LD22-4, an 86 amino acid fragment of basic fibroblast growth factor, is an inhibitor of cell migration. LD22-4 inhibits the migration of various tumor cells, endothelial cells, and fibroblasts in vitro and suppresses tumor growth and angiogenesis in vivo. LD22-4 is effective in the presence of multiple growth factors, either alone or in combination, as well as haptotactic factors. LD22-4 inhibits the rate of malignant gliomas prepared from U87MG cells in an orthotopic mouse model by 90% compared to untreated mice. Employing U87MG cells, we identified the LD22-4 membrane receptor as neuropilin 1 (NRP1). The identification of NRP1 as the LD22-4 receptor was based upon mass spectrometric analysis of proteins that bind to LD22-4, immunoprecipitation of an NRP1-LD22-4 complex formed during incubation of LD22-4 with U87MG cells, LD22-4-NRP1 co-immunoprecipitation studies, and binding of LD22-4 to HEK293 cells expressing NRP1. In contrast, NRP1 binding of an inactive mutant of LD22-4 was substantially reduced. As is typical of NRP1 binding proteins, LD22-4 itself binds to heparin and requires heparan sulfate for binding to cells. Heparin addition to migration assays increased the inhibitory activity of LD22-4. In addition to a heparin binding region, LD22-4 contains a five amino acid C-terminus that matches an NRP1 consensus binding sequence. Thus, direct binding experiments, dependence on heparan sulfate, and the presence of a NRP1 consensus binding sequence indicate that NRP1 is the binding site of LD22-4 and mediates inhibition of cell migration.
Neuropilin 1; glioma cells; receptor; LD22-4; migration
To investigate the effect of the stellate ganglion (SG) and its left-right asymmetry on atrial fibrillation (AF) inducibility, AF duration and atrial electrophysiological properties.
Sixteen adult mongrel dogs were randomly assigned to three groups. The control group (n=4) underwent 6 h rapid atrial pacing (RAP) only; the right SG (RSG) group (n=6) underwent 6 h RSG stimulation plus RAP; and the left SG (LSG) group (n=6) underwent 6 h LSG stimulation plus RAP. AF induction rate, AF duration, effective refractory period (ERP) and dispersion of ERP (dERP) were measured.
In the RSG group, the induction rate of AF was significantly increased in sites in the right atrium (RA) compared with baseline (P<0.05). In the LSG group, the induction rate of AF was significantly increased (P<0.05) compared with baseline in the left atrium (LA), left superior pulmonary vein and left inferior pulmonary vein, respectively. Compared with RSG stimulation, right stellate ganglionectomy markedly decreased the AF induction rate of the RA (P<0.05). Compared with LSG stimulation, left stellate ganglionectomy markedly decreased the AF induction rate of the LA, the left superior pulmonary vein and the left inferior pulmonary vein (P<0.05). In the RSG group, the ERP was significantly shortened (P<0.05) and the dERP was significantly increased (P<0.05) in RA sites (P<0.05). The ERP was significantly shortened in the LSG group (P<0.05). The dERP was significantly increased (P<0.05) in LA and pulmonary vein sites (P<0.05).
Unilateral electrical stimulation of the SG in combination with RAP can successfully establish a canine model of acute AF mediated by excessive sympathetic activity. SG stimulation facilitates AF induction and aggravates electrical remodelling in sites in the atrium and pulmonary vein. Inhibiting sympathetic nerve activation through unilateral stellate ganglionectomy can reduce AF initiation.
Atrial fibrillation; Stellate ganglion; Sympathetic nerve
Background and Aim
Paraventricular nucleus (PVN) of hypothalamus is an important central component in modulating adipose afferent reflex (AAR). Melanocortin receptors (MC3/4Rs) expressions are found in the hypothalamic PVN. This study was designed to determine the roles of MC3/4Rs in the PVN in modulating the AAR and its downstream signaling pathway in normal rats.
Renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded in anaesthetized rats. AAR was evaluated using RSNA and MAP responses to capsaicin injection into the inguinal white adipose tissue (iWAT). Microinjection of the MC3/4R agonist melanotan II (MTII) into the PVN enhanced the AAR. The MC3/4R antagonist SHU9119 or MC4R antagonist HS024 attenuated the AAR and abolished MTII-induced AAR response. The adenylate cyclase (AC) inhibitor SQ22536 or the protein kinase A (PKA) inhibitor Rp-cAMP attenuated the AAR and the effect of MTII on the AAR was abolished by pretreatment with SQ22536 or Rp-cAMP in the PVN. Furthermore, both PVN microinjection of MTII and iWAT injection of capsaicin increased the cAMP level in the PVN. SHU9119 in the PVN abolished the increase in cAMP level which induced by iWAT injection of capsaicin.
The activation of MC4Rs rather than MC3Rs enhances the AAR, and a cAMP-PKA pathway is involved in the effects of MC4Rs in the PVN.
Sympathetic activity involves the pathogenesis of atrial fibrillation (AF). Renal sympathetic denervation (RSD) decreases sympathetic renal afferent nerve activity, leading to decreased central sympathetic drive. The aim of this study was to identify the effects of RSD on AF inducibility induced by hyper-sympathetic activity in a canine model.
To establish a hyper-sympathetic tone canine model of AF, sixteen dogs were subjected to stimulation of left stellate ganglion (LSG) and rapid atrial pacing (RAP) for 3 hours. Then animals in the RSD group (n = 8) underwent radiofrequency ablation of the renal sympathetic nerve. The control group (n = 8) underwent the same procedure except for ablation. AF inducibility, effective refractory period (ERP), ERP dispersion, heart rate variability and plasma norepinephrine levels were measured at baseline, after stimulation and after ablation.
LSG stimulation combined RAP significantly induced higher AF induction rate, shorter ERP, larger ERP dispersion at all sites examined and higher plasma norepinephrine levels (P<0.05 in all values), compared to baseline. The increased AF induction rate, shortened ERP, increased ERP dispersion and elevated plasma norepinephrine levels can be almost reversed by RSD, compared to the control group (P<0.05). LSG stimulation combined RAP markedly shortened RR-interval and standard deviation of all RR-intervals (SDNN), Low-frequency (LF), high-frequency (HF) and LF/HF ratio (P<0.05). These changes can be reversed by RSD, compared to the control group (P<0.05).
RSD significantly reduced AF inducibility and reversed the atrial electrophysiological changes induced by hyper-sympathetic activity.
Objective: This study deals with the effect of phosphoric acid etching and conditioning on enamel micro-tensile bond strengths (μTBSs) of conventional and resin-modified glass ionomer cements (GICs/RMGICs). Methods: Forty-eight bovine incisors were prepared into rectangular blocks. Highly-polished labial enamel surfaces were either acid-etched, conditioned with liquids of cements, or not further treated (control). Subsequently, two matching pre-treated enamel surfaces were cemented together with one of four cements [two GICs: Fuji I (GC), Ketac Cem Easymix (3M ESPE); two RMGICs: Fuji Plus (GC), RelyX Luting (3M ESPE)] in preparation for μTBS tests. Pre-treated enamel surfaces and cement-enamel interfaces were analyzed by scanning electron microscopy (SEM). Results: Phosphoric acid etching significantly increased the enamel μTBS of GICs/RMGICs. Conditioning with the liquids of the cements produced significantly weaker or equivalent enamel μTBS compared to the control. Regardless of etching, RMGICs yielded stronger enamel μTBS than GICs. A visible hybrid layer was found at certain enamel-cement interfaces of the etched enamels. Conclusions: Phosphoric acid etching significantly increased the enamel μTBSs of GICs/RMGICs. Phosphoric acid etching should be recommended to etch the enamel margins before the cementation of the prostheses such as inlays and onlays, using GICs/RMGICs to improve the bond strengths. RMGICs provided stronger enamel bond strength than GICs and conditioning did not increase enamel bond strength.
