BACKGROUND:: Velopharyngeal inadequacy (VPI), which has a significant negative impact on speech intelligibility and resonance quality, may be caused by physiological inadequacy. The current study aimed to investigate the maximal velar and pharyngeal motions and levator muscle shortening in the children with repaired cleft palate and different speech outcomes as well as children without cleft palate by using magnetic resonance imaging techniques without general anesthesia. METHODS:: Three groups of sex- and age-matched children were recruited: children with repaired cleft palate and adequate velopharyngeal function condition (VPC), children with repaired cleft palate and VPI, and the normal controls (noncleft). The children were trained to perform sustained /a:/, /i:/, /ts:/, and /m:/, while keeping the head still during magnetic resonance imaging scan. The maximal velar elevation and stretch, pharyngeal medial constriction, velopharyngeal ratio (VP ratio), and levator muscle shortening ratio were measured and compared across the 3 groups. RESULTS:: The VPI group showed the least maximal velar stretch, lowest maximal velar height, smallest maximal pharyngeal constriction, and lowest maximal VP ratio among the 3 groups. The VPI and VPC groups differed significantly in velar and pharyngeal mobility. The effective VP ratio at rest has a strong correlation with that during sustained phonation across the 3 groups. The maximal velar stretch ratio correlates to the maximal pharyngeal constriction ratio strongly in the VPI group only. CONCLUSIONS:: The VPI group had significantly reduced velar and pharyngeal mobility during speech compared with the VPC and noncleft groups. The possible physiological causes of VPI after primary palatal repair were discussed.

Objective: Recent genome-wide association studies have identified multiple novel loci associated with obesity in Europeans. We hypothesized that these genetic variants may be associated with obesity and type 2 diabetes (T2D) in Chinese. Research Design and Methods: We examined 14 associated single-nucleotide polymorphisms at 12 loci (NEGR1, SEC16B, TMEM18, ETV5/DGKG, GNPDA2, LIN7C/BDNF, MTCH2, BCDIN3D/FAIM2, SH2B1, FTO, MC4R, and KCTD15) in 605 healthy adults, 1087 healthy adolescents and 6013 T2D patients from Hong Kong. Results: The European at-risk alleles at five loci including GNPDA2, BCDIN3D/FAIM2, SH2B1, FTO, and KCTD15 were significantly associated with increased body mass index (BMI), waist circumference (4.5 x 10(-8) < P < 0.024), and/or obesity risk (odds ratio 1.14-1.22, 2.0 x 10(-5) < P < 0.002) in our Chinese populations. The former four loci as well as LIN7C/BDNF were also modestly associated with T2D risk (odds ratio 1.09-1.22, 0.008 < P < 0.041), but the associations were lost after adjustment for BMI, suggesting their roles in T2D risk are mediated through modulation of adiposity. Joint effect analyses of the five adiposity loci revealed an increase of about 0.29 kg/m(2) in BMI with each additional copy of at-risk allele (Ptrend = 4.2 x 10(-12)). Conclusions: Our findings support the important contribution of GNPDA2, BCDIN3D/FAIM2, SH2B1, FTO, and KCTD15 in the regulation of adiposity, which in turn affects T2D risk in Chinese.

Quinolone antibacterial agents are widely used in the clinic because of their high antibacterial activity, broad spectra and favorable pharmacokinetics. However, the adverse effects induced by quinolones, such as tendon/articular toxicity, central nervous system toxicity, photo toxicity and dysglycemia, have greatly restricted their therapeutic use. Differentiated embryo-chondrocyte expressed gene 1 (DEC1), an important transcription factor that has a basic helix-loop-helix domain and is ubiquitously expressed in both human embryonic and adult tissues, has a pivotal function in various biological phenomena, including neurogenesis, neuroregulation, chondrogenesis, cell growth, oncogenesis, immune balance and circandian rhythm. Recently, DEC1 has received increasing attention for its role in maintaining the homeostasis of metabolism and energy. Research has shown that DEC1 may play a vital role in metabolic disease. Although the mechanism of the adverse reactions caused by quinolones has not been clarified, the distribution of these serious adverse effects in tissues and organs is consistent with the expression of DEC1 in corresponding normal tissues. In the present paper, we review evidence showing that DEC1 may take part in the adverse effects induced by quinolone antibiotics. The investigation of the molecular details of the toxicity caused by quinolones may help overcome the shortcomings of the antibiotics and reveal new, useful therapeutic functions besides their antimicrobial effect.

