Severity of tissue injury in occlusive disease is dependent on the extent (number and diameter) of collateral vessels, which varies widely among healthy mice and humans. However, the causative genetic elements are unknown. Recently, much of the variation among different mouse strains, including C57Bl/6J (B6, high extent) and BALB/cByJ (Bc, low), was linked to a QTL on chromosome 7 (Candq1).
We used congenic mapping to refine Candq1 and its candidate genes and create an “isogenic” strain-set with large differences in collateral extent to assess their and Candq1’s impact, alone, on ischemic injury.
Methods and Results
Six congenic strains possessing portions of Candq1 introgressed from B6 into Bc were generated and phenotyped. Candq1 was refined from 27 to 0.737 Mb with full retention of effect, ie, return/rescue of phenotypes from the poor values in Bc to nearly those of wildtype B6 in the B6/B6 congenic mice: 83% rescue of low pial collateral extent, and 4.5-fold increase in blood flow and 85% reduction of infarct volume after middle cerebral artery occlusion; 54% rescue of low skeletal muscle collaterals, and augmented recovery of perfusion (83%) and function after femoral artery ligation. Gene deletion and in-silico analysis further delineated the candidate genes.
We have significantly refined Candq1 (now designated Determinant of collateral extent-1, Dce1), demonstrated that genetic background-dependent variation in collaterals is a major factor underlying differences in ischemic tissue injury, and generated a congenic strain-set with wide, allele-dose-dependent variation in collateral extent for use in investigations of the collateral circulation.
Collateral circulation; ischemic stroke; peripheral vascular disease; stroke genetics; mouse strain; cerebrovascular disease/stroke; genetics; animal models; physiology/pathophysiology
Salinity is a major abiotic stress that limits plant productivity and quality throughout the world. Roots are the sites of salt uptake. To better understand salt stress responses in maize, we performed a comparative proteomic analysis of seedling roots from the salt-tolerant genotype F63 and the salt-sensitive genotype F35 under 160 mM NaCl treatment for 2 days. Under salinity conditions, the shoot fresh weight and relative water content were significantly higher in F63 than in F35, while the osmotic potential was significantly lower and the reduction of the K+/Na+ ratio was significantly less pronounced in F63 than in F35. Using an iTRAQ approach, twenty-eight proteins showed more than 2.0- fold changes in abundance and were regarded as salt-responsive proteins. Among them, twenty-two were specifically regulated in F63 but remained constant in F35. These proteins were mainly involved in signal processing, water conservation, protein synthesis and biotic cross-tolerance, and could be the major contributors to the tolerant genotype of F63. Functional analysis of a salt-responsive protein was performed in yeast as a case study to confirm the salt-related functions of detected proteins. Taken together, the results of this study may be helpful for further elucidating salt tolerance mechanisms in maize.
Horizontal transfer (HT) of transposable elements (TEs) into a new genome is considered as an important force to drive genome variation and biological innovation. However, most of the HT of DNA transposons previously described occurred between closely related species or insects.
In this study, we carried out a detailed analysis of four DNA transposons, which were found in the first sequenced twisted-wing parasite, Mengenilla moldrzyki. Through the homology-based strategy, these transposons were also identified in other insects, freshwater planarian, hydrozoans, and bats. The phylogenetic distribution of these transposons was discontinuous, and they showed extremely high sequence identities (>87%) over their entire length in spite of their hosts diverging more than 300 million years ago (Mya). Additionally, phylogenies and comparisons of transposons versus orthologous gene identities demonstrated that these transposons have transferred into their hosts by independent HTs.
Here, we provided the first documented example of HT of CACTA transposons, which have been so far extensively studied in plants. Our results demonstrated that bats had continuously acquired new DNA elements via HT. This implies that predation on a large quantity of insects might increase bat exposure to HT. In addition, parasite-host interaction might facilitate exchanging of their genetic materials.
Electronic supplementary material
The online version of this article (doi:10.1186/s13100-014-0033-1) contains supplementary material, which is available to authorized users.