Glass ionomer cements; Surface treatments; Bovine enamels; Scanning electron microscopy (SEM); Micro-tensile bond strengths
Infantile hemangiomas are the most common benign vascular tumors in infancy and childhood. As hemangioma could regress spontaneously, it generally does not require treatment unless proliferation interferes with normal function or gives rise to risk of serious disfigurement and complications unlikely to resolve without treatment. Various methods for treating infant hemangiomas have been documented, including wait and see policy, laser therapy, drug therapy, sclerotherapy, radiotherapy, surgery and so on, but none of these therapies can be used for all hemangiomas. To obtain the best treatment outcomes, the treatment protocol should be individualized and comprehensive as well as sequential. Based on published literature and clinical experiences, we established a treatment guideline in order to provide criteria for the management of head and neck hemangiomas. This protocol will be renewed and updated to include and reflect any cutting-edge medical knowledge, and provide the newest treatment modalities which will benefit our patients.
Hemangiomas; treatment; head and neck; sclerotherapy; drug therapy
Myelodysplastic syndromes (MDS) are age-dependent stem cell malignancies that share biological features of activated adaptive immune response and ineffective hematopoiesis. Here we report that myeloid-derived suppressor cells (MDSC), which are classically linked to immunosuppression, inflammation, and cancer, were markedly expanded in the bone marrow of MDS patients and played a pathogenetic role in the development of ineffective hematopoiesis. These clonally distinct MDSC overproduce hematopoietic suppressive cytokines and function as potent apoptotic effectors targeting autologous hematopoietic progenitors. Using multiple transfected cell models, we found that MDSC expansion is driven by the interaction of the proinflammatory molecule S100A9 with CD33. These 2 proteins formed a functional ligand/receptor pair that recruited components to CD33’s immunoreceptor tyrosine-based inhibition motif (ITIM), inducing secretion of the suppressive cytokines IL-10 and TGF-β by immature myeloid cells. S100A9 transgenic mice displayed bone marrow accumulation of MDSC accompanied by development of progressive multilineage cytopenias and cytological dysplasia. Importantly, early forced maturation of MDSC by either all-trans-retinoic acid treatment or active immunoreceptor tyrosine-based activation motif–bearing (ITAM-bearing) adapter protein (DAP12) interruption of CD33 signaling rescued the hematologic phenotype. These findings indicate that primary bone marrow expansion of MDSC driven by the S100A9/CD33 pathway perturbs hematopoiesis and contributes to the development of MDS.
Tm-22 is a coiled coil-nucleotide binding-leucine rich repeat resistance protein that confers durable extreme resistance against Tomato mosaic virus (ToMV) and Tobacco mosaic virus (TMV) by recognizing the viral movement protein (MP). Here we report that the Nicotiana benthamiana J-domain MIP1 proteins (NbMIP1s) associate with tobamovirus MP, Tm-22 and SGT1. Silencing of NbMIP1s reduced TMV movement and compromised Tm-22-mediated resistance against TMV and ToMV. Furthermore, silencing of NbMIP1s reduced the steady-state protein levels of ToMV MP and Tm-22. Moreover, NbMIP1s are required for plant resistance induced by other R genes and the nonhost pathogen Pseudomonas syringae pv. tomato (Pst) DC3000. In addition, we found that SGT1 associates with Tm-22 and is required for Tm-22-mediated resistance against TMV. These results suggest that NbMIP1s function as co-chaperones during virus infection and plant immunity.
Plant pathogens cause considerable yield losses in many vegetables and crops; therefore, understanding the mechanisms of disease resistance can enable crop improvements and provide substantial economic benefits. Here, we examine the signaling pathways of Tm-22, a tomato resistance protein that confers resistance to Tomato mosaic virus (ToMV) and Tobacco mosaic virus (TMV) by detecting the presence of their movement proteins (MPs). We found that in Nicotiana benthamiana, Tm-22-mediated resistance against TMV and ToMV requires MIP1s (NbMIP1s), a group of J-domain proteins that may act as molecular chaperones to assist protein folding and maintain protein structure. Intriguingly, MIP1s are required for both TMV resistance and TMV infection. NbMIP1s interact with and are essential for protein stability of both Tm-22 and the viral MP. NbMIP1s are required for resistance mediated by other resistance proteins and resistance to the bacterial nonhost pathogen Pseudomonas syringae pv. tomato (Pst) DC3000. These new insights into the mechanisms of viral infection and disease resistance may enable future advances in crop protection.
