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1.  Phylodynamic Profile of HIV-1 Subtype B, CRF01_AE and the Recently Emerging CRF51_01B among Men Who Have Sex with Men (MSM) in Singapore 
PLoS ONE  2013;8(12):e80884.
HIV-1 subtype B and CRF01_AE are the predominant infecting subtypes among men who have sex with men (MSM) in Singapore. The genetic history, population dynamics and pattern of transmission networks of these genotypes remain largely unknown. We delineated the phylodynamic profiles of HIV-1 subtype B, CRF01_AE and the recently characterized CRF51_01B strains circulating among the MSM population in Singapore. A total of 105 (49.5%) newly-diagnosed treatment-naïve MSM were recruited between February 2008 and August 2009. Phylogenetic reconstructions of the protease gene (HXB2: 2239 – 2629), gp120 (HXB2: 6942 – 7577) and gp41 (HXB2: 7803 – 8276) of the env gene uncovered five monophyletic transmission networks (two each within subtype B and CRF01_AE and one within CRF51_01B lineages) of different sizes (involving 3 – 23 MSM subjects, supported by posterior probability measure of 1.0). Bayesian coalescent analysis estimated that the emergence and dissemination of multiple sub-epidemic networks occurred between 1995 and 2005, driven largely by subtype B and later followed by CRF01_AE. Exponential increase in effective population size for both subtype B and CRF01_AE occurred between 2002 to 2007 and 2005 to 2007, respectively. Genealogical estimates suggested that the novel CRF51_01B lineages were probably generated through series of recombination events involving CRF01_AE and multiple subtype B ancestors. Our study provides the first insight on the phylodynamic profiles of HIV-1 subtype B, CRF01_AE and CRF51_01B viral strains circulating among MSM in Singapore.
PMCID: PMC3846621  PMID: 24312505
2.  Genome-wide association study in a Chinese population identifies a susceptibility locus for type 2 diabetes at 7q32 near PAX4 
Diabetologia  2013;56(6):1291-1305.
Most genetic variants identified for type 2 diabetes have been discovered in European populations. We performed genome-wide association studies (GWAS) in a Chinese population with the aim of identifying novel variants for type 2 diabetes in Asians.
We performed a meta-analysis of three GWAS comprising 684 patients with type 2 diabetes and 955 controls of Southern Han Chinese descent. We followed up the top signals in two independent Southern Han Chinese cohorts (totalling 10,383 cases and 6,974 controls), and performed in silico replication in multiple populations.
We identified CDKN2A/B and four novel type 2 diabetes association signals with p < 1 × 10−5 from the meta-analysis. Thirteen variants within these four loci were followed up in two independent Chinese cohorts, and rs10229583 at 7q32 was found to be associated with type 2 diabetes in a combined analysis of 11,067 cases and 7,929 controls (pmeta = 2.6 × 10−8; OR [95% CI] 1.18 [1.11, 1.25]). In silico replication revealed consistent associations across multiethnic groups, including five East Asian populations (pmeta = 2.3 × 10−10) and a population of European descent (p = 8.6 × 10−3). The rs10229583 risk variant was associated with elevated fasting plasma glucose, impaired beta cell function in controls, and an earlier age at diagnosis for the cases. The novel variant lies within an islet-selective cluster of open regulatory elements. There was significant heterogeneity of effect between Han Chinese and individuals of European descent, Malaysians and Indians.
Our study identifies rs10229583 near PAX4 as a novel locus for type 2 diabetes in Chinese and other populations and provides new insights into the pathogenesis of type 2 diabetes.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-013-2874-4) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
PMCID: PMC3648687  PMID: 23532257
Chinese; Diabetes; East Asians; Genetics; Genome-wide association study
3.  Inhibition of c-Met Downregulates TIGAR Expression and Reduces NADPH Production Leading to Cell Death 
Oncogene  2010;30(9):1127-1134.
c-Met represents an important emerging therapeutic target in cancer. Here, we demonstrate the mechanism by which c-Met tyrosine kinase inhibition inhibits tumor growth in a highly invasive Asian-prevalent head and neck cancer, nasopharyngeal cancer (NPC). c-Met tyrosine kinase inhibitors (TKIs; AM7 and c-Met TKI tool compound SU11274) downregulated c-Met phosphorylation resulting in markedly inhibited growth and invasion of NPC cells. Strikingly, inhibition of c-Met resulted in marked downregulation of TIGAR (TP53-induced Glycolysis and Apoptosis Regulator) and subsequent depletion of intracellular NADPH. Importantly, overexpression of TIGAR ameliorated the effects of c-Met kinase inhibition, confirming the importance of TIGAR downregulation in growth inhibition induced by c-Met TKI. The effects of c-Met inhibition on TIGAR and NADPH levels were observed with two different c-Met TKIs (AM7 and SU11274) and with multiple cell lines. As NADPH provides a crucial reducing power required for cell survival and proliferation, our findings represent a novel mechanistic action of c-Met TKI, which may represent a key effect of c-Met kinase inhibition. Our data provides the first evidence linking c-Met, TIGAR and NADPH regulation in human cancer cells suggesting that inhibition of a tyrosine kinase/TIGAR/NADPH cascade may have therapeutic applicability in human cancers.
PMCID: PMC3428712  PMID: 21057531
c-Met tyrosine kinase inhibitor; TIGAR; NADPH
4.  Aqua­(imino­diacetato-κ3 O,N,O′)(1,10-phenanthroline-κ2 N,N′)zinc(II) sesquihydrate 
The imino­diacetate dianion in the title compound, [Zn(C4H5NO4)(C12H8N2)(H2O)]·1.5H2O, chelates to the ZnII center with its N and two O atoms. The metal atom is also chelated by the N-heterocycle and coordinated by one water molecule, leading to a distorted octahedral environment. The dianion, and coordinated and uncoordinated water mol­ecules inter­act through O—H⋯O hydrogen bonds, generating a three-dimensional network. One of the two uncoordinated water mol­ecules has half-site occupancy. The crystal studied was a non-merohedral twin with a 15% twin component.