Horizontal transfer; CACTA transposons; Mammals; Recent activity
The aim of this study was to prepare a novel nanoemulsion loaded with poorly water-soluble chlorhexidine acetate (CNE) to improve its solubility, and specifically enhance the antimicrobial activity against Streptococcus mutans in vitro and in vivo. In this study, a novel CNE nanoemulsion with an average size of 63.13 nm and zeta potential of −67.13 mV comprising 0.5% CNE, 19.2% Tween 80, 4.8% propylene glycol, and 6% isopropyl myristate was prepared by the phase inversion method. Important characteristics such as the content, size, zeta potential, and pH value of CNE did not change markedly, stored at room temperature for 1 year. Also, compared with chlorhexidine acetate water solution (CHX), the release profile results show that the CNE has visibly delayed releasing effect in both phosphate-buffered saline and artificial saliva solutions (P<0.005). The minimum inhibitory concentration and minimum bactericidal concentration of CHX for S. mutans (both 0.8 μg/mL) are both two times those of CNE (0.4 μg/mL). Besides, CNE of 0.8 μg/mL exhibited fast-acting bactericidal efficacy against S. mutans, causing 95.07% death within 5 minutes, compared to CHX (73.33%) (P<0.01). We observed that 5 mg/mL and 2 mg/mL CNE were both superior to CHX, significantly reducing oral S. mutans numbers and reducing the severity of carious lesions in Sprague Dawley rats (P<0.05), in an in vivo test. CNE treatment at a concentration of 0.2 μg/mL inhibited biofilm formation more effectively than CHX, as indicated by the crystal violet staining method, scanning electron microscopy, and atomic force microscopy. The cell membrane of S. mutans was also severely disrupted by 0.2 μg/mL CNE, as indicated by transmission electron microscopy. These results demonstrated that CNE greatly improved the solubility and antimicrobial activity of this agent against S. mutans both in vitro and in vivo. This novel nanoemulsion is a promising medicine for preventing and curing dental caries.
nanoemulsion; chlorhexidine acetate; Streptococcus mutans; antibacterial
P. aeruginosa infections are commonly associated with cystic fibrosis, pneumonias, neutropenia and burns. The P. aeruginosa quorum sensing molecule N-(3-oxo-dodecanoyl) homoserine lactone (C12) cause multiple deleterious host responses, including repression of NF-κB transcriptional activity and apoptosis. Inhibition of C12-mediated host responses is predicted to reduce P. aeruginosa virulence. We report here a novel, host-targeted approach for potential adjunctive anti-Pseudomonal therapy based on inhibition of C12-mediated host responses. A high-throughput screen was developed to identify C12 inhibitors that restore NF-κB activity in C12-treated, lipopolysaccharide (LPS)-stimulated cells. Triazolo[4,3-a]quinolines with nanomolar potency were identified as C12-inhibitors that restored NF-κB-dependent luciferase expression in LPS- and TNF-stimulated cell lines. In primary macrophages and fibroblasts, triazolo[4,3-a]quinolines inhibited C12 action to restore cytokine secretion in LPS-stimulated cells. Serendipitously, in the absence of an inflammatory stimulus, triazolo[4,3-a]quinolines prevented C12-mediated responses, including cytotoxicity, elevation of cytoplasmic calcium, and p38 MAPK phosphorylation. In vivo efficacy was demonstrated in a murine model of dermal inflammation involving intradermal C12 administration. The discovery of triazolo[4,3-a]quinolines provides a pharmacological tool to investigate C12-mediated host responses, and a potential host-targeted anti-Pseudomonal therapy.
Krüppel-like factor 8 (KLF8) is a pivotal transcription factor expressed in the human placenta that can regulate cell invasion. The objective of this study was to assess whether a hypoxia–reoxygenation (H/R) environment affects placental KLF8 expression levels and subcellular localization and to evaluate the relationship between KLF8 levels and trophoblast invasion activity. Human first trimester villous tissues from normal pregnancies and third trimester placentas from pregnancies with or without preeclampsia (PE) were used for the detection of KLF8 expression and correlating its levels with metalloproteinase 9 (MMP-9) expression. In addition, HTR8/SVneo cells were used to mimic the effects of an H/R environment on placentas to study KLF8 expression and trophoblast invasion. The KLF8 levels, MMP-9 levels, and trophoblast invasion were similarly altered; the levels peaked at 8 to 10 weeks of gestation and declined thereafter along with oxygen tension increased from hypoxia to normoxia during early pregnancy, decreased in third trimester placentas from PE pregnancies featured by repeated H/R and HTR8/SVneo cells exposed to H/R compared with the control. Moreover, a visible reduction in KLF8 immunoreactivity was present in the nuclei of cytotrophoblast cells in human villous tissues at 11 weeks, and partial cytoplasmic accumulation of KLF8 was observed in HTR8/SVneo cells treated with H/R. In conclusion, these findings strongly suggest that H/R reduces the expression and nuclear localization of KLF8 to inhibit the trophoblast invasion by downregulating MMP-9 levels. The KLF8 may play a vital role in the pathogenesis of PE as a novel oxygen tension sensor.
