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2.  Comparison between two labeled agents in mice using a coinjection-ratio approach in contrast to a conventional group approach 
Nuclear medicine and biology  2013;41(1):10.1016/j.nucmedbio.2013.10.001.
The differences between two agents often need to be accurately defined in vivo. Conventionally they are injected respectively into two groups of subjects. However, if the two agents do not interact with each other in vivo, a coinjection would serve the same purpose. We believe some individual differences in biodistribution may be circumvented through this approach by calculating organ level ratios.
A model system of MORF/cMORF pretargeting (MORF/cMORF is a complementary pair of DNA analogues) was employed in connection with an on-going tumor therapeutic project. Human LS174T cells were implanted into the flank of severely immuno-compromised NOD-scid IL2rgnull mice. The tumor was confirmed to express TAG-72 antigens. At 16 days post tumor inoculation, mice received IV 60 μg of MORF-conjugated CC49 (an antiTAG-72 antibody), followed 2 days later by a low-mass-dose IV coinjection containing 2.5 μg of 90Y-cMORF and 2.5 μg of 99mTc-cMORF. At 3 h post radioactivity injection, the distribution of 99mTc was imaged on a SPECT/CT camera and then organs were excised and counted for 90Y and 99mTc. Because the two labeled cMORFs do not react or interact with each other in vivo, the two groups of 90Y and 99mTc data enabled a conventional group comparison. In a new effort, 90Y/99mTc ratios were calculated. Student’s t-test and retrospective power analysis were performed for both approaches. In the new approach, the ratios were set at 1 as the null hypothesis.
The student’s t-test in the conventional group approach indicated that the two labeled cMORFs distributed similarly, but significant differences were observed in salivary gland and large intestines. The coinjection-ratio approach certainly did not subvert the results of the conventional approach but revealed subtler differences. The P values were reduced, the powers were increased in most organs, and more significant differences were observed. The increased sensitivity was due to the reduced CV%s of the 90Y/99mTc ratios (SD/Average*100%). Therefore, some individual differences were circumvented and notably the ratio approach differentiated individual differences into ratio-correctable and ratio-uncorrectable.
Although the conventional approach is reliable, the coinjection-ratio approach using level ratios is more sensitive and therefore is recommended whenever possible. In addition, it differentiates individual differences into “coinjection correctable” and “coinjection uncorrectable”.
PMCID: PMC3855254  PMID: 24210286
Statistical analysis; in vivo evaluation; biodistribution; translational study; tumor pretargeting
3.  Decrease in Plasma Cyclophilin A Concentration at 1 Month after Myocardial Infarction Predicts Better Left Ventricular Performance and Synchronicity at 6 Months: A Pilot Study in Patients with ST Elevation Myocardial Infarction 
Background: Cyclophilin A (CyPA) concentration increases in acute coronary syndrome. In an animal model of acute myocardial infarction, administration of angiotensin-converting-enzyme inhibitor was associated with lower left ventricular (LV) CyPA concentration and improved LV performance. This study investigated the relationships between changes in plasma CyPA concentrations and LV remodeling in patients with ST-elevation myocardial infarction (STEMI).
Methods and Results: We enrolled 55 patients who underwent percutaneous coronary intervention for acute STEMI. Plasma CyPA, matrix metalloproteinase (MMP), interleukin-6 and high-sensitivity C-reactive protein concentrations were measured at baseline and at one-month follow-up. Echocardiography was performed at baseline and at one-, three-, and six-month follow-up. Patients with a decrease in baseline CyPA concentration at one-month follow-up (n = 28) had a significant increase in LV ejection fraction (LVEF) (from 60.2 ± 11.5% to 64.6 ± 9.9%, p < 0. 001) and preserved LV synchrony at six months. Patients without a decrease in CyPA concentration at one month (n = 27) did not show improvement in LVEF and had a significantly increased systolic dyssynchrony index (SDI) (from 1.170 ± 0.510% to 1.637 ± 1.299%, p = 0.042) at six months. Multiple linear regression analysis showed a significant association between one-month CyPA concentration and six-month LVEF. The one-month MMP-2 concentration was positively correlated with one-month CyPA concentration and LV SDI.
Conclusions: Decreased CyPA concentration at one-month follow-up after STEMI was associated with better LVEF and SDI at six months. Changes in CyPA, therefore, may be a prognosticator of patient outcome.
PMCID: PMC4278253  PMID: 25552928
Acute myocardial infarction; Cyclophilin A; Left ventricular ejection fraction; Left ventricular dyssynchrony; Matrix metalloproteinase.
4.  Black and White men younger than 50 years of age demonstrate similar outcomes after radical prostatectomy 
BMC Urology  2014;14(1):98.
