The novel influenza A(H7N9) virus recently emerged, while influenza A(H5N1) virus has infected humans since 2003 in mainland China. Both infections are thought to be predominantly zoonotic. We compared the epidemiologic characteristics of the complete series of laboratory-confirmed cases of both viruses in mainland China to date.
An integrated database was constructed with information on demographic, epidemiological, and clinical variables of laboratory-confirmed A(H7N9) and A(H5N1) cases that were reported to the Chinese Center for Disease Control and Prevention up to May 24, 2013. We described disease occurrence by age, sex and geography and estimated key epidemiologic parameters.
Among 130 and 43 patients with confirmed A(H7N9) and A(H5N1) respectively, the median ages were 62y and 26y. In urban areas, 74% of cases of both viruses were male whereas in rural areas the proportions were 62% for A(H7N9) and 33% for A(H5N1). Among cases of A(H7N9) and A(H5N1), 75% and 71% reported recent exposure to poultry. The mean incubation periods of A(H7N9) and A(H5N1) were 3.1 and 3.3 days, respectively. On average, 21 and 18 contacts were traced for each A(H7N9) case in urban and rural areas respectively; compared to 90 and 63 for A(H5N1). The hospitalization fatality risk was 35% (95% CI: 25%, 44%) for A(H7N9) and 70% (95% CI: 56%, 83%) for A(H5N1).
The sex ratios in urban compared to rural cases are consistent with poultry exposure driving the risk of infection. However the difference in susceptibility to serious illness with the two different viruses remains unexplained, given that most A(H7N9) cases were in older adults while most A(H5N1) cases were in younger individuals.
Ministry of Science and Technology, China; Research Fund for the Control of Infectious Disease and University Grants Committee, Hong Kong Special Administrative Region, China; and the US National Institutes of Health.
Recent studies have revealed that the central nervous system, particularly the hypothalamus, is critical for regulating insulin sensitivity in peripheral tissues. The aim of our current study is to investigate the possible involvement of hypothalamic activating transcription factor 4 (ATF4) in the regulation of insulin sensitivity in the liver. Here, we show that overexpression of ATF4 in the hypothalamus resulting from intracerebroventricular injection of adenovirus expressing ATF4 induces hepatic insulin resistance in mice and that inhibition of hypothalamic ATF4 by intracerebroventricular adenovirus expressing a dominant-negative ATF4 variant has the opposite effect. We also show that hypothalamic ATF4-induced insulin resistance is significantly blocked by selective hepatic vagotomy or by inhibiting activity of the mammalian target of rapamycin (mTOR) downstream target S6K1. Finally, we show that inhibition of hypothalamic ATF4 reverses hepatic insulin resistance induced by acute brain endoplasmic reticulum (ER) stress. Taken together, our study describes a novel central pathway regulating hepatic insulin sensitivity that is mediated by hypothalamic ATF4/mTOR/S6K1 signaling and the vagus nerve and demonstrates an important role for hypothalamic ATF4 in brain ER stress–induced hepatic insulin resistance. These results may lead to the identification of novel therapeutic targets for treating insulin resistance and associated metabolic diseases.
Obesity is a significant contributing factor to endometrial cancer risk. We previously demonstrated that estrogen-induced endometrial proliferation is enhanced in the context of hyperinsulinemia and insulin resistance. In this study we investigate whether pharmacologic agents that modulate insulin sensitivity or normalize insulin levels will diminish the proliferative response to estrogen.
Zucker fa/fa obese rats and lean controls were used as models of hyperinsulinemia and insulin resistance. Insulin levels were depleted in ovariectomized rats following treatment with Streptozotocin (STZ), or modulated by metformin treatment. The number of BrdU incorporated cells, estrogen dependent proliferative and anti-proliferative gene expression, and activation of mTOR and Erk1/2 MAPK signaling were studied. A rat normal endometrial cell line RENE1 was used to evaluate the direct effects of metformin on endometrial cell proliferation and gene expression in vitro.
STZ lowered circulating insulin levels in obese rats and decreased the number of BrdU labeled endometrial cells even in the presence of exogenous estrogen. Treatment with the insulin-sensitizing drug metformin attenuated estrogen-dependent proliferative expression of c-myc and c-fos in the obese rat endometrium compared to untreated controls and was accompanied by inhibition of phosphorylation of the insulin and IGF1 receptors (IRβ/IGF1R) and ERK1/2. In vitro studies indicated metformin inhibited RENE1 proliferation in a dose dependent manner.
These findings suggest that drugs that modulate insulin sensitivity, such as metformin, hinder estrogen-mediated endometrial proliferation. Therefore, these drugs may be clinically useful for the prevention of endometrial cancer in obese women.