hypoxia–reoxygenation; preeclampsia; KLF8; MMP-9; HTR8/SVneo
Accumulating evidence has shown that the hypoxic microenvironment, which is critical during cancer development, plays a key role in regulating breast cancer progression and metastasis. The effects of hypoxia-inducible factor 1 (HIF-1), a master regulator of the hypoxic response, have been extensively studied during these processes. In this review, we focus on the roles of HIF-1 in regulating breast cancer cell metastasis, specifically its effects on multiple key steps of metastasis, such as epithelial-mesenchymal transition (EMT), invasion, extravasation, and metastatic niche formation. We also discuss the roles of HIF-1-regulated non-coding RNAs in breast cancer metastasis, and therapeutic opportunities for breast cancer through targeting the HIF-1 pathway.
Breast cancer; Hypoxia-inducible factor 1 (HIF-1); Metastasis
Enterovirus 71 (EV71) is the major cause of hand-foot-and-mouth disease in children. In our study, using the complete genome sequences of 42 EV71 representing all three genotypes, we analyzed synonymous codon usage and the relative dinucleotide abundance in EV71 genome. The general correlation between base composition and codon usage bias suggests that mutational pressure rather than natural selection is the main factor that determines the codon usage bias in EV71 genome. Furthermore, we observed that the relative abundance of dinucleotides in EV71 is independent of the overall base composition but is still the result of differential mutational pressure, which also shapes codon usage. In addition, other factors, such as hydrophobicity and aromaticity, also influence the codon usage variation among the genomes of EV71. This study represents the most comprehensive analysis of EV71 codon usage patterns and provides a basic understanding of the mechanisms for codon usage bias.
EV71; Synonymous codon usage; Mutational bias; Dinucleotide bias; Subgenotype
Osterix (Osx), a transcriptional factor essential for osteogenesis, is also critical for in vivo cellular cementum formation. However, the molecular mechanism by which Osx regulates cementoblasts is largely unknown. In this study, we initially demonstrated that overexpression of Osx in a cementoblast cell line upregulated the expression of markers vital to cementogenesis such as osteopontin (OPN), osteocalcin (OCN), and bone sialoprotein (BSP) at both mRNA and protein levels, and enhanced alkaline phosphatase (ALP) activity. Unexpectedly, we demonstrated a sharp increase in the expression of DKK1 (a potent canonical Wnt antagonist), and a great reduction in protein levels of β-catenin and its nuclear translocation by overexpression of Osx. Further, transient transfection of Osx reduced protein levels of TCF1 (a target transcription factor of β-catenin), which were partially reversed by an addition of DKK1. We also demonstrated that activation of canonical Wnt signaling by LiCl or Wnt3a significantly enhanced levels of TCF1 and suppressed the expression of OPN, OCN, and BSP, as well as ALP activity and formation of extracellular mineralized nodules. Importantly, we confirmed that there were a sharp reduction in DKK1 and a concurrent increase in β-catenin in Osx cKO mice (crossing between the Osx loxP and 2.3 Col 1-Cre lines), in agreement with the in vitro data. Thus, we conclude that the key role of Osx in control of cementoblast proliferation and differentiation is to maintain a low level of Wnt-β-catenin via direct up-regulation of DKK1.
cementum; Osterix; DKK1; cementoblast differentiation; Wnt signaling
Newcastle disease virus (NDV) hemagglutinin–neuraminidase (HN) is a multifunctional protein, which possesses both the receptor recognition and neuraminidase activities. The fusion (F) protein is a type I membrane glycoprotein that mediates the merger of the viral envelope to the host cell membrane. Although the functions of the HN and F proteins have been well studied, however, the factors shaping synonymous codon usage bias and nucleotide composition in HN and F genes have been few reported. In our study, we analyzed synonymous codon usage using the 69 NDV HN and F genes, respectively. The general correlation between base composition and codon usage bias suggests that mutational pressure rather than natural selection is the main factor that determines the codon usage bias in HN and F genes. In addition, other factors, such as the aromaticity and hydrophobicity, also influence the codon usage variation among HN and F genes. This study represents the most comprehensive analysis to date of NDV HN and F genes codon usage patterns and provides a basic understanding of the mechanisms for codon usage bias.