PMCID: PMC2967921  PMID: 21581551
5.  Aqua­(imino­diacetato-κ3 O,N,O′)(1,10-phenanthroline-κ2 N,N′)cobalt(II) monohydrate 
The imino­diacetate dianion in the title compound, [Co(C4H5NO4)(C12H8N2)(H2O)]·H2O, chelates to the cobalt(II) atom, its N and two O atoms occupying the fac sites of the distorted octa­hedron around the metal atom. The metal atom is also chelated by the N-heterocycle. The dianion, and coordinated and uncoordinated water mol­ecules inter­act through hydrogen bonds, generating a layer motif. The crystal studied was a racemic twin with a 0.62 (2):0.38 (2) domain ratio.
PMCID: PMC2967887  PMID: 21581514
6.  Atypical Intracranial Epidermoid Cysts: Rare Anomalies with Unique Radiological Features 
Case Reports in Radiology  2015;2015:528632.
Epidermoid cysts are benign slow growing extra-axial tumours that insinuate between brain structures, while their occurrences in intra-axial or intradiploic locations are exceptionally rare. We present the clinical, imaging, and pathological findings in two patients with atypical epidermoid cysts. CT and MRI findings for the first case revealed an intraparenchymal epidermoid cyst that demonstrated no restricted diffusion. The second case demonstrated an aggressive epidermoid cyst that invaded into the intradiploic spaces, transverse sinus, and the calvarium. The timing of ectodermal tissue sequestration during fetal development may account for the occurrence of atypical epidermoid cysts.
PMCID: PMC4312626  PMID: 25667778
7.  Sero-Prevalence and Cross-Reactivity of Chikungunya Virus Specific Anti-E2EP3 Antibodies in Arbovirus-Infected Patients 
Chikungunya virus (CHIKV) and clinically-related arboviruses cause large epidemics with serious economic and social impact. As clinical symptoms of CHIKV infections are similar to several flavivirus infections, good detection methods to identify CHIKV infection are desired for improved treatment and clinical management. The strength of anti-E2EP3 antibody responses was explored in a longitudinal study on 38 CHIKV-infected patients. We compared their anti-E2EP3 responses with those of patients infected with non-CHIKV alphaviruses, or flaviviruses. E2EP3 cross-reactive samples from patients infected with non-CHIKV viruses were further analyzed with an in vitro CHIKV neutralization assay. CHIKV-specific anti-E2EP3 antibody responses were detected in 72% to 100% of patients. Serum samples from patients infected with other non-CHIKV alphaviruses were cross-reactive to E2EP3. Interestingly, some of these antibodies demonstrated clearly in vitro CHIKV neutralizing activity. Contrastingly, serum samples from flaviviruses-infected patients showed a low level of cross-reactivity against E2EP3. Using CHIKV E2EP3 as a serology marker not only allows early detection of CHIKV specific antibodies, but would also allow the differentiation between CHIKV infections and flavivirus infections with 93% accuracy, thereby allowing precise acute febrile diagnosis and improving clinical management in regions newly suffering from CHIKV outbreaks including the Americas.
Author Summary
Chikungunya virus (CHIKV) causes Chikungunya fever in humans. The symptoms, particularly joint pain, can be severe and long lasting, and outbreaks can have serious socioeconomic impact. CHIKV is a mosquito-borne alphavirus that co-exists geographically with other mosquito-borne flaviviruses such as dengue virus (DENV). This causes difficulties in diagnosis because the symptoms are similar between CHIKV and DENV infections. It is important to differentiate between CHIKV and DENV infections, with good diagnostic methods. In this paper, we found that 72%–100% of CHIKV-infected patients had antibodies that recognized E2EP3, a part of a CHIKV protein. In contrast, a low percentage of flavivirus-infected patients had antibodies that recognized E2EP3. This suggests that testing patients for the presence of E2EP3-recognizing antibodies will aid in diagnostic differentiation between CHIKV and DENV infections. Interestingly, patients infected with non-chikungunya alphaviruses had moderate levels of antibodies that recognized E2EP3. While it was generally known that the alphaviruses have fairly conserved amino acid sequences, it was unknown until now, to what extent the antibodies against non-chikungunya viruses would also recognize E2EP3 from CHIKV. This paper provides insights about the E2EP3-recognizing antibodies from patients with different mosquito-borne viral infections and these insights will inform approaches to diagnostics and vaccination.
PMCID: PMC4287563  PMID: 25568956
8.  BARP suppresses voltage-gated calcium channel activity and Ca2+-evoked exocytosis 
The Journal of Cell Biology  2014;205(2):233-249.
The integral membrane glycoprotein BARP associates with voltage-gated calcium channel Cavβ subunits, disrupting their association with Cavα1 subunits and suppressing overall channel activity.
Voltage-gated calcium channels (VGCCs) are key regulators of cell signaling and Ca2+-dependent release of neurotransmitters and hormones. Understanding the mechanisms that inactivate VGCCs to prevent intracellular Ca2+ overload and govern their specific subcellular localization is of critical importance. We report the identification and functional characterization of VGCC β-anchoring and -regulatory protein (BARP), a previously uncharacterized integral membrane glycoprotein expressed in neuroendocrine cells and neurons. BARP interacts via two cytosolic domains (I and II) with all Cavβ subunit isoforms, affecting their subcellular localization and suppressing VGCC activity. Domain I interacts at the α1 interaction domain–binding pocket in Cavβ and interferes with the association between Cavβ and Cavα1. In the absence of domain I binding, BARP can form a ternary complex with Cavα1 and Cavβ via domain II. BARP does not affect cell surface expression of Cavα1 but inhibits Ca2+ channel activity at the plasma membrane, resulting in the inhibition of Ca2+-evoked exocytosis. Thus, BARP can modulate the localization of Cavβ and its association with the Cavα1 subunit to negatively regulate VGCC activity.
