings, followed by a retrospective analysis and review of relevant literature.The operation was successful. Gonad biopsy revealed testis tissue, and PMDS was confirmed by intraoperative findings and related examinations. Good bilateral testicular blood supply was found during the 6-month follow-up after surgery. Medical exome sequencing showed the AMHR2 gene c.1499GA (p.Cys500Tyr) mutant homozygote (A/A) in the patient and his sister and mutant heterozygote (G/A) in his parents.Laparoscopy is definitely effective for the treatment of PMDS. In surgery, the infantile uterus should be removed in case of good blood supply to the testis, and so were the bilateral testes if they cannot be descended. The homozygous mutation in the AMHR2 gene c. 1499GA (p. Cys500Tyr) can lead to male PMDS. Pedigree investigation may provide some evidence for possible fertility in PMDS patients.

Mitochondrial dysfunction in tissue‐specific mesenchymal stem cells (MSCs) plays a critical role in cell fate and the morbidity of chronic inflammation‐associated bone diseases, such as periodontitis and osteoarthritis. However, there is still no effective method to cure chronic inflammation‐associated bone diseases by physiologically restoring the function of mitochondria and MSCs. Herein, it is first found that chronic inflammation leads to excess Ca2+ transfer from the endoplasmic reticulum to mitochondria, which causes mitochondrial calcium overload and further damage to mitochondria. Furthermore, damaged mitochondria continuously accumulate in MSCs due to the inhibition of mitophagy by activating the Wnt/β‐catenin pathway under chronic inflammatory conditions, impairing the differentiation of MSCs. Based on the mechanistic discovery, intracellular microenvironment (esterase and low pH)‐responsive nanoparticles are fabricated to capture Ca2+ around mitochondria in MSCs to regulate MSC mitochondrial calcium flux against mitochondrial dysfunction. Furthermore, the same nanoparticles are able to deliver siRNA to MSCs to inhibit the Wnt/β‐catenin pathway and regulate mitophagy of the originally dysfunctional mitochondria. These precision‐engineered nanoparticles, referred to as “nanorepairers,” physiologically restore the function of mitochondria and MSCs, resulting in effective therapy for periodontitis and osteoarthritis. The concept can potentially be expanded to the treatment of other diseases via mitochondrial quality control intervention.

CD8 T cell infiltration of the central nervous system (CNS) is necessary for host protection but contributes to neuropathology. Antigen presenting cells (APCs) situated at CNS borders are thought to mediate T cell entry into the parenchyma during neuroinflammation. The identity of the CNS-resident APC that presents antigenviamajor histocompatibility complex (MHC) class I to CD8 T cells is unknown. Herein, we characterize MHC class I expression in the naïve and virally infected brain and identify microglia and macrophages (CNS-myeloid cells) as APCs that upregulate H-2Kband H-2Dbupon infection. Conditional ablation of H-2Kband H-2Dbfrom CNS-myeloid cells allowed us to determine that antigen presentationviaH-2Db, but not H-2Kb, was required for CNS immune infiltration during Theiler’s murine encephalomyelitis virus (TMEV) infection and drives brain atrophy as a consequence of infection. These results demonstrate that CNS-myeloid cells are key APCs mediating CD8 T cell brain infiltration.

Objective: The clinical significance of coexistence of HBsAg/anti-HBs in chronic hepatitis B (CHB) patients remains controversial. This study was aimed to assess the association of this serological pattern with hepatocellular carcinoma (HCC) in patients with CHB. Methods: In this cross-section study, 206 CHB patients with coexistence of HBsAg/anti-HBs and 206 CHB patients with HBsAg alone were included to evaluate the risk of HCC development by logistic regression analysis. In addition, a retrospective cohort of 260 patients with CHB was recruited to estimate the cumulative incidence of HCC by Kaplan–Meier analysis. Results: The serological pattern of coexistence of HBsAg/anti-HBs, with high levels of (“High”) HBsAg/low levels of (“Low”) anti-HBs, were considered as independent risk factors for HCC. In particular, patients with “High” HBsAg/“High” anti-HBs [odds ratio (OR), 4.295; 95% confidence interval (CI), 1.104–16.699; p = 0.035] and “Low” HBsAg/ “High” anti-HBs (OR, 3.207; 95%CI, 1.299–7.919; p = 0.012) exhibited significantly higher risk for HCC development. However, only “Low” HBsAg /“High” anti-HBs might increase risk of HCC in CHB patients with high HBV load (logrank p

Background:. Vasovagal syncope (VVS) is common in children and greatly affect both physical and mental health. But the mechanisms have not been completely explained. This study was designed to analyze the gut microbiota in children with VVS and explore its clinical significance. Methods:. Fecal samples from 20 VVS children and 20 matched controls were collected, and the microbiota were analyzed by 16S rRNA gene sequencing. The diversity and microbiota compositions of the VVS cases and controls were compared with the independent sample t test or Mann-Whitney U test. The correlation between the predominant bacteria and clinical symptoms was analyzed using Pearson or Spearman correlation test. Results:. No significant differences in diversity were evident between VVS and controls (P > 0.05). At the family level, the relative abundance of Ruminococcaceae was significantly higher in VVS children than in controls (median [Q1, Q3]: 22.10% [16.89%, 27.36%] vs. 13.92% [10.31%, 20.18%], Z = −2.40, P 4, P

Background It is reported that osteoporosis commonly occurs among patients with rheumatoid arthritis (RA), whereas the association between osteoporosis and osteoarthritis (OA) remains controversial. Our aim in this study was to investigate the association between BMD, as a marker of osteoporosis, and OA and RA among adults 20−59 years of age, using a population-based sample from the National Health and Nutrition Examination Survey (NHANES). Methods Our analysis was based on the NHANES data collected between 2011 and 2018. Data regarding arthritis status and the type of arthritis (OA or RA) were obtained from questionnaires. Lumbar BMD was measured by dual-energy X-ray absorptiometry. The association between OA, RA, and lumbar BMD was evaluated using logistic regression models. Subgroup analyses, stratified by gender and race, were performed. The association between duration of arthritis and lumbar BMD was also investigated. Results A total of 11,094 adults were included in our study. Compared to the non-arthritis group, participants with OA had a higher lumbar BMD (β = 0.023, 95% CI 0.011–0.035), with no significant association between lumbar BMD and RA (β = 0.014, 95% CI − 0.003 to 0.031). On subgroup analyses stratified by gender, males with OA had a higher lumbar BMD compared to those without OA (β = 0.047, 95% CI 0.028–0.066). In females, OA was not associated with lumbar BMD (β = 0.007, 95% CI − 0.008 to 0.021). There was no association between lumbar BMD and RA in both males (β = 0.023, 95% CI − 0.003 to 0.048) and females (β = 0.008, 95% CI − 0.015 to 0.031). Duration of arthritis was not associated with lumbar BMD for both OA (β = − 0.0001, 95% CI − 0.0017 to 0.0015) and RA (β = 0.0006, 95% CI − 0.0012 to 0.0025). Conclusions Lumbar BMD was associated with OA but not with RA. While a higher lumbar BMD was associated with OA in males, but not in females. Our findings may improve our understanding between OA, RA, and bone health.

