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1.  A Rank-Based Test for Comparison of Multidimensional Outcomes 
For comparison of multiple outcomes commonly encountered in biomedical research, Huang et al. (2005) improved O’Brien’s (1984) rank-sum tests through the replacement of the ad hoc variance by the asymptotic variance of the test statistics. The improved tests control the Type I error rate at the desired level and gain power when the differences between the two comparison groups in each outcome variable fall into the same direction. However, they may lose power when the differences are in different directions (e.g., some are positive and some are negative). These tests and the popular Bonferroni correction failed to show important significant difference when applied to compare heart rates from a clinical trial to evaluate the effect of a procedure to remove the cardioprotective solution HTK. We propose an alternative test statistic, taking the maximum of the individual rank-sum statistics, which controls the type I error and maintains satisfactory power regardless of the directions of the differences. Simulation studies show the proposed test to be of higher power than other tests in certain alternative parameter space of interest. Furthermore, when used to analyze the heart rates data the proposed test yields more satisfactory results.
doi:10.1198/jasa.2010.ap09114
PMCID: PMC3102319  PMID: 21625372
Autism spectrum disorder; Behrens-Fisher problem; Cardioprotective solution; Case-control studies; Growth hormones; Multiple outcomes; Non-parametrics; Rank-sum statistics
2.  A Weighted Rank-Sum Procedure for Comparing Samples with Multiple Endpoints 
Statistics and its interface  2009;2(2):197-201.
Summary
For comparing the distribution of two samples with multiple endpoints, O’Brien (1984) proposed rank-sum-type test statistics. Huang et al. (2005) extended these statistics to the general nonparametric Behrens-Fisher hypothesis problem and obtained improved test statistics by replacing the ad hoc variance with the asymptotic variance of the rank-sum statistics. In this paper we generalize the work of O’Brien (1984) and Huang et al. (2005) and propose a weighted rank-sum statistic. We show that the weighted rank-sum statistic is asymptotically normally distributed, permitting the computation of power, p-values and confidence intervals. We further demonstrate via simulation that the weighted rank-sum statistic is efficient in controlling the type I error rate and under certain alternatives, is more powerful than the statistics of O’Brien (1984) and Huang et al.(2005).
PMCID: PMC2759535  PMID: 19823699
Asymptotic normality; Behrens-Fisher problem; Case-Control; Clinical trials; Multiple endpoints; Rank-sum statistics; Weights
3.  Inside the black box: starting to uncover the underlying decision rules used in one-by-one expert assessment of occupational exposure in case-control studies 
Objectives
Evaluating occupational exposures in population-based case-control studies often requires exposure assessors to review each study participants' reported occupational information job-by-job to derive exposure estimates. Although such assessments likely have underlying decision rules, they usually lack transparency, are time-consuming and have uncertain reliability and validity. We aimed to identify the underlying rules to enable documentation, review, and future use of these expert-based exposure decisions.
Methods
Classification and regression trees (CART, predictions from a single tree) and random forests (predictions from many trees) were used to identify the underlying rules from the questionnaire responses and an expert's exposure assignments for occupational diesel exhaust exposure for several metrics: binary exposure probability and ordinal exposure probability, intensity, and frequency. Data were split into training (n=10,488 jobs), testing (n=2,247), and validation (n=2,248) data sets.
Results
The CART and random forest models' predictions agreed with 92–94% of the expert's binary probability assignments. For ordinal probability, intensity, and frequency metrics, the two models extracted decision rules more successfully for unexposed and highly exposed jobs (86–90% and 57–85%, respectively) than for low or medium exposed jobs (7–71%).
Conclusions
CART and random forest models extracted decision rules and accurately predicted an expert's exposure decisions for the majority of jobs and identified questionnaire response patterns that would require further expert review if the rules were applied to other jobs in the same or different study. This approach makes the exposure assessment process in case-control studies more transparent and creates a mechanism to efficiently replicate exposure decisions in future studies.
doi:10.1136/oemed-2012-100918
PMCID: PMC3975600  PMID: 23155187
diesel exhaust; classification; data mining; occupational exposure
4.  Genetic Variation in the Vitamin D Pathway in Relation to Risk of Prostate Cancer – Results from Breast and Prostate Cancer Cohort Consortium (BPC3) 
Background
Studies suggest that vitamin D status may be associated with prostate cancer risk, although the direction and strength of this association differs between experimental and observational studies. Genome-wide association studies have identified genetic variants associated with 25-hydroxyvitamin D (25(OH)D) status. We examined prostate cancer risk in relation to SNPs in four genes shown to predict circulating levels of 25(OH)D.
Methods
SNP markers localized to each of four genes (GC, CYP24A1, CYP2R1, and DHCR7) previously associated with 25(OH)D were genotyped in 10,018 cases and 11,052 controls from the NCI Breast and Prostate Cancer Cohort Consortium. Logistic regression was used to estimate the individual and cumulative association between genetic variants and risk of overall and aggressive prostate cancer.