Electronic supplementary material
The online version of this article (doi:10.1007/s13337-013-0175-7) contains supplementary material, which is available to authorized users.
Newcastle disease virus; Hemagglutinin–neuraminidase; Fusion protein; Synonymous codon usage; Mutational pressure; Natural selection
AIM: To evaluate the role of probiotics in the standard triple Helicobacter pylori therapy.
METHODS: In this meta-analysis, we investigated the efficacy of probiotics in a standard triple H. pylori therapy in adults. Searches were mainly conducted in MEDLINE/PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials. Fourteen studies met our criteria, and the quality of these studies was assessed using the Jadad scale. We used STATA version 12.0 to extract data and to calculate the odds ratios (ORs), which are presented with the corresponding 95% confidence intervals (CIs). The data are presented as forest plots.
RESULTS: The pooled ORs for the eradication rates calculated by intention-to-treat analysis and per-protocol analysis in the probiotic group vs the control group were 1.67 (95%CI: 1.38-2.02) and 1.68 (95%CI: 1.35-2.08), respectively, using the fixed-effects model. The sensitivity of the Asian studies was greater than that of the Caucasian studies (Asian: OR = 1.78, 95%CI: 1.40-2.26; Caucasian: OR = 1.48, 95%CI: 1.06-2.05). The pooled OR for the incidence of total adverse effects was signiﬁcantly lower in the probiotic group (OR = 0.49, 95%CI: 0.26-0.94), using the random effects model, with significant heterogeneity (I2 = 85.7%). The incidence of diarrhea was significantly reduced in the probiotic group (OR = 0.21, 95%CI: 0.06-0.74), whereas the incidence of taste disorders, metallic taste, vomiting, nausea, and epigastric pain did not differ significantly between the probiotic group and the control group.
CONCLUSION: Supplementary probiotic preparations during standard triple H. pylori therapy may improve the eradication rate, particularly in Asian patients, and the incidence of total adverse effects.
Helicobacter pylori; Eradication; Probiotics; Meta-analysis; Adult
Objective: This paper studied the protective effect and mechanism of epimedium combined with oligomeric proanthocyanidins on exercise-induced renal ischemia-reperfusion injury of rats. Methods: In the experiment, the rats were given exhaustive swimming training and then their blood urea nitrogen (BUN) and other biochemical indexes were measured after they were given gastric perfusion with 6.01 g/kg doze of epimedium and 50 mg/kg doze of oligomeric proanthocyanidins for 56 days. Results: The result indicated that 8 weeks of over training led to ischemia-reperfusion injury of rats. Moreover, their kidney tissues were significantly changed pathologically and renal functions drastically damaged. BUN and serum creatinine increased and EOM group (P < 0.05), OPCOM group (P < 0.05) and EOPCOM group (P < 0.01) were lower than OM group. EOPCOM group was lower than OPCOM group. SOD activity decreased, EOM group (P < 0.05), OPCOM group (P < 0.05), EOPCOM group (P < 0.01) higher than OM group, and EOPCOM group (P < 0.05) higher than OPCOM group. The content of MDA increased, EOM group (P < 0.05), OPCOM group (P < 0.05), EOPCOM group (P < 0.01) lower than OM group, and EOPCOM group (P < 0.05) lower than OPCOM group. Conclusion: Both epimedium and oligomeric proanthocyanidins can boost SOD activity, clean oxygen radicals, clean and alleviate peroxidation of lipids, which exert protection on exercise-induced renal ischemia-reperfusion. The two combined yield a much better result.