In vitro assays identified the Golgi peripheral protein GRASP65 as a Golgi stacking factor that links adjacent Golgi cisternae by forming mitotically regulated trans-oligomers. These conclusions, however, require further confirmation in the cell. In this study, we demonstrated that the first 112 amino acids at the N-terminus (including the first PDZ domain, PDZ1) of the protein are sufficient for oligomerization. Systematic electron microscopic analysis showed that expression of non-regulatable GRASP65 mutants in HeLa cells enhanced Golgi stacking in interphase and inhibited Golgi fragmentation during mitosis. Depletion of GRASP65 by small interference RNA (siRNA) reduced the number of cisternae in the Golgi stacks; this reduction was rescued by expressing exogenous GRASP65. These results provided evidence and a molecular mechanism by which GRASP65 stacks Golgi cisternal membranes. Further experiments revealed that inhibition of mitotic Golgi disassembly by expressing non-regulatable GRASP65 mutants did not affect equal partitioning of the Golgi membranes into the daughter cells. However, it delayed mitotic entry and suppressed cell growth; this effect was diminished by dispersing the Golgi apparatus with Brefeldin A treatment prior to mitosis, suggesting that Golgi disassembly at the onset of mitosis plays a role in cell cycle progression.

Liquid droplet sliding is an approach for the transportation and manipulation of fluids in micro/nanofluidics related biosensor applications. Liquid droplet sliding is also instructive to evaluate the degree of boundary slip. In this study, liquid microdroplet sliding is studied with and without the presence of an electric field using atomic force microscopy on a polystyrene surface spin coated on a doped silicon wafer with a silicon oxide coating. Droplets with different diameters are slid with an atomic force microscope tip, and the sliding forces or lateral friction forces are quantitatively measured. Experimental results show that lateral friction force linearly increases with increasing droplet diameters, which can be explained by a droplet sliding model. When the electric field is applied, in addition to the decreased contact angle, diameters of the liquid droplets will increase. As a result, the electric field increases lateral friction force. To further investigate the impact of applied potential on lateral friction force, voltages from 0 to 80 V are applied to a droplet. Lateral friction force is found to increase with applied potential.

OBJECTIVE: To investigate the effect of qingre quyu granule (QQG) for treatment of carotid vulnerable atherosclerotic plaque (CVAP) in patients with coronary heart disease (CHD). METHODS: Eighty-two CHD patients with stable exertional angina, complicated with CVAP and differentiated to phlegm-heat and blood-stasis syndrome type were randomly assigned to two groups equally, the test group treated by Western medical routine therapy combined with QQG, and the control group treated with Western medical routine therapy with placebo. Using high frequency ultrasonography, the number (complex and simple) and Crouse integral of CVAP and the intima-media membranous thickness of carotid artery were measured, and changes in serum levels of CD40L and high-sensitivity C-reactive protein (hs-CRP), liver and renal functions were observed. RESULTS: After treatment, significant improvement were shown in the test group in terms of complex plaques' number, Crouse integral, intima-media thickness and serum levels of CD40L and hs-CRP as compared with that before treatment, also with those in the control group after treatment (P < 0.05 or P < 0.01). No adverse reaction was found in the treatment course. CONCLUSION: QQG has certain stabilizing action on CVAP in patients with CHD.