Results
We observed a decreased risk of aggressive prostate cancer among men with the allele in rs6013897 near CYP24A1 associated with lower serum 25(OH)D (per A allele, OR=0.86, 95%CI=0.80–0.93, p-trend=0.0002), but an increased risk for non-aggressive disease (per a allele: OR=1.10, 95%CI=1.04–1.17, p-trend=0.002). Examination of a polygenic score of the four SNPs revealed statistically significantly lower risk of aggressive prostate cancer among men with a greater number of low vitamin D alleles (OR for 6–8 vs. 0–1 alleles = 0.66, 95% CI = 0.44 – 0.98; p-trend=0.003).
Conclusions
In this large, pooled analysis, genetic variants related to lower 25(OH)D were associated with a decreased risk of aggressive prostate cancer.
Impact
Our genetic findings do not support a protective association between loci known to influence vitamin D levels and prostate cancer risk.
doi:10.1158/1055-9965.EPI-13-0007-T
PMCID: PMC3617077  PMID: 23377224
Vitamin D; prostatic neoplasms; data pooling; genes; SNPs
5.  Cholecystokinin from the entorhinal cortex enables neural plasticity in the auditory cortex 
Cell Research  2013;24(3):307-330.
Patients with damage to the medial temporal lobe show deficits in forming new declarative memories but can still recall older memories, suggesting that the medial temporal lobe is necessary for encoding memories in the neocortex. Here, we found that cortical projection neurons in the perirhinal and entorhinal cortices were mostly immunopositive for cholecystokinin (CCK). Local infusion of CCK in the auditory cortex of anesthetized rats induced plastic changes that enabled cortical neurons to potentiate their responses or to start responding to an auditory stimulus that was paired with a tone that robustly triggered action potentials. CCK infusion also enabled auditory neurons to start responding to a light stimulus that was paired with a noise burst. In vivo intracellular recordings in the auditory cortex showed that synaptic strength was potentiated after two pairings of presynaptic and postsynaptic activity in the presence of CCK. Infusion of a CCKB antagonist in the auditory cortex prevented the formation of a visuo-auditory association in awake rats. Finally, activation of the entorhinal cortex potentiated neuronal responses in the auditory cortex, which was suppressed by infusion of a CCKB antagonist. Together, these findings suggest that the medial temporal lobe influences neocortical plasticity via CCK-positive cortical projection neurons in the entorhinal cortex.
doi:10.1038/cr.2013.164
PMCID: PMC3945883  PMID: 24343575
auditory cortex; neural plasticity; long-term potentiation; entorhinal cortex; hippocampal system; memory formation
6.  Reliable recovery of the optical properties of multi-layer turbid media by iteratively using a layered diffusion model at multiple source-detector separations 
Biomedical Optics Express  2014;5(3):975-989.
Accurately determining the optical properties of multi-layer turbid media using a layered diffusion model is often a difficult task and could be an ill-posed problem. In this study, an iterative algorithm was proposed for solving such problems. This algorithm employed a layered diffusion model to calculate the optical properties of a layered sample at several source-detector separations (SDSs). The optical properties determined at various SDSs were mutually referenced to complete one round of iteration and the optical properties were gradually revised in further iterations until a set of stable optical properties was obtained. We evaluated the performance of the proposed method using frequency domain Monte Carlo simulations and found that the method could robustly recover the layered sample properties with various layer thickness and optical property settings. It is expected that this algorithm can work with photon transport models in frequency and time domain for various applications, such as determination of subcutaneous fat or muscle optical properties and monitoring the hemodynamics of muscle.
doi:10.1364/BOE.5.000975
PMCID: PMC3959844
(170.5280) Photon migration; (170.5270) Photon density waves; (290.1990) Diffusion
7.  Semiparametric inference on the penetrances of rare genetic mutations based on a case-family design 
A formal semiparametric statistical inference framework is proposed for the evaluation of the age-dependent penetrance of a rare genetic mutation, using family data generated under a case-family design, where phenotype and genotype information are collected from first-degree relatives of case probands carrying the targeted mutation. The proposed approach allows for unobserved risk factors that are correlated among family members. Some rigorous large sample properties are established, which show that the proposed estimators were asymptotically semi-parametric efficient. A simulation study is conducted to evaluate the performance of the new approach, which shows the robustness of the proposed semiparamteric approach and its advantage over the corresponding parametric approach. As an illustration, the proposed approach is applied to estimating the age-dependent cancer risk among carriers of the MSH2 or MLH1 mutation.
doi:10.1016/j.jspi.2012.08.006
PMCID: PMC3544474  PMID: 23329866
Case-family design; kin-cohort design; penetrance; proportional hazards model
8.  Exploring the genetic architecture of circulating 25-hydroxyvitamin D 
Genetic epidemiology  2012;37(1):92-98.
