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1.  Ultrashort Echo Time (UTE) Magnetic Resonance Imaging of the Short T2 Components in White Matter of the Brain Using a Clinical 3T Scanner 
NeuroImage  2013;87:32-41.
White matter of the brain contains a majority of long T2 components as well as a minority of short T2 components. These are not detectable using clinical magnetic resonance imaging (MRI) sequences with conventional echo times (TEs). In this study we used ultrashort echo time (UTE) sequences to investigate the ultrashort T2 components in white matter of the brain and quantify their T2*s and relative proton densities (RPDs) (relative to water with a proton density of 100%) using a clinical whole body 3T scanner. An adiabatic inversion recovery prepared dual echo UTE (IR-dUTE) sequence was used for morphological imaging of the ultrashort T2 components in white matter. IR-dUTE acquisitions at a constant TR of 1000 ms and a series of TIs were performed to determine the optimal TI which corresponded to the minimum signal to noise ratio (SNR) in white matter of the brain on the second echo image. T2*s of the ultrashort T2 components were quantified using mono-exponential decay fitting of the IR-dUTE signal at a series of TEs. RPD was quantified by comparing IR-dUTE signal of the ultrashort T2 components with that of a rubber phantom. Nine healthy volunteers were studied. The IR-dUTE sequence provided excellent image contrast for the ultrashort T2 components in white matter of the brain with a mean signal to noise ratio of 18.7 ± 3.7 and a contrast to noise ratio of 14.6 ± 2.4 between the ultrashort T2 white matter and gray matter in a 4.4 min scan time with a nominal voxel size of 1.25×1.25×5.0 mm3. On average a T2* value of 0.42 ± 0.08 ms and a RPD of 4.05 ± 0.88% were demonstrated for the ultrashort T2 components in white matter of the brain of healthy volunteers at 3T.
PMCID: PMC4091919  PMID: 24188809
Ultrashort echo time; adiabatic IR; ultrashort T2; white matter; T2*; proton density
2.  Development of a Comprehensive Osteochondral Allograft MRI Scoring System (OCAMRISS) with Histopathologic, Micro-Computed Tomography, and Biomechanical Validation 
Cartilage  2013;5(1):16-27.
To describe and apply a semi-quantitative MRI scoring system for multi-feature analysis of cartilage defect repair in the knee by osteochondral allografts, and to correlate this scoring system with histopathologic, micro-computed tomography (μCT), and biomechanical reference standards using a goat repair model.
Fourteen adult goats had two osteochondral allografts implanted into each knee: one in the medial femoral condyle (MFC) and one in the lateral trochlea (LT). At 12 months, goats were euthanized and MRI was performed. Two blinded radiologists independently rated nine primary features for each graft, including cartilage signal, fill, edge integration, surface congruity, calcified cartilage integrity, subchondral bone plate congruity, subchondral bone marrow signal, osseous integration, and presence of cystic changes. Four ancillary features of the joint were also evaluated, including opposing cartilage, meniscal tears, synovitis, and fat-pad scarring. Comparison was made with histological and μCT reference standards as well as biomechanical measures. Interobserver agreement and agreement with reference standards was assessed. Cohen’s kappa, Spearman’s correlation, and Kruskal-Wallis tests were used as appropriate.
There was substantial agreement (κ>0.6, p<0.001) for each MRI feature and with comparison against reference standards, except for cartilage edge integration (κ=0.6). There was a strong positive correlation between MRI and reference standard scores (ρ=0.86, p<0.01). OCAMRISS was sensitive to differences in outcomes between the types of allografts.
We have described a comprehensive MRI scoring system for osteochondral allografts and have validated this scoring system with histopathologic and μCT reference standards as well as biomechanical indentation testing.
PMCID: PMC3904392  PMID: 24489999
cartilage repair; osteochondral allografts; MRI scoring system
3.  Coexpression of IQ-Domain GTPase-Activating Protein 1 (IQGAP1) and Dishevelled (Dvl) Is Correlated with Poor Prognosis in Non-Small Cell Lung Cancer 
PLoS ONE  2014;9(12):e113713.
IQ-domain GTPase-activating protein 1 (IQGAP1) binds to Dishevelled (Dvl) and functions as a modulator of Dvl nuclear localization in Xenopus embryos. However, the relationship between IQGAP1 and Dvl in tumor tissues is unclear.
Materials and Methods
We used immunohistochemistry to assess the expressions of IQGAP1 and Dvl in a cohort of 111 non-small cell lung cancer (NSCLC) patients. Association of their localization expressions with clinicopathological factors was also analyzed.