PMCID: PMC4003244  PMID: 24751537
9.  Marital Status and Cognitive Impairment among Community-Dwelling Chinese Older Adults: The Role of Gender and Social Engagement 
To examine the association between marital status and cognitive impairment among community-dwelling Chinese older adults.
We analyzed data from 2,498 Chinese aged 55 and older from the Singapore Longitudinal Aging Study cohort. Cognitive impairment was defined as a Mini-Mental State Examination total score of 23 or below. Odds ratios of associations were reported and adjusted for potential confounders in logistic regression models.
The prevalence of cognitive impairment was 12.2% (n = 306). Being single was associated with about 2.5 times increased odds of cognitive impairment compared to being married (adjusted OR = 2.53, 95% CI: 1.41-4.55). The association between marital status and cognitive impairment was much stronger in men compared to that in women, and was indeed statistically significant only for men. Among the single and widowed persons social engagement was associated with a lower risk of cognitive impairment. Compared with subjects in the lowest tertile of social engagement scores, the odds of having cognitive impairment was lowered by 50% for subjects in the second and the third tertile.
Being single or widowed was associated with higher odds of cognitive impairment compared to being married in a cohort of older Chinese men but not women.
PMCID: PMC4241637  PMID: 25473404
Cognitive impairment; Chinese older adults; Mini-Mental State Examination; Marital status; Social engagement
10.  The psychophysiological effects of Tai-chi and exercise in residential Schizophrenic patients: a 3-arm randomized controlled trial 
Patients with schizophrenia are characterized by high prevalence rates and chronicity that often leads to long-term institutionalization. Under the traditional medical model, treatment usually emphasizes the management of psychotic symptoms through medication, even though anti-psychotic drugs are associated with severe side effects, which can diminish patients’ physical and psychological well-being. Tai-chi, a mind-body exercise rooted in Eastern health philosophy, emphasizes the motor coordination and relaxation. With these potential benefits, a randomized controlled trial (RCT) is planned to investigate the effects of Tai-chi intervention on the cognitive and motor deficits characteristic of patients with schizophrenia.
A 3-arm RCT with waitlist control design will be used in this study. One hundred and fifty three participants will be randomized into (i) Tai-chi, (ii) exercise or (iii) waitlist control groups. Participants in both the Tai-chi and exercise groups will receive 12-weeks of specific intervention, in addition to the standard medication and care received by the waitlist control group. The exercise group will serve as a comparison, to delineate any unique benefits of Tai-chi that are independent of moderate aerobic exercise. All three groups will undergo three assessment phases: (i) at baseline, (ii) at 12 weeks (post-intervention), and (iii) at 24 weeks (maintenance). All participants will be assessed in terms of symptom management, motor coordination, memory, daily living function, and stress levels based on self-perceived responses and a physiological marker.
Based on a promising pilot study conducted prior to this RCT, subjects in the Tai-chi intervention group are expected to be protected against deterioration of motor coordination and interpersonal functioning. They are also expected to have better symptoms management and lower stress level than the other treatment groups.
Trial registration
The trail has been registered in the Clinical Trials Center of the University of Hong Kong (HKCTR-1453).
PMCID: PMC4189583  PMID: 25262346
Tai-chi; Exercise; Schizophrenia; Chinese; Randomized controlled trial (RCT); Salivary cortisol
11.  Comprehensive molecular characterization of gastric adenocarcinoma 
Bass, Adam J. | Thorsson, Vesteinn | Shmulevich, Ilya | Reynolds, Sheila M. | Miller, Michael | Bernard, Brady | Hinoue, Toshinori | Laird, Peter W. | Curtis, Christina | Shen, Hui | Weisenberger, Daniel J. | Schultz, Nikolaus | Shen, Ronglai | Weinhold, Nils | Kelsen, David P. | Bowlby, Reanne | Chu, Andy | Kasaian, Katayoon | Mungall, Andrew J. | Robertson, A. Gordon | Sipahimalani, Payal | Cherniack, Andrew | Getz, Gad | Liu, Yingchun | Noble, Michael S. | Pedamallu, Chandra | Sougnez, Carrie | Taylor-Weiner, Amaro | Akbani, Rehan | Lee, Ju-Seog | Liu, Wenbin | Mills, Gordon B. | Yang, Da | Zhang, Wei | Pantazi, Angeliki | Parfenov, Michael | Gulley, Margaret | Piazuelo, M. Blanca | Schneider, Barbara G. | Kim, Jihun | Boussioutas, Alex | Sheth, Margi | Demchok, John A. | Rabkin, Charles S. | Willis, Joseph E. | Ng, Sam | Garman, Katherine | Beer, David