The spinal cord (SC) and dorsal root ganglion (DRG) are target implantation regions for neural prosthetics, but the tissue-electrode interface in these regions is not well-studied. To improve our understanding of these locations, we characterized the tissue reactions around implanted electrodes. L1, an adhesion molecule shown to maintain neuronal density and reduce gliosis in brain tissue, was then evaluated in SC and DRG implants. Following L1 immobilization onto neural electrodes, the bioactivities of the coatings were verified in vitro using neuron, astrocyte and microglia cultures. Non-modified and L1-coated electrodes were implanted into adult rats for 1 or 4 weeks. Hematoxylin and eosin staining along with cell-type specific antibodies were used to characterize the tissue response. In the SC and DRG, cells aggregated at the electrode-tissue interface. Microglia staining was more intense around the implant site and decreased with distance from the interface. Neurofilament staining in both locations was decreased or absent around the implant when compared to surrounding tissue. With L1, neurofilament staining was significantly increased while neuronal cell death decreased. Our results indicate that L1-modified electrodes may result in an improved chronic neural interface and will be evaluated in recording and stimulation studies.
electrode; interface; biocompatibility; neural prosthesis; surface modification
Hepatic pseudolesions detected by helical computed tomography (CT) are not rare, but it is difficult to make a final diagnosis when the hepatic lesion is complicated by the presence of greatly elevated alpha fetoprotein (AFP). Clinical treatment of non-typical hepatic pseudolesions complicated by greatly elevated AFP should confirm the diagnosis and minimize trauma.
Non-invasive procedures including ultrasonography, CT, and micro-invasive digital subtraction angiography could not safely differentiate this lesion from a malignant focus when it was complicated by greatly elevated AFP. Laparoscopic hepatectomy was performed, and pathological analysis showed chronic hepatitis, nodular regenerative hyperplasia, focal nodular hyperplasia of the liver, and mild vascular malformation. The tissue was HbsAg(−), HbcAg(−), and AFP(+).
Heightened awareness of hepatic pseudolesion complicated by primarily elevated AFP will help physicians avoid unnecessary invasive procedures. Hepatic biopsy is inevitable because of greatly elevated AFP. For suspected hepatic pseudolesion with elevated AFP, needle-core biopsy and follow-up surveillance instead of hepatectomy are recommended to find the source of AFP and make a final diagnosis of pseudolesion.
Hepatic pseudolesion; Alpha fetoprotein; Diagnosis
De-qi refers to the participant's subjective sensations and objective body responses as well as the acupuncturist's perceptions while the acupuncturist needles certain acupoints in the participant's body. In recent years, De-qi is getting increasing attention of the researchers and many efforts have been made to understand its mechanism. By the broad literature survey, this paper explores the subjective De-qi sensation of the patients, its influencing factors, and the resulting physiological responses. The purpose of this paper is expected to find out a possible mechanism of De-qi and to provide certain scientific evidence for acupuncture fundamental research and clinical practice.
Glucocorticoid is an important regulator of energy homeostasis. Glucocorticoid receptor (GR) gene polymorphisms that contribute to variability in glucocorticoid sensitivity have been identified. We explored the associations of single-nucleotide polymorphisms (SNPs) of the GR gene with traditional cardiovascular risk factors in the Chinese Han population.
We recruited 762 consecutive adults who underwent a regular physical examination at Beijing Xuanwu Hospital. Blood pressure, glucose, lipid levels (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein [LDL] cholesterol and triglycerides), body mass index (BMI), and waist-to-hip ratio were measured. Fourteen tag SNPs and 5 functional SNPs were selected and genotyped using the high-throughput Sequenom genotyping platform. Differences between genotypes/alleles for each SNP were adjusted for sex and age and tested using a general linear model procedure. Various models of inheritance, including additive, dominant, and recessive, were tested.
Among the 19 SNPs examined, 5 markers were associated with cardiovascular risk factors. The rs41423247 GG genotype and the rs7701443 AA genotype were associated with higher BMI and systolic blood pressure (P < 0.0004), and the rs17209251 GG genotype was associated with higher systolic blood pressure (P < 0.0004). Lower systolic blood pressure, total cholesterol, and LDL cholesterol were observed among rs10052957 A allele carriers (P < 0.0004), and lower plasma glucose and LDL-cholesterol concentrations were observed among rs2963156 TT carriers (P < 0.0004).