The positive rate of IQGAP1 in primary tumors was 48.6% (54/111) for its cytoplamic expression, 9.0% (10/111) for nuclear expression and 31.5% (35/111) for membranous expression; the positive rate of Dvl was 65.8% (73/111) for cytoplamic expression, 9.9% (11/111) for nuclear expression and 10.8% (12/111) for membranous expression. Coexpression rate of IQGAP1 and Dvl was 77.8% (42/54) in the cytoplasm, 80.0% (8/10) in the nucleus and 8.6% (3/35) in the membrane. Coexpression of IQGAP1 and Dvl in the cytoplasm and nucleus were significantly correlated (P<0.05), but not in the membrane (P>0.05). The positive expression rates of cyclin D1 and c-myc were significantly higher in the group of IQGAP1 and Dvl coexpression in the nucleus than that in the cytoplasm. Coexpression rate of IQGAP1 and Dvl in the cytoplasm and nucleus was significantly higher in lymph nodal metastases (63.3%, 19/30) than in primary growths (38.3%, 31/81), correlating with poor prognosis. Five-year survival time after resection in the group with their coexpression in the cytoplasm and nucleus was significantly lower than that with no coexpression (44.705±3.355 vs 58.403±2.543 months, p<0.05).
Coexpression of IQGAP1 and Dvl in the cytoplasm and nucleus was correlated with the lymph nodal metastase and poor prognosis of NSCLC, and coexpression in nucleus might play a critical role in the activation of canonical Wnt pathway.
PMCID: PMC4249885  PMID: 25436461
4.  Qualitative and quantitative ultrashort-TE MRI of cortical bone 
NMR in biomedicine  2012;26(5):489-506.
Osteoporosis causes over 1.5 million fractures per year, costing about $15 billion annually in the USA. Current guidelines utilize bone mineral density (BMD) to assess fracture risk; however, BMD alone only accounts for 30–50% of fractures. The other two major components of bone, organic matrix and water, contribute significantly to bone mechanical properties, but cannot be assessed with conventional imaging techniques in spite of the fact that they make up about 57% of cortical bone by volume. Conventional clinical MRI usually detects signals from water in tissues without difficulty, but cannot detect the water bound to the organic matrix, or the free water in the microscopic pores of the Haversian and the lacunar-canalicular system of cortical bone, because of their very short apparent transverse relaxation times (T2*). In recent years, a new class of sequences, ultrashort-TE (UTE) sequences, with nominal TEs of less than 100 μs, which are much shorter than the TEs available with conventional sequences, have received increasing interest. These sequences can detect water signals from within cortical bone and provide an opportunity to study disease of this tissue in a new way. This review summarizes the recent developments in qualitative UTE imaging (techniques and contrast mechanisms to produce bone images with high contrast) and quantitative UTE imaging (techniques to quantify the MR properties, including T1, T2* and the magnetization transfer ratio, and tissue properties, including bone perfusion, as well as total, bound and free water content) of cortical bone in vitro and in vivo. The limitations of the current techniques for clinical applications and future directions are also discussed.
PMCID: PMC4206448  PMID: 23280581
cortical bone; osteoporosis; ultrashort TE; contrast mechanism; T1; T2*; bound water; free water
5.  Maximizing MR Signal for 2D UTE Slice Selection in the Presence of Rapid Transverse Relaxation 
Magnetic resonance imaging  2014;32(8):1006-1011.
Ultrashort TE (UTE) sequences allow direct visualization of tissues with very short T2 relaxation times, such as tendons, ligaments, menisci, and cortical bone. In this work, theoretical calculations, simulations, and phantom studies, as well as in vivo imaging were performed to maximize signal-to-noise ratio (SNR) for slice selective RF excitation for 2D UTE sequences. The theoretical calculations and simulations were based on the Bloch equations, which lead to analytic expressions for the optimal RF pulse duration and amplitude to maximize magnetic resonance signal in the presence of rapid transverse relaxation. In steady state, it was found that the maximum signal amplitude was not obtained at the classical Ernst angle, but at an either lower or higher flip angle, depending on whether the RF pulse duration or amplitude was varied, respectively.
PMCID: PMC4134980  PMID: 24814323
RF Optimization; 2D UTE; Short T2; Ernst Angle
6.  Magnetic resonance imaging assessed cortical porosity is highly correlated with μCT porosity 
Bone  2014;66:56-61.
Cortical bone is typically regarded as “MR invisible” with conventional clinical magnetic resonance imaging (MRI) pulse sequences. However, recent studies have demonstrated that free water in the microscopic pores of cortical bone has a short T2* but a relatively long T2, and may be detectable with conventional clinical spin echo (SE) or fast spin echo (FSE) sequences. In this study we describe the use of a conventional two-dimensional (2D) FSE sequence to assess cortical bone microstructure and measure cortical porosity using a clinical 3T scanner. Twelve cadaveric human cortical bone samples were studied with MRI and micro computed tomography (μCT) (downsampled to the same spatial resolution). Preliminary results show that FSE-determined porosity is highly correlated (R2 = 0.83; P < 0.0001) with μCT porosity. Bland Altman analysis suggested a good agreement between FSE and μCT with tight limit of agreement at around 3%. There is also a small bias of -2% for the FSE data, which suggested that the FSE approach slightly underestimated μCT porosity. The results demonstrate that cortical porosity can be directly assessed using conventional clinical FSE sequences. The clinical feasibility of this approach was also demonstrated on six healthy volunteers using 2D FSE sequences as well as 2D ultrashort echo time (UTE) sequences with a minimal echo time (TE) of 8 μs, which provide high contrast imaging of cortical bone in vivo.