Epimedium; oligomeric proanthocyanidins; exercise-induced ischemia-reperfusion
Splenic rupture is a common consequence of blunt abdominal trauma. Emergency splenectomy is indicated when conservative management is not effective. With better understanding of the immunologic function of the spleen, surgeons have begun to perform the splenic-preserving surgery. However, it is technical challenge to perform emergency laparoscopic partial splenectomy for patient with spleen rupture. A 15-year-old male patient suffered from grade III spleen injury basing on the American association for the surgery of trauma splenic injury scale. Conservative treatment failed to success basing on the dramatically decreased hemoglobin level. During the laparoscopic exploration, we found that two individual ruptures were associated with the upper pole of spleen. An emergency laparoscopic partial splenectomy was successfully carried out. The operative time was approximate 150 min and the estimated blood loss was 200 mL. The post-operative course was uneventful and the patient was discharged on the 7th post-operative day.
Laparoscopy; Minimal invasive; Partial splenectomy; Splenic rupture; Splenic trauma
FAM20C is a kinase that phosphorylates secretory proteins. Previous studies have shown that FAM20C plays an essential role in the formation and mineralization of bone, dentin and enamel. The present study analyzed the loss-of-function effects of FAM20C on the health of mouse periodontal tissues.
By crossbreeding 2.3 kb Col 1a1-Cre mice with Fam20Cfl/fl mice, we created 2.3 kb Col 1a1-Cre;Fam20Cfl/fl (cKO) mice, in which Fam20C was inactivated in the cells that express Type I collagen. We analyzed the periodontal tissues in the cKO mice using X-ray radiography, histology, scanning electron microscopy and immunohistochemistry approaches.
The cKO mice underwent a remarkable loss of alveolar bone and cementum, along with inflammation of the periodontal ligament and formation of periodontal pockets. The osteocytes and lacuno-canalicular networks in the alveolar bone of the cKO mice showed dramatic abnormalities. The levels of bone sialoprotein, osteopontin, dentin matrix protein 1 and dentin sialoprotein were reduced in the Fam20C-deficient alveolar bone and/or cementum, while periostin and fibrillin-1 were decreased in the periodontal ligament of the cKO mice.
Loss of Fam20C function leads to periodontal disease in mice. The reduced levels of bone sialoprotein, osteopontin, dentin matrix protein 1, dentin sialoprotein, periostin and fibrillin-1 may contribute to the periodontal defects in the Fam20C-deficient mice.
Diabetic cognitive dysfunction is common in patients with diabetes but its pathogenesis is not clear. The aim of the present study is to investigate the role of 5’, 10’ methylene tetrahydrofolate reductase (MTHFR) in the development of diabetic cognitive impairment and test whether folic acid (FA) supplementation prevents cognitive dysfunction in diabetic rats. In the current study, three months after streptozotocin-induced diabetes onset, rats showed cognitive dysfunction including the prolonged escape latency, the decreased time spent in the target quadrant and the declined number of crossing the platform in Morris water maze test. Diabetic rats also presented elevated plasma homocysteine level and downregulation of MTHFR in hippocampus revealed by Western blotting. The diabetic cognitive dysfunction was attenuated by 30-day dietary FA treatment with a significantly decreased homocysteine level. In conclusion, these results suggest that MTHFR plays a crucial role in diabetic cognitive dysfunction and folate fortification might become a potent therapeutic strategy against diabetic cognitive impairment.
Cognitive dysfunction; diabetes; tetrahydrofolate reductase; folic acid
Enterovirus 71 (EV71) is a highly transmissible pathogenic agent that causes severe central nervous system diseases in infected infants and young children. Here, we reported that EV71 VP1 protein could bind to vimentin intermediate filaments expressed on the host cell surface. Soluble vimentin or an antibody against vimentin could inhibit the binding of EV71 to host cells. Accompanied with the reduction of vimentin expression on the cell surface, the binding of EV71 to cells was remarkably decreased. Further evidence showed that the N terminus of vimentin is responsible for the interaction between EV71 and vimentin. These results indicated that vimentin on the host cell surface may serve as an attachment site that mediated the initial binding and subsequently increased the infectivity of EV71.
IMPORTANCE This study delivers important findings on the roles of vimentin filaments in relation to EV71 infection and provides information that not only improves our understanding of EV71 pathogenesis but also presents us with potentially new strategies for the treatment of diseases caused by EV71 infections.
