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.

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).

BACKGROUND

Androgens and inflammation have been implicated in the etiology of several cancers, including prostate cancer. Serum androgens have been shown to correlate with markers of inflammation and expression of inflammation-related genes.

METHODS

In this report, we evaluated associations between 9,932 single nucleotide polymorphisms (SNPs) marking common genetic variants in 774 inflammation-related genes and four serum androgen levels (total testosterone [T], bioavailable T [BioT]; 5α-androstane-3α, 17β-diol glucuronide [3αdiol G], and 4-Androstene-3,17-dione [androstenedione]), in 560 healthy men (median age 64 years) drawn from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Baseline serum androgens were measured by radioimmunoassay. Genotypes were determined as part of the Cancer Genetic Markers of Susceptibility Study genome-wide scan. SNP-hormone associations were evaluated using linear regression of hormones adjusted for age. Gene-based p-values were generated using an adaptive rank truncated product method.

RESULTS

Suggestive associations were observed for two inflammation-related genes and circulating androgen levels (false discovery rate [FDR] q-value<0.1) in both SNP and gene-based tests. Specifically, T was associated with common variants in MMP2 and CD14, with the most significant SNPs being rs893226G>T in MMP2 and rs3822356T>C in CD14 (FDR q-value=0.09 for both SNPs). Other genes implicated in either SNP or gene-based tests were IK with T and BioT, PRG2 with T, and TNFSF9 with androstenedione.

CONCLUSIONS

These results suggest possible cross-talk between androgen levels and inflammation pathways, but larger studies are needed to confirm these findings and to further clarify the interrelationship between inflammation and androgens and their effects on cancer risk.

Aim. We aimed to integrate evidence from all randomized controlled trials (RCTs) and assess the impact of different doses of exenatide or liraglutide on major gastrointestinal adverse events (GIAEs) in type 2 diabetes (T2DM). Methods. RCTs evaluating different doses of exenatide and liraglutide against placebo or an active comparator with treatment duration ≥4 weeks were searched and reviewed. A total of 35, 32 and 28 RCTs met the selection criteria evaluated for nausea, vomiting, and diarrhea, respectively. Pairwise random-effects meta-analyses and mixed treatment comparisons (MTC) of all RCTs were performed. Results. All GLP-1 dose groups significantly increased the probability of nausea, vomiting and diarrhea relative to placebo and conventional treatment. MTC meta-analysis showed that there was 99.2% and 85.0% probability, respectively, that people with exenatide 10 μg twice daily (EX10BID) was more vulnerable to nausea and vomiting than those with other treatments. There was a 78.90% probability that liraglutide 1.2 mg once daily (LIR1.2) has a higher risk of diarrhea than other groups. A dose-dependent relationship of exenatide and liraglutide on GIAEs was observed. Conclusions. Our MTC meta-analysis suggests that patients should be warned about these GIAEs in early stage of treatment by GLP-1s, especially by EX10BID and LIR1.2, to promote treatment compliance.

Background

The natural history of bacterial vaginosis (BV) is complex given the variability across and within women over time. This paper considers three different transition models for analyzing longitudinal BV data.

Methods

Data from the Longitudinal Study of Vaginal Flora (LSVF) was used to evaluate three transition modeling strategies: 1) A Markov regression, 2) A Markov regression with random effects, and 3) a mover-stayer model. The effect of covariates on the transition process of BV, defined as a Nugent score of 7-10, was estimated using a logistic regression parameterization. Models were compared using various model assessment techniques. We analyzed a subset of women completing all 5 visits (n = 1,731) as well as the complete data (n = 3,626), where one or more visit measurements were missing.

Results

The Markov regression model had a poor fit to the data. A random-effects or mover-stayer model accounted for additional unexplained heterogeneity and had a better fit to the data. Across all models, douching was significantly associated with BV fluctuation. In the mover-stayer model, both douching and number of sexual partners were associated with persisting with (λ11=0.90, p<0.001; λ12= −0.41, p<0.03, respectively) or without (λ01= −0.73, p<0.001; λ02= −0.33, p=0.023, respectively) BV across all visits. Using a random effects model, we demonstrated that an individual propensity to initiate BV was positively associated with their propensity to resolve BV.

Conclusions

Transition models that account for additional heterogeneity provide an attractive approach for describing the effect of covariates on the natural history of BV.