G. | Pennathur, Arjun | Raphael, Benjamin J. | Wu, Hsin-Ta | Odze, Robert | Kim, Hark K. | Bowen, Jay | Leraas, Kristen M. | Lichtenberg, Tara M. | Weaver, Stephanie | McLellan, Michael | Wiznerowicz, Maciej | Sakai, Ryo | Getz, Gad | Sougnez, Carrie | Lawrence, Michael S. | Cibulskis, Kristian | Lichtenstein, Lee | Fisher, Sheila | Gabriel, Stacey B. | Lander, Eric S. | Ding, Li | Niu, Beifang | Ally, Adrian | Balasundaram, Miruna | Birol, Inanc | Bowlby, Reanne | Brooks, Denise | Butterfield, Yaron S. N. | Carlsen, Rebecca | Chu, Andy | Chu, Justin | Chuah, Eric | Chun, Hye-Jung E. | Clarke, Amanda | Dhalla, Noreen | Guin, Ranabir | Holt, Robert A. | Jones, Steven J.M. | Kasaian, Katayoon | Lee, Darlene | Li, Haiyan A. | Lim, Emilia | Ma, Yussanne | Marra, Marco A. | Mayo, Michael | Moore, Richard A. | Mungall, Andrew J. | Mungall, Karen L. | Nip, Ka Ming | Robertson, A. Gordon | Schein, Jacqueline E. | Sipahimalani, Payal | Tam, Angela | Thiessen, Nina | Beroukhim, Rameen | Carter, Scott L. | Cherniack, Andrew D. | Cho, Juok | Cibulskis, Kristian | DiCara, Daniel | Frazer, Scott | Fisher, Sheila | Gabriel, Stacey B. | Gehlenborg, Nils | Heiman, David I. | Jung, Joonil | Kim, Jaegil | Lander, Eric S. | Lawrence, Michael S. | Lichtenstein, Lee | Lin, Pei | Meyerson, Matthew | Ojesina, Akinyemi I. | Pedamallu, Chandra Sekhar | Saksena, Gordon | Schumacher, Steven E. | Sougnez, Carrie | Stojanov, Petar | Tabak, Barbara | Taylor-Weiner, Amaro | Voet, Doug | Rosenberg, Mara | Zack, Travis I. | Zhang, Hailei | Zou, Lihua | Protopopov, Alexei | Santoso, Netty | Parfenov, Michael | Lee, Semin | Zhang, Jianhua | Mahadeshwar, Harshad S. | Tang, Jiabin | Ren, Xiaojia | Seth, Sahil | Yang, Lixing | Xu, Andrew W. | Song, Xingzhi | Pantazi, Angeliki | Xi, Ruibin | Bristow, Christopher A. | Hadjipanayis, Angela | Seidman, Jonathan | Chin, Lynda | Park, Peter J. | Kucherlapati, Raju | Akbani, Rehan | Ling, Shiyun | Liu, Wenbin | Rao, Arvind | Weinstein, John N. | Kim, Sang-Bae | Lee, Ju-Seog | Lu, Yiling | Mills, Gordon | Laird, Peter W. | Hinoue, Toshinori | Weisenberger, Daniel J. | Bootwalla, Moiz S. | Lai, Phillip H. | Shen, Hui | Triche, Timothy | Van Den Berg, David J. | Baylin, Stephen B. | Herman, James G. | Getz, Gad | Chin, Lynda | Liu, Yingchun | Murray, Bradley A. | Noble, Michael S. | Askoy, B. Arman | Ciriello, Giovanni | Dresdner, Gideon | Gao, Jianjiong | Gross, Benjamin | Jacobsen, Anders | Lee, William | Ramirez, Ricardo | Sander, Chris | Schultz, Nikolaus | Senbabaoglu, Yasin | Sinha, Rileen | Sumer, S. Onur | Sun, Yichao | Weinhold, Nils | Thorsson, Vésteinn | Bernard, Brady | Iype, Lisa | Kramer, Roger W. | Kreisberg, Richard | Miller, Michael | Reynolds, Sheila M. | Rovira, Hector | Tasman, Natalie | Shmulevich, Ilya | Ng, Santa Cruz Sam | Haussler, David | Stuart, Josh M. | Akbani, Rehan | Ling, Shiyun | Liu, Wenbin | Rao, Arvind | Weinstein, John N. | Verhaak, Roeland G.W. | Mills, Gordon B. | Leiserson, Mark D. M. | Raphael, Benjamin J. | Wu, Hsin-Ta | Taylor, Barry S. | Black, Aaron D. | Bowen, Jay | Carney, Julie Ann | Gastier-Foster, Julie M. | Helsel, Carmen | Leraas, Kristen M. | Lichtenberg, Tara M. | McAllister, Cynthia | Ramirez, Nilsa C. | Tabler, Teresa R. | Wise, Lisa | Zmuda, Erik | Penny, Robert | Crain, Daniel | Gardner, Johanna | Lau, Kevin | Curely, Erin | Mallery, David | Morris, Scott | Paulauskis, Joseph | Shelton, Troy | Shelton, Candace | Sherman, Mark | Benz, Christopher | Lee, Jae-Hyuk | Fedosenko, Konstantin | Manikhas, Georgy | Potapova, Olga | Voronina, Olga | Belyaev, Smitry | Dolzhansky, Oleg | Rathmell, W. Kimryn | Brzezinski, Jakub | Ibbs, Matthew | Korski, Konstanty | Kycler, Witold | ŁaŸniak, Radoslaw | Leporowska, Ewa | Mackiewicz, Andrzej | Murawa, Dawid | Murawa, Pawel | Spychała, Arkadiusz | Suchorska, Wiktoria M. | Tatka, Honorata | Teresiak, Marek | Wiznerowicz, Maciej | Abdel-Misih, Raafat | Bennett, Joseph | Brown, Jennifer | Iacocca, Mary | Rabeno, Brenda | Kwon, Sun-Young | Penny, Robert | Gardner, Johanna | Kemkes, Ariane | Mallery, David | Morris, Scott | Shelton, Troy | Shelton, Candace | Curley, Erin | Alexopoulou, Iakovina | Engel, Jay | Bartlett, John | Albert, Monique | Park, Do-Youn | Dhir, Rajiv | Luketich, James | Landreneau, Rodney | Janjigian, Yelena Y. | Kelsen, David P. | Cho, Eunjung | Ladanyi, Marc | Tang, Laura | McCall, Shannon J. | Park, Young S. | Cheong, Jae-Ho | Ajani, Jaffer | Camargo, M. Constanza | Alonso, Shelley | Ayala, Brenda | Jensen, Mark A. | Pihl, Todd | Raman, Rohini | Walton, Jessica | Wan, Yunhu | Demchok, John A. | Eley, Greg | Mills Shaw, Kenna R. | Sheth, Margi | Tarnuzzer, Roy | Wang, Zhining | Yang, Liming | Zenklusen, Jean Claude | Davidsen, Tanja | Hutter, Carolyn M. | Sofia, Heidi J. | Burton, Robert | Chudamani, Sudha | Liu, Jia
Nature  2014;513(7517):202-209.
Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein–Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also knownasPD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies.
PMCID: PMC4170219  PMID: 25079317
12.  Value of routine early post-operative computed tomography in determining short-term functional outcome after drainage of chronic subdural hematoma: An evaluation of residual volume 
Computed tomography (CT) scans are widely used in managing chronic subdural hematoma (CSDH). Factors that determine early post-operative volume have not been examined. The value of routine early post-operative residual volume have not been evaluated. Our study aims to compare pre-operative and early post-operative CT findings to determine the factors affecting residual hematoma and evaluate if early post-operative CT scans are useful in the management of CSDH.
Forty-three patients who underwent burr hole drainage of unilateral CSDH from August 2006 to January 2013 and had routine post-operative CT scans within 48 hours of surgery were selected. Data regarding age, sex, neurological deficit, Glasgow Coma Scale (GCS), pre-existing medical conditions, use of antiplatelets or anticoagulation, operative time, usage of drains, and number of burr holes were obtained. The pre-operative CSDH volume, CSDH density, and midline shift were measured. Residual volume was calculated from early post-operative CT scans. Clinical outcome was evaluated with Glasgow Outcome Scale (GOS) at the time of discharge. Statistical analysis was performed to look for correlation between the pre-operative factors and residual volume, and the residual volume and GOS.
Pre-operative volume was found to correlate significantly with post-operative residual volume. There was no significant correlation between all other pre-operative factors and residual volume. There was also no correlation between residual volume and GOS at discharge.
Routine post-operative CT brain for burr hole drainage of CSDH may be unnecessary in view of the good predictive value of pre-operative volume, and also because it is not predictive of the clinical outcome.
PMCID: PMC4174672  PMID: 25298918
Chronic; hematoma; outcome; post-operative computed tomography; residual volume; subdural
13.  Does practice size matter? Review of effects on quality of care in primary care 
The British Journal of General Practice  2013;63(614):e604-e610.
There is a trend towards consolidating smaller primary care practices into larger practices worldwide. However, the effects of practice size on quality of care remain unclear.
This review aims to systematically appraise the effects of practice size on the quality of care in primary care.
Design and setting
A systematic review and narrative synthesis of studies examining the relationship between practice size and quality of care in primary care.
Quantitative studies that focused on primary care practices or practitioners were identified through PubMed, CINAHL, Embase, Cochrane Library, CRD databases, ProQuest dissertations and theses, conference proceedings, and MedNar databases, as well as the reference lists of included studies. Independent variables were team or list size; outcome variables were measures of clinical processes, clinical outcomes, or patient-reported outcomes. A narrative synthesis of the results was conducted.
The database search yielded 371 articles, of which 34 underwent quality assessment, and 17 articles (13 cross-sectional studies) were included. Ten studies examined the association of practice size and clinical processes, but only five found associations of larger practices with selected process measures such as higher specialist referral rates, better adherence to guidelines, higher mammography rates, and better monitoring of haemoglobin A1c. There were mixed results for cytology and pneumococcal coverage. Only one of two studies on clinical outcomes found an effect of larger practices on lower random haemoglobin A1 value. Of the three studies on patient-reported outcomes, smaller practices were consistently found to be associated with satisfaction with access, but evidence was inconsistent for other patient-reported outcomes evaluated.
There is limited evidence to support an association between practice size and quality of care in primary care.
PMCID: PMC3750799  PMID: 23998840
health facility size; primary care; quality of health care
14.  Abnormal Response of the Proliferation and Differentiation of Growth Plate Chondrocytes to Melatonin in Adolescent Idiopathic Scoliosis 
Abnormalities in the melatonin signaling pathway and the involvement of melatonin receptor MT2 have been reported in patients with adolescent idiopathic scoliosis (AIS). Whether these abnormalities were involved in the systemic abnormal skeletal growth in AIS during the peripubertal period remain unknown. In this cross-sectional case-control study, growth plate chondrocytes (GPCs) were cultured from twenty AIS and ten normal control subjects. Although the MT2 receptor was identified in GPCs from both AIS and controls, its mRNA expression was significantly lower in AIS patients than the controls. GPCs were cultured in the presence of either the vehicle or various concentrations of melatonin, with or without the selective MT2 melatonin receptor antagonist 4-P-PDOT (10 µM). Then the cell viability and the mRNA expression of collagen type X (COLX) and alkaline phosphatase (ALP) were assessed by MTT and qPCR, respectively. In the control GPCs, melatonin at the concentrations of 1, 100 nM and 10 µM significantly reduced the population of viable cells, and the mRNA level of COLX and ALP compared to the vehicle. Similar changes were not observed in the presence of 4-P-PDOT. Further, neither proliferation nor differentiation of GPCs from AIS patients was affected by the melatonin treatment. These findings support the presence of a functional abnormality of the melatonin signaling pathway in AIS GPCs, which might be associated with the abnormal endochondral ossification in AIS patients.