Adipokines, including leptin, visfatin, adiponectin, and interleukin-6 (IL)-6, play multiple roles in the pathophysiology of epilepsy and febrile seizures (FS). We aimed to investigate the associations among plasma adipokines, mainly leptin, visfatin, adiponectin, or IL-6, and the prognosis of FS. This prospective cross-sectional study was conducted from January 2017 to December 2018 at the Wuxi Second People' Hospital China. The levels of serum leptin, visfatin, adiponectin, and IL-6 in 55 children with FS (FS group) were compared with 42 febrile children without seizure (FC group) and 48 healthy children (HC group) in an acute phase. The correlation with clinical indicators was determined by logistic regression analysis. Serum adiponectin and IL-6 levels were significantly higher in the FS group than in the FC and HC groups (p < 0.05), but there was no statistical difference between the FC and HC groups. In addition, logistic regression analysis showed that high concentrations of adiponectin and IL-6 were significantly associated with the occurrence of FS. For leptin and visfatin, they were significantly lower in the FS and FC groups than in the normal control group, but there was no statistical difference between the FS and FC groups. Our results suggest that higher plasma levels of IL-6 and adiponectin may serve as an additional biomarker in the early treatment or follow-up of the FS children.

Cerebral palsy (CP), a group of clinical syndromes caused by non-progressive brain damage in the developing fetus or infant, is one of the most common causes of lifelong physical disability in children in most countries. At present, many researchers believe that perinatal cerebral hypoxic ischemic injury or inflammatory injury are the main causes of cerebral palsy. Previous studies including our works confirmed that melatonin has a protective effect against convulsive brain damage during development and that it affects the expression of various molecules involved in processes such as metabolism, plasticity and signaling in the brain. Integral membrane protein plppr5 is a new member of the plasticity-related protein family, which is specifically expressed in brain and spinal cord, and induces filopodia formation as well as neurite growth. It is highly expressed in the brain, especially in areas of high plasticity, such as the hippocampus. The signals are slightly lower in the cortex, the cerebellum, and in striatum. Noteworthy, during development plppr5 mRNA is expressed in the spinal cord, i.e., in neuron rich regions such as in medial motor nuclei, suggesting that plppr5 plays an important role in the regulation of neurons. However, the existing literature only states that plppr5 is involved in the occurrence and stability of dendritic spines, and research on its possible involvement in neonatal ischemic hypoxic encephalopathy has not been previously reported. We used plppr5 knockout (plppr5−/−) mice and their wild-type littermates to establish a model of hypoxicischemic brain injury (HI) to further explore the effects of melatonin on brain injury and the role of plppr5 in this treatment in an HI model, which mainly focuses on cognition, exercise, learning, and memory. All the tests were performed at 3–4 weeks after HI. As for melatonin treatment, which was performed 5 min after HI injury and followed by every 24h. In these experiments, we found that there was a significant interaction between genotype and treatment in novel object recognition tests, surface righting reflex tests and forelimb suspension reflex tests, which represent learning and memory, motor function and coordination, and the forelimb grip of the mice, respectively. However, a significant main effect of genotype and treatment on performance in all behavioral tests were observed. Specifically, wild-type mice with HI injury performed better than plppr5−/− mice, regardless of treatment with melatonin or vehicle. Moreover, treatment with melatonin could improve behavior in the tests for wild-type mice with HI injury, but not for plppr5−/− mice. This study showed that plppr5 knockout aggravated HI damage and partially weakened the neuroprotection of melatonin in some aspects (such as novel object recognition test and partial nerve reflexes), which deserves further study.

Background A prompt diagnosis of HIE remains a challenge clinically. This study aimed to identify potential biomarkers of neonatal hypoxic-ischemic encephalopathy (HIE) via a novel proteomic approach, the isobaric tags for absolute and relative quantification (iTRAQ) method. Methods Blood samples were collected from neonates with mild (n = 4), moderate (n = 4), or severe (n = 4) HIE who were admitted to the neonatal intensive care unit of Children’s Hospital of Soochow University between Oct 2015 and Oct 2017. iTRAQ was performed in HIE patients and healthy controls (n = 4). Bioinformatics analyses including Gene Ontology and KEGG pathway enrichment analysis were performed to evaluate the potential features and capabilities of the identified differentially expressed proteins. Results A total of 51 commonly differentially expressed proteins were identified among the comparisons between mild, moderate, and severe HIE as well as healthy controls. Haptoglobin (HP) and S100A8 were most significantly up-regulated in patients with HIE and further validated via real-time PCR and western blotting. The differentially expressed proteins represented multiple biological processes, cellular components and molecular functions and were markedly enriched in complement and coagulation cascades. Conclusions HP and S100A8 may serve as a potential biomarker for neonatal HIE and reflects the severity of HIE. The complement and coagulation cascades play crucial roles in the development of neonatal HIE.

Background Occlusive granulation tissue formation, as one of the most common sequelae of chronic foreign body aspiration, can cause tracheobronchial obstruction and delayed fixed airway stenosis necessitating interventions. The aim of this study was to explore the clinical efficacy and safety of interventional therapy via flexible bronchoscopy for treatment of granulation tissue related airway obstruction secondary to foreign body aspiration in children. Method Patients with long-term foreign body related granulation tissue were treated with flexible bronchoscopy therapeutic modalities, including forceps, cryotherapy, holmium laser, and balloon dilatation. Clinical efficacy was evaluated by clinical symptoms and endoscopic manifestations. Results A total of eight patients with granulation tissue hyperplasia caused by foreign body in bronchus, with a median age of 29.5 (range, 18-54) months, underwent interventional therapy between January 2016 and December 2019. Four patients received forceps and CO2 cryotherapy and one patient required forceps only. The remaining three patients received holmium laser combined with CO2 cryotherapy, and one of them required additional balloon dilatation. Four cases required a second cryotherapy procedure, and one case received three cryotherapy procedures for extensive granulation tissue. The treatment efficacy was 100% without complications. Conclusion Interventional procedure via flexible bronchoscopy is a safe, reliable, and effective method in the management of tracheobronchial obstruction and stenosis caused by foreign body-related granulation tissue hyperplasia. It is worthy of clinical application.

Mycoplasma pneumoniae (MP) is one of the most common pathogens of respiratory infection in children, while Epstein-Barr virus (EBV) infection is usually subclinical in immunocompetent children. Although single MP infection is common enough, MP and EBV coinfection have received little attention. Especially, the pathogenic role of EBV in lung when coinfection with MP, has not been clarified. The purpose of this study was to investigate the impact of EBV on MP pneumonia (MPP) in hospitalized children. We retrospectively reviewed the clinical data of MPP children who underwent screening for EBV by polymerase chain reaction in bronchoalveolar lavage fluid during hospitalization in 2014. Of total 147 patients, 68 patients were in the MP group and 79 were in the MP/EBV coinfection group. We found longer fever duration and higher CRP, IgA, IgG, interleukin-2 (IL-2), percentage of peripheral neutrophils levels, higher incidence of pulmonary consolidation and percentage of refractory MPP in coinfection group, when compared to those in MP group. In ROC curve analysis, IL-2 was useful for differentiating patients with coinfection from those with MP infection. Logistic regression analysis showed that the IL-2 ≥ 3.35 pg/ml (OR = 3.677) was a significant predictor regarding to MP/EBV coinfection. In conclusion, coinfection of EBV and MP poses a higher risk for prolonged symptoms. IL-2 could be used as a good predictor of coinfection.