Obesity; estrogen; insulin resistance
Obesity-associated hyperestrogenism and hyperinsulinemia contribute significantly to the pathogenesis of endometrial cancer. We recently demonstrated that metformin, a drug long used for treatment of type 2 diabetes, attenuates both insulin- and estrogen-mediated proliferative signaling in the obese rat endometrium. In this study, we sought to identify tissue biomarkers that may prove clinically useful to predict tissue response for both prevention and therapeutic studies. We identified CGRRF1 (Cell growth regulator with ring finger domain 1) as a novel metformin-responsive gene and characterized its possible role in endometrial cancer prevention.
CGRRF1 mRNA expression was evaluated by RT-qPCR in the endometrium of obese and lean rats, and also in normal and malignant human endometrium. CGRRF1 levels were genetically manipulated in endometrial cancer cells, and its effects on proliferation and apoptosis were evaluated by MTT and western blot.
CGRRF1 is significantly induced by metformin treatment in the obese rat endometrium. In vitro studies demonstrate that overexpression of CGRRF1 inhibits endometrial cancer cell proliferation. Analysis of human endometrial tumors reveal that CGRRF1 expression is significantly lower in hyperplasia, Grade 1, Grade 2, Grade 3, MMMT, and UPSC endometrial tumors compared to normal human endometrium (p<0.05), suggesting that loss of CGRRF1 is associated with the presence of disease.
CGRRF1 represents a novel, reproducible tissue marker of metformin response in the obese endometrium. Furthermore, our preliminary data suggests that up-regulation of CGRRF1 expression may prove clinically useful in the prevention or treatment of endometrial cancer.
Obesity; metformin; estrogen; insulin resistance
We examined the demographic and clinical profiles of Parkinson's disease in Shanghai, China, to assist in disease management and provide comparative data on Parkinson's disease prevalence, phenotype, and progression among different regions and ethnic groups.
A door-to-door survey and follow-up clinical examinations identified 180 community-dwelling Han-Chinese Parkinson's disease patients (104 males, 76 females).
The average age at onset was 65.16±9.60 years. The most common initial symptom was tremor (112 patients, 62.22%), followed by rigidity (38, 21.11%), bradykinesia (28, 15.56%) and tremor plus rigidity (2, 1.11%). Tremor as the initial symptom usually began in a single limb (83.04% of patients). The average duration from onset to mild Parkinson's disease (Hoehn-Yahr phase 1–2) was 52.74±45.64 months. Progression from mild to moderate/severe Parkinson's disease (phase≥3) was significantly slower (87.07±58.72 months; p<0.001), except for patients presenting initially with bradykinesia (53.83±24.49 months). Most patients (149/180, 82.78%) took levodopa with or without other drugs. The Hamilton Anxiety Scale revealed symptoms of clinical anxiety in 35 patients, and the Hamilton Depression Scale revealed depressive symptoms in 88 patients. The depressed or anxious subgroup (123 patients) demonstrated a significantly younger age at onset (55.54±7.68 years) compared with the overall mean (p<0.05).
Unilateral limb tremor was the most common initial symptom, and motor function deteriorated slowly over ≈4−9 years. Earlier-onset patients experience greater psychiatric dysfunction.
Parkinson's Disease; Depression; Anxiety; Motor Dysfunction; Dyskinesia; Han Chinese
A foundational library called MORT (Molecular Objects and Relevant Templates) for the development of new software packages and tools employed in computational biology and computer-aided drug design (CADD) is described here.
MORT contains several advantages compared with the other libraries. Firstly, MORT written in C++ natively supports the paradigm of object-oriented design, and thus it can be understood and extended easily. Secondly, MORT employs the relational model to represent a molecule, and it is more convenient and flexible than the traditional hierarchical model employed by many other libraries. Thirdly, a lot of functions have been included in this library, and a molecule can be manipulated easily at different levels. For example, it can parse a variety of popular molecular formats (MOL/SDF, MOL2, PDB/ENT, SMILES/SMARTS, etc.), create the topology and coordinate files for the simulations supported by AMBER, calculate the energy of a specific molecule based on the AMBER force fields, etc.
We believe that MORT can be used as a foundational library for programmers to develop new programs and applications for computational biology and CADD. Source code of MORT is available at
Relational model; MORT; AMBER; Antechamber; Foundational library; CADD
Recent studies suggested an essential role for seryl-tRNA synthetase (SerRS) in vascular development. This role is specific to SerRS among all tRNA synthetases and is independent of its well-known aminoacylation function in protein synthesis. A unique nucleus-directing domain, added at the invertebrate-to-vertebrate transition, confers this novel non-translational activity of SerRS. Previous studies showed that SerRS, in some unknown way, controls VEGFA expression to prevent vascular over-expansion. Using in vitro, cell and animal experiments, we show here that SerRS intervenes by antagonizing c-Myc, the major transcription factor promoting VEGFA expression, through a tandem mechanism. First, by direct head-to-head competition, nuclear-localized SerRS blocks c-Myc from binding to the VEGFA promoter. Second, DNA-bound SerRS recruits the SIRT2 histone deacetylase to erase prior c-Myc-promoted histone acetylation. Thus, vertebrate SerRS and c-Myc is a pair of ‘Yin-Yang’ transcriptional regulator for proper development of a functional vasculature. Our results also discover an anti-angiogenic activity for SIRT2.
