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1.  A longitudinal cohort study of the impact of first- and both-eye cataract surgery on falls and other injuries in Vietnam 
Little information exists on the impact of cataract surgery on falls and other injuries in Vietnam. The aim of this study was to determine the impact of first and both eye cataract surgery on the number of falls and other injuries among bilateral cataract patients in Ho Chi Minh City, Vietnam.
Materials and methods
A longitudinal cohort study was conducted involving 413 bilateral cataract patients aged 50+ years. Participants were assessed at three time points: 1 week before, 1–3 months after, and 1 year after first-eye cataract surgery. Visual measures (visual acuity, contrast sensitivity and stereopsis) were taken, and self-reported falls and injury data were collected. A multilevel longitudinal Poisson regression model was used to investigate change in the number of falls after surgery.
The risk of falls decreased by 78% (incidence-rate ratio [IRR] 0.22, 95% confidence interval [CI] 0.06–0.77; P=0.018) in the year after cataract surgery for participants who had first-eye surgery only and 83% (IRR 0.17, 95% CI 0.04–0.69; P=0.012) for participants who had the second eye operated on compared to before surgery. The risk of falls was three times higher for females than males (IRR 3.13, 95% CI 1.53–6.40; P=0.002). Improved binocular contrast sensitivity was also associated with a decrease in falls (IRR 0.40, 95% CI 0.17–0.97; P=0.042). The prevalence of other injuries also decreased after cataract surgery.
Cataract surgery reduced the number of falls and other injuries in Vietnam. Contrast sensitivity may be important for ophthalmologists to consider when prioritizing patients for surgery and assessing their fall risk.
PMCID: PMC4011894  PMID: 24812501
falls; injuries; cataract surgery; longitudinal; older population; Vietnam
2.  A Fluorescent Styrylquinoline with Combined Therapeutic and Diagnostic Activities against Alzheimer’s and Prion Diseases 
ACS Medicinal Chemistry Letters  2012;4(2):225-229.
(E)-6-Methyl-4′-amino-2-styrylquinoline (3) is a small molecule with the proper features to potentially diagnose, deliver therapy and monitor response to therapy in protein misfolding diseases. These features include compound fluorescent emission in the NIR region and its ability to interact with both Aβ and prion fibrils, staining them with high selectivity. Styrylquinoline 3 also inhibits Aβ self-aggregation in vitro and prion replication in the submicromolar range in a cellular context. Furthermore, it is not toxic and is able to cross the blood brain barrier in vitro (PAMPA test).
PMCID: PMC4027132  PMID: 24900645
Aggregation; protein misfolding diseases; amyloid; fibrillation inhibitors
3.  The impact of cataract surgery on vision-related quality of life for bilateral cataract patients in Ho Chi Minh City, Vietnam: a prospective study 
To determine the impact of cataract surgery on vision-related quality of life (VRQOL) and examine the association between objective visual measures and change in VRQOL after surgery among bilateral cataract patients in Ho Chi Minh City, Vietnam.
A cohort of older patients with bilateral cataract was assessed one week before and one to three months after first eye or both eye cataract surgery. Visual measures including visual acuity, contrast sensitivity and stereopsis were obtained. Vision-related quality of life was assessed using the NEI VFQ-25. Descriptive analyses and a generalized linear estimating equation (GEE) analysis were undertaken to measure change in VRQOL after surgery.
Four hundred and thirteen patients were assessed before cataract surgery and 247 completed the follow-up assessment one to three months after first or both eye cataract surgery. Overall, VRQOL significantly improved after cataract surgery (p < 0.001) particularly after both eye surgeries. Binocular contrast sensitivity (p < 0.001) and stereopsis (p < 0.001) were also associated with change in VRQOL after cataract surgery. Visual acuity was not associated with VRQOL.
Cataract surgery significantly improved VRQOL among bilateral cataract patients in Vietnam. Contrast sensitivity as well as stereopsis, rather than visual acuity significantly affected VRQOL after cataract surgery.
PMCID: PMC3922411  PMID: 24499481
Vision; Public health; Epidemiology; Cataract; Quality of life
4.  From laptop to benchtop to bedside: Structure-based Drug Design on Protein Targets 
Current pharmaceutical design  2012;18(9):1217-1239.