Spermatogenesis is a complex and precise process of differentiation of germ cells, which involves three stages: mitosis of spermatogonia, meiosis of spermatocytes and formation of spermatozoa. The process is controlled by many factors, including regulation of cyclins in spermatogenic cells, which plays a pivotal role. Cyclins form heterologous dimer compounds with protein kinase activity by binding to cyclin-dependent kinases, then phosphorylate multiple proteins and promote the orderly conduct of each phase of the cell cycle. In recent years, cyclins A, B, D and E have been found to play important roles in the regulation of spermatogenesis. This article presents an overview on the roles of these four cyclins in regulating the progression of spermatogenesis.

ObjectivePulmonary tuberculosis (TB) is a severe infectious respiratory disease, the burden of which remains high in China. To provide scientific evidence for developing more targeted prevention and control strategies, this study aimed to determine the incidence trends and explore the epidemiological characteristics of pulmonary TB in Anhui Province, Eastern China between 2013 and 2018.MethodsThe retrospective study analyzed information regarding pulmonary TB cases reported by the National Infectious Disease Reporting System and census data collected from the Anhui Provincial Bureau of Statistics.ResultsOverall, 211,892 cases of TB patients were reported in Anhui Province, China between 2013 and 2018, with an average annual reported incidence rate of 57.7 per 100,000 persons. A significant decrease in the incidence rate of pulmonary TB (p < 0.001) was observed during the study period. Men had a higher incidence rate of pulmonary TB than women (p < 0.001). The highest annual average reported incidence rate was 204.2 per 100,000 persons in those aged 70-74 years. The number of farmers with pulmonary TB, i.e., 155,415, accounted for 73.4% of all cases. Moreover, the peak period of reported cases was from January to March. Four cities along the Yangtze River-Anqing, Tongling, Chizhou, and Wuhu-reported significantly higher incidence rates of pulmonary TB than other cities (p < 0.001).ConclusionsFrom 2013 to 2018, there was a significant decline in the incidence rate of pulmonary TB in Anhui Province, with peaks occurring from January to March. Prevention and control strategies targeting men, people aged 70-74 years, farmers, and the four cities along the Yangtze River should be strengthened.

Aim. Circular RNAs (circRNAs) have been found to contribute to the regulation of many diseases and are abundantly expressed in various organisms. The present study is aimed at systematically characterizing the circRNA expression profiles in patients with senile osteoporotic vertebral compression fracture (OVCF) and predicting the potential functions of the regulatory networks correlated with these differentially expressed circRNAs. Methods. The circRNA expression profile in patients with senile OVCF was explored by using RNA sequencing. The prediction of the enriched signaling pathways and circRNA-miRNA networks was conducted by bioinformatics analysis. Real-time quantitative PCR was used to validate the selected differentially expressed circRNAs from 20 patients with senile OVCF relative to 20 matched healthy controls. Results. A total of 884 differentially expressed circRNAs were identified, of which 554 were upregulated and 330 were downregulated. The top 15 signaling pathways associated with these differentially expressed circRNAs were predicted. The result of qRT-PCR of the selected circRNAs was consistent with RNA sequencing. Conclusions. CircRNAs are differentially expressed in patients with senile OVCF, which might contribute to the pathophysiological mechanism of senile osteoporosis.

Genome-wide associations and HLA genotyping have revealed associations between HLA alleles and susceptibility to primary membranous nephropathy. However, associations with clinical phenotypes and kidney outcome are poorly defined. We previously identified DRB1*1501 and DRB1*0301 as independent risk alleles for primary membranous nephropathy. Here, we investigated HLA associations with demographic characteristics, anti-phospholipase A2 receptor (PLA2R) antibody, treatment response and kidney outcome after a median follow-up of 52 months in 258 patients. DRB1*0301, but not DRB1*1501, was associated with a significantly higher level of PLA2R antibody (odds ratio 1.58, 95% confidence interval 1.13-2.22). Although DRB1*1502, which differs from DRB1*1501 by a single amino acid, was not a risk allele for primary membranous nephropathy (odds ratio 1.01), it was associated with significantly lower estimated glomerular filtration rates both at baseline (1.79, 1.18-2.72) and at last follow-up (1.72, 1.17-2.53), a significantly worse renal outcome by Kaplan-Meier analysis and a significantly higher risk of end-stage renal disease by Cox regression analysis (hazard ratio 4.52, 1.22-16.74). Nevertheless, the absence of remission remained the only independent risk factor for end-stage renal disease by multivariate analysis. DRB1*1502 was also associated with a significantly higher median PLA2R antibody level [161.4 vs. 36.3 U/mL] and showed interaction with DRB1*0301 for this variable. Thus, HLA genes control PLA2R antibody production and primary membranous nephropathy severity and outcome. Additionally, DRB1*1502 behaves like a modifier gene with a strong predictor value when associated with HLA risk alleles. Other modifier genes need further investigations in larger cohorts.

Kallmann syndrome (KS) is a rare clinical and genetic heterogeneity disease, which is familial or sporadic. KS is known to have three patterns of inheritance: X linked recessive inheritance, autosomal dominant inheritance and rare autosomal recessive inheritance. Here, we report a sibling pedigree with autosomal dominant inheritance of KS, and we identified a novel heterozygous frameshift mutation c.299_300insCCGCAGACTCCGGCCTCTATGC (p.C101Rfs*17) in FGFR1 gene using whole-exome sequencing (WES). The mutation and affection status were cosegregated. The mutation is not present in the dbSNP, 1000 Genome, ExAC, and gnomAD databases. The discovery of this new mutation in the FGFR1 gene enriches the spectrum of FGFR1 mutations in patients with KS.Abbreviations: FGFR1: fibroblast growth factor receptor 1; HH: hypogonadotropic hypogonadism; KS: Kallmann syndrome; MRI: magnetic resonance imaging; WES: whole–exome sequencing.

Histone deacetylases (HDAC) plays important roles in the post-translational modifications of histone cores as well as non-histone targets. Many of them are involved in key inflammatory processes. Despite their importance, whether and how HDAC9 is regulated under inflammatory conditions remains unclear. The aim of this study was to evaluate the effects of HDAC9 under chronic inflammation condition in human periodontal ligament stromal cell (PDLSCs) and to explore the underlying regulatory mechanism. PDLSCs from healthy or periodontitis human tissue was compared. The therapeutic effects of HDAC inhibitors was determined in PDLSC pellet transplanted nude mice and LPS-induced rat periodontitis. We report that HDAC9 was the most affected HDAC family member under inflammatory conditions in PDLSCs. HDAC9 impaired osteogenic differentiation capacity of PDLSCs under inflammatory conditions. Downregulation of HDAC9 by HDAC inhibitors or si-HDAC9 rescued the osteogenic differentiation capacity of inflammatory PDLSC to a similar level with the healthy PDLSC. In this context, HDAC9 and miR-17 formed an inhibitory loop. The inhibition of miR-17 aggravated loss of calcified nodules in inflamed PDLSCs and interrupted the effect of HDAC inhibitor in rescuing osteogenesis. In vivo experiments using nude mice and LPS-induced periodontitis model confirmed that HDAC inhibitors could improve new bone formation. We conclude that HDAC inhibitors improved osteogenesis of PDLSCs in vitro and periodontitis in vivo.