The network of blood vessels is one of the earliest structures to develop in a vertebrate embryo. A protein called Vascular Endothelial Growth Factor A (or VEGFA for short) is needed to promote the growth of these blood vessels, but too much VEGFA can cause blood vessels to grow too much and to grow abnormally.
Like most of the DNA in the nucleus, the gene for VEGFA is tightly wrapped around proteins called histones and must be unwrapped before it can be expressed as a protein. For the VEGFA gene, this unwrapping process starts when a protein called c-Myc adds chemical tags to the histones.
Recent research suggested that an enzyme called seryl-tRNA synthetase (or SerRS for short) also controls the expression of VEGFA. This came as a surprise because no other tRNA synthetase has a similar role during development. And although SerRS is known to enter the cell nucleus in vertebrates, researchers did not know what SerRS did in the nucleus to control the expression of VEGFA.
Now, Shi et al. have discovered that SerRS controls blood vessel development in zebrafish embryos by counteracting the activity of c-Myc. It does this in two different ways: first, it directly blocks c-Myc from binding to and unpacking the DNA; and second, SerRS works with another enzyme to remove tags that are already on the histones. Shi et al. found that if the expression of this other enzyme (called SIRT2) was reduced in zebrafish, the fish expressed more VEGFA and their blood vessels grew too much.
Since blood vessel growth is important in the development of cancers, the findings of Shi et al. could also lead to a better understanding of how tumors develop, as well as how blood vessels develop normally.
seryl-tRNA synthetase; c-Myc; VEGFA; SIRT2; angiogenesis; vasculature; human; zebrafish
The Eustachian tube is a small canal that connects the tympanic cavity with the nasal part of the pharynx. The epithelial lining of the Eustachian tube contains a ciliated columnar epithelium at the tympanic cavity and a pseudostratified, ciliated columnar epithelium with goblet cells near the pharynx. The tube serves to equalize air pressure across the eardrum and drains mucus away from the middle ear into the nasopharynx. Blockage of the Eustachian tube is the most common cause of all forms of otitis media, which is common in children. In the present study, we examined the epithelial lining of the Eustachian tube in neonatal and adult gerbils, with a focus on the morphological and functional development of ciliated cells in the mucosa. The length of the tube is ∼8.8 mm in adult gerbils. Scanning electron microscopy showed that the mucosal member near the pharyngeal side contains a higher density of ciliated cells and goblet cells than that near the tympanic side. The cilia beat frequency is 11 Hz. During development, the length of the Eustachian tube increased significantly between postnatal day 1 (P1) and P18. Scanning electron microscopy showed that the mucosa contained a high density of ciliated cells with a few goblet cells at P1. The density of ciliated cells decreased while the density of goblet cells increased during development. At P18, the mucosa appeared to be adult-like. Interestingly, the ciliary beat frequency measured from ciliated cells at P1 was not statistically different from that measured from adult animals. Our study suggests that the Eustachian tube undergoes significant anatomical and histological changes between P1 and P18. The tube is morphologically and functionally mature at P18, when the auditory function (sensitivity and frequency selectivity) is mature in this species.
Berberine is known to improve glucose and lipid metabolism disorders, but it poorly absorbed into the blood stream from the gut. Therefore, the exact underlying mechanism for berberine is still unknown. In this study, we investigated the effect of berberine on glucose metabolism in diabetic rats and tested the hypothesis that berberine acts directly in the terminal ileums.
Rats were divided into a control group, diabetic group (DM), low dose of berberine group (BerL) and high dose of berberine group (BerH). Ileum samples were analyzed using a Roche NimbleGen mRNA array, qPCR and immunohistochemistry.
We found that 8 weeks of treatment with berberine significantly decreased fasting blood glucose levels. An oral glucose tolerance test (OGTT) showed that blood glucose was significantly reduced in the BerL and BerH groups before and at 30 min, 60 min and 120 min after oral glucose administration. Plasma postprandial glucagon-like peptide-1 (GLP-1) levels were increased in the berberine-treated groups. The ileum from the BerH group had 2112 genes with significantly changed expression (780 increased, 1332 decreased). KEGG pathway analyses indicated that all differentially expressed genes included 9 KEGG pathways. The top two pathways were the MAPK signaling pathway and the GnRH signaling pathway. Q-RT-PCR and immunohistochemistry verified that glucagon-like peptide 1 receptor (Glp1r) and mitogen activated protein kinase 10 (Mapk10) were significantly up-regulated, in contrast, gonadotropin releasing hormone receptor (Gnrhr) and gonadotropin-releasing hormone 1 (Gnrh1) were down-regulated in the BerH group.