PMCID: PMC4125420  PMID: 24928498
Fast spin echo; UTE; porosity; cortical bone; μCT
7.  Short T2 contrast with three-dimensional ultrashort echo time imaging 
Magnetic resonance imaging  2011;29(4):470-482.
There is increasing interest in imaging short T2 species which show little or no signal with conventional magnetic resonance (MR) pulse sequences. In this paper, we describe the use of three-dimensional ultrashort echo time (3D UTE) sequences with TEs down to 8 μs for imaging of these species. Image contrast was generated with acquisitions using dual echo 3D UTE with echo subtraction, dual echo 3D UTE with rescaled subtraction, long T2 saturation 3D UTE, long T2 saturation dual echo 3D UTE with echo subtraction, single adiabatic inversion recovery 3D UTE, single adiabatic inversion recovery dual echo 3D UTE with echo subtraction and dual adiabatic inversion recovery 3D UTE. The feasibility of using these approaches was demonstrated in in vitro and in vivo imaging of calcified cartilage, aponeuroses, menisci, tendons, ligaments and cortical bone with a 3-T clinical MR scanner. Signal-to-noise ratios and contrast-to-noise ratios were used to compare the techniques.
PMCID: PMC4123532  PMID: 21440400
Ultrashort TE; Projection reconstruction; 3D imaging; Short T2 contrast; Musculoskeletal imaging
8.  Measurement of T1 of the Ultrashort T2* Components in White Matter of the Brain at 3T 
PLoS ONE  2014;9(8):e103296.
Recent research demonstrates that white matter of the brain contains not only long T2 components, but a minority of ultrashort T2* components. Adiabatic inversion recovery prepared dual echo ultrashort echo time (IR-dUTE) sequences can be used to selectively image the ultrashort T2* components in white matter of the brain using a clinical whole body scanner. The T2*s of the ultrashort T2* components can be quantified using mono-exponential decay fitting of the IR-dUTE signal at a series of different TEs. However, accurate T1 measurement of the ultrashort T2* components is technically challenging. Efficient suppression of the signal from the majority of long T2 components is essential for robust T1 measurement. In this paper we describe a novel approach to this problem based on the use of IR-dUTE data acquisitions with different TR and TI combinations to selectively detect the signal recovery of the ultrashort T2* components. Exponential recovery curve fitting provides efficient T1 estimation, with minimized contamination from the majority of long T2 components. A rubber phantom and a piece of bovine cortical bone were used for validation of this approach. Six healthy volunteers were studied. An averaged T2* of 0.32±0.09 ms, and a short mean T1 of 226±46 ms were demonstrated for the healthy volunteers at 3T.
PMCID: PMC4122467  PMID: 25093859
9.  Ascophyllan Purified from Ascophyllum nodosum Induces Th1 and Tc1 Immune Responses by Promoting Dendritic Cell Maturation 
Marine Drugs  2014;12(7):4148-4164.
Marine-derived sulfated polysaccharides have been shown to possess certain anti-virus, anti-tumor, anti-inflammatory and anti-coagulant activities. However, the in vivo immunomodulatory effects of marine-derived pure compounds have been less well characterized. In this study, we investigated the effect of ascophyllan, a sulfated polysaccharide purified from Ascophyllum nodosum, on the maturation of mouse dendritic cells (DCs) in vitro and in vivo. Ascophyllan induced up-regulation of co-stimulatory molecules and production of pro-inflammatory cytokines in bone marrow-derived DCs (BMDCs). Moreover, in vivo administration of ascophyllan promotes up-regulation of CD40, CD80, CD86, MHC class I and MHC class II and production of IL-6, IL-12 and TNF-α in spleen cDCs. Interestingly, ascophyllan induced a higher degree of co-stimulatory molecule up-regulation and pro-inflammatory cytokine production than fucoidan, a marine-derived polysaccharide with well-defined effect for promoting DC maturation. Ascophyllan also promoted the generation of IFN-γ-producing Th1 and Tc1 cells in the presence of DCs in an IL-12-dependent manner. Finally, myeloid differentiation primary response 88 (MyD88) signaling pathway was essential for DC maturation induced by ascophyllan. Taken together, these results demonstrate that ascophyllan induces DC maturation, and consequently enhances Th1 and Tc1 responses in vivo. This knowledge could facilitate the development of novel therapeutic strategies to combat infectious diseases and cancer.