Black men with prostate cancer are diagnosed at a younger age, present with more aggressive disease, and experience higher mortality. We sought to assess pathological features and biochemical recurrence (BCR) in young men undergoing radical prostatectomy (RP) to determine if there is a difference between black and white men closer to the time of disease initiation.
We identified 551 white and 99 black men at a tertiary cancer center who underwent RP at ≤50 years of age. Baseline and pathological features were compared between the two groups. Cox proportional hazards models were utilized to examine the association of race and BCR, and Kaplan-Meier curves were generated to determine biochemical recurrence-free survival (bRFS).
There were no differences in median age at surgery, biopsy Gleason score, or comorbidity. Black men had higher preoperative PSA (6.1 ng/ml vs 4.7 ng/ml, p = 0.004), but a greater percentage were cT1c (78% vs 63%), compared to white men. On multivariate analysis, black men demonstrated significantly lower odds of non-organ confined disease (OR 0.39; 95% CI: 0.18, 0.81; p = 0.01) and extracapsular extension (ECE) (OR 0.38; 95% CI: 0.18, 0.81, p = 0.01), and had no difference in Gleason score upgrading and seminal vesicle invasion compared to white men. There was no significant difference in bRFS in men with organ-confined disease; however, among men with locally advanced disease black men trended towards greater BCR (p = 0.052). Black men had 2-year bRFS of 56% vs 75% in white men.
In this single institution study, there does not appear to be a racial disparity in outcomes among younger men who receive RP for prostate cancer. Black and white men in our cohort demonstrate similar bRFS with pathologically confirmed organ-confined disease. There may be greater risk of BCR among black men locally advanced disease compared to white men, suggesting that locally advanced disease is biologically more aggressive in black men.
PMCID: PMC4269868  PMID: 25495177
Prostate cancer; Radical prostatectomy; Race; Biochemical recurrence; Disparities; Age
5.  Epidemiological and viral genome characteristics of the first human H7N9 influenza infection in Guangdong Province, China 
Journal of Thoracic Disease  2014;6(12):1785-1793.
The first H7N9 human case in south of China was confirmed in Guangdong Province on August 2013, outside of the typical influenza season. For investigating the H7N9 virus source and transmission in the local community, we analyze the epidemiology and genome features of the virus isolated from the first human infection detected in Guangdong Province.
The data including medical records, exposure history and time line of events for the H7N9 patient and close contacts was collected. Variation and genetic signatures of H7N9 virus in Guangdong was analyzed using ClustalW algorithm and comparison with mutations associated with changes in biological characteristics of the virus.
The female patient had a history of poultry exposure, and she was transferred from a local primary hospital to an intensive care unit (ICU) upon deterioration. No additional cases were reported. Similar to previous infections with avian influenza A (H7N9) virus, the patient presented with both upper and lower respiratory tract symptoms. Respiratory failure progressed quickly, and the patient recovered 4 weeks after the onset of symptoms. Genome analysis of the virus indicated that the predicted antigen city and internal genes of the virus are similar to previously reported H7N9 viruses. The isolated virus is susceptible to neuraminidase (NA) inhibitors but resistant to adamantine. Although this virus contains some unique mutations that were only detected in avian or environment-origin avian influenza A (H7N9) viruses, it is still quite similar to other human H7N9 isolates.
The epidemiological features and genome of the first H7N9 virus in Guangdong Province are similar to other human H7N9 infections. This virus may have existed in the environment and live poultry locally; therefore, it is important to be alert of the risk of H7N9 re-emergence in China, including emergence outside the typical influenza season.
PMCID: PMC4283329  PMID: 25589974
Avian influenza virus; epidemiology; H7N9; viral genome
6.  Pose Measurement Method and Experiments for High-Speed Rolling Targets in a Wind Tunnel 
Sensors (Basel, Switzerland)  2014;14(12):23933-23953.
High-precision wind tunnel simulation tests play an important role in aircraft design and manufacture. In this study, a high-speed pose vision measurement method is proposed for high-speed and rolling targets in a supersonic wind tunnel. To obtain images with high signal-to-noise ratio and avoid impacts on the aerodynamic shape of the rolling targets, a high-speed image acquisition method based on ultrathin retro-reflection markers is presented. Since markers are small-sized and some of them may be lost when the target is rolling, a novel markers layout with which markers are distributed evenly on the surface is proposed based on a spatial coding method to achieve highly accurate pose information. Additionally, a pose acquisition is carried out according to the mentioned markers layout after removing mismatching points by Case Deletion Diagnostics. Finally, experiments on measuring the pose parameters of high-speed targets in the laboratory and in a supersonic wind tunnel are conducted to verify the feasibility and effectiveness of the proposed method. Experimental results indicate that the position measurement precision is less than 0.16 mm, the pitching and yaw angle precision less than 0.132° and the roll angle precision 0.712°.