Lineage differentiation of bone marrow mesenchymal stem cells (BMMSCs) is the key to bone-fat reciprocity in bone marrow. To date, the regulators of BMMSC lineage switching have all been identified to be transcription factors, and researchers have not determined whether other genes control this process. This study aims to reveal a previously unknown role of tissue-nonspecific alkaline phosphatase (TNSALP) in controlling BMMSC lineage selection. Methods: We compared the characteristics of cultured BMMSCs from patients with hypophosphatasia (HPP), which is caused by mutations in the liver/bone/kidney alkaline phosphatase (ALPL) gene, and an ALPL knockout (ko) mouse model. We performed ALPL downregulation and overexpression experiments to investigate the regulatory role of ALPL in BMMSC lineage switching. Using the PathScan array, coimmunoprecipitation experiments and pathway-guided small molecule treatments, we explored the possible mechanism underlying the regulatory effects of ALPL on cell differentiation and evaluated its therapeutic effect on ALPL ko mice. Results: BMMSCs from both patients with HPP and ALPL ko mice exhibited defective lineage differentiation, including a decrease in osteogenic differentiation and a parallel increase in adipogenic differentiation. Mechanistically, TNSALP directly interacted with LRP6 and regulated the phosphorylation of GSK3β, subsequently resulting in lineage switching of BMMSCs. Re-phosphorylation of GSK3β induced by LiCl treatment restored differentiation of BMMSCs and attenuated skeletal deformities in Alpl+/- mice. Conclusion: Based on our findings, TNSALP acts as a signal regulator to control lineage switching of BMMSCs by regulating the LRP6/GSK3β cascade.

The roots of Polygala tenuifolia Willd have a long history of being used as a traditional Chinese medicine for the treatment of insomnia, forgetfulness, sorrow and depression. Tenuifolin (TEN) has been isolated from Polygala tenuifolia Willd roots, and this study was carried out to investigate the potential beneficial effects of TEN on neuronal apoptosis and memory deficits in a mouse model of Alzheimer's disease (AD). TEN treatment reversed spatial learning and memory deficits, as well as neuronal apoptosis in hippocampal areas, in APP/PS1 transgenic AD mice. TEN treatment protected against Aβ25-35-induced apoptosis, loss of mitochondria-membrane potential, and activation of caspases-3 and -9 in SH-SY5Y cells. TEN has potential benefit in treating learning and memory deficits in APP/PS1 transgenic AD mice, and its effects may be associated with reversing AD pathology-induced neuronal apoptosis. These insights pave the way for further analysis of the potential of TEN as an AD therapeutic agent.

'Essence and blood from the same source', as one of basic theories of Chinese medi- cine (CM), is important for syndrome typing and clinical medication. Vascular endothelial growth factor (VEGF) can be produced and secreted in Leydig cells and Sertoli cells, which can not only promote the formation of new blood vessels, but also regulate synthesis of testosterone and the proliferation and dif- ferentiation of germ cells. The roles of VEGF in the spermatogenesis reveal scientific connotations of 'essence and blood from the same source', and it plays an important role in guiding clinical practice of CM.

Metabolic disorders play an important role in the pathogenesis of many neurological diseases. Recent evidence suggests that leptin levels in peripheral blood and brain are lower in patients with epilepsy. Leptin is an energy-regulating hormone that plays a neuroprotective role in neurodegenerative diseases and brain trauma. However, little is known about the effects and molecular mechanisms of leptin treatment on long-term neurobehavioral impairment caused by developmental seizures. The present study evaluated whether chronic leptin treatment protected against neurobehavioral impairments induced by recurrent seizures in newborns treated with flurothyl. We also examined the effect of leptin on the expression of zinc/cPLA2-related autophagy signaling molecules and CaMKII in the cerebral cortex. Twenty Sprague-Dawley rats (6 days after birth, P6) were randomly divided into two groups, a neonatal seizure group and control group. Rats were subdivided on P13 into control, control + leptin (leptin, 2 mg/kg/day, continuous 10 days), seizure (RS), and seizure + leptin group (RS + leptin, 2 mg/kg/day for 10 consecutive days). Neurological behavioral parameters (negative geotaxis reaction reflex, righting reflex, cliff avoidance reflex, forelimb suspension reflex and open field test) were observed from P23 to P30. mRNA and protein levels in the cerebral cortex were detected using real-time RT-PCR and Western blotting, respectively. Flurothyl-induced seizures (RS group) produced long-term abnormal neurobehavior, which was improved with leptin treatment. Chronic leptin treatment restored several expression parameters affected by neonatal seizures, including seizure-induced up-regulated zinc transporter ZnT1/ZIP7, lipid membrane injury-related cPLA2, autophagy marker beclin-1/bcl2, LC3II/LC3I, and its execution molecule cathepsin-E, and down-regulated memory marker CaMK II alpha. Our results suggest that the early use of leptin after neonatal recurrent seizures may exert neuroprotective effects and antagonize the long-term neurobehavioral impairment caused by seizures. Autophagy-mediated Zn/cPLA2 and CaMK II signaling in the cerebral cortex may be involved in the neuroprotective effect of leptin. Our results provide new clues for anti-epileptogenetic treatment.

Recurrent spontaneous abortion (RSA) has a very complicated pathogenesis and male factors for this condition should not to be ignored, which are mainly related to genetics, immunology, infection, sperm quality, and others. In case of RSA, an etiological screening ought to be performed for the husband, which involves general, genetic and immunological examinations and infection detection. According to specific etiological factors, such measures as genetic consultation, immunotherapy, and traditional Chinese medication can be taken, which may contribute to the outcome of pregnancy.复发性流产的病因复杂，其中的男方因素不容忽视，主要包括遗传因素、免疫因素、感染因素、精子质量和其他因素。有复发性流产史的夫妇，应对男方进行相应的病因学筛查，包括一般检查和遗传学、免疫学、感染学检查。针对病因，给予对应的遗传咨询、免疫治疗、中药治疗和其他干预措施，有可能改善妊娠结局。.