PMCID: PMC4113820  PMID: 25026264
ascophyllan; dendritic cells; DC maturation; Th1 cells; Tc1 cells
10.  Age-associated differences in triceps surae muscle composition and strength – an MRI-based cross-sectional comparison of contractile, adipose and connective tissue 
In human skeletal muscles, the aging process causes a decrease of contractile and a concomitant increase of intramuscular adipose (IMAT) and connective (IMCT) tissues. The accumulation of non-contractile tissues may contribute to the significant loss of intrinsic muscle strength typically observed at older age but their in vivo quantification is challenging. The purpose of this study was to establish MR imaging-based methods to quantify the relative amounts of IMCT, IMAT and contractile tissues in young and older human cohorts, and investigate their roles in determining age-associated changes in skeletal muscle strength.
Five young (31.6 ± 7.0 yrs) and five older (83.4 ± 3.2 yrs) Japanese women were subject to a detailed MR imaging protocol, including Fast Gradient Echo, Quantitative Fat/Water (IDEAL) and Ultra-short Echo Time (UTE) sequences, to determine contractile muscle tissue and IMAT within the entire Triceps Surae complex, and IMCT within both heads of the Gastrocnemius muscle. Specific force was calculated as the ratio of isometric plantarflexor force and the physiological cross-sectional area of the Triceps Surae complex.
In the older cohort, total Triceps Surae volume was smaller by 17.5%, while the relative amounts of Triceps Surae IMAT and Gastrocnemius IMCT were larger by 55.1% and 48.9%, respectively. Differences of 38.6% and 42.1% in plantarflexor force and specific force were observed. After subtraction of IMAT and IMCT from total muscle volume, differences in intrinsic strength decreased to 29.6%.
Our data establishes that aging causes significant changes in skeletal muscle composition, with marked increases in non-contractile tissues. Such quantification of the remodeling process is likely to be of functional and clinical importance in elucidating the causes of the disproportionate age-associated decrease of force compared to that of muscle volume.
PMCID: PMC4072482  PMID: 24939372
Intrinsic strength; Muscle composition; UTE imaging; IDEAL; Aging
11.  Dual Inversion Recovery Ultrashort Echo Time (DIR-UTE) Imaging and Quantification of the Zone of Calcified Cartilage (ZCC) 
To develop ultrashort echo time (UTE) magnetic resonance imaging (MRI) techniques to image the zone of calcified cartilage (ZCC), and quantify its T2*, T1 and T1ρ.
In this feasibility study a dual inversion recovery ultrashort echo time (DIR-UTE) sequence was developed for high contrast imaging of the ZCC. T2* of the ZCC was measured with DIR-UTE acquisitions at progressively increasing TEs. T1 of the ZCC was measured with saturation recovery UTE acquisitions at progressively increasing saturation recovery times. T1ρ of the ZCC was measured with spin-locking prepared DIR-UTE acquisitions at progressively increasing spin-locking times.
The feasibility of the qualitative and quantitative DIR-UTE techniques was demonstrated on phantoms and in six cadaveric patellae using a clinical 3T scanner. On average the ZCC has a short T2* ranging from 1.0 to 3.3 ms (mean ± standard deviation = 2.0 ± 1.2 ms), a short T1 ranging from 256 to 389 ms (mean ± standard deviation = 305 ± 45 ms), and a short T1ρ ranging from 2.2 to 4.6 ms (mean ± standard deviation = 3.6 ± 1.2 ms).
UTE MR based techniques have been developed for high resolution imaging of the ZCC and quantitative evaluation of its T2*, T1 and T1ρ relaxation times, providing noninvasive assessment of collagen orientation and proteoglycan content at the zone of calcified cartilage and the bone cartilage interface. These measurements may be useful for non-invasive assessment of the ZCC, including understanding the involvement of this tissue component in osteoarthritis.
PMCID: PMC4051156  PMID: 23025927
Ultrashort echo time; adiabatic inversion recovery; dual inversion recovery; T1ρ; ZCC
12.  Fucoidan Can Function as an Adjuvant In Vivo to Enhance Dendritic Cell Maturation and Function and Promote Antigen-Specific T Cell Immune Responses 
PLoS ONE  2014;9(6):e99396.