Our data suggest that berberine can improve blood glucose levels in diabetic rats. The mechanisms involved may be in the MAPK and GnRh-Glp-1 pathways in the ileum.
Diabetes; Digestive tract; Gene expression; GnRH
AIM: To investigate the role and mechanism of insulin-like growth factor binding protein-related protein 1 (IGFBPrP1) in the development of liver fibrosis.
METHODS: An in vitro model using hepatic stellate cell (HSC)-T6 cells and an in vivo model of rat liver overexpressing IGFBPrP1 were established using an IGFBPrP1-expressing recombinant adenovirus. The expression of IGFBPrP1 was examined by immunofluorescence, and the expression of collagen I and fibronectin was measured by real-time reverse transcription-polymerase chain reaction and Western blot analysis. The expression of Smad2/3 and p-Smad2/3 was examined by Western blot and immunohistochemistry. A shSmad3-expressing recombinant adenovirus (AdshSmad3) was designed and used to knockdown the Smad3 gene in HSC-T6 cells and rat liver fibrosis transfected with IGFBPrP1. The expression of collagen I, fibronectin, and α-smooth muscle actin (α-SMA) was determined by Western blot analysis and immunohistochemistry. Hepatocyte apoptosis was assessed using TUNEL assay.
RESULTS: IGFBPrP1 overexpression induced collagen deposition and up-regulated the expression of α-SMA and p-Smad2/3, and AdshSmad3 inhibited IGFBPrP1-stimulated p-Smad2/3 activation and the expression of α-SMA, collagen I and fibronectin in HSC-T6 cells. Similarly, increased hepatocyte apoptosis (38.56% ± 3.42% vs 0.24% ± 0.03%, P < 0.05), α-SMA positive stained cells (29.84% ± 1.36% vs 5.83% ± 1.47%, P < 0.05), and increased numbers of Smad3 (35.88% ± 2.15% vs 10.24% ± 1.31%, P < 0.05) and p-Smad2/3 positive cells (28.87% ± 2.73% vs 8.23% ± 0.98%, P < 0.05) were detected in the livers of IGFBPrP1-overexpressing rats compared with the control group. Moreover, AdshSmad3 reduced IGFBPrP1-stimulated Smad3 expression and attenuated α-SMA expression (29.84% ± 1.36% vs 8.23% ± 1.28%, P < 0.05), hepatocyte apoptosis (38.56% ± 3.42% vs 6.75% ± 0.52%, P < 0.05), and both collagen I and fibronectin deposition in the livers of AdIGFBPrP1-treated rats.
CONCLUSION: IGFBPrP1 induces liver fibrosis by mediating the activation of hepatic stellate cells and hepatocyte apoptosis in a Smad3-dependent mechanism.
Insulin-like growth factor binding protein-related protein 1; Liver fibrosis; Hepatic stellate cells; Hepatocyte apoptosis; Smad pathway
Appropriate public health responses to infectious disease threats should be based on best-available evidence, which requires timely reliable data for appropriate analysis. During the early stages of epidemics, analysis of ‘line lists’ with detailed information on laboratory-confirmed cases can provide important insights into the epidemiology of a specific disease. The objective of the present study was to investigate the extent to which reliable epidemiologic inferences could be made from publicly-available epidemiologic data of human infection with influenza A(H7N9) virus.
We collated and compared six different line lists of laboratory-confirmed human cases of influenza A(H7N9) virus infection in the 2013 outbreak in China, including the official line list constructed by the Chinese Center for Disease Control and Prevention plus five other line lists by HealthMap, Virginia Tech, Bloomberg News, the University of Hong Kong and FluTrackers, based on publicly-available information. We characterized clinical severity and transmissibility of the outbreak, using line lists available at specific dates to estimate epidemiologic parameters, to replicate real-time inferences on the hospitalization fatality risk, and the impact of live poultry market closure.
Demographic information was mostly complete (less than 10% missing for all variables) in different line lists, but there were more missing data on dates of hospitalization, discharge and health status (more than 10% missing for each variable). The estimated onset to hospitalization distributions were similar (median ranged from 4.6 to 5.6 days) for all line lists. Hospital fatality risk was consistently around 20% in the early phase of the epidemic for all line lists and approached the final estimate of 35% afterwards for the official line list only. Most of the line lists estimated >90% reduction in incidence rates after live poultry market closures in Shanghai, Nanjing and Hangzhou.
We demonstrated that analysis of publicly-available data on H7N9 permitted reliable assessment of transmissibility and geographical dispersion, while assessment of clinical severity was less straightforward. Our results highlight the potential value in constructing a minimum dataset with standardized format and definition, and regular updates of patient status. Such an approach could be particularly useful for diseases that spread across multiple countries.