To determine the physical activity level and factors influencing physical activity among pregnant urban Chinese women.
This prospective cross-sectional study enrolled 1056 pregnant women (18–44 years of age) in Tianjin, China. Their socio-demographic characteristics were recorded, and the Pregnancy Physical Activity Questionnaire was used to assess their physical activity during pregnancy. The data were analyzed by multinomial logistic regression with adjustment for potential confounders.
Median total energy expenditure of pregnant women in each of the three trimesters ranged from 18.50 to 21.90 metabolic equivalents of task (METs) h/day. They expended 1.76–1.85 MET h/day on moderate and vigorous activities and 0.11 MET h/day on exercise. Only 117 of the women (11.1%) met the international guideline for physical activity in pregnancy (≥150 min moderate intensity exercise per week). The most frequent reason given for not being more physically active was the fear of miscarriage. Higher education level (OR: 4.11, 95% CI: 1.59–10.62), habitual exercise before pregnancy (OR: 2.14, 95% CI: 1.39–3.28), and husbands who exercised regularly (OR: 2.21, 95% CI: 1.33–3.67) significantly increased the odds of meeting the guideline (p<0.001). A low pre gravid body mass index (OR: 0.42, 95% CI: 0.20–0.87) significantly decreased the odds (p<0.001).
Few urban Chinese pregnant women met the recommended physical activity guideline. They also expended little energy exercising. Future interventions should be based on the clinic environment and targeting family members as well as the subjects. All pregnant women should be targeted, not just those in high-risk groups.
Obesity induced by antipsychotics severely increases the risk of many diseases and significantly reduces quality of life. Genome Wide Association Studies has identified fat-mass and obesity-associated (FTO) gene associated with obesity. The relationship between the FTO gene and drug-induced obesity is unclear.
Two hundred and fifty drug naïve, Chinese Han patients with first-episode schizophrenia were enrolled in the study, and genotyped for four single nucleotide polymorphisms (SNPs rs9939609, rs8050136, rs1421085 and rs9930506) by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct sequencing. Body weight and body mass index (BMI) were measured at baseline and six months after risperidone treatment.
At baseline, body weight and BMI of TT homozygotes were lower than those of A allele carriers in rs9939609; body weight of AA homozygotes was higher than those of G allele carriers in rs9930506 (p’s < 0.05). After 6 months of risperidone treatment, body weight and BMI of TT homozygotes were lower than those of A allele carriers in rs9939609 (p’s <0.01); body weight and BMI of CC homozygotes were lower than those of A allele carriers in rs8050136 (p’s < 0.05); body weight of AA homozygotes was higher than those of G allele carriers in rs9930506 (p’s < 0.05). After controlling for age, gender, age of illness onset, disease duration, weight at baseline and education, weight gain of TT homozygotes at 6 months remained to be lower than those of A allele carriers in rs9939609 (p < 0.01); weight gain of CC homozygotes at 6 months was lower than those of A allele carriers in rs8050136 (p = 0.01). Stepwise multiple regression analysis suggested that, among 4 SNPs, rs9939609 was the strongest predictor of weight gain after 6 months of risperidone treatment (p = 0.001).
The FTO gene polymorphisms, especially rs9939609, seem to be related to weight gain after risperidone treatment in Chinese Han patients with first episode schizophrenia.
FTO gene; Weight gain; Schizophrenia; Single nucleotide polymorphism (SNP)
Repeated x-ray computed tomography (CT) scans are often required in several specific applications such as perfusion imaging, image-guided biopsy needle, image-guided intervention, and radiotherapy with noticeable benefits. However, the associated cumulative radiation dose significantly increases as comparison with that used in the conventional CT scan, which has raised major concerns in patients. In this study, to realize radiation dose reduction by reducing the x-ray tube current and exposure time (mAs) in repeated CT scans, we propose a prior-image induced nonlocal (PINL) regularization for statistical iterative reconstruction via the penalized weighted least-squares (PWLS) criteria, which we refer to as “PWLS-PINL”. Specifically, the PINL regularization utilizes the redundant information in the prior image and the weighted least-squares term considers a data-dependent variance estimation, aiming to improve current low-dose image quality. Subsequently, a modified iterative successive over-relaxation algorithm is adopted to optimize the associative objective function. Experimental results on both phantom and patient data show that the present PWLS-PINL method can achieve promising gains over the other existing methods in terms of the noise reduction, low-contrast object detection and edge detail preservation.