Polymorphism of the GR gene was associated with cardiovascular risk factors and may contribute to susceptibility to cardiovascular disease.
glucocorticoid receptor gene; polymorphism; cardiovascular disease; risk factor
Two mechanisms that have been proposed to explain success of invasive plants are unusual biotic interactions, such as enemy release or enhanced mutualisms, and increased resource availability. However, while these mechanisms are usually considered separately, both may be involved in successful invasions. Biotic interactions may be positive or negative and may interact with nutritional resources in determining invasion success. In addition, the effects of different nutrients on invasions may vary. Finally, genetic variation in traits between populations located in introduced versus native ranges may be important for biotic interactions and/or resource use. Here, we investigated the roles of soil biota, resource availability, and plant genetic variation using seedlings of Triadica sebifera in an experiment in the native range (China). We manipulated nitrogen (control or 4 g/m2), phosphorus (control or 0.5 g/m2), soil biota (untreated or sterilized field soil), and plant origin (4 populations from the invasive range, 4 populations from the native range) in a full factorial experiment. Phosphorus addition increased root, stem, and leaf masses. Leaf mass and height growth depended on population origin and soil sterilization. Invasive populations had higher leaf mass and growth rates than native populations did in fresh soil but they had lower, comparable leaf mass and growth rates in sterilized soil. Invasive populations had higher growth rates with phosphorus addition but native ones did not. Soil sterilization decreased specific leaf area in both native and exotic populations. Negative effects of soil sterilization suggest that soil pathogens may not be as important as soil mutualists for T. sebifera performance. Moreover, interactive effects of sterilization and origin suggest that invasive T. sebifera may have evolved more beneficial relationships with the soil biota. Overall, seedlings from the invasive range outperformed those from the native range, however, an absence of soil biota or low phosphorus removed this advantage.
FAK and Src signaling play important roles in cell differentiation, survival and migration. However, it remains unclear how FAK and Src activities are regulated at the initial stage of stem cell differentiation. We utilized fluorescence resonance energy transfer (FRET)-based FAK and Src biosensors to visualize these kinase activities at the plasma membrane of human mesenchymal stem cells (HMSCs) under the stimulation of osteogenic, myoblastic, or neural induction reagents. Our results indicate that the membrane FAK and Src activities are distinctively regulated by these differentiation induction reagents. FAK and Src activities were both up-regulated with positive feedback upon osteogenic induction, while myoblastic induction only activated Src, but not FAK. Neural induction, however, transiently activated FAK and subsequently Src, which triggered a negative feedback to partially inhibit FAK activity. These results unravel distinct regulation mechanisms of FAK and Src activities during HMSC fate decision, which should advance our understanding of stem cell differentiation in tissue engineering.
In the central nervous system (CNS), neural stem cells (NSCs) differentiate into neurons, astrocytes, and oligodendrocytes - these cell lineages are considered unidirectional and irreversible under normal conditions. The introduction of a defined set of transcription factors has been shown to directly convert terminally differentiated cells into pluripotent stem cells, reinforcing the notion that preserving cellular identity is an active process. Indeed, recent studies highlight that tumor suppressor genes (TSGs) such as Ink4a/Arf and p53, control the barrier to efficient reprogramming, leaving open the question whether the same TSGs function to maintain the differentiated state. During malignancy or following brain injury, mature astrocytes have been reported to re-express neuronal genes and re-gain neurogenic potential to a certain degree, yet few studies have addressed the underlying mechanisms due to a limited number of cellular models or tools to probe this process. Here, we use a synthetic small-molecule (isoxazole) to demonstrate that highly malignant EGFRvIII-expressing Ink4a/Arf-/-; Pten-/- astrocytes down-regulated their astrocyte character, re-entered the cell cycle, and upregulated neuronal gene expression. As a collateral discovery, isoxazole small-molecules blocked tumor cell proliferation in vitro, a phenotype likely coupled to activation of neuronal gene expression. Similarly, histone deacetylase inhibitors induced neuronal gene expression and morphologic changes associated with the neuronal phenotype, suggesting the involvement of epigenetic-mediated gene activation. Our study assesses the contribution of specific genetic pathways underlying the de-differentiation potential of astrocytes and uncovers a novel pharmacological tool to explore astrocyte plasticity, which may bring insight to reprogramming and anti-tumor strategies.
