One hypothesis is that the 2-hydroxy pathway is protective, whereas the 16α-hydroxyestrone (2-OHE1 : 16α-OHE1) ratio is inversely associated with endometrial cancer risk in postmenopausal women. A total of 179 cases and 336 controls, matching cases on cohort, age and date of blood donation, were included. Levels of 2-OHE1 and 16α-OHE1 were measured using a monoclonal antibody-based enzyme assay.We conducted a case–control study nested within three prospective cohorts to assess whether the circulating 2-hydroxyestrone : 16Ptrend=0.007) for 2-OHE1 and 1.9  for 16α-OHE1 in analyses adjusting for endometrial cancer risk factors. These associations were attenuated and no longer statistically significant after further adjustment for oestrone or oestradiol levels. No significant association was observed for the 2-OHE1 : 16α-OHE1 ratio.Endometrial cancer risk increased with increasing levels of both metabolites, with odds ratios in the top tertiles of 2.4 (95% CI=1.3, 4.6; α-OH pathway, protects against endometrial cancer.Our results do not support the hypothesis that greater metabolism of oestrogen via the 2-OH pathway, relative to the 16 Women were classified as postmenopausal if they had not had menstrual periods for at least 6 months (NYUWHS) or 12 months (ORDET). In the NYUWHS, women who had had a total oophorectomy and women who had had a hysterectomy without total oophorectomy and were 52 years old or older were also classified as postmenopausal. In ORDET, women who had had a bilateral oophorectomy were not eligible to enter the cohort. For NSHDS cases and controls, menopausal status at enrolment was determined retrospectively based on reported age at menopause on baseline or case–control questionnaires. In addition, FSH measurements were used for all women between the ages of 46 and 57 years. Women were classified as postmenopausal if they had FSH levels >20 IU lCase subjects were women who were postmenopausal at enrolment and diagnosed with invasive endometrial cancer  after enrolment and before 1 January 2007 for the NSHDS, 1 July 2003 for the NYUWHS and 1 January 2004 for ORDET. Cases who had been diagnosed with another cancer (except non-melanoma skin cancer) before endometrial cancer were not eligible.For each case, two controls were selected at random from the appropriate risk set, which consisted of all women with an intact uterus and free of cancer at the date of diagnosis of the case and matching the case on cohort, menopausal status at enrolment, age (±6 months) at, and date (±3 months) of, blood donation.α-OHE1 had been added . Serum samples were used for the NYUWHS and ORDET, and EDTA-plasma samples for the NSHDS. Assay variability was assessed by including 10% blinded quality control samples (samples from a pool for the NSHDS and duplicates for the NYUWHS). For serum, the within- and between-batch coefficients of variation were 4% and 6% for 2-OHE1 and 1% and 2% for 16α-OHE1, respectively. For EDTA-plasma, the within- and between-batch coefficients of variation were 2% and 2% for 2-OHE1 and 1% and 4% for 16α-OHE1, respectively.All oestrogen metabolite assays were conducted in the same laboratory, Immuna Care Corporation, , using monoclonal antibody-based enzyme assays . The enzyme immunoassays (EIAs) were developed for urinary samples . Further analyses showed that serum levels  of metabolites could be accurately predicted from plasma levels  using a linear regression model (R2=0.85 for 2-OHE1 and 0.99 for 16α-OHE1). The observed serum 2-OHE1 : 16α-OHE1 ratio was slightly more strongly correlated (r=0.86) with the predicted serum ratio  than with the plasma ratio (r= 0.81). Therefore, and in order to facilitate the combination of the data from the three cohorts as well as the interpretation of the results, we used predicted serum values for the NSHDS participants in all analyses. To predict the serum levels of 2-OHE1 and 16α-OHE1 from the plasma levels for the NSHDS samples, we created 10 imputed data sets using a multiple imputation procedure with the linear regression models fitted in the substudy. We then calculated the serum 2-OHE1 : 16α-OHE1 ratio using the imputed serum levels of 2-OHE1 and 16α-OHE1. The SAS PROC MI and MIANALYZE in SAS 9.2 were used .Because serum was used for the NYUWHS and the ORDET cohorts and EDTA plasma for the NSHDS, a substudy was conducted to compare levels of oestrogen metabolites in serum with levels in EDTA-plasma samples collected at the same visit from 17 NSHDS participants. We found that plasma samples led to much higher values than serum samples: for 2-OHE1 the median was 526 pg mlP-values were then calculated using the t-distribution (SAS PROC MI and MIANALYZE). In addition to analyses by tertiles, analyses were conducted with the oestrogen metabolites and their ratio on the continuous (log transformed) scale. The log2 transformation, which leads to an odds ratio for a doubling in level, was used.The conditional logistic regression model was used to take into account the matched design. The analysis was conducted after classifying participants according to cohort-specific metabolite tertiles using the distribution of cases and controls combined. The lowest tertile was used as reference. Because analyses were conducted using 10 imputed data sets, the means of the odds ratio estimates are reported. The within-imputation variance and between-imputation variances were calculated and combined to yield the total variance using Rubin's method . The 95%−2) were also conducted. Interaction tests were conducted to assess whether the associations of the oestrogen metabolites or their ratio with endometrial cancer risk varied according to strata of these factors. We also assessed whether the oestrogen metabolite–endometrial cancer risk associations differed by cohort.The following known endometrial cancer risk factors were considered as potential confounders: age at menarche, parity, OC use, HRT use, body mass index (BMI) and smoking. Analyses adjusting simultaneously for all these variables are presented in addition to unadjusted analyses. Analyses stratified by age at sampling (<60 and ⩾60 years), age at diagnosis (<65 and ⩾65 years), lag time between blood donation and diagnosis (<7 and ⩾7 years) and BMI  for their ratio. These results were quite similar to those observed by Eliassen et al who reported intra-class correlation coefficients of 0.63 for 2-OHE1, 0.80 for 16α-OHE1 and 0.73 for their ratio, indicating that a single measurement can be used as a marker of average exposure to these metabolites in epidemiologic studies  for 2-OHE1, 0.95  for 16α-OHE1 ratio was not statistically different in cases and controls.A total of 179 cases and 336 controls were included . α-OHE1 were moderately correlated with each other (cohort- and age-adjusted Spearman correlation r=0.20 in controls and 0.19 in cases). The 2-OHE1 : 16α-OHE1 ratio was strongly correlated with levels of 2-OHE1 (r=0.85 in controls and 0.87 in cases) and negatively, but less strongly, correlated with 16α-OHE1 (r=−0.30 in controls and −0.26 in cases). Correlations were low between oestrone and 2-OHE1 (r=0.13 in controls and 0.19 in cases), 16α-OHE1 (r=0.15 in controls and 0.21 in cases) and their ratio (r=0.03 in controls and 0.10 in cases). Correlations of the oestrogen metabolites and their ratio with oestradiol were in the same direction as with oestrone but weaker (data not shown).The 2-OHE1 and 16α-OHE1. The associations remained significant after adjusting for known endometrial cancer risk factors, with odds ratios in the top tertile of 2.4  for 2-OHE1 and 1.9  for 16α-OHE1. Although the odds ratios in the top two tertiles were somewhat elevated, no significant association was observed with the 2-OHE1 : 16α-OHE1 ratio in unadjusted, as well as in adjusted, analyses.