PMCID: PMC4200781  PMID: 25257530
idiopathic scoliosis; melatonin; growth plate; chondrocytes; proliferation; differentiation; MT2 receptor; antagonist; dysfunction
15.  A Review of Pinealectomy-Induced Melatonin-Deficient Animal Models for the Study of Etiopathogenesis of Adolescent Idiopathic Scoliosis 
Adolescent idiopathic scoliosis (AIS) is a common orthopedic disorder of unknown etiology and pathogenesis. Melatonin and melatonin pathway dysfunction has been widely suspected to play an important role in the pathogenesis. Many different types of animal models have been developed to induce experimental scoliosis mimicking the pathoanatomical features of idiopathic scoliosis in human. The scoliosis deformity was believed to be induced by pinealectomy and mediated through the resulting melatonin-deficiency. However, the lack of upright mechanical spinal loading and inherent rotational instability of the curvature render the similarity of these models to the human counterparts questionable. Different concerns have been raised challenging the scientific validity and limitations of each model. The objectives of this review follow the logical need to re-examine and compare the relevance and appropriateness of each of the animal models that have been used for studying the etiopathogenesis of adolescent idiopathic scoliosis in human in the past 15 to 20 years.
PMCID: PMC4200812  PMID: 25238413
adolescent idiopathic scoliosis; melatonin; pinealectomy
16.  A computed tomography morphometric study of occipital bone and C2 pedicle anatomy for occipital-cervical fusion 
Surgical Neurology International  2014;5(Suppl 7):S380-S383.
Occipital-cervical fusion (OCF) has been used to treat instability of the occipito-cervical junction and to provide biomechanical stability after decompressive surgery. The specific areas that require detailed morphologic knowledge to prevent technical failures are the thickness of the occipital bone and diameter of the C2 pedicle, as the occipital midline bone and the C2 pedicle have structurally the strongest bone to provide the biomechanical purchase for cranio-cervical instrumentation. The aim of this study was to perform a quantitative morphometric analysis using computed tomography (CT) to determine the variability of the occipital bone thickness and C2 pedicle thickness to optimize screw placement for OCF in a South East Asian population.
Thirty patients undergoing cranio-cervical junction instrumentation during the period 2008-2010 were included. The thickness of the occipital bone and the length and diameter of the C2 pedicle were measured based on CT.
The thickest point on the occipital bone was in the midline with a maximum thickness below the external occipital protuberance of 16.2 mm (±3.0 mm), which was thicker than in the Western population. The average C2 pedicle diameter was 5.3 mm (±2.0 mm). This was smaller than Western population pedicle diameters. The average length of the both pedicles to the midpoint of the C2 vertebral body was 23.5 mm (±3.3 mm on the left and ±2.3 mm on the right).
The results of this first study in the South East Asian population should help guide and improve the safety in occipito-cervical region instrumentation. Thus reducing the risk of technical failures and neuro-vascular injury.
PMCID: PMC4173205  PMID: 25289166
Cervical pedicle; morphometric study; occipital bone; occipital-cervical fusion
17.  Transcriptional Regulation of the Tumor Suppressor FHL2 by p53 in Human Kidney and Liver Cells 
PLoS ONE  2014;9(8):e99359.
Four and a Half LIM protein 2 (FHL2) is a LIM domain only protein that is able to form various protein complexes and regulate gene transcription. Recent findings showed that FHL2 is a potential tumor suppressor gene that was down-regulated in hepatocellular carcinoma (HCC). Moreover, FHL2 can bind to and activate the TP53 promoter in hepatic cells. In this study, the activity of the two promoters of FHL2, 1a and 1b, were determined in the human embryonic kidney cell line HEK293 and the activation of these two promoters by p53 was investigated. Our results showed that the 1b promoter has a higher activity than the 1a promoter in HEK 293 cells but the 1a promoter is more responsive to the activation by p53 when compared with the 1b promoter. The regulation of FHL2 by p53 was further confirmed in liver cells by the overexpression of p53 in Hep3B cells and the knockdown of p53 in HepG2 cells. Combining promoter activity results of truncated mutants and predictions by bioinformatics tools, a putative p53 binding site was found in the exon 1a of FHL2 from +213 to +232. The binding between the p53 protein and the putative p53 binding site was then validated by the ChIP assay. Furthermore, the expression of FHL2 and TP53 were down-regulated in majority of HCC tumour samples (n = 41) and significantly correlated (P = 0.026). Finally, we found that the somatic mutation 747 (G→T), a hot spot mutation of the TP53 gene, is potentially associated with a higher expression of FHL2 in HCC tumour samples. Taken together, this is the first in-depth study about the transcriptional regulation of FHL2 by p53.
PMCID: PMC4133229  PMID: 25121502
18.  Transgene Expression up to 7 Years in Nonhuman Primates Following Hepatic Transduction with Helper-Dependent Adenoviral Vectors 
Human Gene Therapy  2013;24(8):761-765.
Helper-dependent adenoviral vectors (HDAd) have been shown to mediate a considerably longer duration of transgene expression than first-generation adenoviral vectors. We have previously shown that transgene expression from HDAd-transduced hepatocytes can persist at high levels for up to 2.6 years in nonhuman primates following a single-vector administration. Because duration of transgene expression and long-term toxicity are critical for risk:benefit assessment, we have continued to monitor these animals. We report here that transgene expression has persisted for the entire observation period of up to 7 years for all animals without long-term adverse effects. However, in all cases, transgene expression level slowly declined over time to less than 10% of peak values by the end of the observation period but remained 2.3–111-fold above baseline values. These results will provide important information for a more informed risk:benefit assessment before clinical application of HDAd.
Brunetti-Pierri and colleagues report long-term safety and expression data from baboons treated with a helper-dependent adenoviral vector expressing α-fetoprotein from a liver-specific promoter. In contrast to the transient expression observed with first-generation adenoviral vectors, all animals exhibited sustained, albeit declining, transgene expression, with no apparent vector-related toxicity.