PMCID: PMC4299094  PMID: 25615732
machine vision; pose measurement; high-speed motion; wind tunnel
7.  A multiple imputation approach to the analysis of interval-censored failure time data with the additive hazards model 
This paper discusses regression analysis of interval-censored failure time data, which occur in many fields including demographical, epidemiological, financial, medical, and sociological studies. For the problem, we focus on the situation where the survival time of interest can be described by the additive hazards model and a multiple imputation approach is presented for inference. A major advantage of the approach is its simplicity and it can be easily implemented by using the existing software packages for right-censored failure time data. Extensive simulation studies are conducted which indicate that the approach performs well for practical situations and is comparable to the existing methods. The methodology is applied to a set of interval-censored failure time data arising from an AIDS clinical trial.
PMCID: PMC4240511  PMID: 25419022
9.  House Dust Mite Induced Lung Inflammation Does Not Alter Circulating Vitamin D Levels 
PLoS ONE  2014;9(11):e112589.
Low circulating levels of 25-hydroxyvitamin D [25(OH)D] are associated with chronic lung diseases such as asthma. However, it is unclear whether vitamin D is involved in disease pathogenesis or is modified by the inflammation associated with the disease process. We hypothesized that allergic inflammation decreases the level of circulating 25(OH)D and tested this using a mice model of house dust mite (HDM) induced allergic airway inflammation. Cellular influx was measured in bronchoalvelar lavage (BAL) fluid, and allergic sensitization and 25(OH)D levels were measured in serum. Exposure to HDM caused a robust inflammatory response in the lung that was enhanced by prior influenza infection. These responses were not associated with any change in circulating levels of 25(OH)D. These data suggest that alterations in circulating 25(OH)D levels induced by Th-2 driven inflammation are unlikely to explain the cross-sectional epidemiological association between vitamin D deficiency and asthma.
PMCID: PMC4229241  PMID: 25391140
10.  SnoVectors for nuclear expression of RNA 
Nucleic Acids Research  2014;43(1):e5.
Many long noncoding RNAs (lncRNAs) are constrained to the nucleus to exert their functions. However, commonly used vectors that were designed to express mRNAs have not been optimized for the study of nuclear RNAs. We reported recently that sno-lncRNAs are not capped or polyadenylated but rather are terminated on each end by snoRNAs and their associated proteins. These RNAs are processed from introns and are strictly confined to the nucleus. Here we have used these features to design expression vectors that can stably express virtually any sequence of interest and constrain its accumulation to the nucleus. Further, these RNAs appear to retain normal nuclear associations and function. SnoVectors should be useful in conditions where nuclear RNA function is studied or where export to the cytoplasm needs to be avoided.
PMCID: PMC4288147  PMID: 25378317
11.  Survival Impact of Follow-up Care after Radical Cystectomy for Bladder Cancer 
The Journal of urology  2013;190(5):1698-1703.
With substantial variation in follow-up for patients after radical cystectomy for bladder cancer, we sought to understand the effect of urine tests, laboratory tests, physician visits, and imaging on overall survival.
Materials and Methods
We analyzed a cohort of patients treated in the fee-for-service Medicare population from 1992 through 2007 using Surveillance Epidemiology and End Results - Medicare data. Using propensity score analysis, we assessed the relationship between time- and geography-standardized expenditures on follow-up care and overall survival in three time periods after surgery: peri-operative (0–3 months), early follow-up (4–6 months), and later follow-up (7–24 months). Using instrumental variables analysis, we assessed the overall survival impact of quantity of follow up care by category (doctor visits, imaging, lab tests, urine tests).
We found no improvement in survival from follow-up care in the peri-operative and early follow-up periods. Receipt of follow-up care in the later follow-up period was associated with improved survival [HR 0.23, 95% CI 0.15–0.35; 0.27, 95% CI: 0.18–0.40; 0.47, 95% CI: 0.31–0.71, low, middle and high tertile of expenditures, respectively]. Instrumental variables analysis suggested only doctor visits and urine testing [HRs: 0.96 (0.93–0.99) and 0.95 (0.91–0.99), respectively] improved survival.
Follow-up care after radical cystectomy in the later follow-up period was associated with improved survival. Doctor visits and urine tests were associated with this improved survival. Our results suggest aspects of follow-up care significantly improve patient outcomes, but imaging studies could be used more judiciously after cystectomy.
PMCID: PMC3896325  PMID: 23727308
Urinary bladder neoplasms; Cystectomy; Survival analysis; Follow-up studies
12.  Factors That Affect Proportional Glomerular Filtration Rate After Minimally Invasive Partial Nephrectomy 
Journal of Endourology  2013;27(11):1371-1375.
