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1.  High STOP-Bang score indicates a high probability of obstructive sleep apnoea 
BJA: British Journal of Anaesthesia  2012;108(5):768-775.
The STOP-Bang questionnaire is used to screen patients for obstructive sleep apnoea (OSA). We evaluated the association between STOP-Bang scores and the probability of OSA.
After Institutional Review Board approval, patients who visited the preoperative clinics for a scheduled inpatient surgery were approached for informed consent. Patients answered STOP questionnaire and underwent either laboratory or portable polysomnography (PSG). PSG recordings were scored manually. The BMI, age, neck circumference, and gender (Bang) were documented. Over 4 yr, 6369 patients were approached and 1312 (20.6%) consented. Of them, 930 completed PSG, and 746 patients with complete data on PSG and STOP-Bang questionnaire were included for data analysis.
The median age of 746 patients was 60 yr, 49% males, BMI 30 kg m−2, and neck circumference 39 cm. OSA was present in 68.4% with 29.9% mild, 20.5% moderate, and 18.0% severe OSA. For a STOP-Bang score of 5, the odds ratio (OR) for moderate/severe and severe OSA was 4.8 and 10.4, respectively. For STOP-Bang 6, the OR for moderate/severe and severe OSA was 6.3 and 11.6, respectively. For STOP-Bang 7 and 8, the OR for moderate/severe and severe OSA was 6.9 and 14.9, respectively. The predicted probabilities for moderate/severe OSA increased from 0.36 to 0.60 as the STOP-Bang score increased from 3 to 7 and 8.
In the surgical population, a STOP-Bang score of 5–8 identified patients with high probability of moderate/severe OSA. The STOP-Bang score can help the healthcare team to stratify patients for unrecognized OSA, practice perioperative precautions, or triage patients for diagnosis and treatment.
PMCID: PMC3325050  PMID: 22401881
mass screening; obstructive/ep (epidemiology); polysomnography; prospective studies; questionnaires; sleep apnoea; snoring/di (diagnosis); snoring/ep (epidemiology)
2.  Derivatives of Salicylic Acid as Inhibitors of YopH in Yersinia pestis 
Chemical biology & drug design  2010;76(2):85-99.
Yersinia pestis causes diseases ranging from gastrointestinal syndromes to bubonic plague and could be misused as a biological weapon. As its protein tyrosine phosphatase YopH has already been demonstrated as a potential drug target, we have developed two series of forty salicylic acid derivatives and found sixteen to have micromolar inhibitory activity. We designed these ligands to have two chemical moieties connected by a flexible hydrocarbon linker to target two pockets in the active site of the protein to achieve binding affinity and selectivity. One moiety possessed the salicylic acid core intending to target the phosphotyrosine-binding pocket. The other moiety contained different chemical fragments meant to target a nearby secondary pocket. The two series of compounds differed by having hydrocarbon linkers with different lengths. Before experimental co-crystal structures are available, we have performed molecular docking to predict how these compounds might bind to the protein and to generate structural models for performing binding affinity calculation to aid future optimization of these series of compounds.
PMCID: PMC2908532  PMID: 20560978
click chemistry, docking by simulated annealing; distance-dependent dielectric model; Generalized Born model; sensitivity and specificity of screening models; receiver operating characteristics curve
3.  Docking Flexible Peptide to Flexible Protein by Molecular Dynamics Using Two Implicit-Solvent Models: An Evaluation in Protein Kinase and Phosphatase Systems 
The journal of physical chemistry. B  2009;113(43):14343-14354.
Reliable prediction of protein-ligand docking pose requires proper account of induced fit effects. Treating both the ligand and the protein as flexible molecules is still challenging because many degrees of freedom are involved. Peptides are one type of ligands that are particularly difficult to study because of their extreme flexibility. In this study, we tested a molecular dynamics-based simulated-annealing cycling protocol in docking peptides to four protein kinases and two phosphatases using two implicit-solvent models: a distance-dependent dielectric model (ε(r)=4r) and a version of the Generalized Born model termed GBMV. We found that the simpler ε(r)=4r model identified docking pose better than the more expensive GBMV model. In addition, rescoring structures obtained from one implicit-solvent model with the other identified good docking poses for all six systems studied. Including protein energy in scoring also improved results.