As an important aspect of computer-aided drug design, structure-based drug design brought a new horizon to pharmaceutical development. This in silico method permeates all aspects of drug discovery today, including lead identification, lead optimization, ADMET prediction and drug repurposing. Structure-based drug design has resulted in fruitful successes drug discovery targeting protein-ligand and protein-protein interactions. Meanwhile, challenges, noted by low accuracy and combinatoric issues, may also cause failures. In this review, state-of-the-art techniques for protein modeling (e.g. structure prediction, modeling protein flexibility, etc.), hit identification/optimization (e.g. molecular docking, focused library design, fragment-based design, molecular dynamic, etc.), and polypharmacology design will be discussed. We will explore how structure-based techniques can facilitate the drug discovery process and interplay with other experimental approaches.
PMCID: PMC3820560  PMID: 22316152
Structure-based drug design; protein modeling; focused library design; pharmacophore; flexible docking; high-throughput virtual screening; de novo design; protein-protein interaction; polypharmacology
5.  The Potential Impact of Expanding Antiretroviral Therapy and Combination Prevention in Vietnam: Towards Elimination of HIV Transmission 
Supplemental Digital Content is Available in the Text.
Few studies have assessed the effects of antiretroviral therapy (ART) to prevent HIV transmission in Asian HIV epidemics. Vietnam has a concentrated HIV epidemic with the highest prevalence among people who inject drugs. We investigated the impact of expanded HIV testing and counseling (HTC) and early ART, combined with other prevention interventions on HIV transmission.
A deterministic mathematical model was developed using HIV prevalence trends in Can Tho province, Vietnam. Scenarios included offering periodic HTC and immediate ART with and without targeting subpopulations and examining combined strategies with methadone maintenance therapy and condom use.
From 2011 to 2050, maintaining current interventions will incur an estimated 18,115 new HIV infections and will cost US $22.1 million (reference scenario). Annual HTC and immediate treatment, if offered to all adults, will reduce new HIV infections by 14,513 (80%) and will cost US $76.9 million. Annual HTC and immediate treatment offered only to people who inject drugs will reduce new infections by 13,578 (75%) and will cost only US $23.6 million. Annual HTC and immediate treatment for key populations, combined with scale-up of methadone maintenance therapy and condom use, will reduce new infections by 14,723 (81%) with similar costs (US $22.7 million). This combination prevention scenario will reduce the incidence to less than 1 per 100,000 in 14 years and will result in a relative cost saving after 19 years.
Targeted periodic HTC and immediate ART combined with other interventions is cost-effective and could lead to potential elimination of HIV in Can Tho.
PMCID: PMC3814627  PMID: 23714739
antiretroviral therapy; prevention; elimination; HIV transmission; Vietnam; people who inject drugs
6.  Accurate Prediction of the Bound Form of the Akt Pleckstrin Homology Domain using Normal Mode Analysis to Explore Structural Flexibility 
Journal of chemical information and modeling  2011;51(9):10.1021/ci2001742.
Molecular docking is often performed with rigid receptors. This can be a serious limitation, since the receptor often differs between bound and unbound forms, or between bound forms with different ligands. We recently developed a normal-mode based docking method and showed that it is possible to obtain reasonable estimates of the complexed form of the pleckstrin homology (PH) domain of Akt, starting with the free form of the receptor. With in-ositol (1,3,4,5)-tetrakisphosphate (IP4) as the ligand the docked results agree with the known high-resolution X-ray crystal structure of the IP4-Akt PH domain complex. We also tested our methods with PH4, SC66, and PIT-1, several recently designed PH domain inhibitors. The results are shown to be consistent with available experimental data and previous modeling studies. The method we described can be used for molecular docking analysis even when only an approximation of the experimental structure or model is known.
PMCID: PMC3807676  PMID: 21834588
7.  Facile Pyrolytic Synthesis of Silicon Nanowires 
Solid-state electronics  2010;54(10):1185-1191.