Background and Purpose
Several factors have been shown to impact the overall glomerular filtration (GFR) rate after partial nephrectomy. Change in overall GFR, however, does not necessarily reflect the impact of these factors on the operated kidney. Using preoperative and postoperative renal scintigraphy, we sought to assess the impact of patient, tumor, and operative factors on GFR of the affected kidney (proportional GFR).
Patients and Methods
We identified 73 patients who underwent minimally invasive partial nephrectomy with preoperative and postoperative renal scans from two institutions. Patient, tumor, and operative characteristics were recorded. We used multiple linear regression to determine the patient and clinical factors predictive of postoperative proportional GFR in the operated kidney. We tested for an interaction between preoperative proportional GFR and nephrometry score and ischemia. We further fitted two separate linear models to compare the proportion of variance (R2) explained by ischemia time in change in renal function in the operated kidney with the change in renal function in both kidneys.
Surgical parameters (procedure approach, ischemia time, and estimated blood loss) and preoperative proportional GFR were significantly associated with postoperative proportional GFR. Preoperative proportional GFR (β=5.93, 95% confidence interval [CI]: 3.88, 7.97, P<0.0005) and procedure approach (β=8.67, 95% CI: 4.50, 12.80, P<0.0005) were strongly associated with outcome while ischemia time (β=−1.80, 95% CI: −3.48, −0.11, P=0.04) and estimated blood loss (β=−1.15, 95% CI: −0.29, −0.01, P=0.04) just reached statistical significance. The interaction term between preoperative proportional GFR and nephrometry score or ischemia time was not statistically significant (nephrometry, P=0.2 continuous or P=0.6 categorical, and ischemia, P=0.7, respectively).
Lower preoperative proportional GFR, longer ischemia times, and higher blood loss all negatively impact postoperative proportional GFR while tumor complexity as gauged by morphometry scoring does not. Larger studies are needed to determine whether renal scintigraphy is a more accurate method of measuring the impact of the ischemia time on postoperative proportional GFR.
PMCID: PMC3826578  PMID: 23560653
13.  99mTc-MORF oligomers specific for bacterial ribosomal RNA as potential specific infection imaging agents 
Bioorganic & medicinal chemistry  2013;21(21):10.1016/j.bmc.2013.08.034.
Radiolabeled oligomers complementary to the 16S rRNA in bacteria were investigated as bacterial infection imaging agents.
Methods and Results
Identical sequences with backbones phosphorodiamidate morpholino (MORF), peptide nucleic acid (PNA), and phosphorothioate DNA (PS-DNA) were 99mTc-labeled and evaluated for binding to bacterial RNA. MORF binding to RNA from E. coli strains SM101 and K12 was 4-fold and 150-fold higher compared to PNA, and PS-DNA, respectively. Subsequently MORF oligomer in fluorescence in situ hybridization showed a stronger signal with study MORF compared to control in fixed preparations of two E. coli strains and K. pneumoniae. Flow cytometry analysis showed study MORF accumulation to be 8- and 80-fold higher compared to the control in live K. pneumoniae and S. aureus, respectively. Further, fluorescence microscopy showed increased accumulation of study MORF over control in live E. coli and K. pneumonia. Binding of 99mTc-study MORF to RNA from E. coli SM101 and K12 was 30.4 pmoles and 117.8 pmoles, respectively, per 1010 cells. Mice with K. pneumoniae live or heat-killed (sterile inflammation) in one thigh at 90 min for both 99mTc-study MORF and control showed higher accumulation in target thighs than in blood and all organs other than kidney and small intestines. Whereas accumulation of 99mTc-study MORF was significantly higher (p=0.009) than that of the control in the thigh with sterile inflammation.
A 99mTc-MORF oligomer complimentary to the bacterial 16S rRNA demonstrated binding to bacterial RNA in vitro with specific accumulation into live bacteria. Radiolabeled MORF oligomers antisense to the bacterial rRNA may be useful to image bacterial infection.
PMCID: PMC3826180  PMID: 24054488
MORF; PNA; PS-DNA; bacterial infection imaging; SPECT/CT
14.  Tremor and clinical fluctuation are related to sleep disorders in Chinese patients with Parkinson’s disease 
To study the relationship between sleep disturbances and symptoms in patients with Parkinson’s disease (PD).
The Parkinson’s Disease Sleep Scale-Chinese Version (PDSS-CV) was used to evaluate the sleep disturbances of PD patients in a cross sectional study. The Unified Parkinson’s Disease Rating Scale (UPDRS) parts II-IV, and the Hoehn & Yahr (H&Y) stage were used to determine the level of motor function in PD and the severity of PD. The Spearman correlation and a multiple regression analysis were used to identify the relationship between sleep disturbances and symptoms of PD. The quantities derived from the UPDRS and the H&Y stage and disease duration were compared between groups of patients either with or without sleep disturbances identified by the PDSS. This study was conducted from December 2011 to March 2012 at the First Affiliated Hospital of Sun Yat-sen University, in Guangzhou.