Epidemiological monitoring; Line list; Infectious disease outbreak; Influenza A virus; H7N9 subtype
Mouse embryonic fibroblasts (MEFs) are mesenchymal stem cell (MSC)-like multipotent progenitor cells and can undergo self-renewal and differentiate into to multiple lineages, including bone, cartilage and adipose. Primary MEFs have limited life span in culture, which thus hampers MEFs’ basic research and translational applications. To overcome this challenge, we investigate if piggyBac transposon-mediated expression of SV40 T antigen can effectively immortalize mouse MEFs and that the immortalized MEFs can maintain long-term cell proliferation without compromising their multipotency. Using the piggyBac vector MPH86 which expresses SV40 T antigen flanked with flippase (FLP) recognition target (FRT) sites, we demonstrate that mouse embryonic fibroblasts (MEFs) can be efficiently immortalized. The immortalized MEFs (piMEFs) exhibit an enhanced proliferative activity and maintain long-term cell proliferation, which can be reversed by FLP recombinase. The piMEFs express most MEF markers and retain multipotency as they can differentiate into osteogenic, chondrogenic and adipogenic lineages upon BMP9 stimulation in vitro. Stem cell implantation studies indicate that piMEFs can form bone, cartilage and adipose tissues upon BMP9 stimulation, whereas FLP-mediated removal of SV40 T antigen diminishes the ability of piMEFs to differentiate into these lineages, possibly due to the reduced expansion of progenitor populations. Our results demonstrate that piggyBac transposon-mediated expression of SV40 T can effectively immortalize MEFs and that the reversibly immortalized piMEFs not only maintain long-term cell proliferation but also retain their multipotency. Thus, the high transposition efficiency and the potential footprint-free natures may render piggyBac transposition an effective and safe strategy to immortalize progenitor cells isolated from limited tissue supplies, which is essential for basic and translational studies.
Identifying metabolically active atherosclerotic lesions remains an unmet clinical challenge during coronary intervention. Electrochemical impedance (EIS) increased in response to oxidized low density lipoprotein (oxLDL)-laden lesions. We hereby assessed whether integrating EIS with intravascular ultrasound (IVUS) and shear stress (ISS) provided a new strategy to assess oxLDL-laden lesions in the fat-fed New Zealand White (NZW) rabbits.
Methods and Results
A micro-heat transfer sensor was deployed to acquire the ISS profiles at baseline and post high-fat diet (HD) in the NZW rabbits (n=8). After 9 weeks of HD, serum oxLDL levels (mg/dL) increased by 140-fold, accompanied by a 1.5-fold increase in kinematic viscosity (cP) in the HD group. Time-averaged ISS (ISSave) in the thoracic aorta also increased in the HD group (baseline: 17.61±0.24 vs. 9 weeks: 25.22±0.95 dyne/cm2, n=4), but remained unchanged in the normal diet group (baseline: 22.85±0.53 dyne/cm2 vs. 9 weeks: 22.37±0.57 dyne/cm2, n=4). High-frequency Intravascular Ultrasound (IVUS) revealed atherosclerotic lesions in the regions with augmented ISSave, and concentric bipolar microelectrodes demonstrated elevated EIS signals, which were correlated with prominent anti-oxLDL immuno-staining (oxLDL-free regions: 497±55 Ω, n = 8 vs. oxLDL-rich lesions: 679±125 Ω, n = 12, P < 0.05). The equivalent circuit model for tissue resistance between the lesion-free and ox-LDL-rich lesions further validated the experimental EIS signals.
By applying electrochemical impedance in conjunction with shear stress and high-frequency ultrasound sensors, we provided a new strategy to identify oxLDL-laden lesions. The study demonstrated the feasibility of integrating EIS, ISS, and IVUS for a catheter-based approach to assess mechanically unstable plaque.
Shear Stress; Electrochemical Impedance; Intravascular ultrasound; OxLDL; Atherosclerotic lesions
Lysyl-tRNA synthetase (KRS), a protein synthesis enzyme in the cytosol, relocates to the plasma membrane after a laminin signal and stabilizes a 67-kDa laminin receptor (67LR) that is implicated in cancer metastasis; however, its potential as an antimetastatic therapeutic target has not been explored. We found that the small compound BC-K-YH16899, which binds to KRS, impinged on interaction of KRS with 67LR and suppressed metastasis in 3 different mouse models. The compound inhibited KRS–67LR interaction in two ways. First, it directly blocked the association between KRS and 67LR. Second, it suppressed the dynamic movement of the N-terminal extension of KRS and reduced membrane localization of KRS. However, it did not affect the catalytic activity of KRS. Our results suggest that specific modulation of a cancer-related KRS–67LR interaction may offer a way to control metastasis while avoiding the toxicities associated with inhibition of the normal functions of KRS.