The primary circulating form of vitamin D is 25-hydroxy-vitamin D (25(OH)D), a modifiable trait linked with a growing number of chronic diseases. In addition to environmental determinants of 25(OH)D, including dietary sources and skin ultraviolet B (UVB) exposure, twin and family-based studies suggest that genetics contribute substantially to vitamin D variability with heritability estimates ranging from 43% to 80%. Genome-wide association studies (GWAS) have identified SNPs located in four gene regions associated with 25(OH)D. These SNPs collectively explain only a fraction of the heritability in 25(OH)D estimated by twin and family based studies. Using 25(OH)D concentrations and GWAS data on 5,575 subjects drawn from 5 cohorts, we hypothesized that genome-wide data, in the form of (1) a polygenic score comprised of hundreds or thousands of SNPs that do not individually reach GWAS significance, or (2) a linear-mixed-model for genome-wide complex trait analysis, would explain variance in measured circulating 25(OH)D beyond that explained by known genome-wide significant 25(OH)D associated SNPs. GWAS identified SNPs explained 5.2% of the variation in circulating 25(OH)D in these samples and there was little evidence additional markers significantly improved predictive ability. On average a polygenic score comprised of GWAS identified SNPs explained a larger proportion of variation in circulating 25(OH)D than scores comprised of thousands of SNPs which were on average, non-significant. Employing a linear-mixed-model for genome-wide complex trait analysis explained little additional variability (range 0-22%). The absence of a significant polygenic effect in this relatively large sample suggests an oligogenetic architecture for 25(OH)D.
doi:10.1002/gepi.21694
PMCID: PMC3524394  PMID: 23135809
vitamin D; heritability; genome wide association; polygenic score
9.  Diabetes and risk of pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium 
Cancer causes & control : CCC  2012;24(1):13-25.
Purpose
Diabetes is a suspected risk factor for pancreatic cancer, but questions remain about whether it is a risk factor or a result of the disease. This study prospectively examined the association between diabetes and the risk of pancreatic adenocarcinoma in pooled data from the NCI pancreatic cancer cohort consortium (PanScan).
Methods
The pooled data included 1,621 pancreatic adenocarcinoma cases and 1,719 matched controls from twelve cohorts using a nested case–control study design. Subjects who were diagnosed with diabetes near the time (<2 years) of pancreatic cancer diagnosis were excluded from all analyses. All analyses were adjusted for age, race, gender, study, alcohol use, smoking, BMI, and family history of pancreatic cancer.
Results
Self-reported diabetes was associated with a forty percent increased risk of pancreatic cancer (OR = 1.40, 95 % CI: 1.07, 1.84). The association differed by duration of diabetes; risk was highest for those with a duration of 2–8 years (OR = 1.79, 95 % CI: 1.25, 2.55); there was no association for those with 9+ years of diabetes (OR = 1.02, 95 % CI: 0.68, 1.52).
Conclusions
These findings provide support for a relationship between diabetes and pancreatic cancer risk. The absence of association in those with the longest duration of diabetes may reflect hypoinsulinemia and warrants further investigation.
doi:10.1007/s10552-012-0078-8
PMCID: PMC3529822  PMID: 23112111
Diabetes; Risk factor; Cohort consortium; Pancreatic cancer
10.  Individual Variations in Serum Melatonin Levels through Time: Implications for Epidemiologic Studies 
PLoS ONE  2013;8(12):e83208.
Melatonin, a marker for the circadian rhythm with serum levels peaking between 2AM and 5AM, is hypothesized to possess anti-cancer properties, making it a mechanistic candidate for the probable carcinogenic effect of circadian rhythm disruption. In order to weigh epidemiologic evidence on the association of melatonin with cancer, we must first understand the laboratory and biological sources of variability in melatonin levels measured in samples. Participants for this methodological study were men enrolled in the Prostate Lung Colorectal and Ovarian Cancer Screening Trial (PLCO). We measured serum melatonin levels over a five year period in 97 individuals to test if melatonin levels are steady over time. The Pearson correlation coefficient between two measures separated by 1 year was 0.87, while the correlation between two measures separated by 5 years was to 0.70. In an additional cross-sectional study of 292 individuals, we used Analysis of Variance to identify differences in melatonin levels between different lifestyle and environmental characteristics. Serum melatonin levels were slightly higher in samples collected from 130 individuals during the winter, (6.36±0.59 pg/ml) than in samples collected from 119 individuals during the summer (4.83±0.62 pg/ml). Serum melatonin levels were lowest in current smokers (3.02±1.25 pg/ml, p = 0.007) compared to never (6.66±0.66 pg/ml) and former (5.59±0.50 pg/ml) smokers whereas BMI did not significantly affect serum melatonin levels in this study. In conclusion, the high 5 year correlation of melatonin levels implies that single measurements may be used to detect population level associations between melatonin and risk of cancer. Furthermore, our results reiterate the need to record season of sample collection, and individual characteristics in order to maximize study power and prevent confounding.
doi:10.1371/journal.pone.0083208
PMCID: PMC3871612  PMID: 24376664
11.  Acute and Prolonged Adverse Effects of Temperature on Mortality from Cardiovascular Diseases 
PLoS ONE  2013;8(12):e82678.