In an analysis of 31,717 cancer cases and 26,136 cancer-free controls drawn from 13 genome-wide association studies (GWAS), we observed large chromosomal abnormalities in a subset of clones from DNA obtained from blood or buccal samples. Mosaic chromosomal abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of size >2 Mb were observed in autosomes of 517 individuals (0.89%) with abnormal cell proportions between 7% and 95%. In cancer-free individuals, the frequency increased with age; 0.23% under 50 and 1.91% between 75 and 79 (p=4.8×10−8). Mosaic abnormalities were more frequent in individuals with solid-tumors (0.97% versus 0.74% in cancer-free individuals, OR=1.25, p=0.016), with a stronger association for cases who had DNA collected prior to diagnosis or treatment (OR=1.45, p=0.0005). Detectable clonal mosaicism was common in individuals for whom DNA was collected at least one year prior to diagnosis of leukemia compared to cancer-free individuals (OR=35.4, p=3.8×10−11). These findings underscore the importance of the role and time-dependent nature of somatic events in the etiology of cancer and other late-onset diseases.

We conducted a genome-wide association study (GWAS) of breast cancer by genotyping 528,173 single nucleotide polymorphisms (SNPs) in 1,145 cases of invasive breast cancer among postmenopausal white women, and 1,142 controls. We identified a set of four SNPs in intron 2 of FGFR2, a tyrosine kinase receptor previously shown to be amplified and/or over-expressed in some breast cancers, as highly associated with breast cancer and we confirmed this association in 1,776 cases and 2,072 controls from three additional studies. In both association testing and ancestral recombination graph analysis, FGFR2 haplotypes were associated with risk of breast cancer. Across the four studies the association with all four SNPs was highly statistically significant (Ptrend for the most strongly associated SNP, rs1219648 = 1.1 × 10−10; population attributable risk = 16%). Four SNPs at other chromosomal loci most strongly associated with breast cancer in the initial GWAS were not associated with risk in the three replication studies. Our summary results from the GWAS are freely available online in a form that should speed the identification of additional loci conferring risk.

Background

Serum measurements of cytokines, mediators of various B cell and T cell activities, are important markers of inflammation and immune dysregulation. We assessed the reproducibility of serum cytokine measurements over a five-year period among participants in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO).

Methods

Levels of 13 cytokines [interleukin (IL) 1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, interferon-gamma (IFNγ), granulocyte macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-α (TNFα)] in stored sera from three collections (study baseline, +1 yr, and +5 yr) among 28 randomly selected PLCO participants were measured using a high-sensitivity Luminex xMap-based multiplex panel. Within- and between-subject components of variance were estimated from random effects models and were used to calculate the coefficient of variation (CV) and intraclass correlation coefficient (ICC) for analytes with <30% of samples below the limit of detection (LOD). Spearman correlation coefficients between measurements of the same analyte over time and between analytes were also calculated.

Results

Among the six cytokines with <30% of samples below the LOD, we observed excellent reproducibility for IL-6, IL-7, IL-13, and TNFα (ICC ≥ 0.73), and fair to good reproducibility for IL-8 (ICC = 0.55) and IL-10 (ICC = 0.60). Spearman correlation coefficients comparing paired measurements of each cytokine at baseline and at +5 yr were high (ρ ≥ 0.74) with the exception of IL-10 (ρ = 0.44).

Conclusions

These results suggest that measurements of most of the cytokines evaluated in this study were highly reproducible over a five-year period.