X-ray computed tomography; prior image; statistical iterative reconstruction; penalized weighted least-squares; regularization
To develop a population pharmacokinetics model of oxcarbazepine in Chinese pediatric patients with epilepsy, and to study the interactions between oxcarbazepine and other antiepileptic drugs (AEDs).
A total of 688 patients with epilepsy aged 2 months to 18 years were divided into model (n=573) and valid (n=115) groups. Serum concentrations of the main active metabolite of oxcarbazepine, 10-hydroxycarbazepine (MHD), were determined 0.5–48 h after the last dosage. A population pharmacokinetics (PPK) model was constructed using NLME software. This model was internally evaluated using Bootstrapping and goodness-of-fit plots inspection. The data of the valid group were used to calculate the mean prediction error (MPE), mean absolute prediction error (MAE), mean squared prediction error (MSE) and the 95% confidence intervals (95% CI) to externally evaluate the model.
The population values of pharmacokinetic parameters estimated in the final model were as follows: Ka=0.83 h-1, Vd=0.67 L/kg, and CL=0.035 L·kg−1·h−1. The enzyme-inducing AEDs (carbamazepine, phenytoin, phenobarbital) and newer generation AEDs (levetiracetam, lamotrigine, topiramate) increased the weight-normalized CL value of MHD by 17.4% and 10.5%, respectively, whereas the enzyme-inhibiting AED valproic acid decreased it by 3%. No significant association was found between the CL value of MHD and the other covariates. For the final model, the evaluation results (95% CI) were MPE=0.01 (−0.07–0.10) mg/L, MAE=0.46 (0.40–0.51) mg/L, MSE=0.39 (0.27–0.51) (mg/L)2.
A PPK model of OXC in Chinese pediatric patients with epilepsy is established. The enzyme-inducing AEDs and some newer generation AEDs (lamotrigine, topiramate) could slightly increase the metabolism of MHD.
epilepsy; oxcarbazepine; 10-hydroxycarbazepine; population pharmacokinetics; drug interaction; CYP450; pediatric patients; Chinese children
The present meta-analysis aimed at assessing the effectiveness and safety of tranexamic acid (TXA) in reducing blood loss and transfusion in spinal surgery.
Systematic searches of all studies published through March 2012 were identified from PubMed, EMBase, Cochrane library, Science Direct, and other databases. Only randomized controlled trials (RCTs) were included in the present study. Two independent reviewers searched and assessed the literature. Mean difference (MD) of blood loss and blood transfusions, risk ratios (RR) of transfusion rate and of deep vein thrombosis rate in the TXA-treated group versus placebo group were pooled throughout the study. The meta-analysis was conducted by RevMan 5.1 software.
Six placebo-controlled RCTs encompassing 411 patients met the inclusion criteria for our meta-analysis. The use of TXA significantly reduced both total blood loss [MD = −285.35, 95 % CI (−507.03 to −63.67), P = 0.01] as well as the number of patients requiring blood transfusion [RR = 0.71, 95 % CI (0.54–0.92), P = 0.01]. None of the patients in the treatment group had deep-vein thrombosis (DVT) or pulmonary embolism.
Intravenous use of TXA for patients undergoing spinal surgery is effective and safe. It reduces total blood loss and the need for blood transfusion, particularly in the using of high dosage of TXA (≥15 mg/kg), yet does not increase the risk of postoperative DVT. Due to the limitation of the quality of the evidence currently available, high-quality RCTs are required.
Tranexamic acid; Spine; Blood loss; Surgical; Meta-analysis
The retinal degeneration 11 (rd11) mouse is a newly discovered, naturally occurring animal model with early photoreceptor dysfunction and rapid rod photoreceptor degeneration followed by cone degeneration. The rd11 mice carry a spontaneous mutation in the lysophosphatidylcholine acyltransferase 1 (Lpcat1) gene. Here, we evaluate whether gene replacement therapy using the fast-acting tyrosine-capsid mutant AAV8 (Y733F) can arrest retinal degeneration and restore retinal function in this model.