Background
Cardiovascular diseases are the leading causes of death worldwide, especially for developed countries. Elevated mortality from cardiovascular diseases has been shown related to extreme temperature. We thus assessed the risk of mortality from cerebrovascular diseases, heart diseases, and ischemic heart disease (IHD) in relation to temperature profiles in four subtropical metropolitans (Taipei, Taichung, Tainan, and Kaohsiung) from 1994 to 2007 in Taiwan.
Methods
Distributed lag non-linear models were applied to estimate the cumulative relative risks (RRs) with confidence intervals of cause-specific mortality associated with daily temperature from lag 0 to 20 days, and specific effect of extreme temperature episodes with PM10, NOx, and O3, and other potential confounders controlled. Estimates for cause-specific mortalities were then pooled by random-effect meta-analysis.
Results
Comparing to centered temperature at 27°C, the cumulative 4-day (lag 0 to 3) risk of mortality was significantly elevated at 31°C for cerebrovascular diseases (RR = 1.14; 95% CI: 1.00, 1.31) and heart diseases (RR =  1.22; 95% CI: 1.02, 1.46) , but not for IHD (RR =  1.09; 95% CI: 0.99, 1.21). To the other extreme, at 15°C, the cumulative 21-day (lag 0 to 20) risk of mortality were also remarkably increased for cerebrovascular diseases, heart diseases, and IHD (RRs  =  1.48 with 95% CI: 1.04, 2.12, 2.04 with 95% CI: 1.61, 2.58, and 1.62 with 95% CI: 1.30, 2.01, respectively). Mortality risks for cardiovascular diseases were generally highest on the present day (lag 0) of extreme heat. No particular finding was detected on prolonged extreme temperature event by pooling estimations for cause-specific mortality.
Conclusions
Low temperature was associated with greater risk of mortality from cardiovascular diseases in comparison with that of high temperature. Adverse effects of extreme temperatures are acute at the beginning of exposure.
doi:10.1371/journal.pone.0082678
PMCID: PMC3857249  PMID: 24349335
12.  Total synthesis of the endogenous inflammation resolving lipid resolvin D2 using a common lynchpin 
Summary
The total synthesis of the endogenous inflammation resolving eicosanoid resolvin D2 (1) is described. The key steps involved a Wittig reaction between aldehyde 5 and the ylide derived from phosphonium salt 6 to give enyne 17 and condensation of the same ylide with aldehyde 7 to afford enyne 11. Desilylation of 11 followed by hydrozirconation and iodination gave the vinyl iodide 4 and Sonogashira coupling between this compound and enyne 3 provided alkyne 18. Acetonide deprotection, partial reduction and ester hydrolysis then gave resolvin D2 (1).
doi:10.3762/bjoc.9.310
PMCID: PMC3869264  PMID: 24367439
catalysis; eicosanoid; natural product; resolvin D2; Sonogashira coupling; total synthesis; Wittig reaction
13.  Noninvasive positive pressure ventilation for the treatment of acute respiratory distress syndrome following esophagectomy for esophageal cancer: a clinical comparative study 
Journal of Thoracic Disease  2013;5(6):777-782.
Objective
To evaluate the therapeutic efficacy of noninvasive positive pressure ventilation (NPPV) in the treatment of acute respiratory distress syndrome (ARDS) following esophagectomy for esophageal cancer.
Methods
In this retrospective evaluation, we included 64 patients with ARDS following esophagectomy for esophageal cancer between January 2009 and December 2011. The primary evaluations were 28-day fatality and actual fatality. The secondary evaluations were sex, age, onset time, pH value, PaO2/FiO2, sequential organ failure assessment (SOFA) score, acute physiology and chronic health evaluation (APACHE-II) score, and presence or absence after surgery of major surgery-related complications such as cardiac arrest, anastomotic fistula, and acute renal dysfunction.
Results
NPPV applied as the first-line intervention for ARDS following esophagectomy for esophageal cancer avoided intubation in 30 patients (30/64, 48.4%). There were no significant differences in gender, age, PaO2/FiO2, SOFA score, or APACHE-II score between the NPPV group and the patients who required invasive positive pressure ventilation (IPPV group) (P>0.05) at the time of onset, while differences in the PaO2/FiO2 (P<0.05) after 24 h of NPPV and presence of major surgery-related complications were highly significant (P<0.01).