Since Bechara et al. pioneered its development, the Iowa Gambling Task (IGT) has been widely applied to elucidate decision behavior and medial prefrontal function. Although most decision makers can hunch the final benefits of IGT, ventromedial prefrontal lesions generate a myopic choice pattern. Additionally, the Iowa group developed a revised IGT (inverted IGT, iIGT) to confirm the IGT validity. Each iIGT trial was generated from the trial of IGT by multiplying by a “−” to create an inverted monetary value. Thus, bad decks A and B in the IGT become good decks iA and iB in the iIGT; additionally, good decks C and D in the IGT become bad decks iC and iD in the iIGT. Furthermore, IGT possessed mostly the gain trials, and iIGT possessed mainly the loss trials. Therefore, IGT is a frequent-gain–based task, and iIGT is a frequent-loss–based task. However, a growing number of IGT-related studies have identified confounding factors in IGT (i.e., gain-loss frequency), which are demonstrated by the prominent deck B phenomenon (PDB phenomenon). Nevertheless, the mirrored PDB phenomenon and guiding power of gain-loss frequency in iIGT have seldom been reexamined. This experimental finding supports the prediction based on gain-loss frequency. This study identifies the mirrored PDB phenomenon. Frequent small losses override occasional large gains in deck iB of the iIGT. Learning curve analysis generally supports the phenomenon based on gain-loss frequency rather than final outcome. In terms of iIGT and simple versions of iIGT, results of this study demonstrate that high-frequency loss, rather than a satisfactory final outcome, dominates the preference of normal decision makers under uncertainty. Furthermore, normal subjects prefer “no immediate punishment” rather than “final reward” under uncertainty.

OBJECTIVE

To test the hypothesis that high circulating concentrations of maternal anti-angiogenic factors are associated with increased risk of respiratory distress syndrome (RDS).

STUDY DESIGN

This is a nested case-control study of nulliparous women who delivered less than 37 weeks of gestation within the Calcium for Preeclampsia Prevention (CPEP) trial. The study included 116 women with preeclampsia or gestational hypertension and 323 normotensive controls. Soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor [PlGF] and soluble endoglin [sEng] in maternal serum were measured at 21–32 weeks of gestation.

RESULTS

Preterm infants born to hypertensive mothers were more likely to develop RDS (22.5 % versus 20.9%, P=0.03). After adjustment for gestational age at delivery, the odds ratio for the relationship between hypertension in pregnancy and RDS was 2.18 (95% C.I. 1.08, 4.39). In hypertensive pregnancies women whose infants developed RDS had significantly higher circulating mean sFlt1 levels during mid-pregnancy (21–32 weeks of gestation) even after adjustment for gestational age at delivery (21,516 pg/mL versus 7,000 pg/mL, P = 0.01).

CONCLUSIONS

Preterm preeclampsia and gestational hypertension, characterized by high circulating levels of sFlt1, are associated with a twofold increased risk of RDS in infants delivered before 37 weeks. Among women with these hypertensive pregnancies circulating sFlt1 concentrations during mid-pregnancy were substantially higher in women whose infants developed RDS.

Background

Genetic variants in inflammation-related genes have been associated with biliary stones and biliary tract cancers in previous studies.

Methods

To follow-up on these findings, we examined 35 single nucleotide polymorphism (SNPs) in 5 genes related to inflammation (IL8, NFKBIL, RNASEL, TNF, and VEGFA) in 456 participants with incident biliary tract cancer cases (262 gallbladder, 141 extrahepatic bile duct, 53 ampulla of Vater), 982 participants with biliary stones, and 860 healthy controls in a population–based case–control study in Shanghai, China.

Results

Suggestive associations were observed for SNPs in VEGFA with biliary stones, IL8 with gallbladder and ampulla of Vater cancers, and RNASEL with ampulla of Vater cancer (false discovery rate≤0.2).

Conclusion

These findings provide additional support for the role of inflammation in biliary stones and biliary tract cancer risk and need further validation.

Background

Vitamin D compounds inhibit prostate tumorigenesis experimentally, but epidemiological data are inconsistent with respect to prostate cancer risk, with some studies suggesting non-significant positive associations.

Methods

The 25-hydroxyvitamin D [25(OH)D]-prostate cancer relation was examined in a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of 50–69 year old Finnish men. We matched 1,000 controls to 1,000 cases diagnosed during up to 20 years of follow-up based on age (± 1 year) and blood collection date (± 30 days). Conditional multivariate logistic regression models estimated odds ratios (OR) and 95% confidence intervals (CI). All statistical significance testing was two-sided.