α-OHE1 and no association with the ratio, although odds ratios for 2-OHE1 and 16α-OHE1 were slightly higher in the subgroup than in the whole-group analyses. The table also shows that adjusting for either oestrone or oestradiol, in addition to adjusting for known risk factors, resulted in an attenuation of the odds ratios associated with 2-OHE1 and 16α-OHE1, which were no longer statistically significant. On the other hand, the strong associations of oestrone and oestradiol with endometrial cancer risk remained highly significant after adjusting for the two oestrogen metabolites.Results in analyses limited to the 142 sets whose case subject had an endometrioid-type tumour were similar to the overall results (data not shown). There was no evidence of heterogeneity by cohort in any of the analyses. There was also no evidence of effect modification by age at blood donation, age at diagnosis, lag time between blood donation and diagnosis or BMI.α-OHE1 ratio did not have a decreased risk of endometrial cancer as compared with women with a lower ratio. Regarding absolute levels of 2-OHE1 and 16α-OHE1, we found that both were directly associated with risk in unadjusted analyses as well as in analyses adjusting for known risk factors of endometrial cancer. These associations, though, were no longer significant after adjusting for oestrone, which is positively associated with both risk of endometrial cancer . Further, the Spearman correlation coefficients for the ratio based on the two methods were only 0.17 for the 2-OHE1 : 16α-OHE1 ratio and 0.25 for the 2-pathway : 16α-pathway ratio  than when measured in serum (for the NYUWHS and ORDET) samples. Several reasons may have contributed to the higher concentrations observed with EDTA-plasma samples, such as binding of EDTA with cations  which are cofactors in the stabilisation of the enzymes used in assay  and differences in protein composition. Because the validation study we conducted showed that serum concentrations could be accurately predicted from plasma concentrations in Swedish participants for whom EDTA-plasma and serum samples collected at the same time were available, we predicted serum values for the NSHDS participants and presented results combining the three cohorts. It should be noted that analyses conducted within each cohort separately showed similar results, suggesting that the type of samples did not affect the conclusions.α-OH pathway, protects against endometrial cancer. Indeed our results are more suggestive of an increase in risk, rather than a decrease, with higher levels of 2-OHE1. Assays measuring a broad panel of oestrogen metabolites, including catecholestrogens, should be used in future studies to assess the role of various oestrogen metabolic pathways in the development of oestrogen-related cancers.In conclusion, our results do not support the hypothesis that greater metabolism of oestrogen via the 2-OH pathway, relative to the 16


It is of clinical interest to maintain patient comfort in the ICU and yet preserve their intellectual function, arousal and interaction. Recently, dexmedetomidine (DEX) was demonstrated in the ANIST Trial to preserve intellectual function as compared with propofol (PRO) when used as conscious sedation in both agitated neurologically intact and brain-injured critically ill patients . The purpost-hoc analysis of the prospective randomized, double-blinded cross-over designed ANIST trial that compared cognitive differences between PRO and DEX on the validated 100-point Hopkins ACE. This current study further investigated differences by analyzing the five subscales of the ACE, which consist of Orientation, Language, Registration, Attention/Calculation and Recall. Analysis included a generalized estimating equations approach to estimate differences between drugs while accounting for within-subject correlation arising from the crossover design. We examined unadjusted and adjusted models both with and without inclusion of potential period effects. We also accounted for period effects, and robust variance estimates were used to calculate standard errors.We preformed a P < 0.01), while DEX improved adjusted scores on two of the subscales . The other estimates for the effects of PRO and DEX on the ACE subscales were not statistically significant using a significance level of 0.05. The positive and significant difference in the change of ACE score between DEX versus PRO held up in all of the subscales.Sedation with PRO diminished adjusted scores on four of the ACE subscales (Our findings indicate that DEX not only preserved but also improved Attention/Calculation and Recall in ICU patients who were awake, agitated and required sedation. This was evident by higher mean ACE subscale scores when compared with their baseline. Our findings suggest that DEX improved overall cognitive function without significantly compromising the ability to focus and recall events.


Introduction. Constipation is a common adverse drug reaction. Objective. Study associations between drugs and constipation in nursing home residents. Design. Cross-sectional study. Material and Methods. Nursing home residents above 60 years of age were included. Demographics, diet, physical activity, activity of daily living, nutritional status, use of drugs, and diseases were recorded. Constipation was defined as functional constipation or constipation-predominant IBS according to the Rome III criteria and/or regular use of laxatives. Drugs were classified according to the Anatomical-Therapeutic-Chemical Classification System (ATC), and anticholinergic effect was noted. Results. In all, 79 men and 188 women with a mean age of 85.4 (SD 7.1) years were included. The prevalence of constipation was 71.5%. Use of drugs in general, including polypharmacy, was not associated with constipation. Reduced activity of daily living , other antidepressants (N06AX) , and benzodiazepine derivatives (N05BA)  were significantly associated with constipation; drugs with markedly anticholinergic effect , natural opium alkaloid (N02AA) , and propionic acid derivatives (M01AE)  showed a trend. Conclusion. In elderly with constipation, focus should be on specific groups of drugs and nonpharmacological factors, not on drugs in general. Chronic functional constipation affects 17–40% of the elderly and reduces quality of life [Gastrointestinal symptoms including constipation are common adverse drug reactions . Drugs hIn general, the use of drugs is high in elderly in nursing homes –13. FraiThis cross-sectional study aimed at finding the impact of drugs on constipation in elderly in nursing homes.In 2008-2009, this cross-sectional study was performed in nursing homes in the counties of Oppland and Hedmark, Norway. Registered and auxiliary nurses with good knowledge of the residents collected data from the medical records and got information from the residents and their next of kin. A blood sample was collected.Residents above 60 years of age living in nursing homes for more than 8 weeks and without organic gastrointestinal diseases that could cause constipation were included in the study.The following variables were recorded: age, gender, weight, height, smoking habits, use of alcohol, somatic and psychiatric diseases, physical activity , activity of daily living (Katz' Activity of Daily Living (ADL) index (score 0 (very dependent)–6 (independent)), nutritional status  [Constipation was defined according to the Rome III criteria for functional constipation  except