astrocyte plasticity; de-differentiation; epigenetics; glioblastoma; cancer stem cell
Allelic deletion of the RPS14 gene is a key effector of the hypoplastic anemia in patients with myelodysplastic syndrome (MDS) and chromosome 5q deletion [del(5q)]. Disruption of ribosome integrity liberates free ribosomal proteins to bind to and trigger degradation of MDM2, with consequent p53 transactivation. Herein we show that p53 is overexpressed in erythroid precursors of primary bone marrow del(5q) MDS specimens accompanied by reduced cellular MDM2. More importantly, we show that lenalidomide acts to stabilize MDM2, thereby accelerating p53 degradation. Biochemical and molecular analyses showed that lenalidomide inhibits the haplodeficient PP2Acα phosphatase resulting in hyperphosphorylation of inhibitory serine-166 and serine-186 residues on MDM2, and displaces binding of RPS-14 to suppress MDM2 auto-ubiquitination; whereas PP2Acα over expression promotes drug resistance. Bone marrow specimens from del(5q) MDS patients resistant to lenalidomide over-expressed PP2Acα accompanied by restored accumulation of p53 in erythroid precursors. Our findings indicate that lenalidomide restores MDM2 functionality in the 5q- syndrome to overcome p53 activation in response to nucleolar stress, and therefore may warrant investigation in other disorders of ribosomal biogenesis.
The interactions of DNA with oxaliplatin (Pt(R,R-DACH)) or its enantiomer (Pt(S,S-DACH)) were investigated using magnetic tweezers and atomic force microscope. In the process of DNA condensation induced by Pt-DACH, only diadducts and micro-loops are formed at low Pt-DACH concentrations, while at high Pt-DACH concentrations, besides the diadducts and micro-loops, long-range cross-links are also formed. The diadduct formation rate of Pt(R,R-DACH) is higher than that of Pt(S,S-DACH). However, the proportions of micro-loops and long-range cross-links for Pt(S,S-DACH) are higher than those for Pt(R,R-DACH). We propose a model to explain these differences between the effect of Pt(R,R-DACH) and that of Pt(S,S-DACH) on DNA condensation. The study has strong implications for the understanding of the effect of chirality on the interaction between Pt-DACH and DNA and the kinetics of DNA condensation induced by platinum complexes.
To explore the relationship between Health belief model (HBM) and children and adolescents' unintentional injury risk behavior, to add some useful information for injury prevention.
We investigated injury related health risk behavior and health belief status of students at primary schools grade 3 to 4, in a Safe Community, in Shanghai. Self-administered injury questionnaires were used to investigate risk behavior of students and HBM factors.
The prevalence of risk behavior among students reported in this community was high. HBM scores showed differences between two groups of students classified by whether they had risk behavior or not. Self-efficacy was highly related with the status of socio-psychological behavior.
HBM has been widely used in explaining the disease-related behavior; however, it has been seldom used in injury-related behavior. The study demonstrated important relation of HBM to students' injury issues, and HBM could explain injury related behavior as well, especially for traffic injury-related behavior. When developing injury prevention strategies, we can take it into account.
Quality assessment of pediatric randomized controlled trials (RCTs) in China is limited. The aim of this study was to evaluate the quantitative trends and quality indicators of RCTs published in mainland China over a recent 10-year period.
We individually searched all 17 available pediatric journals published in China from January 1, 2002 to December 30, 2011 to identify RCTs of drug treatment in participants under the age of 18 years. The quality was evaluated according to the Cochrane quality assessment protocol.