Fucoidan, a sulfated polysaccharide purified from brown algae, has a variety of immune-modulation effects, including promoting antigen uptake and enhancing anti-viral and anti-tumor effects. However, the effect of fucoidan in vivo, especially its adjuvant effect on in vivo anti-tumor immune responses, was not fully investigated. In this study, we investigated the effect of fucoidan on the function of spleen dendritic cells (DCs) and its adjuvant effect in vivo. Systemic administration of fucoidan induced up-regulation of CD40, CD80 and CD86 expression and production of IL-6, IL-12 and TNF-α in spleen cDCs. Fucoidan also promoted the generation of IFN-γ-producing Th1 and Tc1 cells in an IL-12-dependent manner. When used as an adjuvant in vivo with ovalbumin (OVA) antigen, fucoidan promoted OVA-specific antibody production and primed IFN-γ production in OVA-specific T cells. Moreover, fucoidan enhanced OVA-induced up-regulation of MHC class I and II on spleen cDCs and strongly prompted the proliferation of OVA-specific CD4 and CD8 T cells. Finally, OVA immunization with fucoidan as adjuvant protected mice from the challenge with B16-OVA tumor cells. Taken together, these results suggest that fucoidan can function as an adjuvant to induce Th1 immune response and CTL activation, which may be useful in tumor vaccine development.
PMCID: PMC4049775  PMID: 24911024
13.  Class I ADP-Ribosylation Factors Are Involved in Enterovirus 71 Replication 
PLoS ONE  2014;9(6):e99768.
Enterovirus 71 is one of the major causative agents of hand, foot, and mouth disease in infants and children. Replication of enterovirus 71 depends on host cellular factors. The viral replication complex is formed in novel, cytoplasmic, vesicular compartments. It has not been elucidated which cellular pathways are hijacked by the virus to create these vesicles. Here, we investigated whether proteins associated with the cellular secretory pathway were involved in enterovirus 71 replication. We used a loss-of-function assay, based on small interfering RNA. We showed that enterovirus 71 RNA replication was dependent on the activity of Class I ADP-ribosylation factors. Simultaneous depletion of ADP-ribosylation factors 1 and 3, but not three others, inhibited viral replication in cells. We also demonstrated with various techniques that the brefeldin-A-sensitive guanidine nucleotide exchange factor, GBF1, was critically important for enterovirus 71 replication. Our results suggested that enterovirus 71 replication depended on GBF1-mediated activation of Class I ADP-ribosylation factors. These results revealed a connection between enterovirus 71 replication and the cellular secretory pathway; this pathway may represent a novel target for antiviral therapies.
PMCID: PMC4049829  PMID: 24911624
Journal of orofacial pain  2011;25(4):345-353.
To quantify short T2* properties of a disc from human temporomandibular joint (TMJ) using ultrashort time-to-echo magnetic resonance imaging (UTE MRI) technique, and to corroborate regional T2* values with biomechanical properties and histologic appearance.
A cadaveric human TMJ was sliced sagittally and imaged using conventional and UTE MRI techniques. The slices were then subjected to either biomechanical indentation testing or histologic evaluation for comparison to T2* maps obtained from UTE MRI data, using linear regression. Feasibility of in vivo UTE MRI was assessed in two volunteers.
UTE MRI technique of specimens provided images of TMJ disc with greater signal-to-noise ratio (~3 fold) and contrast against surrounding tissues compared to conventional techniques. Higher T2* values correlated with lower indentation stiffness (softer) and less collagen organization as indicated by polarized light microscopy. T2* values were also obtained from volunteers.
UTE MRI facilitates quantitative characterization of TMJ discs, which may reflect structural and functional properties related to TMJ dysfunction.
PMCID: PMC4048068  PMID: 22247930
temporomandibular joint disc; magnetic resonance imaging; ultrashort time-to-echo; osteoarthritis; indentation
15.  Cellular Uptake and Antitumor Activity of DOX-hyd-PEG-FA Nanoparticles 
PLoS ONE  2014;9(5):e97358.
A PEG-based, folate mediated, active tumor targeting drug delivery system using DOX-hyd-PEG-FA nanoparticles (NPs) were prepared. DOX-hyd-PEG-FA NPs showed a significantly faster DOX release in pH 5.0 medium than in pH 7.4 medium. Compared with DOX-hyd-PEG NPs, DOX-hyd-PEG-FA NPs increased the intracellular accumulation of DOX and showed a DOX translocation from lysosomes to nucleus. The cytotoxicity of DOX-hyd-PEG-FA NPs on KB cells was much higher than that of free DOX, DOX-ami-PEG-FA NPs and DOX-hyd-PEG NPs. The cytotoxicity of DOX-hyd-PEG-FA NPs on KB cells was attenuated in the presence of exogenous folic acid. The IC50 of DOX-hyd-PEG-FA NPs and DOX-hyd-PEG NPs on A549 cells showed no significant difference. After DOX-hyd-PEG-FA NPs were intravenously administered, the amount of DOX distributed in tumor tissue was significantly increased, while the amount of DOX distributed in heart was greatly decreased as compared with free DOX. Compared with free DOX, NPs yielded improved survival rate, prolonged life span, delayed tumor growth and reduced the cardiotoxicity in tumor bearing mice model. These results indicated that the acid sensitivity, passive and active tumor targeting abilities were likely to act synergistically to enhance the drug delivery efficiency of DOX-hyd-PEG-FA NPs. Therefore, DOX-hyd-PEG-FA NPs are a promising drug delivery system for targeted cancer therapy.