To identify the negative effect on treatment results of reserving damaged intervertebral discs when treating type B and type C spinal fracture-dislocations through a one-stage posterior approach.
This is a retrospective review of 53 consecutive patients who were treated in our spine surgery center from January 2005 to May 2012 due to severe thoracolumbar spinal fracture-dislocation. The patients in Group A (24 patients) underwent long-segment instrumentation laminectomy with pedicle screw-rod fixators for neural decompression. In Group B (29 patients), the patients underwent long-segment instrumentation laminectomy with pedicle screw-rod fixators for neural decompression evacuating of the ruptured disc and inserting of a bone graft into the evacuated disc space for interbody fusion. The mean time between injury and operation was 4.1 days (range 2–15 days). The clinical, radiologic and complication outcomes were analyzed retrospectively.
Periodic follow-ups were carried out until an affirmative union or treatment failure took place. A progressive kyphosis angle larger than 10°, loss of disc height, pseudoarthrosis, recurrence of dislocation or subluxation, or instrument failure before fusion were considered treatment failures. Treatment failures were detected in 13 cases in Group A (failure rate was 54.2%). In Group B, there were 28 cases in which definitive bone fusion was demonstrated on CT scans, and CT scans of the other cases demonstrated undefined pseudoarthrosis without hardware failure. There were statistically significant differences between the two groups (p<0.001 chi-square test). The neurologic recoveries, assessed by the ASIA scoring system, were not satisfactory for the neural deficit patients in either group, indicating there was no significant difference with regard to neurologic recovery between the two groups (p>0.05 Fisher's exact test).
Intervertebral disc damage is a common characteristic in type B and C spinal fracture-dislocation injuries. The damaged intervertebral disc should be removed and substituted with a bone graft because reserving the damaged disc in situ increases the risk of treatment failure.
Antimicrobial peptides have attracted much interest as a novel class of antibiotics against a variety of microbes including antibiotics resistant strains. In this study, a new cationic antimicrobial peptide Hp1404 was identified from the scorpion Heterometrus petersii, which is an amphipathic α-helical peptide and has a specific inhibitory activity against gram-positive bacteria including methicillin-resistant Staphylococcus aureus. Hp1404 can penetrate the membrane of S. aureus at low concentration, and disrupts the cellular membrane directly at super high concentration. S. aureus does not develop drug resistance after multiple treatments with Hp1404 at sub MIC concentration, which is possibly associated with the antibacterial mechanism of the peptide. In addition, Hp1404 has low toxicity to both mammalian cells (HC50 = 226.6 µg/mL and CC50 > 100 µg/mL) and balb-c mice (Non-toxicity at 80 mg/Kg by intraperitoneal injection and LD50 = 89.8 mg/Kg by intravenous injection). Interestingly, Hp1404 can improve the survival rate of the MRSA infected balb-c mice in the peritonitis model. Taken together, Hp1404 may have potential applications as an antibacterial agent.
The aim of the present study was to investigate the levels of vascular endothelial growth factor (VEGF)-antagonizing cytokines and VEGF-influenced vascular stabilizing cytokines in patients with moyamoya disease (MMD) and the association with postoperative collateral vessel formation. The study population included 53 MMD patients that had undergone indirect bypass surgery and 50 healthy controls. Serum levels of VEGF, thrombospondin-1 (TSP-1), TSP-2, soluble VEGF receptor-1 (sVEGFR-1), sVEGFR-2, endostatin, angiopoietin-1 (Ang-1) and Ang-2 were measured at the baseline (preoperative) and at day seven following surgery. Postoperative collateralization assessment was conducted upon the six-month follow-up cerebral angiography. Cytokine levels were compared between patients with good or poor collateral formation. Compared with the healthy controls, MMD patients exhibited lower baseline levels of sVEGFR-1 (P<0.0001) and sVEGFR-2 (P<0.0001), but higher VEGF expression (P<0.0001). Ang-1 and Ang-2 levels did not exhibit any difference between the two groups. On day seven following surgery, MMD patients exhibited an almost unchanged sVEGFR-1 and sVEGFR-2 expression level, but upregulated expression of VEGF (P<0.0001), Ang-1 (P<0.0001) and TSP-2 (P<0.0001). The six-month follow-up angiographies revealed that 21 patients (45.65%) that had undergone the same surgical procedure achieved good collateralization. Patients with good collateral formation appeared to have lower sVEGFR-1 and sVEGFR-2 levels prior to (P=0.029 and P=0.045, respectively) and at day seven (P=0.044 and P=0.047, respectively) following bypass surgery when compared with the patients with worse collateralization. Therefore, sVEGFR-1 and sVEGFR-2 may play a role in the pathogenesis of MMD. Lower levels of sVEGFR-1 and sVEGFR-2 indicated better postoperative collateralization in the six months following indirect bypass surgery. However, Ang-1 and Ang-2 may not be specifically involved in the course of MMD.