PMCID: PMC2785084  PMID: 19845408
simulated annealing; distance-dependent dielectric model; generalized Born model; protein kinase A; insulin receptor protein kinase; insulin-like growth factor 1 receptor kinase; cyclic dependent protein kinase 2; protein tyrosine phosphatase 1B; YopH in Yersinia pestis
4.  Beyond Thermodynamics: Drug Binding Kinetics Could Influence Epidermal Growth Factor Signaling 
Journal of medicinal chemistry  2009;52(18):5582-5585.
We modeled the kinetics of drug binding to protein kinases in the EGF signaling pathway relevant to non-small cell lung cancer and found that binding kinetics could influence therapeutic potential, that fast binding kinetics was advantageous for most targets with a couple of exceptions, that targeting some protein kinases could enhance rather than attenuate the pathway, and that IC50 could be sensitive to the kinetic parameters of drug binding.
PMCID: PMC2746254  PMID: 19702309
5.  A Computational Study of the Phosphorylation Mechanism of the Insulin Receptor Tyrosine Kinase 
The journal of physical chemistry. A  2009;113(17):5144-5150.
Although various groups have studied the phosphorylation mechanism of the insulin receptor tyrosine kinase (IRK), an unanimous picture has not yet emerged. In this work, we performed a computational study to gain further insights. We first built a structural model of the reactant complex with the guide of several crystal structures and previous computational studies of the cyclic AMP-dependent protein kinase. We then optimized the structure by performing geometry optimization using a quantum mechanical model containing nearly 300 atoms. A reaction path was then traced between the reactant and the product using a multiple coordinate-driven method. The calculations mapped out a sequence of structural changes depicting the conversion of the reactant to the product. Analysis of the structural changes revealed the formation of a dissociative transition state and the the involvement of a proton transfer from the hydroxyl group of the tyrosyl residue of the peptide substrate to a conserved aspartate in the active site of the enzyme. The proton transfer began well before the transition state was reached and finished only shortly before the product was completely formed. In addition, the formation of a hydrogen bonding network among Arg1136, Asp1132, the γ-phosphate of ATP, and the tyrosine residue of the substrate appeared to hold the latter two in a near-attack position for reaction. The model estimated a reaction barrier of 14 kcal/mol, semi-quantitatively in accord with experiment.
PMCID: PMC2785087  PMID: 19334696
6.  Rapid Solid-Phase Extraction Method to Quantify [11C]-Verapamil, and its [11C]-Metabolites, in Human and Macaque Plasma 
Nuclear medicine and biology  2008;35(8):911-917.
P-glycoprotein (P-gp), an efflux transporter, is a significant barrier to drug entry into the brain and the fetus. The Positron Emmison Topography (PET) ligand, [11C]-verapamil, has been used to measure in vivo P-gp activity at various tissue-blood barriers of humans and animals. Since verapamil is extensively metabolized in vivo, it is important to quantify the extent of verapamil metabolism in order to interpret such P-gp acitivity. Therefore, we developed a rapid solid phase extraction (SPE) method to separate, and then quantify, verapamil and its radiolabeled metabolites in plasma.
Using high performance liquid chromatography (HPLC), we established that the major identifiable circulating radioactive metabolite of [11C]-verapamil in plasma of humans and the nonhuman primates, M. nemestrina, was [11C]-D-617. Using sequential and differential pH elution on C8 SPE cartridges, we developed a rapid method to separate [11C]-verapamil and [11C]-D-617. Recovery was measured by spiking the samples with the corresponding non-radioactive compounds and assaying these compounds by HPLC.
Verapamil and D-617 recovery with the SPE method was >90%. When the method was applied to PET studies in humans and nonhuman primates, significant plasma concentration of D-617 and unknown polar metabolite(s) were observed. The SPE and the HPLC methods were not significantly different in the quantification of verapamil and D-617.
The SPE method simultaneously processes multiple samples in less than 5 min. Given the short half-life of [11C], this method provides a valuable tool to rapidly determine the concentration of [11C]-verapamil and its [11C]-metabolites in human and nonhuman primate plasma.
PMCID: PMC2740738  PMID: 19026953
P-glycoprotein; PET; SPE; human; M. nemestrina; [11C]-verapamil; metabolites; macaque
7.  Angiotensin-converting enzyme gene insertion/deletion polymorphism is associated with risk of oral precancerous lesion in betel quid chewers 
British Journal of Cancer  2005;93(5):602-606.