Of 1287 journal issues containing 44398 articles, a total of 2.4% (1077/44398) articles were included in the analysis. The proportion of RCTs increased from 0.28% in 2002 to 0.32% in 2011. Individual sample sizes ranged from 10 to 905 participants (median 81 participants); 2.3% of the RCTs were multiple center trials; 63.9% evaluated Western medicine, 32.5% evaluated traditional Chinese medicine; 15% used an adequate method of random sequence generation; and 10.4% used a quasi-random method for randomization. Only 1% of the RCTs reported adequate allocation concealment and 0.6% reported the method of blinding. The follow-up period was from 7 days to 96 months, with a median of 7.5 months. There was incomplete outcome data reported in 8.3%, of which 4.5% (4/89) used intention-to-treat analysis. Only 0.4% of the included trials used adequate random sequence allocation, concealment and blinding. The articles published from 2007 to 2011 revealed an improvement in the randomization method compared with articles published from 2002 to 2006 (from 2.7% to 23.6%, p = 0.000).
In mainland China, the quantity of RCTs did not increase in the pediatric population, and the general quality was relatively poor. Quality improvements were suboptimal in the later 5 years.
Children; Drugs; Randomized controlled trials; Quality assessment
Background: Matrix metalloproteinase 10 (MMP10) plays an important role in ischemic stroke and has a close relationship with some stroke risk factors. The aim of this study was to investigate the relationship between two single nucleotide polymorphisms (SNP) in the exon regions of the MMP10 gene and atherothrombotic cerebral infarction risk. Methods: Five hundred and thirty-seven hospital-based patients who had suffered first atherothrombotic cerebral infarction and 580 unrelated healthy controls were enrolled. Demographic and clinical features of the subjects were recorded, and two polymorphisms, rs17435959 (G>C), rs17293607 (C>T) were chosen to be genotyped by real-time polymerase chain reaction-restriction TaqMan probes using the ABI 7300 TaqMan platform. Results: There were several clinical parameters, such as blood pressure, fasting blood glucose, total cholesterol, homocysteine, as well as carotid plaque and smoking, but not average age and sex ratios that showed significant differences between patients and control subjects. For rs17435959, there was no significant difference between the ischemic stroke group and the healthy control group in genotype frequency (OR=1.295, P=0.187, 95% CI (0.882-1.899)) or allele frequency (OR=1.267, P=0.202, 95% CI (0.881-1.823)). Moreover, in smoking, none smoking, having carotid plaque, no carotid plaque, male or female subtypes, there was significant difference between patients and control subjects in genotype frequencies or allele frequencies. The minor allele frequency of rs17293607 was 0.92%, prohibiting further study of this allele. Conclusions: These findings suggest that the rs17435959 SNP may not associated with atherothrombotic cerebral infarction risk. We also found that rs17293607 is not polymorphic in our study population.
Matrix metalloproteinase 10; polymorphism; genetic; genetic predisposition to disease; atherothrombotic cerebral infarction
Nonstructural protein 3 (NS3) of hepatitis C virus (HCV), codes for protease and helicase carrying NTPase enzymatic activities, plays a crucial role in viral replication and an ideal target for diagnosis, antiviral therapy and vaccine development. In this study, monoclonal antibodies (mAbs) to NS3 helicase were characterized by epitope mapping and biological function test. A total of 29 monoclonal antibodies were produced to the truncated NS3 helicase of HCV-1b (T1b-rNS3, aa1192–1459). Six mAbs recognized 8/29 16mer peptides, which contributed to identify 5 linear and 1 discontinuous putative epitope sequences. Seven mAbs reacted with HCV-2a JFH-1 infected Huh-7.5.1 cells by immunofluorescent staining, of which 2E12 and 3E5 strongly bound to the exposed linear epitope 1231PTGSGKSTK1239 (EP05) or core motif 1373IPFYGKAI1380 (EP21), respectively. Five other mAbs recognized semi-conformational or conformational epitopes of HCV helicase. MAb 2E12 binds to epitope EP05 at the ATP binding site of motif I in domain 1, while mAb 3E5 reacts with epitope EP21 close to helicase nucleotide binding region of domain 2. Epitope EP05 is totally conserved and EP21 highly conserved across HCV genotypes. These two epitope peptides reacted strongly with 59–79% chronic and weakly with 30–58% resolved HCV infected blood donors, suggesting that these epitopes were dominant in HCV infection. MAb 2E12 inhibited 50% of unwinding activity of NS3 helicase in vitro. Novel monoclonal antibodies recognize highly conserved epitopes at crucial functional sites within NS3 helicase, which may become important antibodies for diagnosis and antiviral therapy in chronic HCV infection.