Conclusions
NPPV may be an effective option for the treatment of ARDS/acute lung injury (ALI) following esophagectomy for esophageal cancer. However, conversion to invasive mechanical ventilation should be considered in patients with severe postoperative complications such as acute renal dysfunction and cardiac arrest and in those with PaO2/FiO2 <180 after 2 h of NPPV.
doi:10.3978/j.issn.2072-1439.2013.09.09
PMCID: PMC3886700  PMID: 24409355
Noninvasive positive pressure ventilation (NPPV); esophagectomy; acute respiratory distress syndrome (ARDS)
14.  Cure of metastatic growth of EMT6 tumor cells in mice following manipulation of CD200:CD200R signaling 
In previous studies, we observed that regulation of expression of CD200, both on cells of a transplantable breast cancer, EMT6, and of the host, as well as of the receptor, CD200R in host mice, regulated local tumor growth and metastasis in immunocompetent animals. This in turn led to an improved ability to document immunity to EMT6 in CD200R1KO mice. In the current study, we have explored the ability to cure BALB/c CD200KO or CD200R1KO mice of tumors ≤1 cm3 in size by surgical resection of localized tumor, followed by immunization with irradiated EMT6 cells along with CpG as adjuvant. While control animals treated in this fashion developed significant pulmonary and liver metastases within 30 days of surgery, significant protection was seen in both CD200KO or CD200R1KO mice, with no macroscopic lung/liver metastases observed in CD200R1KO mice on sacrifice at day 300. Following surgical resection and immunization, draining lymph nodes from control mice contained tumor cells cloned at limiting dilution in vitro even before pulmonary and hepatic metastasis was seen. In contrast, within the limits of detection of the assay used (sensitivity ~1 in 107 cells), no tumor cells were detected at limiting dilution in similarly treated CD200R1KO mice, and significant reductions were seen in CD200KO mice. Infusion of anti-CD4, but less so anti-CD8, mAb into surgically treated and immunized CD200R1KO mice attenuated protection from both macroscopic (liver/lung) and microscopic (assayed by limiting dilution of DLN) metastasis. Adoptive transfer of lymphocytes from treated CD200R1KO mice to surgically treated control mice also attenuated metastatic growth of tumor, which was abolished by pretreatment of transferred cells with anti-CD4 mAb. Our data suggest that CD200:CD200R attenuates a potentially tumor-protective CD4 host response to breast cancer.
Electronic supplementary material
The online version of this article (doi:10.1007/s10549-013-2735-3) contains supplementary material, which is available to authorized users.
doi:10.1007/s10549-013-2735-3
PMCID: PMC3832754  PMID: 24166280
Breast cancer; Metastasis; CD200R1KO; CD200R1KO; Immunotherapy
15.  Genome-wide association studies of gastric adenocarcinoma and esophageal squamous cell carcinoma identify a shared susceptibility locus in PLCE1 at 10q23 
Nature genetics  2012;44(10):1090-1097.
We conducted a genome-wide association study of gastric cancer (GC) and esophageal squamous cell carcinoma (ESCC) in ethnic Chinese subjects in which we genotyped 551,152 single nucleotide polymorphisms (SNPs). We report a combined analysis of 2,240 GC cases, 2,115 ESCC cases, and 3,302 controls drawn from five studies. In logistic regression models adjusted for age, sex, and study, multiple variants at 10q23 had genome-wide significance for GC and ESCC independently. A notable signal was rs2274223, a nonsynonymous SNP located in PLCE1, for GC (P=8.40×1010; per allele odds ratio (OR) = 1.31) and ESCC (P=3.85×10−9; OR = 1.34). The association with GC differed by anatomic subsite. For tumors located in the cardia the association was stronger (P=4.19 × 10−15; OR= 1.57) and for those located in the noncardia stomach it was absent (P=0.44; OR=1.05). Our findings at 10q23 could provide insight into the high incidence rates of both cancers in China.
doi:10.1038/ng.2411
PMCID: PMC3513832  PMID: 22960999
16.  Comparing statistical methods for removing seasonal variation from vitamin D measurements in case-control studies 
Statistics and its interface  2011;4(1):85-93.
Vitamin D deficiency has been shown to be associated with multiple clinical outcomes, including osteoporosis, multiple sclerosis and colorectal cancer. In studies of vitamin D effect on disease outcome, vitamin D status is usually measured by a serum biomarker, namely 25-hydroxy vitamin D [25(OH)D]. Since the circulating 25(OH)D concentration varies from season to season and not all blood samples are collected at the same time, the disease-vitamin D relationship can be obscured if the seasonal variation is not adjusted properly. In the literature, a two-step procedure is usually adopted, with the vitamin D level adjusted for the seasonal variation being obtained in the first step, and the effect of vitamin D being assessed based on the adjusted vitamin D level at the second step. This two-step method can generate misleading results as the estimation variance arising from the first step is not taken into account in the second step analysis. We consider three alternative procedures that unify the two steps into a single model. We conduct an extensive simulation study to evaluate the performance of these methods and demonstrate their applications in a study of 25(OH)D effect on prostate cancer risk.