ft-test, Mann-Whitney U test, Fisher's exact test, and Chi-square for trend. Three multivariable analyses (stepwise backward logistics regression) were performed with constipation as dependent factor and either number of drugs, drugs with markedly anticholinergic effect, or groups of drugs at ATC-level 4 with P ≤ 0.2 in bivariate analyses as independent variables. In addition, variables presumed to be associated with constipation , and other variables associated with constipation with P ≤ 0.05 in the bivariate analyses were included in the analyses. The cut-off point for groups of drugs was set to P < 0.2 to avoid loss of any group of drugs since this was the primary aim of the study. The cut-off point for other variables was P < 0.05 to reduce the number of covariates in the calculations. Since a drug is highly associated with the disease under treatment, both the group of drugs and the disease were included if one of them was associated with constipation with P ≤ 0.2 in the bivariate analyses. The one with the lowest impact on the outcome in the multivariable analyses was removed. Age and gender were maintained in all analyses, and number of drugs and the anticholinergic effect were maintained in the respective analyses, independent of degree of significance. Other variables were removed one by one in the backward regression analyses until only variables with P < 0.1 remained in the equation. Foreseeable interactions were controlled for.Associations between constipation and the recorded variables were analyzed with Student's P values ≤ 0.05 were regarded as statistically significant and P ≤ 0.10 as a trend. PASW Statistics 18 was used for the analyses. The power to detect a statistically significant difference (α ≤ 0.05) of 1.4 in the mean number of drugs used by subjects with and without constipation was 80%.Multiple imputation for missing data was performed with all variables included in the analyses . Two-sidThis study was approved by the Regional Committee for Medical and Health Research Ethics, Central Norway, and by Privacy Ombudsman for Research at Oslo University Hospital and performed in accordance with the Declaration of Helsinki. All residents or their next of kin gave written informed consent to participate. Residents giving consent themselves were informed by the nursing staff. Next of kin or legally acceptable representative to residents unable to provide informed consent were given oral and written information during a visit to the nursing home or by post and phone before giving informed consent.Out of 24 invited nursing homes, 13 participated. In the participating nursing homes, 267 out of 647 residents (41.3%) participated in the study. Other antidepressants (N06AX) was significantly associated with constipation, and vitamin B12 (B03BA) and thyroid hormones (H03AA) with less constipation.Tables Other antidepressants and benzodiazepine derivatives (anxiolytics) (N05BA) were significantly associated with constipation; natural opium alkaloids (N02AA) and propionic acid derivatives (M01AE) showed a trend. Vitamin B12 and thyroid hormones were associated with less constipation. Analyses performed on original and imputed data did not differ in principal.Constipation was more prevalent in this study (71.5%) than in most corresponding studies –6. CompaThe main finding was that use of drugs in general, including polypharmacy, was not significantly associated with constipation in this nursing home population with a high prevalence of constipation and polypharmacy. Most studies, reviews, and guidelines focus on drugs and polypharmacy as risk factors for constipation in elderly , 14, 24.The prevalence of use of drugs with markedly anticholinergic effect was three times higher in subjects with constipation than in those without. The constipating effect of drugs with anticholinergic effect has been reported in several studies and in reviews, and the nonsignificant finding in this study is probably due to low power since rather few subjects used this type of drugs –7, 9, 25Other antidepressants, which have also been associated with constipation in other studies, and benzodiazepine derivatives were significantly associated with constipation [Propionic acid derivatives (M01AE) and natural opium alkaloids (N02AA) showed a trend; the ORs were 7 and 5, respectively. The high ORs show that the prevalence of constipation was much higher in users than nonusers of these drugs and the lack of statistical significance was probably a type II error due to few users. The constipating effect of these drugs is known from several studies and reviews [A few groups of drugs were associated with constipation. tipation , 26. Pro reviews , 26.Thyroxin hormones and vitamin B12 and less constipation have previously not been described. However, thyroxin has been associated with diarrhoea [To our knowledge, the significant associations between iarrhoea .Reduced activity of daily living was highly statistically significantly associated with constipation. Inactivity and dietary factors are explanations of this association, which is reported also in other studies and reviews , 9, 28. The participating rate was lower than desired. Exclusion of 11 out of 24 nursing homes probably occurred by chance. The low participation rate in participating nursing homes (41.7%) might have influenced the external validity. Informed consent was easier to obtain from residents able to provide informed consent themselves than from the next of kin. This might explain why the prevalence of dementia was somewhat lower than in some other studies. The most frail and dement residents might therefore have been underrepresented , 11, 12.More information than normally in clinical studies was based on information from the nurses, next of kin and the medical journals, and less from the residents themselves, since the majority of the participants had cognitive impairment. This might have reduced the validity of the data, but use of deputies was inevitable.Groups of drugs were analyzed at ATC-level 4, which are drugs with similar chemical structure and uniform side effects. Analyses on ATC-level 5 would have resulted in too small groups, and ATC-level 3, or higher combine drugs with different side effects.P = 0.05–0.10) have been reported because the associations might be of clinical significance, and the lack of statistically significance might be due to low power (few users of these drugs). The constipating effect of some groups of drugs used by few subjects might have been missed.The power of the study allows the exclusion of an effect of drugs in general, including polypharmacy, on constipation. The study also indicates an unfavourable effect of drugs with markedly anticholinergic effects (OR 3.7). Some associations between groups of drugs and constipation with high OR but not statistically significant associations (benzodiazepine derivatives, other antidepressants, natural opium alkaloid, propionic acid derivatives, and drugs with markedly anticholinergic effects, in addition to nonpharmacological interventions like activity of daily living.Use of drugs in general, including polypharmacy, was not associated with constipation in elderly in nursing homes, but some specific groups of drugs were. Therefore, in elderly with constipation, focus should be on specific groups of drugs and not drugs in general. This study indicated that focus should be on