This study was designed to determine whether there is a relationship between serum vitamin D levels and neurodevelopment and anthropometry in Chinese infants. A prospective cohort study with 160 women who gave birth to 160 healthy full-term infants and who were followed up for 6 mo was done. It included 80 pregnant women with vitamin D deficiency, and the other 80 pregnant women were enrolled matching the age and delivery method with a 25(OH)D level of more than 50 nmol/L. There was a signicant intergroup difference in length, weight or head circumference at birth (p

To study the safety and efficacy of Bushen Daozhuo Granules (BDG) in the treatment of type Ⅲ prostatitis.This multicenter randomized controlled clinical trial included 478 patients with type Ⅲ prostatitis, 290 in the trial group and 188 as controls, the former treated with BDG at 200 ml bid and the latter with tamsulosin hydrochloride sustainedrelease capsules at 0.2 mg qd, both for 4 weeks. Before treatment, after 4 weeks of medication, and at 4 weeks after drug withdrawal, we obtained the NIH Chronic Prostatitis Symptom Index (NIHCPSI) scores and compared the safety and effectiveness rate between the two groups of patients.Compared with the baseline, the NIHCPSI score was markedly decreased in the control group after 4 weeks of medication (21.42 ± 4.02 vs 15.67 ± 3.65, P0.05) but showed no statistically significant difference from that at 4 weeks after drug withdrawal (19.03 ± 3.86) (P0.05), while the NIHCPSI score in the trial group was remarkably lower than the baseline both after 4 weeks of medication and at 4 weeks after drug withdrawal (10.92 ± 2.06 and 12.91 ± 2.64 vs 21.58 ± 3.67, P0.05). The trial group exhibited both a higher rate of total effectiveness and safety than the control (P0.05).BDG is safe and effective for the treatment of type Ⅲ prostatitis.目的： 探讨补肾导浊颗粒治疗Ⅲ型前列腺炎的安全性和有效性。 方法： 采用多中心随机对照研究，对照组口服盐酸坦索罗辛缓释胶囊，0.2 mg/次，每天1次；治疗组口服补肾导浊颗粒，每次200 ml，每日2次，两组的治疗期为4周。分别于治疗前、治疗4周、停药4周行慢性前列腺炎症状评分（CPSI），评估两组的安全性和有效性。 结果： 共有478例患者完成本研究，其中对照组188例，治疗组290例。对照组在治疗4周后的CPSI为（15.67±3.65）分，显著低于治疗前（21.42±4.02）分（P0.05），停药4周后CPSI为（19.03±3.86）分，与治疗前相比较，无显著差异（P0.05）。治疗组在治疗4周、停药4周的CPSI分别为（10.92±2.06）分、（12.91±2.64）分，显著低于治疗前（21.58±3.67）分（P0.05），与对照组相比较，均有显著差异（P0.05）。治疗组的疾病有效率和总有效率均高于对照组（P0.05）。治疗组的安全性优于对照组（P0.05）。结论： 补肾导浊颗粒治疗Ⅲ型前列腺炎的安全、有效。.

Background— A portion of sudden cardiac deaths can be attributed to structural heart diseases, such as hypertrophic cardiomyopathy (HCM) or cardiac channelopathies such as long-QT syndrome (LQTS); however, the underlying molecular mechanisms are distinct. Here, we identify a novel CACNA1C missense mutation with mixed loss-of-function/gain-of-function responsible for a complex phenotype of LQTS, HCM, sudden cardiac death, and congenital heart defects. Methods and Results— Whole exome sequencing in combination with Ingenuity variant analysis was completed on 3 affected individuals and 1 unaffected individual from a large pedigree with concomitant LQTS, HCM, and congenital heart defects and identified a novel CACNA1C mutation, p.Arg518Cys, as the most likely candidate mutation. Mutational analysis of exon 12 of CACNA1C was completed on 5 additional patients with a similar phenotype of LQTS plus a personal or family history of HCM-like phenotypes and identified 2 additional pedigrees with mutations at the same position, p.Arg518Cys/His. Whole cell patch clamp technique was used to assess the electrophysiological effects of the identified mutations in Ca V 1.2 and revealed a complex phenotype, including loss of current density and inactivation in combination with increased window and late current. Conclusions— Through whole exome sequencing and expanded cohort screening, we identified a novel genetic substrate p.Arg518Cys/His-CACNA1C, in patients with a complex phenotype including LQTS, HCM, and congenital heart defects annotated as cardiac-only Timothy syndrome. Our electrophysiological studies, identification of mutations at the same amino acid position in multiple pedigrees, and cosegregation with disease in these pedigrees provide evidence that p.Arg518Cys/His is the pathogenic substrate for the observed phenotype.

The aim of the present study was to investigate the periodontitis-associated changes in the number, proliferation and differentiation potential of human periodontal ligament stem cells (PDLSCs). Cultures of human periodontal ligament cells (PDLCs) were established from healthy donors and donors with periodontitis. The numbers of stem cell were characterized using flow cytometry. PDLSCs were isolated from the PDLCs by immunomagnetic bead selection. Colony‑forming abilities, osteogenic and adipogenic potential, gene expression of cementoblast phenotype, alkaline phosphatase activity and in vivo differentiation capacities were then evaluated. Periodontitis caused an increase in the proliferation of PDLSCs and a decrease in the commitment to the osteoblast lineage. This is reflected by changes in the expression of osteoblast markers. When transplanted into immunocompromised mice, PDLSCs from the healthy donors exhibited the capacity to produce cementum PDL‑like structures, whereas, the inflammatory PDLSCs transplants predominantly formed connective tissues. In conclusion, the data from the present study suggest that periodontitis affects the proliferation and differentiation potential of human PDLSCs in vitro and in vivo.

Polo-like kinase 1 (PLK1) is highly expressed in many cancers and therefore a biomarker of transformation and potential target for the development of cancer-specific small molecule drugs. RO3280 was recently identified as a novel PLK1 inhibitor, however its therapeutic effects in leukemia treatment are still unknown. We found that the PLK1 protein was highly expressed in leukemia cell lines as well as 73.3% (11/15) of pediatric acute myeloid leukemia (AML) samples. PLK1 mRNA expression was significantly higher in AML samples compared with control samples (82.95 ± 110.28 vs. 6.36 ± 6.35, p &lt, 0.001). Kaplan-Meier survival analysis revealed that shorter survival time correlated with high tumor PLK1 expression (p = 0.002). The 50% inhibitory concentration (IC50) of RO3280 for acute leukemia cells was between 74 and 797 nM. The IC50 of RO3280 in primary acute lymphocytic leukemia (ALL) and AML cells was between 35.49 and 110.76 nM and 52.80 and 147.50 nM, respectively. RO3280 induced apoptosis and cell cycle disorder in leukemia cells. RO3280 treatment regulated several apoptosis-associated genes. The regulation of DCC, CDKN1A, BTK, and SOCS2 was verified by western blot. These results provide insights into the potential use of RO3280 for AML therapy, however, the underlying mechanisms remain to be determined.