moyamoya disease; vascular endothelial growth factor; soluble vascular endothelial growth factor receptor; angiopoietin
Methylation of DNA CpG sites is a major mechanism of epigenetic gene silencing and plays important roles in cell division, development and carcinogenesis. One of its regulators is the 64-residue C-terminal Transcriptional Repressor Domain (the TRD) of MBD1, which recruits several repressor proteins such as MCAF1, HDAC3 and MPG that are essential for the gene silencing. Using NMR spectroscopy, we have characterized the solution structure of the C-terminus of MBD1 (MBD1-c, residues D507 to Q605), which included the TRD (A529 to P592). Surprisingly, the MBD1-c is intrinsically disordered. Despite its lack of a tertiary folding, MBD1-c could still bind to different partner proteins in a selective manner. MPG and MCAF1Δ8 showed binding to both the N-terminal and C-terminal residues of MBD1-c but HDAC3 preferably bound to the C-terminal region. This study reveals how MBD1-c discriminates different binding partners, and thus, expands our understanding of the mechanisms of gene regulation by MBD1.
Submerged macrophyte communities are frequently subjected to disturbance of various frequency and strength. However, there is still little experimental evidence on how mechanical disturbance affects the performance and species composition of such plant communities. In a greenhouse experiment, we constructed wetland communities consisting of five co-occurring clonal submerged macrophyte species (Hydrilla verticillata, Elodea canadensis, Ceratophyllum demersum, Chara fragilis, and Myriophyllum spicatum) and subjected these communities to three mechanical disturbance regimes (no, moderate and strong disturbance). Strong mechanical disturbance greatly decreased overall biomass, number of shoot nodes and total shoot length, and increased species diversity (evenness) of the total community. It also substantially decreased the growth of the most abundant species (H. verticillata), but did not affect growth of the other four species. Our data reveal that strong disturbance can have different effects on different submerged macrophyte species and thus alters the performance and species composition of submerged macrophyte communities.
To explore the relationship between non-alcoholic fatty liver disease (NAFLD) and the metabolic syndrome (MetS), and evaluate the value of NAFLD as a marker for predicting the risk of MetS in a large scale prospective cohort from northern urban Han Chinese population.
Materials and Methods
A total of 17,920 MetS-free at baseline cohort members was included in the current study between 2005 and 2011. The baseline characteristics of the cohort were compared by NAFLD status at baseline, MetS status after follow-up. Cox proportional hazards models were used to estimate the unadjusted or adjusted hazard ratios (HRs) for NAFLD at baseline predicting the risk of MetS.
2,183 (12.18%) new cases of MetS occurred between 2005 and 2011. In unadjusted model, HRs (95% CIs) for NAFLD predicting MetS was 3.65 (3.35, 3.97). After adjusting the confounding factors of age, gender, the metabolic factors, smoke and exercise, the HRs (95% CIs) was 1.70 (1.55, 1.87). Gender difference was observed, adjusted HRs (95% CIs) of NAFLD for predicting MetS were 2.06(1.72, 2.46) and 1.55(1.39, 1.72) in female and male population, respectively. Moreover, 163 participants developed MetS among participants without any MetS component at baseline, and its adjusted HRs was still significant, 1.87 (1.12, 3.13).
The present study indicates that NAFLD is an independent risk factor for predicting the risk of MetS in northern urban Han Chinese population, and the people with NAFLD should initiate weight and dietary control to prevent the occurrence of MetS.
The Xeroderma pigmento-sum group D gene (XPD) plays a key role in nucleotide excision repair. Single nucleotide polymorphisms (SNP) located in its functional region may alter DNA repair capacity phenotype and cancer risk. Many studies have demonstrated that XPD polymorphisms are significantly associated with digestive tract cancers risk, but the results are inconsistent. We conducted a comprehensive meta-analysis to assess the association between XPD Lys751Gln polymorphism and digestive tract cancers risk. The digestive tract cancers that our study referred to, includes oral cancer, esophageal cancer, gastric cancer and colorectal cancer.
We searched PubMed and EmBase up to December 31, 2012 to identify eligible studies. A total of 37 case-control studies including 9027 cases and 16072 controls were involved in this meta-analysis. Statistical analyses were performed with Stata software (version 11.0, USA). Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association.
The results showed that XPD Lys751Gln polymorphism was associated with the increased risk of digestive tract cancers (homozygote comparison (GlnGln vs. LysLys): OR = 1.12, 95% CI = 1.01–1.24, P = 0.029, P
heterogeneity = 0.133). We found no statistical evidence for a significantly increased digestive tract cancers risk in the other genetic models. In the subgroup analysis, we also found the homozygote comparison increased the susceptibility of Asian population (OR = 1.28, 95% CI = 1.01–1.63, P = 0.045, P
heterogeneity = 0.287). Stratified by cancer type and source of control, no significantly increased cancer risk was found in these subgroups. Additionally, risk estimates from hospital-based studies and esophageal studies were heterogeneous.