PMCID: PMC4020841  PMID: 24828815
16.  Quantitative 3D Ultrashort Time-to-Echo (UTE) MRI and Micro-CT (μCT) Evaluation of the Temporomandibular Joint (TMJ) Condylar Morphology 
Skeletal radiology  2013;43(1):19-25.
Temporomandibular dysfunction involves osteoarthritis of the TMJ, including degeneration and morphologic changes of the mandibular condyle. Purpose of this study was to determine accuracy of novel 3D-UTE MRI versus micro-CT (μCT) for quantitative evaluation of mandibular condyle morphology.
Material & Methods
Nine TMJ condyle specimens were harvested from cadavers (2M, 3F; Age 85 ± 10 yrs., mean±SD). 3D-UTE MRI (TR=50ms, TE=0.05 ms, 104 μm isotropic-voxel) was performed using a 3-T MR scanner and μCT (18 μm isotropic-voxel) was performed. MR datasets were spatially-registered with μCT dataset. Two observers segmented bony contours of the condyles. Fibrocartilage was segmented on MR dataset. Using a custom program, bone and fibrocartilage surface coordinates, Gaussian curvature, volume of segmented regions and fibrocartilage thickness were determined for quantitative evaluation of joint morphology. Agreement between techniques (MRI vs. μCT) and observers (MRI vs. MRI) for Gaussian curvature, mean curvature and segmented volume of the bone were determined using intraclass correlation correlation (ICC) analyses.
Between MRI and μCT, the average deviation of surface coordinates was 0.19±0.15 mm, slightly higher than spatial resolution of MRI. Average deviation of the Gaussian curvature and volume of segmented regions, from MRI to μCT, was 5.7±6.5% and 6.6±6.2%, respectively. ICC coefficients (MRI vs. μCT) for Gaussian curvature, mean curvature and segmented volumes were respectively 0.892, 0.893 and 0.972. Between observers (MRI vs. MRI), the ICC coefficients were 0.998, 0.999 and 0.997 respectively. Fibrocartilage thickness was 0.55±0.11 mm, as previously described in literature for grossly normal TMJ samples.
3D-UTE MR quantitative evaluation of TMJ condyle morphology ex-vivo, including surface, curvature and segmented volume, shows high correlation against μCT and between observers. In addition, UTE MRI allows quantitative evaluation of the fibrocartilaginous condylar component.
PMCID: PMC4000774  PMID: 24092237
Temporomandibular Joint (TMJ); Joint Morphology; 3D Ultrashort Time to Echo (UTE); MRI; Micro-CT (μCT)
17.  Inhibition of Enterovirus 71 Replication by 7-Hydroxyflavone and Diisopropyl-Flavon7-yl Phosphate 
PLoS ONE  2014;9(3):e92565.
Enterovirus 71 (EV71) is the major causative agent of hand, foot, and mouth disease, which has been continuously prevalent in Asia in recent years. In children, severe cases can lead to death, and no prophylactic or therapeutic measures against EV71 infection are available. The 3C proteases of EV71 play an important role in viral replication and are an ideal drug target. In previous work, we resolved the crystal structure for EV71 3Cpro. In this report, we took advantage of the automated docking program AutoDock 4.0 to simulate EV71 3Cpro-ligand conformation. 7-hydroxyflavone (HF) and its phosphate ester(FIP) were predicted to bind with EV71 3Cpro.In an in vitro protease inhibition assay, FIP inhibited EV71 3Cpro protease activity. Both flavones were highly active against EV71, protecting cells from EV71 infection. Replication of viral RNA and formation of EV71 plaque were all strongly inhibited in cells. These results indicated that HF and FIP may serve as potential protective agents in the treatment of patients with chronic EV71 infection.
PMCID: PMC3963929  PMID: 24664133
18.  Analysis of nitric oxide synthase gene polymorphisms in neonatal respiratory distress syndrome among the Chinese Han population 
To evaluate the association of NOS1 and NOS3 gene polymorphisms with the risk/severity of neonatal respiratory distress syndrome (RDS) among preterm infants.
The patient group was 189 preterm infants diagnosed with RDS. The control group was 227 preterm neonates who did not develop RDS. NOS genotyping was performed using an improved multiplex ligation detection reaction (iMLDR) technique based on LDR.
It was found that genotype and allele frequencies of rs2682826 of the NOS1 gene and rs1799983 of the NOS3 gene were not significantly different between the RDS group and the control group. However, when the preterm infants were divided into two and three groups based on gestational age and birth weight, a study of the SNP rs1799983 of the NOS3 gene showed that the GG genotype and G allele frequencies were significantly increased in the RDS groups, the GT genotype and A allele were less frequent among the RDS groups in 26–32.9 weeks of gestational age and in a birth weight subgroup of <1.5 Kg.