To evaluate the association between polymorphisms involved in DNA repair and oxidative stress genes and mean dose to whole breast on acute skin reactions (erythema) in breast cancer (BC) patients following single shot partial breast irradiation (SSPBI) after breast conservative surgery.XRCC1(Arg399Gln/Arg194Trp), XRCC3 (A4541G-5'UTR/Thr241Met), GSTP1, GSTA1 and RAD51(untranslated region). SNPs were determined in 57 BC patients by the Pyrosequencing analysis. Univariate(ORs and 95% CI) and logistic multivariate analyses (MVA) were performed to correlate polymorphic genes with the risk of developing acute skin reactions to radiotherapy.Acute toxicity was assessed using vers.3 criteria. single nucleotides polymorphisms(SNPs) in genes: XRCC1Arg194Trp, mut/het XRCC3Thr241Met, wt/het XRCC3A4541G-5'UTR. Similarly a higher erythema rate was also found in the presence of mut/het of XRCC1Arg194Trp or wt of GSTA1. Whereas, a lower erythema rate was observed in patients with mut/het of XRCC1Arg194Trp or wt of XRCC1Arg399Gln. The mean dose to whole breast(p = 0.002), the presence of either mut/het XRCC1Arg194Trp or wt XRCC3Thr241Met (p = 0.006) and the presence of either mut/het XRCC1Arg194Trp or wt GSTA1(p = 0.031) were confirmed as predictors of radiotherapy-induced erythema by MVA.After SSPBI on the tumour bed following conservative surgery, grade 1 or 2 acute erythema was observed in 19 pts(33%). Univariate analysis indicated a higher significant risk of developing erythema in patients with polymorphic variant wt The Whole breast mean dose together with the presence of some polymorphic genes involved in DNA repair or oxidative stress could explain the erythema observed after SSPBI, but further studies are needed to confirm these results in a larger cohort.NCT01316328ClinicalTrials.gov Identifier:  Breast cancer is the most common type of cancer among women with an incidence rate of 13%. It is also one of the most leading causes of death in the European Union in breast cancer women  [Breast radiation therapy (RT) after conservative surgery is now widely accepted as a standard of care for patients with early breast cancer using a multidisciplinary approach. RT destroys the breast cancer cells that remain after surgery, reducing the risk of breast cancer recurrence by about 70%. However RT could also generate radiation-induced side-effects in the surrounding normal tissues ,5. An imXRCC1 (x-ray repair cross-complementation group 1) is one of the molecules involved in the restoration phase of the base excision repair (BER) pathway. XRCC3 (x-ray repair cross-complementation group 3) allows double strand breaks to be efficiently repaired via the homologous recombination repair pathway, for correct chromosomal segregation and of DNA cross links repair [GSTs) are activated as a result of RT [RAD51 is a member of the RAD51 protein family, involved in the Homologous Recombination (HR) and repair of DNA. This protein is thought to play a role in homologous pairing and the strand transfer of DNA, and is also found to interact with BRCA1 and BRCA2 in the cellular response to DNA damage.Ionising radiation acts directly on cellular macromolecules , or indirectly through the production of reactive oxygen species and subsequent by-products able to modify bio-molecules. The response of eukaryotic cells to ionising radiation includes and influences several DNA damage repair pathways with subsequent full 'biological' recovery or cell death ,9. In pas repair . Antioxilt of RT  and are Various authors ,8,12-16 A number of studies ,17-21 reThe aim of this study is to identify marker genes able to predict an increased risk of acute skin toxicity in patients undergoing a single high dose of PBI after BCS at the Regina Elena Italian National Cancer Institute.XRCC1 , XRCC3 (A4541G-5'UTR and Thr241Met), GSTP1 , GSTA1 and RAD51 (untranslated region) in order to assess the relationship with an increased susceptibility of acute adverse effects induced by radiotherapy.In particular, we investigated the following specific polymorphic genes: From March 2006 to January 2008, patients who underwent BCS and sentinel node biopsy and/or axillary dissection for early breast adenocarcinoma and who met the eligibility criteria were treated in prone position. An adjuvant single dose 3D conformal radiation therapy (3D-CRT) APBI schedule was administered to the Index Area. The eligibility criteria included: Age ≥ 48 years with a life expectancy of at least 5 years, post-menopausal status, histologically proven, non lobular, adenocarcinoma of the breast, primary tumours ≤ 3 cm, negative surgical margins (≥ 2 mm), negative sentinel nodes or < 4 positive axillary nodes, no extra-capsular extension, no previous radiotherapy. The exclusion criteria comprised of the following: multicentric disease, extended intraductal component (EIC > 25%), Paget's disease, lobular adenocarcinoma, distant metastases. All the above criteria enable the identification of patients at low risk of local recurrence. The study was conducted in accordance with the Helsinki Declaration. Each patient was informed in advance about the study protocol in written form (informed consent) and verbal. The patient was given ample opportunity to request relevant information regarding the study and decide with full autonomy whether to participate in the protocol. The protocol was approved by the local Ethics and Scientific Committee of the Regina Elena Italian National Cancer Institute (reference number IFO-84/10).From March 2006 to January 2008, 57 patients matched the eligibility criteria and provided a written informed consent. Instead of given an equivalent conventional treatment consisting of 50 Gy (25 daily fractions of 2 Gy in 5-6 week treatments) a single dose was used. The dose of 18 Gy was used in the first 4 patients to test the feasibility of the protocol and whether it was well tolerateda dose a of 21 Gy was administered to the other patients. The dose was delivered to a portion of breast parenchyma corresponding to the tumour bed after surgery. Dose volume constraints were used in order to reduce the dose to normal breast tissue and skin. The major technical details of our approach were reported previously in a separate paper .GST, XRCC1, XRCC3 and RAD51.The SSPBI trial was designed as a prospective Phase II single-arm study. The use of a single dose tumour bed is expected to be very effective in terms of tumour control, but it could increase the incidence of radiation induced erythema. Therefore, we assumed that a decreased DNA repair capability, as well as a reduced detoxification of the damage caused by oxidative stress could explain the increased acute toxicity, i.e. a higher incidence of erythema after a single dose. It is for this reason we decided to investigate SNPs of genes involved in antioxidant and DNA damage repair pathways such as We assumed an erythema rate of 20% and 54% in patient groups at low and high risk, respectively, . Thus the minimum sample size was 56 patients with α = 0.05, 2-tailed test and a power of the study of 80%.Acute toxicity (i.e. erythema), was the end-point described in the analysis and was assessed using the Regina Elena Italian National Cancer Institute common terminology criteria for adverse events  , and wasAll subjects enrolled in the study provided samples of blood, approximately 5 ml, in sterile tubes containing ethylenediaminetetracetic acid (EDTA). Whole blood samples for DNA analyses were immediately frozen at -80°C until processing.XRCC3 C18067T (Thr241Met), XRCC3 A4541G (5'-UTR untranslated region), XRCC1 G28152A (Arg399Gln), GSTP1 A313G  RAD51 G135C (untranslated region).Genomic DNA was isolated from cells in the venous blood using QIAmp kit , following the manufacturer's instructions, and the DNA quality was evaluated by the spectrophotometer analysis (NanoDrop instrument). Specific primers included in