Results

Cases had non-significantly 3% higher serum 25(OH)D(P=0.19). ORs (95% CIs) for increasing season-specific quintiles of 25(OH)D concentrations were 1.00 (reference), 1.29 (0.95–1.74), 1.34 (1.00–1.80), 1.26 (0.93–1.72), and 1.56(1.15–2.12)(Ptrend=0.01). Analyses based on pre-specified clinical categories and season-adjusted values yielded similar results. These findings appeared stronger for aggressive disease (OR [95% CI] for fifth quintile of serum 25(OH)D=1.70 [1.05–2.76]), and among men with greater physical activity (1.85 (1.26–2.72), Ptrend=0.002), higher serum total cholesterol (2.09 (1.36–3.21), Ptrend=0.003) or alpha-tocopherol (2.00 (1.30–3.07), Ptrend=0.01), higher intakes of total calcium (1.82 (1.20–2.76), Ptrend=0.01) or vitamin D (1.69 (1.04–2.75), Ptrend=0.08), or those who had received the trial alpha-tocopherol supplements (1.74 (1.15–2.64), Ptrend=0.006).

Conclusion

Our findings indicate that men with higher vitamin D blood levels are at increased risk of developing prostate cancer.

Impact

Greater caution is warranted with respect to recommendations for high-dose vitamin D supplementation and higher population target blood levels.

We report a genome-wide association study in 10,286 cases and 9,135 controls of European ancestry, in the Cancer Genetic Markers of Susceptibility (CGEMS) initiative, identifying a new association with prostate cancer risk on chromosome 8q24 (rs620861, p=1.3×10-10, heterozygote OR = 1.17, 95% CI 1.10 – 1.24; homozygote OR = 1.33; 95% CI 1.21 – 1.45). This defines a new prostate locus on 8q24, Region 4, previously associated with breast cancer.

Previous genome-wide association studies have identified two independent variants in HNF1B as susceptibility loci for prostate cancer risk. To fine-map common genetic variation in this region, we genotyped 79 single nucleotide polymorphisms (SNPs) in the 17q12 region harboring HNF1B in 10 272 prostate cancer cases and 9123 controls of European ancestry from 10 case–control studies as part of the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. Ten SNPs were significantly related to prostate cancer risk at a genome-wide significance level of P < 5 × 10−8 with the most significant association with rs4430796 (P = 1.62 × 10−24). However, risk within this first locus was not entirely explained by rs4430796. Although modestly correlated (r2= 0.64), rs7405696 was also associated with risk (P = 9.35 × 10−23) even after adjustment for rs4430769 (P = 0.007). As expected, rs11649743 was related to prostate cancer risk (P = 3.54 × 10−8); however, the association within this second locus was stronger for rs4794758 (P = 4.95 × 10−10), which explained all of the risk observed with rs11649743 when both SNPs were included in the same model (P = 0.32 for rs11649743; P = 0.002 for rs4794758). Sequential conditional analyses indicated that five SNPs (rs4430796, rs7405696, rs4794758, rs1016990 and rs3094509) together comprise the best model for risk in this region. This study demonstrates a complex relationship between variants in the HNF1B region and prostate cancer risk. Further studies are needed to investigate the biological basis of the association of variants in 17q12 with prostate cancer.

AIM: To explore the association between methylation in leukocyte DNA and colorectal cancer (CRC) risk in male smokers using the α-tocopherol, β-carotene cancer prevention study.

METHODS: About 221 incident CRC cases, and 219 controls, frequency-matched on age and smoking intensity were included. DNA methylation of 1505 CpG sites selected from 807 genes were evaluated using Illumina GoldenGate Methylation Cancer Panel I in pre-diagnostic blood leukocytes of study subjects. Tertiles of methylation level classified according to the distribution in controls for each CpG site were used to analyze the association between methylation level and CRC risk with logistic regression. The time between blood draw to cancer diagnosis (classifying cases according to latency) was incorporated in further analyses using proportional odds regression.

RESULTS: We found that methylation changes of 31 CpG sites were associated with CRC risk at P < 0.01 level. Though none of these 31 sites remained statistically significant after Bonferroni correction, the most statistically significant CpG site associated with CRC risk achieved a P value of 1.0 × 10-4. The CpG site is located in DSP gene, and the risk estimate was 1.52 (95% CI: 0.91-2.53) and 2.62 (95% CI: 1.65-4.17) for the second and third tertile comparing with the lowest tertile respectively. Taking the latency information into account strengthened some associations, suggesting that the methylation levels of corresponding sites might change over time with tumor progression.

CONCLUSION: The results suggest that the methylation level of some genes were associated with cancer susceptibility and some were related to tumor development over time. Further studies are warranted to confirm and refine our results.