Surflex-Dock was applied to study interactions between 30 thiourea analogs and neuraminidase (NA). The docking results showed that hydrogen bonding and electrostatic interactions were highly correlated with the activities of neuraminidase inhibitors (NIs), followed by hydrophobic and steric factors. Moreover, there was a strong correlation between the predicted binding affinity (total score) and experimental pIC(50) (correlation coefficient r = 0.870; P < 0.0001). A three dimensional holographic vector of atomic interaction field (3D-HoVAIF) was employed to construct a QSAR model. The r (2), q (2) and r (2) (test) values of the optimal QSAR model were 0.849, 0.724 and 0.689, respectively. From the QSAR model, it could be seen that electrostatic, hydrophobic and steric interactions were closely related to inhibitory activity, which was consistent with the docking results. Based on the docking and QSAR results, five new compounds with high predicted activities were designed.

Human CMTM is a novel gene family consisting of CKLF and CMTM1-8. CMTM4 is the most conserved gene and has three RNA splicing forms designated as CMTM4-v1, -v2 and -v3, but in many types of tissue and cell lines, only CMTM4-v1 and -v2 could be detected. CMTM4-v2 is the full length cDNA product, which has been highly conserved during e volution. CMTM4-v1 and - v2 a re b roadly expressed in normal types of tissue. They are distributed on the cell membrane and across the cytoplasm in a speckled pattern. Overexpression of CMTM4-v1 and -v2 can inhibit HeLa cell growth via G2/M phase accumulation without inducing apoptosis. Therefore, CMTM4 might be an important gene involved in cell growth and cell cycle regulation.

Surgical treatment of complex severe spinal deformity, involving a scoliosis Cobb angle of more than 90 degrees and kyphosis or vertebral and rib deformity, is challenging. Preoperative two-dimensional images resulting from plain film radiography, computed tomography (CT) and magnetic resonance imaging provide limited morphometric information. Although the three-dimensional (3D) reconstruction CT with special software can view the stereo and rotate the spinal image on the screen, it cannot show the full-scale spine and cannot directly be used on the operation table. This study was conducted to investigate the application of computer-designed polystyrene models in the treatment of complex severe spinal deformity. The study involved 16 cases of complex severe spinal deformity treated in our hospital between 1 May 2004 and 31 December 2007; the mean +/- SD preoperative scoliosis Cobb angle was 118 degrees +/- 27 degrees . The CT scanning digital imaging and communication in medicine (DICOM) data sets of the affected spinal segments were collected for 3D digital reconstruction and rapid prototyping to prepare computer-designed polystyrene models, which were applied in the treatment of these cases. The computer-designed polystyrene models allowed 3D observation and measurement of the deformities directly, which helped the surgeon to perform morphological assessment and communicate with the patient and colleagues. Furthermore, the models also guided the choice and placement of pedicle screws. Moreover, the models were used to aid in virtual surgery and guide the actual surgical procedure. The mean +/- SD postoperative scoliosis Cobb angle was 42 degrees +/- 32 degrees , and no serious complications such as spinal cord or major vascular injury occurred. The use of computer-designed polystyrene models could provide more accurate morphometric information and facilitate surgical correction of complex severe spinal deformity.

In this paper, ZnSe nanoparticles, which were modified with mercaptoacetic acid (MAA), worked as novel fluorescence sensors for the quantitative determination of copper(II) and nickel(II). Under the optimal conditions, the fluorescence intensities of functionalized ZnSe nanoparticles were quenched by the addtion of copper(II) or nickel(II) ions, there were linear relationships between the relative fluorescence intensity (logF(0)/F) and the concentration in the range of 140-2,000 mug/L for copper(II) (R = 0.9973) and 30-1,000 mug/L for nickel(II) (R = 0.9992), the limits of detection were 50 mug/L and 5 mug/L, respectively.

Glutamate receptor-mediated excitatory neurotransmission plays a key role in neural development, differentiation and synaptic plasticity. However, excessive stimulation of glutamate receptors induces neurotoxicity, a process that has been defined as excitotoxicity. Excitotoxicity is considered to be a major mechanism of cell death in a number of central nervous system diseases including stroke, brain trauma, epilepsy and chronic neurodegenerative disorders. Unfortunately clinical trials with glutamate receptor antagonists, that would logically prevent the effects of excessive receptor activation, have been associated with untoward side effects or little clinical benefit. Therefore, uncovering molecular pathways involved in excitotoxic neuronal death is of critical importance to future development of clinical treatment of many neurodegenerative disorders where excitotoxicity has been implicated. This review discusses the current understanding of the molecular and cellular mechanisms of excitotoxicity and their roles in the pathogenesis of diseases of the central nervous system.