the Radiotherapy Response kit  were used in the DNA amplification experiments. The desired DNA was amplified by Real-Time PCR using Rotorgene Instrument (Corbett) following polymerase chain reaction (PCR) conditions provided by the manufacturer. The following polymorphisms were evaluated: GSTA1 and XRCC1 Arg194Trp, which were not included in the above kit, were carried out and tested. The ad-hoc designed primers for these genes are illustrated in Table 2+free), Takara 50 mM Mg2+, EvaGreen TM Dye 20 × and Takara Ex TaqR-PCR Custom (5U/ul). Reaction conditions were as follows: initial denaturation at 95°C for 3 min then 35-cycles of denaturation at 95°C for 30 sec; annealing at 56°C (GSTA1) or at 62°C (XRCC1 Arg194Trp) for 30 sec; elongation at 72°C for 30 sec and final extension at 60°C for 5 min, then 5-cycles of green channel signal acquisition at 60°C for 30 sec. PCR products were evaluated on 2.5 % agarose gel stained with ethidium bromide. In addition, one control for each genotype of GSTA1 and XRCC1 Arg194Trp was generated.Other polymorphisms such as GSTA1 and XRCC1 Arg194Trp were also reported in Table The target sequence containing the polymorphic site was amplified using standard PCR conditions in which one of the primers was biotinylated. A single-strand template was generated by removing the non-biotinylated strand on streptavidin coated beads (matrix). The bound DNA template on the affinity matrix was separated by denaturation in NaOH and used for the following synthesis of a short strand (10-15 bases) of DNA adjacent to the SNP site. The specific sequence primers used for XRCC3 C18067T (Thr241Met), XRCC3 A4541G (5'-UTR), XRCC1 G28152A (Arg399Gln), GSTP1 A313G  RAD51, G135C (untranslated region) GSTA1 and XRCC1 Arg194Trp. In addition, we also analyzed combined genotypes according to the literature.In order to determine predictors of acute toxicity, retrospectively, we evaluated the following polymorphisms: Odds ratios (ORs) and 95% confidence intervals (CIs), Chi-squared and Fisher exact (2-sided) tests were calculated. A OR > 1.0 indicates an increased risk of erythema in patients with a polymorphic gene.Patient characteristics, polymorphisms and dosimetric data, selected as significant by the Univariate analysis, were included in a logistic regression analysis in the multivariate model, which included mean dose to whole breast (WB) and to skin, age at the time of treatment and all polymorphisms.Statistically significant associations between polymorphisms and side effects were indicated by a p-value < 0.05. The sample size was calculated with Sample Power, the odds risks with an R-package, and the Forest plots with Medcalc.For the purpose of this study, 57 eligible patients were available for determining polymorphisms. Out of the 57 patients, 15 (26%) were also treated with adjuvant non-concomitant chemotherapy, as reported in Table However, there was no evidence of chemotherapy induced toxicity at the start of RT. Patient, tumour and treatment related characteristics are listed in Table Pyrosequencing is a sequencing method performed by synthesis, a simple to use technique for accurate and consistent analysis of large numbers of short to medium length DNA sequences. Each result, called a "pyrogram", indicates a determined polymorphic position, providing useful information to identify a category of patients with increased risk of toxicity.GSTA1 and XRCC1 Arg194Trp polymorphisms that are not included in the Radiotherapy kit, a method assay to validate them was developed and the typical pyrograms obtained are depicted in Figure GSTA1 and XRCC1 Arg194Trp are depicted inside the yellow area. Each gene can generate three distinct pyrosequencing patterns, corresponding to homozygote wild type, heterozygote or homozygote mutant. The polymorphism was determined and the results are shown in Table For Acute erythema was observed in 19 patients (33%), divided in Grade 1 (G1) in 11 (19%) and Grade 2 (G2) in 8 (14%) patients. No erythema was detected in 38 patients (67%). A statistically significant correlation was found between the ≥G1 erythema and the mean dose to WB (p = 0.008).XRCC1 Arg194Trp with greater odds . The allelic variant wt of XRCC3 Thr241Met is associated with a lower rate of erythema . A toxic role of allelic variant (wt/het i.e AA/Aa) of XRCC3A4541G-5'UTR was also found .The ORs of any grade of erythema  are reported in Table XRCC1 Arg194Trp or of GSTP1 . The presence of the polymorphic variant mut/het of XRCC1 Arg194Trp and wt of XRCC3 Thr241Met results significantly in the protection towards developing an erythema with lower odds .Our results show a level that is not statistically significant in the protection towards developing an erythema, i.e. lower odds , in the presence of at least one allelic variant (mut/het i.e. aa/Aa) of XRCC1 Arg194Trp and the wt of XRCC1 Arg399Gln shows a protective role towards erythema . While, the association between the polymorphic variant mut/het of XRCC1 Arg194Trp or wt of GSTA1 results in a higher risk of erythema .Furthermore, the association between the polymorphic variant mut/het of XRCC1 Arg194Trp was found, in contrast to data by Mangoni et al. [XRCC1 Arg399Gln as toxic agent was observed according to data reported by Popanda et al. [XRCC3 Thr241Met was found, according to Chang-Claude et al. [GSTA1, as reported by Ambrosone et al. [GSTP1 in contrast to Ambrosone et al. [GSTP1 was found to distinguish acute toxicity in patients in either of the studies. Finally, no correlation was found between acute toxicity and mut/het RAD51. Multivariate analysis confirmed the mean dose to WB (p = 0.002), the presence of mut/het XRCC1 Arg194Trp or wt XRCC3 Thr241Met (p = 0.006) and the presence of mut/het XRCC1 Arg194Trp or wt GSTA1 (p = 0.031) as predictors of erythema. In addition, when identifying the low and high risk groups, according to the absence or presence of mut/het XRCC1 Arg194Trp or wt XRCC3 Thr241Met, the observed erythema in our cohort was 20% and 59%, respectively. Assuming an α = 0.05 and a 2-tailed test, the power of the study was 78% with 38 and 19 patients in low and high risk groups respectively; when assuming an α = 0.05 and a 1-tailed test was used the power of the study was 80%.Forest plots , XRCC3(A4541G-5'UTR /Thr241Met), GSTP1, GSTA1 and RAD51(untranslated region), which are involved in oxidative stress-related mechanisms (GSTs) and in DNA repair.In this paper we evaluated the effects of polymorphisms in encoding genes for enzymes involved in DNA repair and in protection from ROS (reactive oxygen species), in relation to acute skin side effects of RT. In particular, the following polymorphic genes are involved in oxidative stress-related mechanisms (GSTs) and in DNA repair were taken into consideration: XRCC1 Arg194Trp, confirming the trend reported by Chang-Claude J et al. [XRCC1 Arg194Trp and skin reactions was also been described by Mangoni M. et al. [XRCC3 Thr241Met showed a trend for having a protective role towards of erythema, according to data reported by Popanda et al. [A statistically significant positive connection was found between the ≥G1 erythema and wt J et al. . Likewis. et al. . Also ina et al.  and Manga et al. .XRCC3A4541G-5'UTR, a non-coding polymorphism in the 5'UTR of the gene with an un-clarified effect on protein expression, in rectal cancer patients. The Authors suggested a protective role of the variant allele XRCC3A4541G-5'UTR toward radiation injury. It is important to stress that a statistically significant positive association correspondence was found between ≥G1 erythema and wt/het XRCC3A4541G-5'UTR also in our study, indicating the