Flupirtine (Flu), a triaminopyridine derivative, is a centrally acting, non-opiate analgesic agent. In this study, effects of Flu on K+ currents were explored in two types of motor neuron-like cells. Cell exposure to Flu decreased the amplitude of delayed rectifier K+ current (IK(DR)) with a concomitant raise in current inactivation in NSC-34 neuronal cells. The dissociation constant for Flu-mediated increase of IK(DR) inactivation rate was about 9.8 μM. Neither linopirdine (10 μM), NMDA (30 μM), nor gabazine (10 μM) reversed Flu-induced changes in IK(DR) inactivation. Addition of Flu shifted the inactivation curve of IK(DR) to a hyperpolarized potential. Cumulative inactivation for IK(DR) was elevated in the presence of this compound. Flu increased the amplitude of M-type K+ current (IK(M)) and produced a leftward shift in the activation curve of IK(M). In another neuronal cells (NG108-15), Flu reduced IK(DR) amplitude and enhanced the inactivation rate of IK(DR). The results suggest that Flu acts as an open-channel blocker of delayed-rectifier K+ channels in motor neurons. Flu-induced block of IK(DR) is unlinked to binding to NMDA or GABA receptors and the effects of this agent on K+ channels are not limited to its action on M-type K+ channels.

Genome-wide association studies have identified prostate cancer susceptibility alleles on chromosome 11q13. As part of the Cancer Genetic Markers of Susceptibility (CGEMS) Initiative, the region flanking the most significant marker, rs10896449, was fine mapped in 10 272 cases and 9123 controls of European origin (10 studies) using 120 common single nucleotide polymorphisms (SNPs) selected by a two-staged tagging strategy using HapMap SNPs. Single-locus analysis identified 18 SNPs below genome-wide significance (P< 10−8) with rs10896449 the most significant (P= 7.94 × 10−19). Multi-locus models that included significant SNPs sequentially identified a second association at rs12793759 [odds ratio (OR) = 1.14, P= 4.76 × 10−5, adjusted P= 0.004] that is independent of rs10896449 and remained significant after adjustment for multiple testing within the region. rs10896438, a proxy of previously reported rs12418451 (r2= 0.96), independent of both rs10896449 and rs12793759 was detected (OR = 1.07, P= 5.92 × 10−3, adjusted P= 0.054). Our observation of a recombination hotspot that separates rs10896438 from rs10896449 and rs12793759, and low linkage disequilibrium (rs10896449–rs12793759, r2= 0.17; rs10896449–rs10896438, r2= 0.10; rs12793759–rs10896438, r2= 0.12) corroborate our finding of three independent signals. By analysis of tagged SNPs across ∼123 kb using next generation sequencing of 63 controls of European origin, 1000 Genome and HapMap data, we observed multiple surrogates for the three independent signals marked by rs10896449 (n= 31), rs10896438 (n= 24) and rs12793759 (n= 8). Our results indicate that a complex architecture underlying the common variants contributing to prostate cancer risk at 11q13. We estimate that at least 63 common variants should be considered in future studies designed to investigate the biological basis of the multiple association signals.

The resampling-based test, which often relies on permutation or bootstrap procedures, has been widely used for statistical hypothesis testing when the asymptotic distribution of the test statistic is unavailable or unreliable. It requires repeated calculations of the test statistic on a large number of simulated data sets for its significance level assessment, and thus it could become very computationally intensive. Here, we propose an efficient p-value evaluation procedure by adapting the stochastic approximation Markov chain Monte Carlo algorithm. The new procedure can be used easily for estimating the p-value for any resampling-based test. We show through numeric simulations that the proposed procedure can be 100–500 000 times as efficient (in term of computing time) as the standard resampling-based procedure when evaluating a test statistic with a small p-value (e.g. less than 10 − 6). With its computational burden reduced by this proposed procedure, the versatile resampling-based test would become computationally feasible for a much wider range of applications. We demonstrate the application of the new method by applying it to a large-scale genetic association study of prostate cancer.