The AAV8 (Y733F)-smCBA-Lpcat1 was delivered subretinally to postnatal day 14 (P14) rd11 mice in one eye only. At 10 weeks after injection, treated rd11 mice were examined by visually-guided behavior, electroretinography (ERG) and spectral domain optical coherence tomography (SD-OCT), and then killed for morphologic and biochemical examination.
Substantial scotopic and photopic ERG signals were maintained in treated rd11 eyes, whereas untreated eyes in the same animals showed extinguished signals. The SD-OCT (in vivo) and light microscopy (in vitro) showed a substantial preservation of the outer nuclear layer in most parts of the treated retina only. Almost wild-type LPCAT1 expression in photoreceptors with strong rod rhodopsin and M/S cone opsin staining, and normal visually-guided water maze behavioral performances were observed in treated rd11 mice.
The results demonstrate that the tyrosine-capsid mutant AAV8 (Y733F) vector is effective for treating rapidly degenerating models of retinal degeneration and, moreover, is more therapeutically effective than AAV2 (Y444, 500, 730F) vector with the same promoter-cDNA payload. To our knowledge, this is the first demonstration of phenotypic rescue by gene therapy in an animal model of retinal degeneration caused by Lpcat1 mutation.
This is a comprehensive morphologic, biochemical, electrophysiologic and behavioral analysis of tyrosine capsid mutant AAV8 (Y733F) or triple mutant AAV2 (Y444, 500, 730F)-mediated photoreceptor rescue in rd11 mice, a naturally occurring retinal degeneration model caused by Lpcat1 mutation.
rd11; gene therapy; mice; Lpcat1; AAV
Dentin matrix protein 1 (DMP1) is essential to odontogenesis. Its mutations in human subjects lead to dental problems such as dental deformities, hypomineralization and periodontal impairment. Primarily, DMP1 is considered as an extracellular matrix protein that promotes hydroxyapatite formation and activates intracellular signaling pathway via interacting with αvβ3 integrin. Recent in vitro studies suggested that DMP1 might also act as a transcription factor. In this study, we examined whether full-length DMP1 could function as a transcription factor in the nucleus and regulate odontogenesis in vivo. We first demonstrated that a patient with the DMP1 M1V mutation, which presumably causes a loss of the secretory DMP1 but does not affect the nuclear translocation of DMP1, shows a typical rachitic tooth defect. Furthermore, we generated transgenic mice expressing NLSDMP1, in which the endoplasmic reticulum (ER) entry signal sequence of DMP1 was replaced by a nuclear localization signal (NLS) sequence, under the control of a 3.6 kb rat type I collagen promoter plus a 1.6 kb intron 1. We then crossbred the NLSDMP1 transgenic mice with Dmp1 null mice to express the NLSDMP1 in Dmp1-deficient genetic background. Although immunohistochemistry demonstrated that NLSDMP1 was localized in the nuclei of the preodontoblasts and odontoblasts, the histological, morphological and biochemical analyses showed that it failed to rescue the dental and periodontal defects as well as the delayed tooth eruption in Dmp1 null mice. These data suggest that the full-length DMP1 plays no apparent role in the nucleus during odontogenesis.
autosomal recessive hypophosphatemic rickets; dentin matrix protein 1; development; odontoblast; odontogenesis
A purely laparoscopic four-port approach was created for left hepatectomy in pigs. A polyethylene loop was placed on the left two hepatic lobes for traction and lift. Next, penetrating ligation of the lobes using of a double row of silk sutures was performed to control bleeding. A direct hepatic transection was completed using a monopolar hook electrode without meticulous dissection of the left hepatic vein. The raw surface of the liver was coagulated and sealed with fibrin glue. Lobes were retrieved through an enlarged portal. Laparoscopic hepatic lobectomy was completed in all pigs without the use of specialized instruments and with a mean operative time of 179 ± 9 min. No significant perioperative complications were observed. The average weight of each resected lobe was 180 ± 51 g. Complete blood count as well as serum organics and enzyme levels normalized after about 2 weeks. During necropsy, adhesion of the hepatic raw surface to the gastric wall and omentum were observed. No other abnormalities were identified. This minimally invasive left hepatectomy technique in swine could serve as a useful model for investigating liver diseases and regeneration, and offer preclinical information to improve hepatobiliary surgical procedures.
hepatectomy; laparoscopy; left; pigs; technique