PMCID: PMC3746245  PMID: 23902403
19.  Role of Cognitive Enhancer Therapy in Alzheimer’s Disease with Concomitant Cerebral White Matter Disease: Findings from a Long-Term Naturalistic Study 
Drugs in R&D  2014;14(3):195-203.
Evidence is lacking for cognitive enhancer therapy in patients with Alzheimer’s disease (AD) and concomitant cerebrovascular disease (mixed AD) as such patients would have been excluded from clinical trials. Earlier studies of mixed AD have focused on large vessel cerebrovascular disease. The influence of small vessel cerebrovascular disease (svCVD) in the form of white matter hyperintensity (WMH) on treatment outcomes in mixed AD has not been addressed.
In this long-term naturalistic study, we evaluated the effectiveness of cognitive enhancers in patients with mixed AD with svCVD.
We conducted a retrospective analysis of a prospective clinical database from a memory clinic of a tertiary hospital. Magnetic resonance imaging WMH was used as a marker of svCVD. Demographic, cognitive, and treatment data were analysed. Linear mixed models with patient-specific random effects were used to evaluate cognitive outcomes over time while adjusting for confounders.
Patients with mixed AD (n = 137) or AD without svCVD (pure AD) (n = 28) were studied over a median duration of 28.7 months. Patients with mixed AD had a higher prevalence of hypertension (62.8 vs. 35.7 %, p = 0.011). The majority (75.2 %) of the study sample were managed with monotherapy. Mini Mental State Examination (MMSE) scores decreased over time (−0.04, p = 0.007), and the decrease was similar for both diagnosis groups (−0.03, p = 0.246). Annual estimated mean MMSE decline was 0.84 for pure AD and 0.48 for mixed AD. Similar trends were observed with Montreal Cognitive Assessment (MoCA) scores, with annual estimated mean reduction of 0.72 and 0.48 for pure AD and mixed AD, respectively.
Cognitive enhancers are effective in slowing the rate of cognitive decline in patients with AD with svCVD. These findings would need to be confirmed in randomized clinical trials.
PMCID: PMC4153975  PMID: 25063270
20.  Role of Cognitive Enhancer Therapy in Alzheimer’s Disease with Concomitant Cerebral White Matter Disease: Findings from a Long-Term Naturalistic Study 
Drugs in R&D  2014;14(3):195-203.
Evidence is lacking for cognitive enhancer therapy in patients with Alzheimer’s disease (AD) and concomitant cerebrovascular disease (mixed AD) as such patients would have been excluded from clinical trials. Earlier studies of mixed AD have focused on large vessel cerebrovascular disease. The influence of small vessel cerebrovascular disease (svCVD) in the form of white matter hyperintensity (WMH) on treatment outcomes in mixed AD has not been addressed.
In this long-term naturalistic study, we evaluated the effectiveness of cognitive enhancers in patients with mixed AD with svCVD.
We conducted a retrospective analysis of a prospective clinical database from a memory clinic of a tertiary hospital. Magnetic resonance imaging WMH was used as a marker of svCVD. Demographic, cognitive, and treatment data were analysed. Linear mixed models with patient-specific random effects were used to evaluate cognitive outcomes over time while adjusting for confounders.
Patients with mixed AD (n = 137) or AD without svCVD (pure AD) (n = 28) were studied over a median duration of 28.7 months. Patients with mixed AD had a higher prevalence of hypertension (62.8 vs. 35.7 %, p = 0.011). The majority (75.2 %) of the study sample were managed with monotherapy. Mini Mental State Examination (MMSE) scores decreased over time (−0.04, p = 0.007), and the decrease was similar for both diagnosis groups (−0.03, p = 0.246). Annual estimated mean MMSE decline was 0.84 for pure AD and 0.48 for mixed AD. Similar trends were observed with Montreal Cognitive Assessment (MoCA) scores, with annual estimated mean reduction of 0.72 and 0.48 for pure AD and mixed AD, respectively.
Cognitive enhancers are effective in slowing the rate of cognitive decline in patients with AD with svCVD. These findings would need to be confirmed in randomized clinical trials.
PMCID: PMC4153975  PMID: 25063270
21.  Clinical features and treatment outcomes of Hodgkin's lymphoma in Hong Kong Chinese 
Archives of Medical Science : AMS  2014;10(3):498-504.
Little information is available on the outcomes of Hodgkin's lymphoma in Chinese patients. We analyzed the clinical and histopathological characteristics, treatment types, clinical course and treatment outcomes of Hong Kong Chinese patients.
Material and methods
Patients with Hodgkin's lymphoma diagnosed from January 1991 to December 2010 were recruited. A retrospective analysis of these patients was performed.
Sixty-seven Chinese patients (38 males and 29 females) were identified and the median age was 36 (range 16–80). Nodular sclerosis was the most common histology (54%), followed by mixed cellularity (36%). Twenty-four patients had early favorable, 20 patients had early unfavorable and 23 patients had advanced-stage diseases. The most common presentation was palpable lymph node or mass (85%) followed by fever, weight loss, night sweating and mediastinal mass. Ninety percent of patients received chemotherapy and 40% received radiotherapy as consolidation. Seven patients with stage I lymphoma received radiotherapy alone. ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) was the most commonly used chemotherapeutic regimen. Following treatment, 87% of patients achieved complete remission. Six patients relapsed after first remission and 3 achieved second remission after re-induction therapy. The 5-year overall survival of the entire cohort was 89% and the freedom from treatment failure (FFTF) at 5 years was 82%. The 5-year overall survival rate for early favorable, early unfavorable and advanced stages was 95.7%, 95.0% and 74.7%, respectively.
Despite the relatively low incidence of Hodgkin's lymphoma in Hong Kong Chinese, the treatment outcomes are comparable to Caucasian patients.