Our study raises the possibility that a genetic variation of NOS3 could be implicated in the pathophysiology of RDS in the Chinese Han population, especially in very preterm and very low birth weight infants.
PMCID: PMC3996033  PMID: 24602444
Nitric oxide synthase; Respiratory distress syndrome; Preterm infants; Multiplex ligation detection reaction; Polymorphism
19.  Anti-Enterovirus 71 Effects of Chrysin and Its Phosphate Ester 
PLoS ONE  2014;9(3):e89668.
Enterovirus 71 (EV71) can cause severe disease and even lead to death in children, and an effective antiviral drug is currently unavailable. The anti-EV71 effect of chrysin (5,7-dihydroxyflavone), a natural flavonoid commonly found in many plants, was tested in this report. By using the predicting program Autodock 4.0 and an in vitro protease inhibition assay, we found that chrysin could suppress viral 3Cpro activity. Replication of viral RNA and production of viral capsid protein and the infectious virion were strongly inhibited by chrysin, without noticeable cytotoxicity. Cytopathic effects on cells were also prevented. Diisopropyl chrysin-7-yl phosphate (CPI), the phosphate ester for chrysin, was generated through a simplified Atheron-Todd reaction to achieve stronger anti-viral activity. CPI was also able to bind with and inhibit viral 3Cpro activity in vitro. As expected, CPI demonstrated more potent antiviral activity against EV71.
PMCID: PMC3943725  PMID: 24598537
20.  Recombinant Human Coxsackievirus B3 from Children with Acute Myocarditis in China 
Journal of Clinical Microbiology  2013;51(9):3083-3086.
Recombination events were found in two human coxsackievirus B3 strains, Beijing0811 and SD2012CHN. The strains were isolated separately from five newborns diagnosed with severe hospital-acquired acute myocarditis in Beijing in 2008 and from two children diagnosed with hand, foot, and mouth disease with concurrent acute myocarditis in Shandong in 2012.
PMCID: PMC3754657  PMID: 23804378
21.  Factors associated with one year retention to methadone maintenance treatment program among patients with heroin dependence in China 
The aim of this study was to evaluate the risk factors associated with dropout from Methadone Maintenance Treatment (MMT) clinics within a 1 year follow-up cohort study in China.
A data analysis is to explore the adherence of MMT during one year from three hundred and twenty patients with heroin dependence at five clinics (3 in Shanghai, 2 in Kunming) in China. All participants were from the part of China-United States cooperation project entitled “Research about improving the compliance and efficacy of methadone maintenance treatment in China”. Our data analysis includes the patients’ attendance in the 6 months clinical study and the data in another 6 months afterward. The data of patients at baseline were collected with the Addiction Severity Index (ASI) which is a semi-structured questionnaire covering socio-demographic characteristics and drug use history. The one year attendance after recruitment at the clinics and daily dose were abstracted from the MMT clinic register system. The Cox proportional hazards model were used to explore the risk factor of dropout, defined as seven consecutive days without methadone.
By the end of 1 year of treatment 86 patients still remained in MMT without dropout (87% in Shanghai and 13% patients in Kunming). Over the entire 1-year period the median days of remaining in the program were 84 days (in Shanghai and Kunming were 317 days and 22 days).The factors associated with retention included age (HR = 0.98, 95%C.I.:0.96-0.99, P = 0.0062) and ASI alcohol scores (HR = 5.72, 95%C.I.:1.49-21.92, P = 0.0109) at baseline.
One year retention of newly recruited patients with heroin dependence was related to age and ASI alcohol scores at baseline. The adherence is poorer for the patients who are young and having more serious alcohol problems.
PMCID: PMC3974188  PMID: 24565169
Heroin dependence; Methadone maintenance treatment; Survival analysis
22.  Evaluation of Video-Assisted Thoracoscopic Surgery for Pulmonary Metastases: A Meta-Analysis 
PLoS ONE  2014;9(1):e85329.
To evaluate the evidence comparing video-assisted thoracic surgery (VATS) and open thoracotomy in the treatment of metastatic lung cancer using meta-analytical techniques.
A literature search was undertaken until July 2013 to identify the comparative studies evaluating disease-free survival rates and survival rates. The pooled odds ratios (OR) and the 95% confidence intervals (95% CI) were calculated with the fixed or random effect models.
Six retrospective studies were included in our meta-analysis. These studies included a total of 546 patients: 235 patients were treated with VATS, and 311 patients were treated with open thoracotomy. The VATS and the thoracotomy did not demonstrate a significant difference in the 1-,3-,5-year survival rates and the 1-year disease-free survival rate. There were significant statistical differences between the 3-year disease free survival rate (p = 0.04), which favored open thoracotomy.