One-dimensional nanostructures such as silicon nanowires (SiNW) are attractive candidates for low power density electronic and optoelectronic devices including sensors. A new simple method for SiNW bulk synthesis[1, 2] is demonstrated in this work, which is inexpensive and uses low toxicity materials, thereby offering a safe, energy efficient and green approach. The method uses low flammability liquid phenylsilanes, offering a safer avenue for SiNW growth compared with using silane gas. A novel, duo-chamber glass vessel is used to create a low-pressure environment where SiNWs are grown through vapor-liquid-solid mechanism using gold nanoparticles as a catalyst. The catalyst decomposes silicon precursor vapors of diphenylsilane and triphenylsilane and precipitates single crystal SiNWs, which appear to grow parallel to the substrate surface. This opens up possibilities for synthesizing nano-junctions amongst wires which is important for the grid architecture of nanoelectronics proposed by Likharev[3]. Even bulk synthesis of SiNW is feasible using sacrificial substrates such as CaCO3 that can be dissolved post-synthesis. Furthermore, by dissolving appropriate dopants in liquid diphenylsilane, a controlled doping of the nanowires is realized without the use of toxic gases and expensive mass flow controllers. Upon boron doping, we observe a characteristic red shift in photoluminescence spectra. In summary, an inexpensive and versatile method for SiNW is presented that makes these exotic materials available to any lab at low cost.
PMCID: PMC2919782  PMID: 20711489
Silicon nanowires; dopants; photoluminescence; gold nanoparticles; HR-TEM
8.  Overexpression of Laminin-8 in Human Dermal Microvascular Endothelial Cells Promotes Angiogenesis-Related Functions 
This study examined the effects of endogenous overexpression of laminin-8 on angiogenesis and wound healing in primary human dermal microvascular endothelial cells (HDMECs). HDMECs expressed laminin-8 and laminin-10, but no other laminins, as determined by radioimmunoprecipitation assay using a panel of antibodies to individual laminin chains. To study laminin-8 function, full-length human laminin α4 cDNA was retrovirally transferred to HDMEC, and specific overexpression of laminin-8 was verified by Western blot. Laminin-8 overexpression promoted endothelial cell spreading and migration in scratch assays and accelerated angiogenic tubule formation in collagen gel overlay assays. Strong inhibitory effect of β1 integrin and weak inhibition by αvβ3 integrin antibodies were observed in laminin-8-stimulated cell migration, but only β1 integrin antibodies affected tubule formation. These studies suggest that laminin-8 overexpression may prove to be a useful method to engineer HDMECs to promote angiogenesis and wound repair.
PMCID: PMC2535788  PMID: 16374451
9.  Brain Atrophy in Long-Term Abstinent Alcoholics Who Demonstrate Impairment on a Simulated Gambling Task 
NeuroImage  2006;32(3):1465-1471.
We recently demonstrated impairment on the Simulated Gambling Task (SGT) in long-term abstinent alcoholics (AbsAlc). Brain regions that have been shown to be necessary for intact SGT performance are the ventromedial prefrontal cortex (VMPFC) and the amygdala; patients with VMPFC or amygdalar damage demonstrate SGT impairments similar to those of substance abusing populations. We examined these brain regions, using T1-weighted MRIs, in the 101 participants from our previous study using voxel-based morphometry (VBM). VBM was performed using a modification we developed (Fein et al., 2006) of Baron’s procedure, (Baron et al., 2001), in which we use skull-stripped images as input. We also restricted the analysis to a ROI consisting of the amygdala and VMPFC as defined by the Talairach Daemon resource. Compared to the controls, the AbsAlc participants had significant foci of reduced gray matter density within the amygdala. Thus, SGT decision-making deficits are associated with reduced gray matter in the amygdala, a brain region previously implicated in similar decision-making impairments in neurological samples. This structurally based abnormality may be the result of long-term alcohol abuse or dependence, or it may reflect a pre-existing factor that predisposes one to severe alcoholism. From an image analysis perspective, this work demonstrates the increased sensitivity that results from using skull-stripped inputs and from restricting the analysis to a ROI. Without both of these methodological advances, no statistically significant finding would have been forthcoming from this work.
PMCID: PMC1868686  PMID: 16872844
Simulated Gambling Task; Alcohol Abuse; Long-Term Abstinence; MRI; Amygdala; Ventromedial Prefrontal Cortex; Decision-Making
10.  Statistical Parametric Mapping of Brain Morphology: Sensitivity is Dramatically Increased by Using Brain-Extracted Images as Inputs 
NeuroImage  2006;30(4):1187-1195.