PMCID: PMC4107256  PMID: 25097580
Hodgkin disease; treatment outcome
22.  Plasma Bmi1 mRNA as a potential prognostic biomarker for distant metastasis in colorectal cancer patients 
Molecular and Clinical Oncology  2014;2(5):817-820.
Bmi1 is overexpressed in gastrointestinal cancers, including colorectal cancer (CRC); however, its role as a non-invasive biomarker in CRC has not been established. The aim of this study was to compare the plasma Bmi1 mRNA levels prior to and following curative resection of the primary tumor in CRC patients and to determine their association with the clinicopathological parameters. The plasma Bmi1 mRNA level was measured by quantitative polymerase chain reaction and expressed as cycle threshold value. There was no significant difference between the overall pre- and postoperative plasma Bmi1 mRNA level (31.73±2.63 vs. 31.93±2.88, respectively; P=0.614) in 45 CRC patients. However, when grouped into non-metastatic and metastatic CRC patients, the postoperative Bmi1 transcript level was found to be significantly lower compared to the preoperative level in patients with non-metastatic CRC (32.13±2.677 31.44±2.764, respectively; P=0.041), whereas there was a trend towards a higher postoperative Bmi1 transcript level compared to the preoperative level in the metastatic counterpart (30.85±3.916 vs. 33.27±0.718, respectively; P=0.164). Furthermore, when the patients were categorized into two groups according to their plasma Bmi1 postoperative vs. preoperative level status, we observed that patients without a reduction in the postoperative plasma Bmi1 mRNA levels exhibited a significantly higher rate of distant metastasis following primary resection (P=0.017) and a significantly worse prognosis regarding disease-free survival (P=0.016) when compared to the reduced postoperative plasma Bmi1 level counterparts. In conclusion, plasma Bmi1 mRNA levels may serve as a non-invasive biomarker for monitoring occult metastasis and predicting the development of distant metastasis.
PMCID: PMC4106668  PMID: 25054051
Bmi1; colorectal cancer; metastasis
23.  Foot Placement and Arm Position Affect the Five Times Sit-to-Stand Test Time of Individuals with Chronic Stroke 
BioMed Research International  2014;2014:636530.
Objectives. To investigate the effect of two foot placements (normal or posterior placement) and three arm positions (hands on the thighs, arms crossed over chest, and augmented arm position with elbow extended) on the five times sit-to-stand (FTSTS) test times of individuals with chronic stroke. Design. Cross-sectional study. Setting. University-based rehabilitation clinic. Participants. A convenience sample of community-dwelling individuals with chronic stroke (N = 45). Methods. The times in completing the FTSTS with two foot placements and the three arm positions were recorded by stopwatch. Results. Posterior foot placement led to significantly shorter FTSTS times when compared with normal foot placement in all the 3 arm positions (P ≤ 0.001). In addition, hands on thigh position led to significantly longer FTSTS times than the augmented arm position (P = 0.014). Conclusion. Our results showed that foot placement and arm position could influence the FTSTS times of individuals with chronic stroke. Standardizing the foot placement and arm position in the test procedure is essential, if FTSTS test is intended to be used repeatedly on the same subject.
PMCID: PMC4083881  PMID: 25032220
24.  Translation and Initial Validation of the Chinese (Cantonese) Version of Community Integration Measure for Use in Patients with Chronic Stroke 
BioMed Research International  2014;2014:623836.
Objectives. To (1) translate and culturally adapt the English version Community Integration Measure into Chinese (Cantonese), (2) report the results of initial validation of the Chinese (Cantonese) version of CIM (CIM-C) including the content validity, internal consistency, test-retest reliability, and factor structure of CIM-C for use in stroke survivors in a Chinese community setting, and (3) investigate the level of community integration of stroke survivors living in Hong Kong. Design. Cross-sectional study. Setting. University-based rehabilitation centre. Participants. 62 (n = 62) subjects with chronic stroke. Methods. The CIM-C was produced after forward-backward translation, expert panel review, and pretesting. 25 (n = 25) of the same subjects were reassessed after a 1-week interval. Results. The items of the CIM-C demonstrated high internal consistency with a Cronbach's α of 0.84. The CIM-C showed good test-retest reliability with an intraclass correlation coefficient (ICC) of 0.84 (95% confidence interval, 0.64–0.93). A 3-factor structure of the CIM-C including “relationship and engagement,” “sense of knowing,” and “independent living,” was consistent with the original theoretical model. Hong Kong stroke survivors revealed a high level of community integration as measured by the CIM-C (mean (SD): 43.48 (5.79)). Conclusions. The CIM-C is a valid and reliable measure for clinical use.
PMCID: PMC4065661  PMID: 24995317
25.  Development of microsatellites in Labisia pumila (Myrsinaceae), an economically important Malaysian herb1 
Applications in Plant Sciences  2014;2(6):apps.1400019.
• Premise of the study: The exploitation of Labisia pumila for commercial demand is gradually increasing. It is therefore important that conservation is prioritized to ensure sustainable utilization. We developed microsatellites for L. pumila var. alata and evaluated their polymorphism across var. alata, var. pumila, and var. lanceolata.
• Methods and Results: Ten polymorphic microsatellites of L. pumila were developed using the magnetic bead hybridization selection approach. A total of 84, 48, and 66 alleles were observed in L. pumila var. alata, var. pumila, and var. lanceolata, respectively. The species is likely a tetraploid, with the majority of the loci exhibiting up to four alleles per individual.
• Conclusions: This is the first report on the development of microsatellites in L. pumila. The microsatellites will provide a good basis for investigating the population genetics of the species and will serve as a useful tool for DNA profiling.
PMCID: PMC4103438  PMID: 25202631
kacip fatimah; Labisia pumila; medicinal plant; microsatellites; Myrsinaceae; tetraploid

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