To investigate whether angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism is related to the risk of oral precancerous lesions (OPL) in Taiwanese subjects who chew betel quid, a total of 61 betel quid chewers having OPL were compared with 61 asymptomatic betel quid chewers matched for betel quid chewing duration and dosage. The frequency of homozygote for ACE D variant is significantly higher in the case subjects than that of the controls (44.3 vs 24.6%; P=0.0108). The adjusted odds ratio of the D homozygous for the risk of OPL is 8.10 (95% confidence interval (CI)=2.04–32.19, P=0.003). In the allelic base analysis, the D allele is also significantly associated with higher risk of OPL. When grouping the study subjects by smoking status, the association between ACE I/D polymorphism and risk of OPL was only observed in nonsmokers. Our results support the theory that genetic factors may contribute to the susceptibility of OPL and suggest that smoking and genetic factors may be differently involved in the development of OPL.
PMCID: PMC2361601  PMID: 16136034
betel quid; angiotensin-converting enzyme; oral precancerous lesions
8.  In Situ Activation of Helper T Cells in the Lung 
Infection and Immunity  2001;69(8):4790-4798.
To better understand the lung and systemic responses of helper T cells mediating memory immunity to Mycobacterium tuberculosis, we used three- and four-color flow cytometry to study the surface phenotype of CD4+ lymphocytes. Bronchoalveolar lavage (BAL) fluid and peripheral blood (PB) samples were obtained from a total of 25 subjects, including 10 tuberculosis (TB)-infected subjects, 8 purified-protein-derivative-negative subjects, and 7 purified-protein-derivative-positive subjects. In marked contrast to CD4+ lymphocytes from PB (9% ± 5% expressing CD45RA and CD29), the majority (55% ± 16%) of CD4+ lymphocytes in BAL (ALs) simultaneously expressed CD45RA, a naïve T-cell marker, and CD29, members of the very late activation family. Further evaluation revealed that CD4+ ALs expressed both CD45RA and CD45RO, a memory T-cell marker. In addition, the proportion of CD4+ lymphocytes expressing CD69, an early activation marker, was drastically increased in BAL fluid (83% ± 9%) compared to PB (1% ± 1%), whereas no significant difference was seen in the expression of CD25, the low-affinity interleukin 2 receptor (34% ± 15% versus 40% ± 16%). More importantly, we identified a minor population of CD69bright CD25bright CD4+ lymphocytes in BAL (10% ± 6%) that were consistently absent from PB (1% ± 1%). Thus, CD4+ lymphocytes in the lung paradoxically coexpress surface molecules characteristic of naïve and memory helper T cells as well as surface molecules commonly associated with early and late stages of activation. No difference was observed for ALs obtained from TB-infected and uninfected lung segments in this regard. It remains to be determined if these surface molecules are induced by the alveolar environment or if CD4+ lymphocytes coexpressing this unusual combination of surface molecules are selectively recruited from the circulation. Our data suggest that ex vivo experiments on helper T-cell subsets that display distinctive phenotypes may be pivotal to studies on the human immune response to potential TB vaccines.
PMCID: PMC98566  PMID: 11447152
9.  Anti-inflammatory cytokines in asthma and allergy: interleukin-10, interleukin-12, interferon-gamma. 
Mediators of Inflammation  2001;10(2):51-59.
Interleukin-10 (IL-10) is a cytokine derived from CD4+ T-helper type 2 (T(H2)) cells identified as a suppressor of cytokines from T-helper type 1(T(H1)) cells. Interleukin-12 (IL-12) is produced by B cells, macrophages and dendritic cells, and primarily regulates T(H1) cell differentiation, while suppressing the expansion of T(H2) cell clones. Interferon-gamma (IFN-gamma) is a product of T(H1) cells and exerts inhibitory effects on T(H2) cell differentiation. These cytokines have been implicated in the pathogenesis of asthma and allergies. In this context, IL-12 and IFN-gamma production in asthma have been found to be decreased, and this may reduce their capacity to inhibit IgE synthesis and allergic inflammation. IL-10 is a potent inhibitor of monocyte/macrophage function, suppressing the production of many pro-inflammatory cytokines. A relative underproduction of IL-10 from alveolar macrophages of atopic asthmatics has been reported. Therapeutic modulation of T(H1)/T(H2) imbalance in asthma and allergy by mycobacterial vaccine, specific immunotherapy and cytoline-guanosine dinucleotide motif may lead to increases in IL-12 and IFN-gamma production. Stimulation of IL-10 production by antigen-specific T-cells during immunotherapy may lead to anergy through inhibition of CD28-costimulatory molecule signalling by IL-10s anti-inflammatory effect on basophils, mast cells and eosinophils.