A major attraction of voxel-based morphometry (VBM) is that it allows researchers to explore large datasets with minimal human intervention. However, the validity and sensitivity of the Statistical Parametric Mapping (SPM2) approach to VBM is the subject of considerable debate. We visually inspected the SPM2 gray matter segmentations for 101 research participants and found a gross inclusion of non-brain tissue surrounding the entire brain as gray matter in five subjects, and focal areas bordering the brain in which non-brain tissue was classified as gray matter in many other subjects. We also found many areas in which the cortical grey matter was incorrectly excluded from the segmentation of the brain. The major source of these errors was the misregistration of individual brain images with the reference T1-weighted brain template. These errors could be eliminated if SPM2 operated on images from which non-brain tissues (scalp, skull, and meninges) are removed (brain-extracted images). We developed a modified SPM2 processing pipeline that used brain-extracted images as inputs to test this hypothesis. We describe the modifications to the SPM2 pipeline that allow analysis of brain-extracted inputs. Using brain-extracted inputs eliminated the non-brain matter inclusions and the cortical gray matter exclusions noted above, reducing the residual mean square errors (RMSEs, the error term of the SPM2 statistical analyses) by over thirty percent. We show how this reduction in the RMSEs profoundly affects power analyses. SPM2 analyses of brain-extracted images may require sample sizes only half as great as analyses of non-brain extracted images.
PMCID: PMC1987363  PMID: 16442817
brain segmentation; voxel-based morphometry (VBM); statistical probability mapping; SPM2
11.  Prevalence and Morphologic Features of Ponticulus Posticus in Koreans: Analysis of 312 Radiographs and 225 Three-dimensional CT Scans 
Asian Spine Journal  2007;1(1):27-31.
Study Design
A retrospective review of three-dimensional CT scan images and radiographs.
To investigate the prevalence and morphologic features of ponticulus posticus in Koreans.
Overview of Literature
There has been little reported on the prevalence or morphologic characteristics of ponticulus posticus in Asians, predisposing them to vertebral artery injury during screw placement in the lateral mass of the atlas.
The presence and types of ponticulus posticus were investigated on 225 consecutive cervical three-dimensional CT scans and 312 consecutive digital lateral cephalometric head radiographs.
Various spectra of ponticulus posticus were found in 26% of the CT scans and 14% of the radiographs.
Ponticulus posticus is a relatively common anomaly in Koreans. Therefore, the presence of this anomaly should be carefully examined for on radiographs before lateral mass screw placement. If ponticulus posticus is suspected or confirmed on radiographs, three-dimensional CT scanning should be considered before placement of lateral mass screws into the posterior arch, especially given its wide variation of size and shape.
PMCID: PMC2857493  PMID: 20411149
Ponticulus posticus; Atlas; Lateral mass screw
12.  Lineage-specific variations of congruent evolution among DNA sequences from three genomes, and relaxed selective constraints on rbcL in Cryptomonas (Cryptophyceae) 
Plastid-bearing cryptophytes like Cryptomonas contain four genomes in a cell, the nucleus, the nucleomorph, the plastid genome and the mitochondrial genome. Comparative phylogenetic analyses encompassing DNA sequences from three different genomes were performed on nineteen photosynthetic and four colorless Cryptomonas strains. Twenty-three rbcL genes and fourteen nuclear SSU rDNA sequences were newly sequenced to examine the impact of photosynthesis loss on codon usage in the rbcL genes, and to compare the rbcL gene phylogeny in terms of tree topology and evolutionary rates with phylogenies inferred from nuclear ribosomal DNA (concatenated SSU rDNA, ITS2 and partial LSU rDNA), and nucleomorph SSU rDNA.
Largely congruent branching patterns and accelerated evolutionary rates were found in nucleomorph SSU rDNA and rbcL genes in a clade that consisted of photosynthetic and colorless species suggesting a coevolution of the two genomes. The extremely accelerated rates in the rbcL phylogeny correlated with a shift from selection to mutation drift in codon usage of two-fold degenerate NNY codons comprising the amino acids asparagine, aspartate, histidine, phenylalanine, and tyrosine. Cysteine was the sole exception. The shift in codon usage seemed to follow a gradient from early diverging photosynthetic to late diverging photosynthetic or heterotrophic taxa along the branches. In the early branching taxa, codon preferences were changed in one to two amino acids, whereas in the late diverging taxa, including the colorless strains, between four and five amino acids showed changes in codon usage.