PURPOSE: TNF-related apoptosis-inducing ligand (TRAIL) functions as a soluble cytokine and has been demonstrated significant antitumor activity against a variety of cancer cell lines without toxicity to most normal cells. Cisplatin is a potent anticancer agent and is widely used in the clinical for treatment of human cancers. Adeno-associated virus (AAV2) is a promising gene delivery vehicle for its advantage of low pathogenicity and long-term gene expression. However, lack of tissue specificity caused low efficiency of AAV transfer to target cells. The promoter of human telomerase reverse transcriptase (hTERT) is a good candidate to enhance targeting efficiency of AAV in cancer cells. Although AAV-mediated TRAIL controlled by hTERT promoter (AAV-hTERT-TRAIL) has obvious antitumor activity, the tumor cannot be completely eradicated. In this study, we first examined the effectiveness of combination therapy of cisplatin and AAV-hTERT-TRAIL on human hepatocellular carcinoma (HCC) in vitro and in vivo. METHODS: For in vitro experiments, tumor cell lines were treated with cisplatin, virus, or both. The transgene TRAIL expression controlled by hTERT promoter was evaluated in BEL7404 HCC cell line. Cytotoxicity was performed by MTT analysis. Cell apoptosis was detected by flow cytometry analysis. The in vivo antitumor efficacy of combination treatment with cisplatin and AAV-hTERT-TRAIL was assessed in human hepatocellular carcinoma xenografts mouse model. RESULTS: The enhanced TRAIL expression was observed in BEL7404 cells treated with AAV-hTERT-TRAIL plus cisplatin. Treatment with both AAV-hTERT-TRAIL and cisplatin exhibited stronger cytotoxicity and induced more significant apoptosis in cancer cells compared with AAV-hTERT-TRAIL or cisplatin alone, respectively. Moreover, in animal experiments, the combined treatment greatly suppressed tumor growth and resulted in tumor cell death. CONCLUSIONS: AAV-mediated therapeutic gene expression in combination with chemotherapy provides a promising therapeutic strategy for human cancers. These data suggest that combined use of AAV-hTERT-TRAIL and cisplatin may have potential clinical application.

HAb18G is a recently identified hepatoma-associated antigen and its association with tumor growth, invasion, and angiogenesis has been studied in a variety of tumors. However, its role in the tumor progression of breast cancer has not been explored. HAb18G expression was examined by immunohistochemistry in pathological sections of 1,637 breast tissue samples and by in situ hybridization in 41 cases of invasive breast carcinomas (BC). While not detected in any cases of tumor-like conditions or benign tumors of breast, and only rarely in normal tissue (4.4%), HAb18G expression was gradually up-regulated from atypical ductal hyperplasia (27.3%), to ductal carcinoma-in situ (59.8%), and to BC (61.4%) (P < 0.01). Its expression in BC was correlated positively with C-erbB-2 expression and histologic grade (P < 0.001), and negatively with the expression of estrogen and progesterone receptors (P < 0.001). Significant differences of expression were also identified among the subgroups of BC examined: in decreasing order from invasive micropapillary carcinoma, ductal carcinoma, lobular carcinoma, papillary carcinoma, medullary carcinoma, to mucinous adenocarcinoma (P = 0.001), corresponding to their known clinical aggressiveness. In an expanded group of 186 BC patients with proper follow up, our previous findings were confirmed: HAb18G expression was significantly associated with local recurrence, distant metastasis and tumor mortality (P < 0.01). We also demonstrated that up-regulated tumor expression of HAb18G was a significant predictor of reduced disease progression-free survival rate and a shorter overall survival, independent of systemic therapies. In conclusion, this study suggests that HAb18G expression is associated with BC progression and prognosis. Further evaluation of this new marker in breast cancer is indicated.