The VATS approach is a safe and feasible treatment in terms of the survival rate for metastatic lung cancer compared with the thoracotomy. The 3-year disease-free survival rate in the VATS group is inferior to that of open thoracotomy. The VATS approach could not completely replace open thoracotomy.
PMCID: PMC3887046  PMID: 24416392
23.  Pilot Trial of a Recovery Management Intervention for Heroin Addicts Released from Compulsory Rehabilitation in China 
China faces the challenge of dual epidemics of drug use and HIV/AIDS. Despite the high relapse rate among heroin addicts released from compulsory rehabilitation facilities, there are few programs available in China to assist these addicts in the community. We pilot-tested in China a Recovery Management Intervention (RMI) program designed to facilitate early detection of relapse and prompt linkage from compulsory rehabilitation to the community and, if participants relapse, to community-based methadone maintenance treatment (MMT) programs. One hundred heroin addicts were randomly assigned to either the Standard Care group (n=50) or the RMI group (n=50). At the end of the 3-month trial, participants in the RMI group, relative to the standard care group, demonstrated positive outcomes in recidivism due to relapse (0 vs. 6%, p=0.08; d=0.354), MMT participation (8% vs. 0, p=0.6; d=0.417), and employment (33% vs. 2%, p<.001; d=0.876), although no difference was found in urine testing results (8.5% vs. 8.7%; d=0.013) among interviewed participants. These pilot study results were based on a small sample size and short-term observation, suggesting the need for more research to further improve and test RMI effectiveness with larger samples over a longer period of time in order to provide evidence in support of RMI as an effective strategy for community reintegration among addicts released from rehabilitation facilities in China.
PMCID: PMC3404204  PMID: 22520276
Recovery management; compulsory rehabilitation; China
24.  Hippocampal and thalamic neuronal metabolism in a putative rat model of schizophrenia 
Neural Regeneration Research  2013;8(26):2415-2423.
The transcription factor early growth response protein 3 (EGR3) is involved in schizophrenia. We developed a putative rat model of schizophrenia by transfecting lentiviral particles carrying the Egr3 gene into bilateral hippocampal dentate gyrus. We assessed spatial working memory using the Morris water maze test, and neuronal metabolite levels in bilateral hippocampus and thalamus were determined by 3.0 T proton magnetic resonance spectroscopy. Choline content was significantly greater in the hippocampus after transfection, while N-acetylaspartate and the ratio of N-acetylaspartate to creatine/phosphocreatine in the thalamus were lower than in controls. This study is the first to report evaluation of brain metabolites using 3.0 T proton magnetic resonance spectroscopy in rats transfected with Egr3, and reveals metabolic abnormalities in the hippocampus and thalamus in this putative model of schizophrenia.
PMCID: PMC4146111  PMID: 25206551
neural regeneration; neuroimaging; schizophrenia; proton magnetic resonance spectroscopy; early growth response protein 3; hippocampus; thalamus; gene; neuroregeneration
25.  Reliability and Validity of the CogState Battery Chinese Language Version in Schizophrenia 
PLoS ONE  2013;8(9):e74258.
Cognitive impairment in patients with schizophrenia is a core symptom of this disease. The computerized CogState Battery (CSB) has been used to detect seven of the most common cognitive domains in schizophrenia. The aim of this study was to examine the reliability and validity of the Chinese version of the CSB (CSB-C), in Chinese patients with schizophrenia.
Methodology/Principal Findings
Sixty Chinese patients with schizophrenia and 58 age, sex, and education matched healthy controls were enrolled. All subjects completed the CSB-C and the Repeated Battery for the Assessment of Neuropsychological Status (RBANS). To examine the test-retest reliability of CSB-C, we tested 33 healthy controls twice, at a one month interval. The Cronbach α value of CSB-C in patients was 0.81. The test-retest correlation coefficients of the Two Back Task, Gronton Maze Learning Task, Social Emotional Cognition Task, and Continuous Paired Association Learning Task were between 0.39 and 0.62 (p<0.01) in healthy controls. The composite scores and all subscores for the CSB-C in patients were significantly (p<0.01) lower than those of healthy controls. Furthermore, composite scores for patients on the RBANS were also significantly lower than those of healthy controls. Interestingly, there was a positive correlation (r  =  0.544, p<0.001) between the composite scores on CSB-C and RBANS for patients. Additionally, in the attention and memory cognitive domains, corresponding subsets from the two batteries correlated significantly (p<0.05). Moreover, factor analysis showed a two-factor model, consisting of speed, memory and reasoning.
The CSB-C shows good reliability and validity in measuring the broad cognitive domains of schizophrenia in affected Chinese patients. Therefore, the CSB-C can be used as a cognitive battery, to assess the therapeutic effects of potential cognitive-enhancing agents in this cohort.
PMCID: PMC3759436  PMID: 24023931

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