Zinc transporter 3 (ZnT3)-dependent “zincergic” vesicular zinc accounts for approximately 20% of the total zinc content of the mammalian telencephalon. Elevated hippocampal ZnT3 expression is acknowledged to be associated with mossy fiber sprouting and cognitive deficits. However, no studies have compared the long-term neurobehavioral phenotype with the expression of ZnT3 in the cerebral cortex following status epilepticus (SE). The aim of this study was to investigate changes in the long-term neurobehavioral phenotype as well as the expression of ZnT3 and calcium homeostasis-related CB-D28k in the cerebral cortex of rats subjected to neonatal SE and to determine the effects of leptin treatment immediately after neonatal SE. Fifty Sprague-Dawley rats (postnatal day 6, P6) were randomly assigned to two groups: the pilocarpine hydrochloride-induced status epilepticus group (RS, n = 30) and control group (n = 20). Rats were further divided into the control group without leptin (Control), control-plus-leptin treatment group (Leptin), RS group without leptin treatment (RS), and RS-plus-leptin treatment group (RS + Leptin). On P6, all rats in the RS group and RS + Leptin group were injected intraperitoneally (i.p.) with lithium chloride (5 mEq/kg). Pilocarpine (320 mg/kg, i.p.) was administered 30 min after the scopolamine methyl chloride (1 mg/kg) injection on P7. From P8 to P14, animals of the Leptin group and RS + Leptin group were given leptin (4 mg/kg/day, i.p.). The neurological behavioral parameters (negative geotaxis reaction reflex, righting reflex, cliff avoidance reflex, forelimb suspension reflex, and open field test) were observed from P23 to P30. The protein levels of ZnT3 and CB-D28k in the cerebral cortex were detected subsequently by the western blot method. Pilocarpine-treated neonatal rats showed long-term abnormal neurobehavioral parameters. In parallel, there was a significantly downregulated protein level of CB-D28k and upregulated protein level of ZnT3 in the cerebral cortex of the RS group. Leptin treatment soon after epilepticus for 7 consecutive days counteracted these abnormal changes. Taken together with the results from our previous reports on another neonatal seizure model, which showed a significant positive inter-relationship between ZnT3 and calcium/calmodulin-dependent protein kinase IIα (CaMKIIα), the data here suggest that ZnT3/CB-D28k–associated Zn (2+)/Ca(2+) signaling might be involved in neonatal SE-induced long-term brain damage in the aspects of neurobehavioral impairment. Moreover, consecutive leptin treatment is effect at counteracting these hyperexcitability-related changes, suggesting a potential clinical significance.

Essential language sites and the arcuate fasciculus (AF) have been extensively researched. However, the relationship between them remains insufficiently studied, especially in healthy people. Navigated transcranial magnetic stimulation (nTMS) is increasingly used in language mapping. While enjoying the advantage of non-invasiveness, it is also capable of inducing a virtual lesion in the brain. Thus, it offers the possibility of using the virtual-lesion method to study the healthy brain. This study combined nTMS and diffusion tensor imaging (DTI) tractography to investigate the relationship between essential language sites and the AF in 30 healthy right-handed volunteers. A total of 143 essential language sites were identified using nTMS, and a total of 175 AF terminations were identified using DTI tractography. Sixty-six sites had a direct correlation with the AF, accounting for 46% of the total essential language sites. Forty-seven AF terminations harbored essential language sites, accounting for 27% of the total AF terminations. Upon data rendering to the cortical parcellation system, a region-related heterogeneity of the correlation rate was found. This study provides the first data on the relationship between essential language sites and the AF in healthy adults.

Background The effect of alterations in tidal volume on mortality of acute respiratory distress syndrome (ARDS) is determined by respiratory system compliance. We aimed to investigate the effects of different tidal volumes on lung strain in ARDS patients who had various levels of respiratory system compliance. Methods Nineteen patients were divided into high (Chigh group) and low (Clow group) respiratory system compliance groups based on their respiratory system compliance values. We defined compliance ≥0.6 ml/(cmH2O/kg) as Chigh and compliance

Because of troubling reports of high urinary metabolite levels and adverse reproductive health effects in workers exposed to di(2-ethylhexyl)phthalate (DEHP) in occupational settings, concern about exposure to DEHP in occupational settings is increasing. However, the contributions of different routes of exposure to DEHP are unclear. We used personal air sampling and biomonitoring to determine the contribution of inhalation exposure to the body burden of DEHP in the workplace. Eighty-nine workers (high-exposure group: 66 raw-materials workers; low-exposure group: 23 administrative workers) were recruited from three polyvinyl chloride (PVC) factories. Urinary levels of mono(2-ethylhexyl) phthalate (MEHP), (mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) were measured in pre-shift and post-shift samples. The geometric means of airborne concentrations of DEHP were 5.3 μg/m3 (low-exposure group) and 32.7 μg/m3 (high-exposure group) (P

Brain-derived neurotrophic factor (BDNF) increases in failing hearts, but BDNF roles in cardiac remodeling following myocardial infarction (MI) are unclear. Male BDNF+/+[wild-type (WT)] and BDNF+/−heterozygous (HET) mice at 6–9 mo of age were subjected to MI and evaluated at days 1, 3, 5, 7, or 28 post-MI. At day 28 post-MI, 76% of HET versus 40% of WT survived, whereas fractional shortening improved and neovascularization levels were reduced in the HET (all, P < 0.05). At day 1, post-MI, matrix metalloproteinase-9, and myeloperoxidase (MPO) increased in WT, but not in HET. Concomitantly, monocyte chemotactic protein-1 and -5 levels increased and vascular endothelial growth factor (VEGF)-A decreased in HET. Neutrophil infiltration peaked at days 1–3 in WT mice, and this increase was blunted in HET. To determine if MPO administration could rescue the HET phenotype, MPO was injected at 3 h post-MI. MPO restored VEGF-A levels without altering matrix metalloproteinase-9 or neutrophil content. In conclusion, reduced BDNF levels modulated the early inflammatory and neovascularization responses, leading to improved survival and reduced cardiac remodeling at day 28 post-MI. Thus reduced BDNF attenuates early inflammation following MI by modulating MPO and angiogenic response through VEGF-A.

High tumor targeting and sustained drug concentration are key points for successful anti-tumor therapy, however, it is a challenging task. In this work, a novel micelle formulation of paclitaxel (PTX) has been prepared for the purpose of prolonging the blood circulation time as well as improving the accumulation of the drug within the tumor tissue. PEGylated P(CL-co-LLA) (poly(ε-caprolactone-co-L-lactide)) micelles containing PTX were prepared by solid dispersion-sonication method with a higher drug-loading efficiency and encapsulation ratio (28.4% and 94.7%, respectively). Pharmacokinetic study revealed that the drug-loading micelles exhibited a higher AUC values and a prolonged residence time of drug in the blood circulation than those of PTX injection. As demonstrated by tissue distribution and anti-tumor study in S180 tumor-bearing mice, the PEG-P(CL-co-LLA)/PTX micelles displayed modified tissue distribution of PTX and increased accumulation of PTX in tumor, therefore, resulted in anti-tumor effects enhancement and drug concentration in the normal tissues reduction. Furthermore, the preliminary safety tests were performed by measuring the body weight, histopathology, blood cell counts and clinical chemistry parameters, and the results showed no subacute toxicity to hematological system, major organs or tissues in mice. Taken together, our valuation shows that PEG-P(CL-co-LLA) micelles is a potential drug delivery system of PTX for the effective treatment of the tumor and systematic toxicity reduction, thus, the micellar formulation can provide a useful alternative dosage form for i.v. administration of PTX.

Gene therapy is a potentially viable approach for treating hormone-refractory prostate cancer (HRPC), it requires efficient delivery systems and a target gene. Inducing carcinoma cell apoptosis by inhibition of heat shock protein 70 (HSP70) overexpression has been emerging as an attractive strategy for cancer therapy. In our study, the high tumor-specificity of human telomerase reverse transcriptase (HTERT) expression prompted the use of an HTERT/cytomegalovirus (CMV) chimeric promoter to drive HSP70-ShRNA expression to induce HRPC 22RV1 cell apoptosis. At the same time, sonoporation induced by ultrasound-targeted microbubble destruction (UTMD) was utilized for delivery of plasmid loaded with HTERT/CMV promoter. Our results indicated the combination of sonoporation, low-dose liposomes and HTERT/CMV chimeric promoter as a delivery system has the potential to promote efficient gene transfer with lower cytotoxicity.