protective role of the variant allele towards radiation injury also regards to breast cancer. Whereas, no statistically significant correlation was found with other polymorphisms and erythema.It is worthy to note that, Cecchin et al.  investigDue to the limited number of studies involving polymorphisms and also the limited number of toxic events reported in literature, a pooled analysis was performed for acute toxicity and was been shown as a Forest plot. This analysis has confirmed the role of some polymorphic variants as predictors of acute toxicity, although in many cases only as a trend Figure .We also performed tests to assess the association of different genes involved in developmental clinical radio-sensitivity. Particular, we tested whether there was a possible association between the variant mut/het of different genes.XRCC1 Arg194Trp or wt of XRCC1 Arg399Gln showed evidence of a protective role towards erythema. On the contrary, in the study by Mangoni et al. [XRCC1 Arg194Trp variant allele and XRCC1 Arg399Gln wt allele suggested a significant risk of toxicity induced by radiotherapy.The presence of the polymorphic variant mut/het of i et al.  the presXRCC1 Arg194Trp or of the wt XRCC3 Thr241Met, indicating the protective role of these alleles.In the present study, a correlation was also found between the absence of erythema and the presence of a mut/het of XRCC1 Arg194Trp or mut/het of GSTP1 was also found to be statistically significant indicating the protective role of these polymorphisms. In addition, a high rate of erythema was correlated with the mut/het of XRCC1 Arg194Trp or with of the wt GSTA1, while a trend toward having a protective factor was observed when a mut/het of XRCC1 Arg194Trp or the wt XRCC1 Arg399Gln alleles were expressed.Further, the association of erythema with the presence of a mut/het of XRCC3A4541G-5'UTR polymorphism, indicating a protective role of the variant allele towards radiation injury in BC patients who underwent SSPBI. The reported multivariate analysis suggests that SNP (XRCC1 or wt XRCC3 Thr241Met and XRCC1 or GSTA1) and dosimetric data (mean dose to whole breast) may be successfully used to predict acute toxicity in BC patients undergoing RT with/without adjuvant chemotherapy. All of these promising data strongly point to the need for further investigation in order to set up valuable strategies to prevent RT-induced damage in cancer patients.This study shows a statistically significant positive relationship between ≥G1 erythema and the wt/het AE: Adverse Event; APBI: accelerated partial breast irradiation; BER: base excision repair; BC: breast cancer; BCS: breast conserving surgery; CEU: frequencies in European population; CIs: confidence intervals; CMF: cyclophosphamide methotrexate 5-fluorouracile; CTCAE: common terminology criteria for adverse events; dNTP: deoxynucleotide triphosphate; EC: epirubicin cyclophosphamide; EDTA: ethylenediaminetetracetic acid; EIC: extended intraductal component; FEC: 5-fluorouracile epirubicin cyclophosphamide; GSTs: glutathione-S-transferases; HR: homologous recombination; ID: identification; MVA: multivariate analysis; NCBI:National Center for Biotechnology Information; ORs: odds ratios; PCR: polymerase chain reaction; PBI: partial breast irradiation; pts: patients; RT: radiation therapy; rs: reference sequence; ROS: reactive oxygen species; SSPBI: shot partial breast irradiation; SNPs: single nucleotides polymorphisms; XRCC1: x-ray repair cross-complementation group 1; XRCC3: x-ray repair cross-complementation group 3; WBI: whole breast irradiation; 3D-CRT: 3D conformal radiation therapy.The authors declare that they have no competing interests.The authors declare that they have no competing interests.EF, PP, LS conceived the study and obtained grant funding, participated in the coordination of the original study, coordinated genotyping efforts, supervised data analysis, and drafted the manuscript. IS, AS and DDA participated in the data management and statistical analysis, and in drafting the manuscript. CG and SA participated in the design of the original study, data collection and patient management, and in drafting the final manuscript. CG, PM, and GB participated in the design of the original study, and participated in drafting the final manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/11/291/prepub


A number of observational studies have been conducted to investigate the association of IL-10 gene polymorphisms with tuberculosis (TB) susceptibility. However, the results of different studies were inconsistent. The aim of this study was to investigate the relationship between IL-10 -1082G/A, -819T/C, and -592A/C polymorphisms and TB risk by meta-analysis.A literature search was conducted among six English databases  and two Chinese databases  to identify studies involving association between IL-10 −1082G/A, −819T/C, and −592A/C polymorphisms and TB susceptibility before May. 2013. Statistical analysis was performed using Revman 5.0 and Stata 12.0.P = 0.01) and Americans , and IL-10 -819T/C  and -592A/C  polymorphisms were significantly associated with TB risk in Asians.A total of 31 studies with 6,559 cases and 7,768 controls were included in this meta-analysis. The results showed that three polymorphisms  in the IL-10 gene were not associated with the risk of TB in general population. In the subgroup analysis by ethnicity, IL-10 -1082G/A polymorphism was associated with TB risk in Europeans (AA+AG vs. GG: OR =  0.57, 95% CI = 0. 0.37–0.89, This meta-analysis provides strong evidence that IL-10-1082G/A polymorphism was associated with TB risk in Europeans and Americans, and IL-10 -819T/C and -592A/C polymorphisms could be risk factors for TB in Asians. Additional well designed large studies were required for the validation of our results. Mycobacterium tuberculosis (M. tuberculosis), only 5% to 10% develop symptomatic TB M. tuberculosis develop uncontrolled disease and others have an effective immune response to limit the spread of the pathogen remains unknown. The genetic influence on TB infection was established by several studies of monozygotic and dizygotic twins, linkage and candidate gene analysis, indicating that genetics may play a role in the susceptibility to TB infection Tuberculosis (TB) is a chronic infectious disease that occurs worldwide, leading to 1.6 million deaths annually worldwide et al. demonstrated that increased susceptibility to reactivation tuberculosis in the mouse model is strongly influenced by the expression of IL-10 during the chronic or latent phase of the infection M. tuberculosis persistence in humans by blocking phagosome maturation in macrophages A major determinant for the clinical expression of the different forms of TB, and their final outcome, is the interaction between the pathogen and the host immune system. Cytokines play an important role in anti-TB immune response, and cytokines interleukin -10 (IL-10) have been implicated in the pathogenesis of TB Certain single nucleotide polymorphisms within the promoter region of the IL-10 gene have been associated with altered levels of circulating IL-10, such as −1082G/A, −819T/C, and −592A/C Mycobacterium tuberculosis”, “single nucleotide polymorphism”, “variant”, “genotype”, “mutation”. To minimize potential publication bias, no restrictions were placed on language, sample size, and time period.A literature search was conducted among six English databases  and two Chinese databases  to identify studies involving association between IL-10 −1082G/A, −819T/C, and −592A/C polymorphisms and TB susceptibility before May. 2013. Key words used in the research