doi:10.4310/SII.2011.v4.n1.a9
PMCID: PMC3786447  PMID: 24089626
25-hydroxy vitamin D; partial linear model; locally weighted polynomial regression; penalized regression splines; prostate cancer; seasonal pattern; sine curve
17.  Combined treatment for cutaneous Rosai-Dorfman disease: a report of 2 cases 
We report 2 cases of cutaneous Rosai-Dorfman disease (CRDD). One was a 46-year-old Chinese woman who presented with a 10-year history of multiple papules and nodules on the left cheek. Another one was a 57-year-old Chinese woman who presented with a 7-month history of erythematous pruritic plaque on the Dorsum nasi. Their lesions consisted of proliferative large histiocytes occasionally showing emperipolesis. Immunohistochemistry showed these histiocytes were positive for CD68 and S-100, but negative for CD1a. A diagnosis of CRDD was made. Their lesions were improved after intralesional treatment with Compound Betamethasone, interferon and acitretin. To our knowledge, we for the first time reported the application of intralesional Compound Betamethasone and Lidocaine, intramuscular injection of interferon, and oral acitretin in the treatment of CRDD, and favorable outcome was achieved without recurrence over a 1-year follow-up period.
PMCID: PMC3798220  PMID: 24179578
Cutaneous Rosai-Dorfman disease; intralesional Compound Betamethasone and lidocaine; intramuscular injection of interferon; oral acitretin; Chinese
18.  Asymmetric allylic alkylation of Morita–Baylis–Hillman carbonates with α-fluoro-β-keto esters 
Summary
In the presence of a commercially available Cinchona alkaloid as catalyst, the asymmetric allylic alkylation of Morita–Baylis–Hillman carbonates, with α-fluoro-β-keto esters as nucleophiles, have been successfully developed. A series of important fluorinated adducts, with chiral quaternary carbon centres containing a fluorine atom, was achieved in good yields (up to 93%), with good to excellent enantioselectivities (up to 96% ee) and moderate diastereoselectivities (up to 4:1 dr).
doi:10.3762/bjoc.9.216
PMCID: PMC3778419  PMID: 24062852
allylic alkylation; asymmetric catalysis; fluorine; fluoro-β-keto esters; Morita–Baylis–Hillman carbonates; natural product
19.  Different TLR4 expression and microglia/macrophage activation induced by hemorrhage in the rat spinal cord after compressive injury 
Background
Hemorrhage is a direct consequence of traumatic injury to the central nervous system and may cause innate immune reactions including cerebral Toll-like receptor (TLR) 4 upregulation which usually leads to poor outcome in the traumatic brain injury. In spinal cord injury (SCI), however, how hemorrhage induces innate immune reaction in spinal parenchyma remains unknown. The present study aimed to see whether blood component and/or other factor(s) induce TLR4 and microglia/macrophages involved innate immune reactions in the rat spinal cord after traumatic injury.
Methods
Using the compressive SCI model of the rat, hemorrhage in the spinal cord was identified by hematoxylin-eosin staining. Microglia/macrophage activation, TLR4 expression, and cell apoptosis were investigated by immunohistochemistry. Nuclear factor (NF)-κB p50 level of the two segments of the cord was detected by western blotting assay. With carbon powder injection, blood origination of the hematoma was explored. The blood-spinal cord barrier (BSCB) states of the lesion site and the hematoma were compared with immunohistochemistry and tannic acid-ferric chloride staining.
Results
Histological observation found blood accumulated in the center of compression lesion site (epicenter) and in the hematoma approximately 1.5 cm away from the epicenter. TLR4 expression, microglia//macrophage activation, and subsequent apoptosis in the area of far-away hematoma were late and weak in comparison to that in epicenter. In addition, TLR4 positive microglia/macrophages appeared to be phagocytotic in the far-away hematoma more obviously than that in the epicenter. Injected carbon powder indicated that accumulated blood of the far-away hematoma originated from the bleeding of the lesion epicenter, and the BSCB around the hematoma was not compromised in the early phase. Accordingly, at 3 days post injury, NF-κB p50 was upregulated based on the similar levels of blood component hemoglobin, and cell apoptosis was obvious in the epicenter but not in the far-away hematoma.
Conclusion
These data suggest that besides blood component, BSCB compromise and the extent of tissue injury contribute more to TLR4 and microglia/macrophage responses to the spinal cord hemorrhage. Therefore, the innate immune environment is a necessary consideration for the SCI therapy targeting TLR4 and microglia/macrophages.
doi:10.1186/1742-2094-10-112
PMCID: PMC3847110  PMID: 24015844
Hemorrhage; Toll-like receptor 4; Microglia/macrophage; Spinal cord injury; Blood-spinal cord barrier; Rat
20.  Frequency and pattern of Chinese herbal medicine prescriptions for urticaria in Taiwan during 2009: analysis of the national health insurance database 
Background
Large-scale pharmaco-epidemiological studies of Chinese herbal medicine (CHM) for treatment of urticaria are few, even though clinical trials showed some CHM are effective. The purpose of this study was to explore the frequencies and patterns of CHM prescriptions for urticaria by analysing the population-based CHM database in Taiwan.