Purpose To examine the content of phosphorylated myosin regulatory light chain (P-MLC20) and myosin light-chain kinase (MLCK) in the common bile duct of pediatric patients with pancreaticobiliary maljunction (PBM) accompanied by bile duct dilatation (BDD), and investigate their potential role in PBM accompanied by BDD. Methods Twenty-one specimens of the common bile duct from pediatric patients with PBM accompanied by BDD were collected. P-MLC20 was examined with immunohistochemistry. The expression of P-MLC20 and MLCK was also examined with Western blot. Twenty-one specimens of the common bile duct from pediatric patients without PBM and BDD were used as controls. Results The mean optical density (MOD), mean labeling intensity (MLI) and minimum qualifying scores (MQS) of P-MLC20 were 115.6856 ± 58.1634, 21.7125 % ± 9.6555 and 21.3531 ± 6.5255, respectively. In the control group, MOD, MLI and MQS were 96.5581 ± 9.7859, 11.1813 % ± 3.6208 and 10.7819 ± 3.5323, respectively. There was no significant difference in MOD between the two groups (P > 0.05), whereas there was a significant difference in MLI and MQS between the two groups (P

Inflammatory microenvironment causes the change of epigenetic modification in periodontal ligament stem cells derived from periodontitis tissues (P-PDLSCs), which results in defective osteogenic differentiation compared to cells from healthy tissues. It’s urgent to explore therapeutic strategies aimed at epigenetic targets associated with the regenerative ability of PDLSCs. Osthole, a small-molecule compound extracted from Chinese herbs, has been documented to promote osteogenesis and cell sheets formation of healthy PDLSCs. However, whether osthole shows same effect on P-PDLSCs and the mechanism of promotive effect is still unknown. The purpose of this study was to determine whether Osthole could restore defective osteogenic differentiation of P-PDLSCs via epigenetic modification. We demonstrated that 10−7 Mol/L of Osthole was the best concentration for osteogenic differentiation and proliferation of P-PDLSCs. Mechanistically, we also found that Osthole upregulated MOZ and MORF, histone acetylases that specifically catalyze acetylation of Histone3 lisine9 (H3K9) and Histone3 lisine14 (H3K14), which are key regulators in osteogenic differentiation of P-PDLSCs. Furthermore, Osthole treatment improved cell sheet formation and enhanced the bone formation of PDLSC sheets in animal models of periodontitis. Our study suggests that Osthole is a promising drug to cure periodontitis via regulating epigenetic modification in cell sheets engineering.

Salbutamol is a short-acting β2-adrenergic receptor agonist that has been used for many years for relief of bronchospasm. However, studies on the pharmacokinetic profile of orally inhaled salbutamol doses used in clinical practice have not yet been reported in Chinese subjects.The aim of this study was to compare the pharmacokinetics and evaluate the bioequivalence of two orally inhaled salbutamol formulations.A single-dose randomized fasting two-period, two-treatment and two-sequence crossover open-label bioequivalence study was conducted in 24 healthy Chinese adult male volunteers, with a 1-week washout period between treatments. Plasma concentrations of salbutamol were determined using liquid chromatography coupled to tandem mass spectrometry. Pharmacokinetic parameters, including AUC0-0.33 h, AUC0-24 h and Cmax were calculated and the 90% confidence intervals of the ratio (test/reference) pharmacokinetic parameters were obtained by analysis of variance on logarithmically transformed data.The mean (SD) pharmacokinetic parameters of the reference drug were AUC0-0.33 h, 227.2 (89.9) pg·h/ml; AUC0-24 h, 2551.9 (1008.0) pg·h/ml; Cmax, 801.3 (307.3) pg/ml and t1/2, 5.14(1.36) h. Those of the test drug were AUC0-0.33 h, 244.0 (104.4) pg·h/ml; AUC0-24 h, 2664.4 (1081.8) pg·h/ml; Cmax, 873.7 (374.4) pg/ml, t1/2, 5.29 (1.23) h. The median value for Tmax was 0.25 h for both formulations. The 90% confidence intervals for the AUC0-0.33 h, AUC0-24 h and Cmax were in the range of 0.892-1.208, 0.876-1.195 and 0.911-1.203, respectively.This single-dose study found that the test and reference products met the regulatory criteria for bioequivalence of China in healthy Chinese volunteers.

Item does not contain fulltext Histone demethylase upregulation has been observed in human cancers, yet it is unknown whether this is a bystander event or a driver of tumorigenesis. We found that overexpression of lysine-specific demethylase 4A (KDM4A, also known as JMJD2A) was positively correlated with Gleason score and metastasis in human prostate tumors. Overexpression of JMJD2A resulted in the development of prostatic intraepithelial neoplasia in mice, demonstrating that JMJD2A can initiate prostate cancer development. Moreover, combined overexpression of JMJD2A and the ETS transcription factor ETV1, a JMJD2A-binding protein, resulted in prostate carcinoma formation in mice haplodeficient for the phosphatase and tensin homolog (Pten) tumor-suppressor gene. Additionally, JMJD2A cooperated with ETV1 to increase expression of yes associated protein 1 (YAP1), a Hippo pathway component that itself was associated with prostate tumor aggressiveness. ETV1 facilitated the recruitment of JMJD2A to the YAP1 promoter, leading to changes in histone lysine methylation in a human prostate cancer cell line. Further, YAP1 expression largely rescued the growth inhibitory effects of JMJD2A depletion in prostate cancer cells, indicating that YAP1 is a downstream effector of JMJD2A. Taken together, these data reveal a JMJD2A/ETV1/YAP1 axis that promotes prostate cancer initiation and that may be a suitable target for therapeutic inhibition.

A novel active and multi-dose dry powder inhaler (DPI) was developed and evaluated to deliver a small quantity (100-500 μg) of pure drug without any excipient. This dry powder inhaler utilized two compressed air flows to dispense and deliver drug powder: the primary flow aerosolizes the drug powder from its pocket and the secondary flow further disperses the aerosol. In vitro tests by Anderson Cascade Impactor (ACI) indicated that the fine particle fraction (FPF) (4.7 μm) of drug delivery could reach over a range of 50-70% (w/w). Emitted dose tests showed that delivery efficiency was above 85% and its relative standard deviation (RSD) was under 10%. Confocal microscopy was used to confirm the deposition of fluorescently labeled spray-dried powder in rabbit lungs. Also, a chromatographic method was used to quantify drug deposition. The results of animal tests showed that 57% of aerosol deposited in the rabbit lung and 24% deposited in its trachea. All the results implied that this novel active dry powder inhaler could efficiently deliver a small quantity of fine drug particles into the lung with quite high fine particle fraction.