included “interleukin”, “interleukin-10”, “cytokine”, “tuberculosis”, “Inclusion and Exclusion CriteriaAll included studies have to fulfill the following characteristics and inclusion criteria: (a) case-control studies focused on associations between IL-10 -1082G/A, -819T/C, and −592A/C polymorphisms and the risk of TB; (b) the diagnosis of TB should meet the internationally accepted criteria; (c) genotype distribution in both cases and controls were available for estimating an odds ratio (OR) with 95% confidence interval (CI). The exclusion criteria of the meta-analysis were: (a) animal studies; (b) meta-analyses, letters, reviews, meeting abstracts, or editorial comments; (c) studies with duplicate data, incomplete data, and unavailable data. When an individual author published several articles obtained from the same patient population, only the newest or most complete article was included in the analysis.Data were independently abstracted by two reviewers (Liang and Li) using a standard protocol and data-collection according to the inclusion criteria. The following data were collected from each study: first author’s name, year of publication, country, ethnicity, source of controls, sample size, genotyping method, and number of cases and controls for IL-10 −1082G/A, −819T/C, and −592A/C polymorphisms. An attempt was made to contact authors if data presentation was incomplete or if it was necessary to resolve an apparent conflict or inconsistency in the article. Any disagreements were resolved by consensus.P<0.05 was considered significant. The pooled ORs were calculated for allele model , dominant model (WM+MM versus WW), recessive model (MM versus WM+WW), homozygote comparison (MM versus WW), and heterozygote comparison (WM versus WW), respectively. Two models of pooling data for dichotomous outcomes were conducted: the random-effects model and the fixed-effects model. Heterogeneity assumption was assessed by the Chisquare based Q test and was regarded to be statistically significant if P<0.10. When the P≥0.10, the pooled statistical analysis was calculated by the fixed-effects model, otherwise, a random-effect model was used. To evaluate the ethnicity-specific effects, subgroup analyses were performed by ethnic group. The potential publication bias was assessed by Begg’s funnel plot and Egger’s test Review manager 5.0 program provided by the Cochrane Library and Stata  were used to perform all the statistical analysis. The combined odds ratio (OR) with its 95% confident interval (CI) was used to assess the strength of the association between the IL-10 polymorphisms and TB risk. The significance of the combined OR was determined by the Z-test, in which The flow chart that displays the study selection process was shown in The evaluation of association between IL-10 polymorphisms and TB risk was presented in P = 0.81; AA+GA vs. GG: OR =  0.95, 95% CI  =  0.68–1.34, P = 0.79; AA vs. GA+ GG: OR =  0.92, 95% CI = 0.75–1.14, P = 0.46; AA vs. GG: OR =  0.90, 95% CI = 0.61–1.33, P = 0.59; GA vs. GG: OR =  0.99, 95% CI = 0.72–1.36, P = 0.96) (P = 0.01) and heterozygous model . However, no significant association between this polymorphism and TB risk was observed in other comparison models in European group. Moreover, significant increased TB risk was observed in dominant model (P<0.01), homozygous model , and heterozygous model  in American group.Of the 31 studies investigating the association between IL-10 -1082G/A polymorphism and TB susceptibility, 29 provided enough data to calculate ORs, including 6,199 cases and 7,406 controls. The results of pooling all studies showed that the IL10 -1082 G/A polymorphism was not associated with TB susceptibility in general population under all genetic models  . In the  = 0.96)   (P = 0.01), homozygous model , and heterozygous model .A total of 3,584 cases and 4,584 controls from 14 case-control studies were included for data synthesis. The results showed that there was no statistically significant association between IL-10 -819C/T polymorphism and TB risk in general population  . In the P = 0.90; CC+AC vs. AA: OR = 0.89, 95% CI  =  0.74–1.08, P = 0.25; CC vs. AC+AA: OR =  0.92, 95% CI = 0.78–1.09, P = 0.32; CC vs. AA: OR =  0.87, 95% CI = 0.68–1.11, P = 0.27; AC vs. AA: OR = 0.90, 95% CI = 0.76–1.07, P = 0.24) , but not in Europeans, Africans, and Americans, suggesting genetic diversity among ethnicities.A total of 4,063 cases and 5,326 controls from 16 case-control studies were included for data synthesis. In the current meta-analysis, we did not find a significant relationship between IL-10 -592A/C polymorphism and TB risk  . In the P = 0.953; -819T/C, P = 0.661; -592A/C, P = 0.685) , which indicated low risk of publication bias in this meta-analysis.Begg’s funnel plot and Egger’s test were performed to assess the publication bias of included studies. The shapes of the funnel plots did not reveal any evidence of obvious asymmetry under the dominant model  . Egger’sTo date, convincing evidence indicate that the outcome of TB is modulated by the environment as well as bacterial and host genetic components. Many investigations have confirmed that cytokines appear to play the critical roles in the development of TB. Polymorphisms in several cytokine genes have been described and demonstrated to influence gene transcription, leading to interindividual variations in cytokine et al. found that -819C/T and -592A/C polymorphisms do not affect susceptibility to TB, while the -1082G/A polymorphism was significantly associated with decreased risk of TB only in Europeans Based on a meta-analysis from 18 studies that contained 4740 cases and 5919 controls, Zhang J, As recent reports showed that genotype frequencies at IL-10 vary greatly in different populations, particularly in individuals of different ethnicities Some limitations of this meta-analysis should be considered when explaining our results. First, given that only published studies were included in the meta-analysis, publication bias may be present, although our results of publication bias showed no significance. Second, some studies were not in agreement with the HWE, making the sample a poor representation. Third, significant between-study heterogeneity was observed in some comparisons, and as such, results may be distorted. Different ethnic populations and different sources of controls may contribute to the heterogeneity. Forth, the interaction of different susceptibility genes and environment factors leaded to the disease, but our study could not assess gene-gene and gene-environment interactions due to the limited information of included studies. Last, but not the least, meta-analysis remains a retrospective research that is subject to the methodological deficiencies of the included studies. In view of these limitations, further studies should focus on the associations of gene polymorphisms and clinical or laboratory characteristic in a large cohort of TB patients.In conclusion, despite the several considerations mentioned above, this meta-analysis indicated that three polymorphisms  in the IL-10 gene were not associated with the risk of TB in general population. In the subgroup analysis, IL-10 -1082G/A polymorphism was associated with TB risk in Europeans and Americans, and IL-10 -819T/C and -592A/C polymorphisms were significantly associated with TB risk in Asians. In the future, additional large studies are warranted to validate our findings. Future studies should include multi-ethnic groups and use standardized unbiased genotyping methods, and well-matched controls.Checklist S1PRISMA 2009 Checklist.(WIZ)Click here for additional data file.