In order to analyze and evaluate different trace metals on surface water of the Changjiang River, concentrations of dissolved trace metals (Cu, Ni, Fe, Co, Sc, Al, Zn, Pb, Cd, Se, As, Cr, and Hg), major elements(Ca and Mg), and nutrient(NO[Formula: see text] were measured. Samples were taken at 76 positions along Changjiang River in flood and dry seasons during 2007-2008. Spatial distributions identified two main large zones mainly influenced by mineral erosion (sites 1-22) and anthropogenic action (sites 23-76), respectively. Principal component analysis (PCA) and hierarchical cluster analysis were used to identify the variance distinguishing the origin of water. Four significant components were extracted by PCA, explaining 74.91% of total variable. Cu, Ni, Fe, Co, Sc, Al, Ca, and Mg were mainly associated with the weathering and erosion of various rocks and minerals, while an anthropogenic source was identified for Cd and As. Although erosion was one source of Pb and Zn, they were also input by atmospheric deposition and industrial pollutions. NO[Formula: see text] and Se were mainly associated with agriculture activities. However, Hg and Cr showed different sources. CA confirmed and completed the results obtained by PCA, classifying the data into two large groups representing different areas. Group 1 referred to the upper reaches which represented samples mainly corresponding to natural background areas. Group 2 referred to the middle and lower reaches including samples under anthropogenic influence. Meanwhile, group 2 was subdivided into three new groups, representing agricultural, industrial, and various artificial pollution sources, respectively.

BACKGROUND: -Amid recent efforts to reduce cardiovascular risk, whether rates of acute myocardial infarction (AMI) in the United States have declined for elderly patients is unknown. Methods and Results-Medicare fee-for-service patients hospitalized in the United States with a principal discharge diagnosis of AMI were identified through the use of data from the Centers for Medicare and Medicaid Services from 2002 to 2007, a time period selected to reduce changes arising from the new definition of AMI. The Medicare beneficiary denominator file was used to determine the population at risk. AMI hospitalization rates were calculated annually per 100 000 beneficiary-years with Poisson regression analysis and stratified according to age, sex, and race. The annual AMI hospitalization rate in the fee-for-service Medicare population fell from 1131 per 100 000 beneficiary-years in 2002 to 866 in 2007, a relative 23.4% decline. After adjustment for age, sex, and race, the AMI hospitalization rate declined by 5.8%/y. From 2002 to 2007, white men experienced a 24.4% decrease in AMI hospitalizations, whereas black men experienced a smaller decline (18.0%; P<0.001 for interaction). Black women had a smaller decline in AMI hospitalization rate compared with white women (18.4% versus 23.3%, respectively; P<0.001 for interaction). Conclusions-AMI hospitalization rates fell markedly in the Medicare fee-for-service population between 2002 and 2007. However, black men and women appeared to have had a slower rate of decline compared with their white counterparts.

BACKGROUND: There are increasing calls for regionalization of acute myocardial infarction (AMI) care in the United States to hospitals with the capacity to perform percutaneous coronary intervention (PCI). Whether regionalization will improve outcomes depends in part on the magnitude of existing differences in outcomes between PCI and non-PCI hospitals within the same health care region. METHODS: A 100% sample of claims from Medicare fee-for-service beneficiaries 65 years or older hospitalized for AMI between January 1, 2004, and December 31, 2006, was used to calculate hospital-level, 30-day risk-standardized mortality rates (RSMRs). The RSMRs between PCI and local non-PCI hospitals were compared within local health care regions defined by hospital referral regions (HRRs). RESULTS: A total of 523 119 AMI patients was admitted to 1382 PCI hospitals, and 194 909 AMI patients were admitted to 2491 non-PCI hospitals in 295 HRRs with at least 1 PCI and 1 non-PCI hospital. Although PCI hospitals had lower RSMRs than non-PCI hospitals (mean, 16.1% vs 16.9%; P < .001), considerable overlap was seen in RSMRs between non-PCI and PCI hospitals within the same HRR. In 80 HRRs, the RSMRs at the best-performing PCI hospital were lower than those at local non-PCI hospitals by 3% or more. Among the remaining HRRs, the RSMRs at the best-performing PCI hospital were lower by 1.5% to 3.0% in 104 HRRs and by greater than 0 to 1.5% in 74 HRRs. In 37 HRRs, the RSMRs at the best-performing PCI hospital were no better or were higher than at local non-PCI hospitals. CONCLUSIONS: The magnitude of benefit from comprehensively regionalizing AMI care to PCI hospitals appears to vary greatly across HRRs. These findings support a tailored regionalization policy that targets areas with the greatest outcome differences between PCI and local non-PCI hospitals.