The introduction of BCR-ABL1 tyrosine kinase inhibitors (TKIs) for treatment of chronic myelogenous leukemia in chronic phase (CML-CP) has revolutionized therapy, altering the outcome from one of shortened life expectancy to long-term survival. With over 10 years of long-term treatment with imatinib and several years of experience with the next generation of TKIs, including nilotinib, dasatinib, bosutinib, and ponatinib, it is becoming clear that many clinical parameters have great impact on the prognosis of patients with CML. Emerging novel gene expression profiling and molecular techniques also provide new insights into CML pathogenesis and have identified potential prognostic markers and therapeutic targets. This review presents the supporting data and discusses how certain clinical characteristics at diagnosis, the depth of early response, the presence of certain kinase domain mutations, and additional molecular changes serve as prognostic factors that may guide individualized treatment decisions for patients with CML-CP.
Chronic myelogenous leukemia; BCR-ABL1; Philadelphia chromosome; Kinase domain mutation; Imatinib resistance; Tyrosine kinase inhibitors; Prognosis
Symptomatic osteoarthritis (OA) is a common painful disease with limited treatment options. A rising number of OA patients have been treated with intraarticular injections of hyaluronic acid, including the high molecular weight hylan G-F 20, which is injected following arthrocentesis. This study investigated the effectiveness of hylan G-F 20 to lower coefficient of friction (COF) and prevent chondrocyte apoptosis in vitro.
A disc-on-disc bovine cartilage bearing was used to measure the static and kinetic COF when lubricated with hylan G-F 20, human synovial fluid (HSF) and phosphate buffered saline (PBS). Following friction testing, we stained paraffin embedded sections of these cartilage bearings for activated caspase-3, a marker of apoptosis.
Bearings lubricated with hylan G-F 20 had kinetic COF values that were similar to bearings lubricated with PBS, but significantly higher than those lubricated with HSF. There were no significant differences in static COF values in bearings lubricated with hylan G-F 20 as compared to PBS or HSF. However, bearings lubricated with HSF had a significantly lower static COF values compared to bearings lubricated with PBS. The mean percentage of caspase-3 positive chondrocytes in the superficial and upper intermediate zones of bearings lubricated with hylan G-F 20 were significantly higher when compared to bearings lubricated with HSF or unloaded controls, but significantly lower than those lubricated with PBS.
These findings indicate that joint lubrication may prevent chondrocyte apoptosis by lowering the COF. Furthermore, removal of synovial fluid prior to hylan G-F 20 injection may be detrimental to cartilage health.
articular cartilage; chondrocyte; apoptosis; synovial fluid; hylan
Hemorrhagic fever with renal syndrome (HFRS) is highly endemic in mainland China, where human cases account for 90% of the total global cases. Zibo City is one of the most serious affected areas in Shandong Province China with the HFRS incidence increasing sharply from 2009 to 2012. However, the hotspots of HFRS in Zibo remained unclear. Thus, a spatial analysis was conducted with the aim to explore the spatial, spatial-temporal and seasonal patterns of HFRS in Zibo from 2009 to 2012, and to provide guidance for formulating regional prevention and control strategies.
The study was based on the reported cases of HFRS from the National Notifiable Disease Surveillance System. Annualized incidence maps and seasonal incidence maps were produced to analyze the spatial and seasonal distribution of HFRS in Zibo City. Then spatial scan statistics and space-time scan statistics were conducted to identify clusters of HFRS.
There were 200 cases reported in Zibo City during the 4-year study period. One most likely cluster and one secondary cluster for high incidence of HFRS were identified by the space-time analysis. And the most likely cluster was found to exist at Yiyuan County in October to December 2012. The human infections in the fall and winter reflected a seasonal characteristic pattern of Hantaan virus (HTNV) transmission. The secondary cluster was detected at the center of Zibo in May to June 2009, presenting a seasonal characteristic of Seoul virus (SEOV) transmission.
To control and prevent HFRS in Zibo city, the comprehensive preventive strategy should be implemented in the southern areas of Zibo in autumn and in the northern areas of Zibo in spring.