During mammalian secondary palate development, the palatal shelves undergo dramatic morphological changes to elevate from a vertical to a horizontal plane in the oral-nasal cavity. We found that E14.5 mouse embryos displayed marked variations in shelf morphology that represent various intermediate states of the elevation process. With these variations, we reconstructed the sequence of shelf morphological changes that take place during the elevation process and discovered distinct patterns in different regions along the anterior-posterior (AP) axis. Moreover, our study revealed that during the elevation process, shelf morphological changes are accompanied by tongue morphological changes, which also show distinct characteristics along the AP axis. We further discuss how to divide the palate along the AP axis based on morphological criteria. Our study provides a framework that recognizes variation in timing of palatal morphogenesis along the AP axis that will aid in the investigation of the mechanisms regulating palatal shelf elevation.

Background

Published studies suggesting a relationship between vitamin D and some common cancers sparked interest in the association of vitamin D with head and neck cancers. Prolonged darker months in Finland are associated with lower levels of ultraviolet B radiation, raising concerns about low vitamin D levels.

Methods

We used a nested case-control study in the prospective Alpha-Tocopherol Beta Carotene (ATBC) Study of male smokers in Finland, to examine the relationship between serum 25(OH)D and risk of developing squamous cancers of the head and neck. Using conditional logistic regression we calculated the multivariate adjusted odds ratio (OR) and confidence interval (CI) comparing those with serum 25(OH)D adequate levels of 50–<75 nmol/L to those <25.0.

Results

We identified incident cancers of the oral cavity (n=134), pharynx (n=48), and larynx (n=158). Median serum vitamin D was 31 nmol/L (interquartile range 21–48), which is below the 50 nmol/L cutoff considered adequate for bone and overall health. Comparing those with serum 25(OH)D below 25 nmol/L to those 50–<75 nmol/L as the referent, the OR was 1.35 (95% CI: 0.53, 3.43, p-trend=0.65) for overall head and neck cancers. Stratification by cancer sub-sites of the oral cavity, pharynx and larynx (p-trend= 0.93, 0.78, 0.26 respectively) or by season of blood draw also showed no association.

Conclusions

Our study showed no association between serum 25(OH)D and risk of head and neck cancers.

Impact

This study does not support the hypothesis that greater vitamin D exposure would reduce the risk of developing head and neck squamous cancers.

To determine the role of toll-like receptors (TLRs) myeloid differentiation factor 88 (MyD88) dependent pathway in the spinal cord secondary injury, compression injury was made at T8 segment of the spinal cord in adult male Sprague-Dawley rats. Shown by RT-PCR, TLR4 mRNA in the spinal cord was quickly elevated after compression injury. Intramedullary injection of MyD88 inhibitory peptide (MIP) resulted in significant improvement in locomotor function recovery at various time points after surgery. Meanwhile, injury area, p38 phosphorylation, and proinflammation cytokines in the injured spinal cord were significantly reduced in MIP-treated animals, compared with control peptide (CP) group. These data suggest that TLRs MyD88-dependent pathway may play an important role in the development of secondary spinal cord injury, and inhibition of this pathway at early time after primary injury could effectively protect cells from inflammation and apoptosis and therefore improve the functional recovery.

Objectives

We compared the patterns of medically attended injuries between children with and without disabilities and explored the residential environment risks in five counties of Hubei Province in the People's Republic of China by a 1∶1 matched case-control study based on the biopsychosocial model of the International Classification of Functioning, Disability and Health – ICF.

Methods

1201 children aged 1–14 with disabilities and 1201 their healthy counterparts matched as having the same gender, same age, and lived in the same neighborhood were recruited in our study. Characteristics of injuries in the past 12 months were compared between children with and without disabilities. The associations among disability status, home environment factors and injuries were examined in logistic regression analysis taking into account sociodemographic factors.

Results

Children with disabilities had a significantly higher prevalence of injury than children without disabilities (10.2% vs. 4.4%; P<.001). The two groups differed significantly in terms of number of injury episodes, injury place and activity at time of injury. Falls were the leading mechanism of injury regardless of disability status. Most of the injury events happened inside the home and leisure activities were the most reported activity when injured for both groups. The univariate OR for injury was 4.46 (2.57–7.74) for the disabled children compared with the non-disabled children. Disabled children whose family raised cat/dog(s) were 76% more likely to be injured during the last 12 months (OR = 1.76; 95% CI = 1.02, 3.02),comparing with those whose family did not have any cat/dog. And for children without disabilities, those whose family had cat/dog(s) were over 3 times more likely to having injuries comparing with those whose family did not have any cat/dog.