Our meta-analysis suggested that the XPD 751Gln/Gln genotype was a low-penetrate risk factor for developing digestive tract cancers, especially in Asian populations.
A modified quick, easy, cheap, effective, rugged (QuEChERS) method with multi-walled carbon nanotubes (MWCNTs) as reversed-dispersive solid phase extraction (r-DSPE) material was applied to the analysis of pirimiphos-methyl and deltamethrin residues in stored rice. Two dustable powder (DP) formulations (2% pirimiphos-methyl and deltamethrin DP; 5% pirimiphos-methyl DP) were applied in simulated storehouse trials in the lab. The residues and dissipation of the two pesticides in stored rice were investigated. Slow dissipation of both pesticides was observed in stored rice. The half-lives of pirimiphos-methyl were 23.9–28.9 days, and those of deltamethrin were 23.9–24.8 days. Residues of pirimiphos-methyl from application rates of 4.5–6.75 a.i. mg/kg (active ingredient milligram per kilogram) and 10–15 a.i. mg/kg were 1.6–3.8 mg/kg and 3.0–4.5 mg/kg at 60 days Pre-harvest Interval (PHI). Residues of deltamethrin from an application rate of 0.5–0.75 a.i. mg/kg were 0.13–0.14 mg/kg at 60 days PHI. Both pesticides residues were below the Maximum Residue Limits (MRLs) established by the Codex Alimentarius Commission (CAC). Therefore, at the recommended dosages they are safe for use on stored rice.
pirimiphos-methyl; deltamethrin; rice; post-harvest treatment; residue; dissipation
The aim of the present study was to investigate the expression of glucose-related protein 78 (GRP78) and heparanase (HPA) in oral squamous cell carcinoma (OSCC) and their relationship with clinicopathological parameters and potential implications for survival.
A total of 46 patients with OSCC and 10 normal individuals were recruited for the study. GRP78 and HPA expression were determined in the lesion tissues using immunohistochemical analysis. The correlation between GRP78 and HPA was assessed using the Spearman correlation analysis. The associations of GRP78 and HPA with clinicopathological characteristics and survival were examined using the x2-test, Kaplan–Meier, or Cox regression.
Patients with OSCC showed a statistically significant higher prevalence of GRP78 and HPA expression than normal oral tissues. GRP78 and HPA expression was positively correlated with size, TNM stage, histological grade, lymphatic metastasis, and distant metastasis in OSCC patients. GRP78 expression was also positively correlated with HPA expression. Positive GRP78 and HPA expression was inversely correlated with survival in OSCC patients.
HPA expression was found to be positively correlated with GRP78 expression. GRP78 and HPA are biomarkers that may have the potential to guide the treatment of oral cancer patients.
Glucose-related proteins 78; Heparanase; Immunohistochemistry; Oral squamous cell carcinoma; Prognosis
To report on the perioperative outcomes of laparoscopic partial nephrectomy (LPN) for multilocular cystic renal cell carcinoma (MCRCC) and evaluate the feasibility of this minimally invasive technique as a potential gold standard treatment for MCRCC.
We retrospectively reviewed the database of surgically pathological findings of patients who were diagnosed with MCRCC at Peking University First Hospital and Chinese PLA General Hospital (Beijing, China) between May 2009 and January 2013. A total of 42 patients with an average age of 48.3 years who were treated with LPN were collected. The patients’ perioperative outcomes were reported and analyzed.
All operations were performed successfully without massive hemorrhage or open conversion. None of patients received lymph node dissection or metastasectomy. Two patients required postoperative transfusion with a mean amount of 175 cc packed red blood cells. Only three patients experienced mild postoperative complications. The mean operative time was 2.4 ± 1.2 hours, including the mean warm ischemia time (WIT) of 23.2 ± 5.7 minutes. The mean estimated blood loss was 72.0 ± 49.6 ml. The mean retroperitoneal drainage was 4.4 ± 1.7 days. The mean postoperative hospital stay was 6.1 ± 1.9 days. Pathologically, 40 (95.2%) of the tumors presented as stage pT1abN0M0, while the remaining two (4.8%) presented as stage pT2aN0M0. No recurrences or new lesions occurred in these patients at a mean follow-up time of 30.0 months.
Although the effective option of LPN is not yet the gold standard treatment for conventional renal cell carcinoma, it should be strongly recommended as a potential gold standard treatment for MCRCC due to the benign nature of MCRCC and the excellent perioperative outcomes provided by LPN.
Multilocular cystic renal cell carcinoma; Laparoscopic; Partial nephrectomy; Gold standard; Perioperative outcomes