A total of 136 PD patients were included in this study. The overall total PDSS score in PD patients was 107.58 ± 23.35 points (range: 30–146). There were significant differences in the disease duration, the H&Y stage, and the UPDRS section subscores between groups of patients either with or without sleep disturbances (Kruskal-Wallis Test, p <0.05). There were significant negative correlations between PDSS scores and the UPDRS subscores, the H&Y stage and the disease duration (Spearman correlation, p < 0.05). The multiple regression analysis indicated that sleep disturbances identified by the PDSS were only associated with daily life activity, tremor intensity and clinical fluctuation (R2 = 0.22, F(3,132) = 12.4, p < 0.001). The correlations were also significant when the contribution of the other two factors was excluded using partial correlations.
The level of daily life activity and the occurrences of tremor and clinical fluctuation are likely to be important factors that lead to PD patients’ sleep disturbances. This study may elucidate an important clue for the relationship between sleep disturbances and PD symptoms.
PMCID: PMC4209517  PMID: 25349692
Sleep disorders; Parkinson’s disease; Parkinson’s disease sleep scale-Chinese Version(PDSS-CV); Unified Parkinson’s Disease Rating Scale (UPDRS)
15.  Sculpting the UMLS Refined Semantic Network 
The Refined Semantic Network (RSN) for the UMLS was previously introduced to complement the UMLS Semantic Network (SN). The RSN partitions the UMLS Metathesaurus (META) into disjoint groups of concepts. Each such group is semantically uniform. However, the RSN was initially an order of magnitude larger than the SN, which is undesirable since to be useful, a semantic network should be compact. Most semantic types in the RSN represent combinations of semantic types in the UMLS SN. Such a “combination semantic type” is called Intersection Semantic Type (IST). Many ISTs are assigned to very few concepts. Moreover, when reviewing those concepts, many semantic type assignment inconsistencies were found. After correcting those inconsistencies many ISTs, among them some that contradicted UMLS rules, disappeared, which made the RSN smaller.
The authors performed a longitudinal study with the goal of reducing the size of the RSN to become compact. This goal was achieved by correcting inconsistencies and errors in the IST assignments in the UMLS, which additionally helped identify and correct ambiguities, inconsistencies, and errors in source terminologies widely used in the realm of public health.
In this paper, we discuss the process and steps employed in this longitudinal study and the intermediate results for different stages. The sculpting process includes removing redundant semantic type assignments, expanding semantic type assignments, and removing illegitimate ISTs by auditing ISTs of small extents. However, the emphasis of this paper is not on the auditing methodologies employed during the process, since they were introduced in earlier publications, but on the strategy of employing them in order to transform the RSN into a compact network. For this paper we also performed a comprehensive audit of 168 “small ISTs” in the 2013AA version of the UMLS to finalize the longitudinal study.
Over the years it was found that the editors of the UMLS introduced some new inconsistencies that resulted in the reintroduction of unwarranted ISTs that had already been eliminated as a result of their previous corrections. Because of that, the transformation of the RSN into a compact network covering all necessary categories for the UMLS was slowed down. The corrections suggested by an audit of the 2013AA version of the UMLS achieve a compact RSN of equal magnitude as the UMLS SN. The number of ISTs has been reduced to 336. We also demonstrate how auditing the semantic type assignments of UMLS concepts can expose other modeling errors in the UMLS source terminologies, e.g., SNOMED CT, LOINC, and RxNORM that are important for health informatics. Such errors would otherwise stay hidden.
It is hoped that the UMLS curators will implement all required corrections and use the RSN along with the SN when maintaining and extending the UMLS. When used correctly, the RSN will support the prevention of the accidental introduction of inconsistent semantic type assignments into the UMLS. Furthermore, this way the RSN will support the exposure of other hidden errors and inconsistencies in health informatics terminologies, which are sources of the UMLS. Notably, the development of the RSN materializes the deeper, more refined Semantic Network for the UMLS that its designers envisioned originally but had not implemented.
PMCID: PMC4235323  PMID: 25422719
UMLS; Semantic Network; Refined Semantic Network; Abstraction Network; Refined Semantic Types; Intersection Semantic Types; Correction of Inconsistencies
16.  Recognition of Protein-coding Genes Based on Z-curve Algorithms 
Current Genomics  2014;15(2):95-103.