Conclusions

Children with disabilities had a significantly increased risk for injury. Interventions to prevent residential injury are an important public health priority in children with disabilities.

Recent genome-wide association studies have identified independent susceptibility loci for prostate cancer (CaP) that could influence risk through interaction with other, possibly undetected, susceptibility loci. We explored evidence of interaction between pairs of 13 known susceptibility loci and single nucleotide polymorphisms (SNPs) across the genome to generate hypotheses about the functionality of CaP susceptibility regions. We used data from Cancer Genetic Markers of Susceptibility: Stage I included 523,841 SNPs in 1175 cases and 1100 controls; Stage II included 27,383 SNPs in an additional 3941 cases and 3964 controls. Power calculations assessed the magnitude of interactions our study is likely to detect. Logistic regression was used with alternative methods that exploit constraints of gene-gene independence between unlinked loci to increase power. Our empirical evaluation demonstrated that an empirical Bayes (EB) technique is powerful and robust to possible violation of the independence assumption. Our EB analysis identified several noteworthy interacting SNP pairs, although none reached genome-wide significance. We highlight a Stage II interaction between the major CaP susceptibility locus in the subregion of 8q24 that contains POU5F1B and an intronic SNP in the transcription factor EPAS1, which has potentially important functional implications for 8q24. Another noteworthy result involves interaction of a known CaP susceptibility marker near the prostate protease genes KLK2 and KLK3 with an intronic SNP in PRXX2. Overall, the interactions we have identified merit follow-up study, particularly the EPAS1 interaction which has implications not only in CaP but also in other epithelial cancers that are associated with the 8q24 locus.

Background

Host genetic factors might affect the risk of progression from infection with carcinogenic human papillomavirus (HPV), the etiologic agent for cervical cancer, to persistent HPV infection, and hence to cervical precancer and cancer.

Methodology/Principal Findings

We assessed 18,310 tag single nucleotide polymorphisms (SNPs) from 1113 genes in 416 cervical intraepithelial neoplasia 3 (CIN3)/cancer cases, 356 women with persistent carcinogenic HPV infection (median persistence of 25 months) and 425 randomly selected women (non-cases and non-HPV persistent) from the 10,049 women from the Guanacaste, Costa Rica HPV natural history cohort. For gene and SNP associations, we computed age-adjusted odds ratio and p-trend. Three comparisons were made: 1) association with CIN3/cancer (compared CIN3/cancer cases to random controls), 2) association with persistence (compared HPV persistence to random controls), and 3) progression (compared CIN3/cancers with HPV-persistent group). Regions statistically significantly associated with CIN3/cancer included genes for peroxiredoxin 3 PRDX3, and ribosomal protein S19 RPS19. The single most significant SNPs from each gene associated with CIN3/cancer were PRDX3 rs7082598 (Ptrend<0.0001), and RPS19 rs2305809 (Ptrend=0.0007), respectively. Both SNPs were also associated with progression.

Conclusions/Significance

These data suggest involvement of two genes, RSP19 and PRDX3, or other SNPs in linkage disequilibrium, with cervical cancer risk. Further investigation showed that they may be involved in both the persistence and progression transition stages. Our results require replication but, if true, suggest a role for ribosomal dysfunction, mitochondrial processes, and/or oxidative stress, or other unknown function of these genes in cervical carcinogenesis.

The asymmetric unit of the title compound, C6H9ClN4, contains four independent mol­ecules (A, B, C and D). Their main difference is the torsion angles, ranging from 1.6 (5) to 5.9 (5)°, between the methyl group and the pyrimidine plane. A pair of inter­molecular N—H⋯N hydrogen bonds link mol­ecules A and C into a twisted dimer with a dihedral angle of 32.9 (1)° between the two pyrimidine rings, creating an R 2 2(8) motif. In the packing, each two mol­ecules of B, C and D form centrosymmetric dimers through two inter­molecular N—H⋯N hydrogen bonds, locally creating R 2 2(8) motifs. The dimers of C and D are alternately bridged by A into an infinite zigzag strip, locally creating two different R 2 2(8) motifs with dihedral angles of 32.9 (1) and 63.4 (1)° between the pyrimidine rings. Finally, these strips together with the dimers of B associate into a complicated three-dimensional framework.