Introduction: Antiviral drug-resistance patterns of hepatitis B virus (HBV) mutants are complex and currently partly understood. The aim of this study was to monitor the genotypic resistance profile in patients with chronic hepatitis B (CHB) receiving nucleos(t)ide analogues (NAs) in Huzhou, eastern China. Methodology: Serum samples of 139 CHB patients undergoing NA treatment were obtained from Huzhou Central Hospital. The full-length HBV reverse transcriptase regions were amplified and sequenced. The NA resistance mutation positions, including rtL80, rtI169, rtV173, rtL180, rtA181, rtT184, rtA194, rtS202, rtM204, rtI233, rtN236, and rtM250 were analyzed. Results: Genotypic resistance mutations were detected in 41.72% (58/139) of patients with CHB. Drug resistance mutations were detected at positions rt80, rt173, rt180, rt181, rt194, rt202, rt204, rt236, and rt250, but were not observed at positions rt169, rt184, and rt233. The prevalence of mutations at rtM204 was 54.44% in 90 patients who were treated with lamivudine (LAM) or telbivudine (LDT). RtN236 mutations were detected in 7.14% (2/28) of the patients receiving adefovir (ADV) therapy. Additionally, rtA181 mutations were observed in 4 patients with LAM, ADV, and LDT-based therapy, but not in those patients treated with entecavir (ETV). Among patients who harbored rtM204 combination mutations, rtM204I and rtM204V were significantly associated with rtL80I/V and rtL180M, respectively. Conclusions: The mutation patterns of NA-resistant HBV are complicated in CHB patients in the current clinical setting. Thus, it is necessary to persistently monitor the resistance mutations of HBV for optimizing antiviral therapy strategy and for preventing an outbreak of clinical resistance.

Lumbar disc herniation is a common male disease. In the past, More academic attention was directed to its relationship with lumbago and leg pain than to its association with andrological diseases. Studies show that central lumber intervertebral disc herniation may cause cauda equina injury and result in premature ejaculation, erectile dysfunction, chronic pelvic pain syndrome, priapism, and emission. This article presents an overview on the correlation between central lumbar intervertebral disc herniation and andrological diseases, focusing on the aspects of etiology, pathology, and clinical progress, hoping to invite more attention from andrological and osteological clinicians.

This study investigated the effect of isoflavone aglycone (IA) on the learning and memory performance of senescence-accelerated mice, and explored its neural protective mechanism. Results showed that SAM-P/8 senescence-accelerated mice treated with IA performed significantly better in the Y-maze cognitive test than the no treatment control (P < 0.05). The cortex AchE activity, serum SOD and GSH-Px activities were notably higher (P < 0.05). MDA concentration and the β-secretase activity in the hippocampal tissue were both lower (P < 0.05). Additionally, the number of hippocampal neurons was increased and cell morphology was significantly improved. Data suggested that IA could indirectly increase concentration of the cholinergic neural transmitter Ach through regulation of AchE, therefore improving the central cholinergic function and enhancing the learning and memory ability. By reducing the β-secretase activity, IA could decrease the formation and deposition of insoluble Adebris, relieve the resulted toxicity and damage to neurons, and thereby effectively protect the nervous system.

The development of HIV protease inhibitors (PIs) has been one of the most significant advances of the past decade in controlling HIV infection. Unfortunately, the benefits of HIV PIs are compromised by serious side effects. One of the most frequent and deleterious side effects of HIV PIs is severe gastrointestinal (GI) disorders including mucosal erosions, epithelial barrier dysfunction, and leak-flux diarrhea, which occurs in 16–62% of patients on HIV PIs. Although the underlying mechanisms behind HIV PI-associated serious adverse side effects remain to be identified, our recent studies have shown that activation of endoplasmic reticulum (ER) stress response plays a critical role in HIV PI-induced GI complications. The objective of this study was to develop a novel self micro-emulsifying drug delivery system (SMEDDS) using various antioxidants as surfactants and co-surfactants to reduce the GI side effects of the most commonly used HIV PI, ritonavir. The biological activities of this SMSDDS of ritonavir were compared with that of Norvir®, which is currently used in the clinic. Rat normal intestinal epithelial cells (IEC-6) and mouse Raw 264.7 macrophages were used to examine the effect of new SMEDDS of ritonavir on activation of ER stress and oxidative stress. The Sprague-Dawley rats and C57/BL6 mice were used for pharmacokinetic studies and in vivo studies. The intracellular and plasma drug concentrations were determined by HPLC analysis. Activation of ER stress was detected by western blot analysis and secreted alkaline phosphatase (SEAP) reporter assay. Reactive oxygen species (ROS) was measured using dichlorodihydrofluorescein diacetate as a probe. Cell viability was determined by Roche’s cell proliferation reagent WST-1. Protein levels of inflammatory cytokines (TNF-α and IL-6) were determined by Enzyme-linked immunosorbent assays (ELISA). The intestinal permeability was assessed by luminal enteral administration of fluorescein isothiocyanate conjugated dextran (FITC-dextran, 4 kDa). The pathologic changes in intestine were determined by histological examination. The results indicated that incorporation of antioxidants in this new SMEDDS not only significantly reduced ritonavir-induced ER stress activation, ROS production and apoptosis in intestinal epithelial cells and macrophages, but also improved the solubility, stability and bioavailability of ritonavir, and significantly reduced ritonavir-induced disruption of intestinal barrier function in vivo. In conclusion, this new SMEDDS of ritonavir has better bioavailability and less GI side effects as compared to Norvir®. This new SMEDDS can be used for other HIV PIs and any insoluble anti-viral drug with serious GI side effects.

Epilepsy in children is associated with a broad spectrum of cognitive deficits, which is associated with hippocampal mossy fiber sprouting. The underlying molecular mechanisms involved in mossy fiber sprouting in hippocampus following developmental seizures are not completely known. We studied the timing of cognitive dysfunction following neonatal seizures and the relation of this cognitive impairment to zinc transporter 1 (ZnT-1), 3 (ZnT-3), calcium/calmodulin-dependent protein kinase II (CaMK II), plasticity-related gene 1 (PRG-1) expression in hippocampus. A seizure was induced by inhalant flurothyl daily in neonatal Sprague-Dawley rats from postnatal day 6 (P6). Rats were assigned into the single-seizure group (SS), the recurrent-seizure group (RS, seizures induced in six consecutive days), and the control group. During P41–P46 and P85–P90, the rats were tested for spatial learning and memory abilities with automatic Morris water maze task. At P90, mossy fiber sprouting and gene expression in hippocampus were determined subsequently by Timm staining and RT-PCR methods. The escape latencies from the water maze were significantly longer in rats of RS group than those of the control and SS groups at d4 of the first maze test and at d3, d4 of the second maze test. As far as Spatial Probe Test was concerned, the frequency of passing through the platform quadrant was significantly decreased in RS group than that in control and SS groups in the entire two probe tests. In rats with recurrent seizures (RS group), there was an increased distribution of Timm granules in both the supragranular region of the dentate gyrus and the stratum pyramidale of CA3 subfield in RS group, while remaining barely visible in control and SS groups; the Timm scores in CA3 and dentate gyrus in the RS animals were significantly higher than that in the control and SS groups. RT-PCR densitometry analysis showed that the ratios of hippocampal ZnT-1 to β-actin of SS and RS group were decreased significantly compared with that of control group. Meanwhile, CaMK II to β-actin of RS group was markedly lower compared with those of SS and control groups. Our results suggest that the long-term adverse effects of recurrent neonatal seizures on cognition and mossy fiber sprouting may be associated with the down-regulated expression of ZnT-1 and CaMK II in hippocampus.