PMCID: PMC1781697  PMID: 11405550
10.  1,N(2)-propanodeoxyguanosine adduct formation in aortic DNA following inhalation of acrolein. 
Environmental Health Perspectives  2001;109(3):219-224.
Recent reports indicate that many of the cytotoxic and health-threatening components of environmental tobacco smoke (ETS) reside in the vapor phase of the smoke. We have reported previously that inhalation of 1,3-butadiene, a prominent vapor phase component of ETS, accelerates arteriosclerotic plaque development in cockerels. In this study we asked whether inhaled acrolein, a reactive aldehyde that is also a prominent vapor-phase component of ETS, damages artery-wall DNA and accelerates plaque development. Cockerels inhaled 0, 1, or 10 ppm acrolein mixed with HEPA-filtered air for 6 hr. Half were killed immediately (day 1 group) for detection of the stable, premutagenic 1,N(2)-propanodeoxyguanosine acrolein adduct (AdG3) in aortic DNA via a (32)P-postlabeling/HPLC method, and half were killed after 10 days (day 10 group) for indirect assessment of adduct repair. In the day 1 group, acrolein-DNA adducts were 5 times higher in the 1 and 10 ppm groups than in HEPA-filtered air controls. However, in the day 10 group, adduct levels in the 1 and 10 ppm acrolein groups were reduced to the control adduct level. For the plaque studies, cockerels inhaled 1 ppm acrolein (6 hr/day, 8 weeks), mixed with the same HEPA-filtered air inhaled by controls. Plaque development was measured blind by computerized morphometry. Unlike butadiene inhalation, acrolein inhalation did not accelerate plaque development. Thus, even though repeated exposure to acrolein alone has no effect on plaque size under the exposure conditions described here, a single, brief inhalation exposure to acrolein elicits repairable DNA damage to the artery wall. These results suggest that frequent exposure to ETS may lead to persistent artery-wall DNA damage and thus provide sites on which other ETS plaque accelerants can act.
PMCID: PMC1240238  PMID: 11333181
11.  Inhibition of self-splicing group I intron RNA: high-throughput screening assays. 
Nucleic Acids Research  1996;24(24):5051-5053.
High-throughput screening assays have been developed to rapidly identify small molecule inhibitors targeting catalytic group I introns. Biochemical reactions catalyzed by a self-splicing group I intron derived from Pneumocystis carinii or from bacteriophage T4 have been investigated. In vitro biochemical assays amenable to high-throughput screening have been established. Small molecules that inhibit the functions of group I introns have been identified. These inhibitors should be useful in better understanding ribozyme catalysis or in therapeutic intervention of group I intron-containing microorganisms.
PMCID: PMC146325  PMID: 9016680
12.  Stopping drinking and risk of oesophageal cancer. 
BMJ : British Medical Journal  1995;310(6987):1094-1097.
OBJECTIVE--To examine the effect of stopping drinking on the risk of oesophageal cancer. DESIGN--Hospital based case-control study. SETTING--Surgical departments of four district general hospitals and general practices in Hong Kong. SUBJECTS--Cases were 400 consecutive admissions of patients with histologically confirmed diagnosis of oesophageal cancer during a 21 month period in 1989-90 (87% response rate). Controls were 1598 patients selected from the same surgical departments as the cases and from the general practices from which the cases were originally referred (95% response rate). MAIN OUTCOME MEASURE--Relative risk of developing oesophageal cancer after stopping drinking (adjusted for age, education, place of birth, smoking, and diet). RESULTS--Current light drinking (< 200g ethanol/week) was not associated with significant increase in risk. Among former drinkers risk fell more quickly in moderate (200-599 g/week) than heavy (> or = 600 g/week) drinkers. Even among heavy drinkers, however, risk had dropped substantially after five to nine years of not drinking. The results suggest that the time taken for risk to return to that in subjects who never drink was 10-14 years for moderate drinkers and 15 years or more, if ever, for heavy drinkers. CONCLUSION--Risk of oesophageal cancer decreases fairly rapidly with time after abstaining from drinking. This new finding could be used in health promotion to encourage behavioural changes, especially in heavy drinkers, who have a very high risk of developing oesophageal cancer. It also suggests that alcoholic beverages have a strong effect on the late stage of carcinogenesis.
PMCID: PMC2549497  PMID: 7742674

Results 1-13 (13)