Recognition of protein-coding genes, a classical bioinformatics issue, is an absolutely needed step for annotating newly sequenced genomes. The Z-curve algorithm, as one of the most effective methods on this issue, has been successfully applied in annotating or re-annotating many genomes, including those of bacteria, archaea and viruses. Two Z-curve based ab initio gene-finding programs have been developed: ZCURVE (for bacteria and archaea) and ZCURVE_V (for viruses and phages). ZCURVE_C (for 57 bacteria) and Zfisher (for any bacterium) are web servers for re-annotation of bacterial and archaeal genomes. The above four tools can be used for genome annotation or re-annotation, either independently or combined with the other gene-finding programs. In addition to recognizing protein-coding genes and exons, Z-curve algorithms are also effective in recognizing promoters and translation start sites. Here, we summarize the applications of Z-curve algorithms in gene finding and genome annotation.
PMCID: PMC4009845  PMID: 24822027
Genome annotation; Genome re-annotation; Z-curve algorithm; ZCURVE; ZCURVE_V.
17.  Maternal caffeine intake during pregnancy is associated with risk of low birth weight: a systematic review and dose–response meta-analysis 
BMC Medicine  2014;12(1):174.
Considerable controversy exists regarding the relation between maternal caffeine intake during pregnancy and risk of low birth weight (birth weight <2,500 g). We aim to assess this association using a systematic review and dose–response meta-analysis of prospective studies.
Potential articles were identified by searching MEDLINE and SCOPUS databases through 17 July 2013. Two authors independently extracted information on study design, participant characteristics and estimates of associations. Random-effects models were used to derive the summary relative risks (RRs) and corresponding 95% confidence intervals (CIs). Dose–response relationships were assessed using generalized least-squares trend estimation.
In our meta-analysis, we included 13 prospective studies: 9 with low birth weight as a binary outcome variable (90,747 participants and 6,303 cases) and 6 with birth weight as a continuous outcome variable (10,015 participants; 2 studies reported both types of outcomes). Compared with the reference category with no or very low caffeine intake, the RR (95% CI) of low birth weight was 1.13 (1.06 to 1.21; I2 0.0%) for low intake (50 to 149 mg/day), 1.38 (1.18 to 1.62; I2 31.9%) for moderate intake (150 to 349 mg/day), and 1.60 (1.24 to 2.08; I2 65.8%) for high intake (≥350 mg/day). In the dose–response analysis, each 100-mg/day increment in maternal caffeine intake (around one cup of coffee) was associated with 13% (RR 1.13, 1.06 to 1.21) higher risk of low birth weight. The association persisted in strata defined according to various study characteristics. Moderate (−33 g, 95% CI −63 to −4; I2 0.3%) and high (−69 g, 95% CI −102 to −35; I2 0.0%) caffeine intakes were also associated with a significantly lower birth weight as compared with the reference category.
Higher maternal caffeine intake during pregnancy was associated with a higher risk of delivering low birth weight infants. These findings support recommendations to restrict caffeine intake during pregnancy to low levels.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-014-0174-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4198801  PMID: 25238871
Coffee; Caffeine; Low birth weight; Small for gestational age; Intrauterine growth restriction; Systematic review; Meta-analysis
18.  The association between statin medication and progression after surgery for localized renal cell carcinoma 
The Journal of urology  2013;191(4):914-919.
Evidence suggests statins may influence pathways of RCC proliferation, though no study has examined the influence of statin medications on progression of RCC in humans.
Materials and Methods
We identified 2608 patients with localized RCC who were treated surgically between 1995–2010 at our tertiary referral center. Competing risks Cox proportional hazards models were used to evaluate the relationship between statin use and time to local recurrence or progression (metastases or death from RCC) and overall survival. Statin use was modeled as a time-dependent covariate as a sensitivity analysis. Models were adjusted for clinical and demographic features.
Of 2608 patients, 699 (27%) were statin users at surgery. Statin users had similar pathological characteristics compared to nonusers. With a median follow-up of 36 months, there were 247 progression events. Statin use was associated with a 33% reduction in the risk of progression after surgery (HR 0.67, 95% CI 0.47–0.96, p=0.028) and an 11% reduction in overall mortality that was not significant (HR 0.89, 95% CI 0.71–1.13, p=0.3). Modeling statin use as time-dependent covariate attenuated the risk reduction in progression to 23% (HR 0.77, p=0.12) and augmented the risk reduction in overall survival (HR 0.71; p=0.002).
In our cohort, statin use was associated with a reduced risk of progression and overall mortality, though this effect was sensitive to method of analysis. If validated in other cohorts, this finding warrants consideration of prospective research on statins in the adjuvant setting.
PMCID: PMC4167747  PMID: 24291547
Kidney neoplasms; hydroxymethylglutaryl-CoA reductase inhibitors; nephrectomy; disease progression; chemoprevention
19.  Whole-Genome Sequences of Two Clinical Isolates of Extensively Drug-Resistant Mycobacterium tuberculosis from Zunyi, China 
Genome Announcements  2014;2(5):e00910-14.