Nucleomorph and plastid gene phylogenies indicate that loss of photosynthesis in the colorless Cryptomonas strains examined in this study possibly was the result of accelerated evolutionary rates that started already in photosynthetic ancestors. Shifts in codon usage are usually considered to be caused by changes in functional constraints and in gene expression levels. Thus, the increasing influence of mutation drift on codon usage along the clade may indicate gradually relaxed constraints and reduced expression levels on the rbcL gene, finally correlating with a loss of photosynthesis in the colorless Cryptomonas paramaecium strains.
PMCID: PMC1285359  PMID: 16232313
13.  Native interface of the SAM domain polymer of TEL 
TEL is a transcriptional repressor containing a SAM domain that forms a helical polymer. In a number of hematologic malignancies, chromosomal translocations lead to aberrant fusions of TEL-SAM to a variety of other proteins, including many tyrosine kinases. TEL-SAM polymerization results in constitutive activation of the tyrosine kinase domains to which it becomes fused, leading to cell transformation. Thus, inhibitors of TEL-SAM self-association could abrogate transformation in these cells. In previous work, we determined the structure of a mutant TEL-SAM polymer bearing a Val to Glu substitution in center of the subunit interface. It remained unclear how much the mutation affected the architecture of the polymer, however.
Here we determine the structure of the native polymer interface. To accomplish this goal, we introduced mutations that block polymer extension, producing a heterodimer with a wild-type interface. We find that the structure of the wild-type polymer interface is quite similar to the mutant structure determined previously. With the structure of the native interface, it is possible to evaluate the potential for developing therapeutic inhibitors of the interaction. We find that the interacting surfaces of the protein are relatively flat, containing no obvious pockets for the design of small molecule inhibitors.
Our results confirm the architecture of the TEL-SAM polymer proposed previously based on a mutant structure. The fact that the interface contains no obvious potential binding pockets suggests that it may be difficult to find small molecule inhibitors to treat malignancies in this way.
PMCID: PMC126206  PMID: 12193272
14.  Discovery of Fully Human Anti-MET Monoclonal Antibodies with Antitumor Activity against Colon Cancer Tumor Models In Vivo1 
Neoplasia (New York, N.Y.)  2009;11(4):355-364.
The receptor tyrosine kinase MET is a major component controlling the invasive growth program in embryonic development and in invasive malignancies. The discovery of therapeutic antibodies against MET has been difficult, and antibodies that compete with hepatocyte growth factor (HGF) act as agonists. By applying phage technology and cell-based panning strategies, we discovered two fully human antibodies against MET (R13 and R28), which synergistically inhibit HGF binding to MET and elicit antibody-dependent cellular cytotoxicity. Cell-based phosphorylation assays demonstrate that R13 and R28 abrogate HGF-induced activation of MET, AKT1, ERK1/2, and HGF-induced migration and proliferation. FACS experiments suggest that the inhibitory effect is mediated by “locking” MET receptor in a state with R13, which then increases avidity of R28 for the extracellular domain of MET, thus blocking HGF binding without activating the receptor. In vivo studies demonstrate that the combination of R13/28 significantly inhibited tumor growth in various colon tumor xenograft models. Inhibition of tumor growth was associated with induction of hypoxia. Global gene expression analysis shows that inhibition of HGF/MET pathway significantly upregulated the tumor suppressors KLF6, CEACAM1, and BMP2, the negative regulator of phosphatidylinositol-3-OH-kinase PIK3IP1, and significantly suppressed SCF and SERPINE2, both enhancers of proliferation and invasiveness. Moreover, in an experimental metastasis model, R13/28 increased survival by preventing the recurrence of otherwise lethal lung metastases. Taken together, these results underscore the utility of a dual-antibody approach for targeting MET and possibly other receptor tyrosine kinases. Our approach could be expanded to drug discovery efforts against other cell surface proteins.
PMCID: PMC2657888  PMID: 19308290

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