Methods
This study was linked to and processed through the complete traditional CHM database of the National Health Insurance Research Database in Taiwan during 2009. We calculated the frequencies and patterns of CHM prescriptions used for treatment of urticaria, of which the diagnosis was defined as the single ICD-9 Code of 708. Frequent itemset mining, as applied to data mining, was used to analyse co-prescription of CHM for patients with urticaria.
Results
There were 37,386 subjects who visited traditional Chinese Medicine clinics for urticaria in Taiwan during 2009 and received a total of 95,765 CHM prescriptions. Subjects between 18 and 35 years of age comprised the largest number of those treated (32.76%). In addition, women used CHM for urticaria more frequently than men (female:male = 1.94:1). There was an average of 5.54 items prescribed in the form of either individual Chinese herbs or a formula in a single CHM prescription for urticaria. Bai-Xian-Pi (Dictamnus dasycarpus Turcz) was the most commonly prescribed single Chinese herb while Xiao-Feng San was the most commonly prescribed Chinese herbal formula. The most commonly prescribed CHM drug combination was Xiao-Feng San plus Bai-Xian-Pi while the most commonly prescribed triple drug combination was Xiao-Feng San, Bai-Xian-Pi, and Di-Fu Zi (Kochia scoparia).
Conclusions
In view of the popularity of CHM such as Xiao-Feng San prescribed for the wind-heat pattern of urticaria in this study, a large-scale, randomized clinical trial is warranted to research their efficacy and safety.
doi:10.1186/1472-6882-13-209
PMCID: PMC3751558  PMID: 23947955
Urticaria; Chinese herbal medicine; National health insurance database; Taiwan
21.  Increased Levels of Circulating Cytokines with HIV-Related Immunosuppression 
Abstract
Cytokines may contribute to the severity of CD4 cell depletion with human immunodeficiency virus (HIV) infection, but quantitative relationships are not well defined. Serum and plasma from 181 HIV-infected individuals were tested with Millipore 30-plex Luminex cytokine assays. Within-individual correlations among cytokines were summarized by two-dimensional hierarchical cluster analysis. Associations with age, sex, race, CD4 count, and HIV viral load were determined with linear regression models. Tests for statistical significance were corrected for multiple comparisons, using a false discovery rate of 0.1. African-Americans had significantly higher levels than whites of six cytokines (IL-2, IL-5, IL-7, IL-15, fractalkine, and IFN-γ), and lower levels of MCP-1. Females had higher fractalkine levels than males. Age was not associated with levels of any cytokine. Six cytokines, including the T-helper (Th) type 1 cytokine IL-15, the Th2 cytokines IL-1ra and IL-10, the chemokines fractalkine and MCP-1, and the growth factor G-CSF were each inversely associated with CD4 count; no cytokine was directly associated with CD4 count. Fractalkine was directly associated with HIV viral load, adjusted for CD4 count. Cytokines clustered by primary function (e.g., Th1, Th2, proinflammatory, chemokines, or growth factors) whereas individuals clustered according to cytokine levels (generally high, intermediate, or low) had significantly different CD4 counts [medians (interquartile range) of 60 (17–162), 131 (62–321), and 155 (44–467), respectively; p<0.0001]. CD4 deficiency is associated with generalized increases in cytokines of various functions. Racial differences in cytokine response to HIV infection could contribute to disparities in disease progression.
doi:10.1089/aid.2011.0144
PMCID: PMC3399552  PMID: 21962239
22.  Genetic Variants in Epidermal Growth Factor Receptor Pathway Genes and Risk of Esophageal Squamous Cell Carcinoma and Gastric Cancer in a Chinese Population 
PLoS ONE  2013;8(7):e68999.
The epidermal growth factor receptor (EGFR) signaling pathway regulates cell proliferation, differentiation, and survival, and is frequently dysregulated in esophageal and gastric cancers. Few studies have comprehensively examined the association between germline genetic variants in the EGFR pathway and risk of esophageal and gastric cancers. Based on a genome-wide association study in a Han Chinese population, we examined 3443 SNPs in 127 genes in the EGFR pathway for 1942 esophageal squamous cell carcinomas (ESCCs), 1758 gastric cancers (GCs), and 2111 controls. SNP-level analyses were conducted using logistic regression models. We applied the resampling-based adaptive rank truncated product approach to determine the gene- and pathway-level associations. The EGFR pathway was significantly associated with GC risk (P = 2.16×10−3). Gene-level analyses found 10 genes to be associated with GC, including FYN, MAPK8, MAP2K4, GNAI3, MAP2K1, TLN1, PRLR, PLCG2, RPS6KB2, and PIK3R3 (P<0.05). For ESCC, we did not observe a significant pathway-level association (P = 0.72), but gene-level analyses suggested associations between GNAI3, CHRNE, PAK4, WASL, and ITCH, and ESCC (P<0.05). Our data suggest an association between specific genes in the EGFR signaling pathway and risk of GC and ESCC. Further studies are warranted to validate these associations and to investigate underlying mechanisms.