Before 2013, 92 countries reported extensively drug-resistant Mycobacterium tuberculosis cases to the WHO. Here, we announce the genome sequences of two clinical isolates of extensively drug-resistant tuberculosis (XDR-TB) from Zunyi, China. The genome sequences are composed of 4,411,507 bp and 4,411,515 bp with 2,210 and 2,071 variants, respectively, when compared to the H37Rv genome.
PMCID: PMC4172270  PMID: 25237021
20.  A mouse line for inducible and reversible silencing of specific neurons 
Molecular Brain  2014;7(1):68.
Genetic methods for inducibly and reversibly inhibiting neuronal activity of specific neurons are critical for exploring the functions of neuronal circuits. The engineered human glycine receptor, called ivermectin (IVM)-gated silencing receptor (IVMR), has been shown to possess this ability in vitro.
Here we generated a mouse line, in which the IVMR coding sequence was inserted into the ROSA26 locus downstream of a loxP-flanked STOP cassette. Specific Cre-mediated IVMR expression was revealed by mis-expression of Cre in the striatum and by crossing with several Cre lines. Behavioral alteration was observed in Rosa26-IVMR mice with unilateral striatal Cre expression after systemic administration of IVM, and it could be re-initiated when IVM was applied again. A dramatic reduction in neuron firing was recorded in IVM-treated free moving Rosa26-IVMR;Emx1-Cre mice, and neuronal excitability was reduced within minutes as shown by recording in brain slice.
This Rosa26-IVMR mouse line provides a powerful tool for exploring selective circuit functions in freely behaving mice.
Electronic supplementary material
The online version of this article (doi:10.1186/s13041-014-0068-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4177062  PMID: 25231486
Neuron silencing; Ligand-gated channel; Ivermectin; Rosa26
21.  LRP1 protects the vasculature by regulating levels of Connective Tissue Growth Factor and HtrA1 
LRP1 is a large endocytic and signaling receptor that is abundant in vascular smooth muscle cells (SMC). Mice in which the lrp1 gene is deleted in SMC (smLRP1-/-) on an LDLr-deficient background display excessive PDGF signaling, SMC proliferation, aneurysm formation, and increased susceptibility to atherosclerosis. The objectives of the current studies were to examine the potential of LRP1 to modulate vascular physiology under non-atherogenic conditions.
Approach and Results
We found smLRP1-/- mice to have extensive in vivo aortic dilatation accompanied by disorganized and degraded elastic lamina along with medial thickening of the arterial vessels resulting from excess matrix deposition. Surprisingly, this was not due to excessive PDGF signaling. Rather, quantitative differential proteomic analysis revealed that smLRP1-/- vessels contain a 4-fold increase in protein levels of high-temperature requirement factor A1 (HtrA1) which is a secreted serine protease that is known to degrade matrix components and to impair elastogenesis resulting in fragmentation of elastic fibers. Importantly, our studies discovered that HtrA1 is a novel LRP1 ligand. Proteomics analysis also identified excessive accumulation of connective tissue growth factor (CTGF), an LRP1 ligand and a key mediator of fibrosis.
Our findings suggest a critical role for LRP1 in maintaining the integrity of vessels by regulating protease activity as well as matrix deposition by modulating HtrA1 and CTGF protein levels. These studies highlight two new molecules, CTGF and HtrA1, which contribute to detrimental changes in the vasculature and therefore represent new target molecules for potential therapeutic intervention to maintain vessel wall homeostasis.
PMCID: PMC3892666  PMID: 23868935
LRP1; CTGF; HtrA1; elastic lamina; collagen
22.  Relationship between TLR4 and NF-κB p65 protein expressions and clinical radiosensitivity of patients with esophageal squamous cell carcinoma 
Objective: To study the relationship between TLR4 and NF-κB p65 protein expressions in tumor tissues after radiotherapy and clinical radiosensitivity of patients with esophageal squamous cell carcinoma.
Methods: A total of 93 patients with esophageal squamous cell carcinoma first treated in our hospital by radiotherapy and surgeries from November 2010 to December 2013 were selected. They were then divided into a severe reaction group, a moderate reaction group and a mild reaction group according to the postoperative pathological examination results of tumor tissues. The expressions of TLR4 and NF-κB p65 in the tumor samples were detected by Western blotting.
Results: Compared with the severe reaction group, the expression levels of TLR4 and NF-κB p65 in the moderate reaction group significantly increased (P<0.05). Similarly, the expression levels of the mild reaction group were significantly higher than those of the moderate reaction group (P<0.05).
Conclusion: Reducing the expression levels of TLR4 and NF-κB p65 proteins may increase the radiosensitivity of patients with esophageal cancer.