Rpa1, an essential gene involved in DNA replication and genome maintenance, is syntenic and linked to Trp53 in mice and humans. To study the genetic interaction between Rpa1 and Trp53 in tumorigenesis, we generated compound Rpa1(L230P/+); Trp53(+/-) mutant mice with the mutant alleles in either trans or cis configuration. We demonstrate that the Rpa1(L230P) missense mutation significantly alters the tumor phenotype and spectrum of Trp53 mutant mice by modifying the genetic mechanisms underlying tumorigenesis. Importantly, when the Rpa1(L230P) and Trp53 mutant alleles are in cis, the tumor phenotype is attenuated and altered and loss of heterozygosity (LOH) at the Trp53 wild-type locus is selected against, whereas in the trans configuration, Rpa1(L230P) enhances the Trp53(+/-) tumor phenotype even though Rpa1(L230P) is ultimately lost by LOH. These studies indicate that polymorphic genetic variants in cell essential genes can genetically affect closely linked tumor suppressor loci via allelic phasing, which can result in profound phenotypic variations in tumorigenesis.

The function of microRNAs (miRNAs) in hematopoietic stem cells (HSCs), committed progenitors, and leukemia stem cells (LSCs) is poorly understood. We show that miR-29a is highly expressed in HSC and down-regulated in hematopoietic progenitors. Ectopic expression of miR-29a in mouse HSC/progenitors results in acquisition of self-renewal capacity by myeloid progenitors, biased myeloid differentiation, and the development of a myeloproliferative disorder that progresses to acute myeloid leukemia (AML). miR-29a promotes progenitor proliferation by expediting G1 to S/G2 cell cycle transitions. miR-29a is overexpressed in human AML and, like human LSC, miR-29a-expressing myeloid progenitors serially transplant AML. Our data indicate that miR-29a regulates early hematopoiesis and suggest that miR-29a initiates AML by converting myeloid progenitors into self-renewing LSC.

Liver repair is key to resuming homeostasis and preventing fibrogenesis as well as other liver diseases. Farnesoid X receptor (FXR, NR1H4) is an emerging liver metabolic regulator and cell protector. Here we show that FXR is essential to promote liver repair after carbon tetrachloride (CCl4)-induced injury. Expression of hepatic FXR in wild-type mice was strongly suppressed by CCl4 treatment, and bile acid homeostasis was disrupted. Liver injury was induced in both wild-type and FXR(-/-) mice by CCl4, but FXR(-/-) mice had more severe defects in liver repair than wild-type mice. FXR(-/-) livers had a decreased peak of regenerative DNA synthesis and reduced induction of genes involved in liver regeneration. Moreover, FXR(-/-) mice displayed increased mortality and enhanced hepatocyte deaths. During the early stages of liver repair after CCl4 treatment, we observed overproduction of TNFalpha and a strong decrease of phosphorylation and DNA-binding activity of signal transducer and activator of transcription 3 in livers from FXR(-/-) mice. Exogenous expression of a constitutively active signal transducer and activator of transcription 3 protein in FXR(-/-) liver effectively reduced hepatocyte death and liver injury after CCl4 treatment. These results suggest that FXR is required to regulate normal liver repair by promoting regeneration and preventing cell death.