doi:10.1371/journal.pone.0068999
PMCID: PMC3715462  PMID: 23874846
23.  The association between the PPARγ2 Pro12Ala polymorphism and nephropathy susceptibility in type 2 diabetes: a meta-analysis based on 9,176 subjects 
Diagnostic Pathology  2013;8:118.
Background
The polymorphism Pro12Ala in peroxisome proliferator-activated receptor­γ2 gene (PPARγ2) has been reported to be associated with diabetic nephropathy (DN) in some studies, though the results remain inconclusive. To explore this relationship between PPARγ2 Pro12Ala polymorphism and the susceptibility for DN, a cumulative meta-analysis was performed in this study.
Method
PubMed, Medline, Embase and Web of Science databases have been systematically searched to identify relevant studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated.
Results
18 studies were included in this meta-analysis, involving 3,361 cases and 5,815 controls. The PPARγ2 Ala12 allele was significantly associated with decreased risk of DN based on dominant model (OR=0.778; 95%CI=0.618–0.981; Pheterogeneity=0.008; P=0.034). In the stratified analysis by ethnicity, significantly decreased risks were found among Caucasians for dominant model (OR=0.674; 95%CI=0.500–0.909; Pheterogeneity=0.079; P=0.010), while there was no significant association was found in Asians.
Conclusions
The results from the present meta-analysis indicated that the Pro12Ala polymorphism in PPARγ2 gene is not a risk factor for DN in type 2 diabetes (T2D). Further large and well-designed studies are needed to confirm this conclusion.
Virtual slides
The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7491348341027320.
doi:10.1186/1746-1596-8-118
PMCID: PMC3751054  PMID: 23856170
PPARγ2; Meta-analysis; Diabetic nephropathy; Polymorphisms
24.  Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer 
Carcinogenesis  2012;33(7):1384-1390.
Four loci have been associated with pancreatic cancer through genome-wide association studies (GWAS). Pathway-based analysis of GWAS data is a complementary approach to identify groups of genes or biological pathways enriched with disease-associated single-nucleotide polymorphisms (SNPs) whose individual effect sizes may be too small to be detected by standard single-locus methods. We used the adaptive rank truncated product method in a pathway-based analysis of GWAS data from 3851 pancreatic cancer cases and 3934 control participants pooled from 12 cohort studies and 8 case–control studies (PanScan). We compiled 23 biological pathways hypothesized to be relevant to pancreatic cancer and observed a nominal association between pancreatic cancer and five pathways (P < 0.05), i.e. pancreatic development, Helicobacter pylori lacto/neolacto, hedgehog, Th1/Th2 immune response and apoptosis (P = 2.0 × 10−6, 1.6 × 10−5, 0.0019, 0.019 and 0.023, respectively). After excluding previously identified genes from the original GWAS in three pathways (NR5A2, ABO and SHH), the pancreatic development pathway remained significant (P = 8.3 × 10−5), whereas the others did not. The most significant genes (P < 0.01) in the five pathways were NR5A2, HNF1A, HNF4G and PDX1 for pancreatic development; ABO for H. pylori lacto/neolacto; SHH for hedgehog; TGFBR2 and CCL18 for Th1/Th2 immune response and MAPK8 and BCL2L11 for apoptosis. Our results provide a link between inherited variation in genes important for pancreatic development and cancer and show that pathway-based approaches to analysis of GWAS data can yield important insights into the collective role of genetic risk variants in cancer.
doi:10.1093/carcin/bgs151
PMCID: PMC3405651  PMID: 22523087
25.  Minimally Invasive Thoracic Surgery in Pediatric Patients: The Taiwan Experience 
BioMed Research International  2013;2013:850840.
Minimally invasive technology or laparoscopic surgery underwent a major breakthrough over the past two decades. The first experience of thoracoscopy in children was reported around 1980 for diagnosis of intrathoracic pathology and neoplasia. Up until the middle of the 1990s, the surgical community in Taiwan was still not well prepared to accept the coming era of minimally invasive surgery. In the beginning, laparoscopy was performed in only a few specialties and only relatively short or simple surgeries were considered. But now, the Taiwan's experiences over the several different clinical scenarios were dramatically increased. Therefore, we elaborated on the experience about pectus excavatum: Nuss procedure, primary spontaneous hemopneumothorax, thoracoscopic thymectomy, and empyema in Taiwan.
doi:10.1155/2013/850840
PMCID: PMC3683426  PMID: 23819123

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