PMCID: PMC4163217  PMID: 25225511
Esophageal cancer; Radiotherapy; TLR4; NF-κB
23.  Parameters Identification for Photovoltaic Module Based on an Improved Artificial Fish Swarm Algorithm 
The Scientific World Journal  2014;2014:859239.
A precise mathematical model plays a pivotal role in the simulation, evaluation, and optimization of photovoltaic (PV) power systems. Different from the traditional linear model, the model of PV module has the features of nonlinearity and multiparameters. Since conventional methods are incapable of identifying the parameters of PV module, an excellent optimization algorithm is required. Artificial fish swarm algorithm (AFSA), originally inspired by the simulation of collective behavior of real fish swarms, is proposed to fast and accurately extract the parameters of PV module. In addition to the regular operation, a mutation operator (MO) is designed to enhance the searching performance of the algorithm. The feasibility of the proposed method is demonstrated by various parameters of PV module under different environmental conditions, and the testing results are compared with other studied methods in terms of final solutions and computational time. The simulation results show that the proposed method is capable of obtaining higher parameters identification precision.
PMCID: PMC4163354  PMID: 25243233
24.  A cross-sectional analysis of the relationship between uric acid and coronary atherosclerosis in patients with suspected coronary artery disease in China 
Although many studies have examined the relationship between uric acid (UA) and coronary artery disease (CAD), whether UA is an independent risk factor contributing to progression of CAD is still controversial. Whether UA plays a different role in different sexes is also unclear.
A total of 1116 individuals with suspected CAD were stratified into four groups according to their serum UA quartiles in total (men and women combined), in men, and in women. The association of UA with coronary atherosclerosis was assessed by univariable and multivariable logistic regression.
In total and in women, the prevalence of any plaques and significant/severe stenosis was significantly increased with an increase in quartiles of UA (all P < 0.05). The proportion of triple-vessel disease and left main artery lesion was highest in the fourth quartile (both p < 0.05). Increasing quartiles of UA were significantly associated with a coronary artery calcium score (CACS) >10 (all P < 0.01). As UA levels increased in women, the incidence of double-vessel lesions (p = 0.017) and the proportion of mixed plaques (p = 0.022) were significantly increased. The proportion of a CACS of 0 in total, in men and women was highest in the first quartile (all P < 0.01). UA was the strongest predictor of significant stenosis, multivessel disease, and mixed plaques in women (all p < 0.05). UA was the only risk factor for mixed plaques in total (P = 0.046).
The level of UA was significantly associated with coronary atherosclerosis in women, but not men.
PMCID: PMC4236559  PMID: 25128201
Uric acid; Coronary atherosclerosis; Coronary computed tomography angiography; Gender; Calcium score
25.  Involvement of the Carboxyl-Terminal Region of the Yeast Peroxisomal Half ABC Transporter Pxa2p in Its Interaction with Pxa1p and in Transporter Function 
PLoS ONE  2014;9(8):e104892.
The peroxisome is a single membrane-bound organelle in eukaryotic cells involved in lipid metabolism, including β-oxidation of fatty acids. The human genetic disorder X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene (encoding ALDP, a peroxisomal half ATP-binding cassette [ABC] transporter). This disease is characterized by defective peroxisomal β-oxidation and a large accumulation of very long-chain fatty acids in brain white matter, adrenal cortex, and testis. ALDP forms a homodimer proposed to be the functional transporter, whereas the peroxisomal transporter in yeast is a heterodimer comprising two half ABC transporters, Pxa1p and Pxa2p, both orthologs of human ALDP. While the carboxyl-terminal domain of ALDP is engaged in dimerization, it remains unknown whether the same region is involved in the interaction between Pxa1p and Pxa2p.
Methods/Principal Findings
Using a yeast two-hybrid assay, we found that the carboxyl-terminal region (CT) of Pxa2p, but not of Pxa1p, is required for their interaction. Further analysis indicated that the central part of the CT (designated CT2) of Pxa2p was indispensable for its interaction with the carboxyl terminally truncated Pxa1_NBD. An interaction between the CT of Pxa2p and Pxa1_NBD was not detected, but could be identified in the presence of Pxa2_NBD-CT1. A single mutation of two conserved residues (aligned with X-ALD-associated mutations at the same positions in ALDP) in the CT2 of the Pxa2_NBD-CT protein impaired its interaction with Pxa1_NBD or Pxa1_NBD-CT, resulting in a mutant protein that exhibited a proteinase K digestion profile different from that of the wild-type protein. Functional analysis of these mutant proteins on oleate plates indicated that they were defective in transporter function.
The CT of Pxa2p is involved in its interaction with Pxa1p and in transporter function. This concept may be applied to human ALDP studies, helping to establish the pathological mechanism for CT-related X-ALD disease.
PMCID: PMC4132065  PMID: 25118695

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