Loxostege sticticalis L. is a long-range migratory pest of many crops in the northern temperate zone from 36°N to 55°N, with larval populations often exploding in regions receiving immigrants. In laboratory experiments, we examined (i) the reproductive costs of migratory flight by tethered flight, and (ii) the reproductive traits contributing to larval outbreaks of immigrant populations. Our results suggest that the beet webworm does not initiate migratory flight until the 2nd or 3rd night after emergence. Preoviposition period, lifetime fecundity, mating capacity, and egg hatch rate for adults that experienced prolonged flight after the 2nd night did not differ significantly from unflown moths, suggesting these traits are irrelevant to the severity of beet webworm outbreaks after migration. However, the period of first oviposition, a novel parameter developed in this paper measuring synchrony of first egg-laying by cohorts of post-migratory females, for moths flown on d 3 and 5 of adulthood was shorter than that of unflown moths, indicating a tightened time-window for onset of oviposition after migration. The resulting synchrony of egg-laying will serve to increase egg and subsequent larval densities. A dense population offers potential selective advantages to the individual larvae comprising it, whereas the effect from the human standpoint is intensification of damage by an outbreak population. The strategy of synchronized oviposition may be common in other migratory insect pests, such as locust and armyworm species, and warrants further study.Identifying the reproductive consequences of insect migration is critical to understanding its ecological and evolutionary significance. However, many empirical studies are seemingly contradictory, making recognition of unifying themes elusive and controversial. The beet webworm,  Melitaea cinxia, lifetime fecundity was higher in the more dispersive females than in the less dispersive individuals Gryllus texensis, the mating capacity and ovary weight of the flight-capable morph is generally poorer than that of the short-winged morph, but is comparable when measured after the former has experienced flight Migration is an important life history option for adapting to seasonal and temporal changes in habitat Drosophila melanogasterHeliothis virescens, Pseudoplusia includens and Spodoptera exemptaOncopeltus fasciatus, and migratory grasshopper, Melanoplus sanguinipesAphis fabaeSpodoptera exiguaOscinella frit, and oriental armyworm, Mythimna separata varies with flight age Studies on the reproductive consequences of flight have been mostly focused on lifetime fecundity, ovarian development or length of the POP, and mating capacity. Inferences of cost depend on the species and the reproductive trait investigated. Lifetime fecundity may be decreased, as in the fruit fly, Loxostege sticticalis L. , is a destructive pest of crops and fodder plants grown in many areas of the northern temperate zone from 36°N to 55°N, including North America, Eastern Europe and Asia L. sticticalis is an adaptation to seasonal and regional variation in environmental elements L. sticticalis may play important roles in the resulting outbreaks of larval populations, we suspected that the reproductive capacity of L. sticticalis moths after migration may be enhanced. This is because captures of 10,000 and 5,000 adults per night by a single blacklight trap  have been used in China since the 1980s as thresholds for predicting outbreaks in source and immigrant areas, respectively L. sticticalis moths mediated by migratory flight could perhaps serve to promote outbreaks among progeny of a cohort of immigrants. If so, we do not know which reproductive trait is improved and how the outbreaks of larval populations are enhanced, because there are no reports on the reproductive consequences for L. sticticalis moths after migration.The beet webworm, L. sticticalis larvae.We therefore studied the interplay between migratory flight and reproduction with an eye to possible mechanisms that could promote larval population outbreaks. We first determined the likely migratory flight age based on flight and reproductive data from adults of different ages that experienced tethered-flight of various periods. We then evaluated the effects of migratory flight on general reproductive traits and a novel parameter that serves as a measure of population-level synchrony of egg-laying, the period of first oviposition (PFO). Finally, we discussed the role that each post-migration reproductive trait may play in enhancing outbreaks of F3, 130 = 7.36, P<0.0001) of L. sticticalis, as determined by tethered-flight technique during a 12-h test period, varied greatly with moth age , but did not significantly differ among the latter three age groups (P>0.50). Flight distance of 3-d-old adults also proportionally and significantly increased as the flight test period extended from 12 h to 24 h  (P≤0.001), but the flight distances reached by the12-h and 18-h flight groups were not significantly different (P = 0.07).The flight distance (moth age . Distanc<0.0001) . Moths oF4, 132 = 11.00, P<0.0001), ranging from 5.5 to 8.6 d (P<0.0001). The POP of adults flown at d 2, 3 and 5, did not differ significantly from each other or from the control moths (P>0.05). Mean POPs of the 3-d-old adults in the experiment testing extended flight periods ranged from 5.4 to 6.7 d .POP was significantly affected by age at which the adult was flown  , percentage of moths that mated , and egg hatch rate  , mating frequency , percentage of moths that mated , and egg hatch rate  (Mean lifetime fecundity of moths flown at different ages ranged from 318 (d5) to 363 (d2), but none of the differences were significant ( = 0.18) . Similar = 0.07) . In the  = 0.76) .L. sticticalis was significantly affected by age at time of flight  (P<0.0001), but it was not significantly prolonged over that of the control (P = 0.06). Mean PFOs of moths flown at d 3 and d 5 were significantly shorter than that of unflown control moths (P<0.05). Mean PFOs between the paired treatments of d 2 and control, d 2 and d 3, d 3 and d 5 were not significantly different (P>0.05), but that of the moths flown at d 5 was significantly shorter than that of the moths flown at d 2 (P = 0.01). Thus, the timing of initial oviposition was more synchronous in moths flown at 3–5 d of age than among those flown at 1 d of age or among those not flown at all.PFO of adult <0.0001) . Moths fF3, 107 = 13.60, P<0.0001) (P≤0.002), but did not differ significantly from each other among these 3 flown groups (P≥0.08). In other words, initiation of oviposition was more synchronous among moths in the flown treatments than in the unflown controls.Among 3-d-old moths, mean PFO was significantly affected by flight test duration (<0.0001) , which wL. sticticalis demonstrated great flight capacity in the tethered flight tests of the two experiments . When larvae matured, sterilized soil containing ca 10% water was added to the cages to a depth of 8–10 cm, which served as substrate for cocoon formation. When adults emerged, pair of male and female were transferred into a transparent 245-ml (5×12.5 cm) plastic cage and provided with 10% glucose solution (w/v) ad libitum, which was changed daily until the moths were tested. Adults, eggs, larvae and pupae were maintained at a constant temperature of 22±1°C, 75%±5% RH, and photoperiod of L16: D8.The colony of L. sticticalis in the field L. sticticalis moths occasionally extends past dawn and into daytime in the field Two interconnected experiments were designed to examine reproductive parameters after flight. The first experiment focused on the effects of flight at different days after emergence on reproductive parameters of the flown moths. This experiment consisted of 5 treatments, which included unflown moths (controls), and those flown at d 1, 2, 3 or 5 of adult life. The flight test period for all age groups was 12 h, corresponding to the normal overnight migratory activity of L. sticticalis flight Flight tests were conducted using a 32-channel flight mill system. Each moth was tethered to a flight mill following the techniques used in previous studies The tether was carefully removed from the moth after completion of the flight test. The moth was paired and transferred into the original plastic cage of 245-ml, and maintained in the rearing chamber together with the control moths. Daily, egg output of moths was recorded, and supplemental food was changed until the adults were dead. At death, the female was dissected and the number of spermatophores in the bursa was determined. This revealed whether a pair was mated and the number of matings per pair, and allowed calculation of the mating percentage and other reproductive parameters.The POP, PFO, lifetime fecundity, mating frequency, mating percentage, and egg hatch rate were used to evaluate changes in reproduction in response to different flight treatments. These parameters, except PFO and egg hatch rate, were determined following the methods employed in previous studies All numeric values are presented as means ± SEM. Egg hatch rate data were arcsine transformed before testing for a normal distribution by the Shapiro-Wilk test. Differences between treatments were evaluated by one-way analysis of variance. Significant differences among multiple means were determined by Tukey's HSD test. Differences in mating percentage between the treatments were compared by Chi-squared tests. All statistical analyses were performed using SPSS version 16.0 software .


Objective. This study was conducted for development and validation of the Sasang Digestive Function Inventory (SDFI) with type-specific digestive function-related symptoms for identification of Sasang type and pathological pattern. Methods and Materials. We selected questionnaire items for pathophysiological symptoms using internal consistency analysis and examined construct validity using 193 healthy participants. Test-retest reliability with a four-week interval as well as convergent validity was examined using the Nepean Dyspepsia Index-Korean (NDIK), Functional Dyspepsia-Related Quality of Life (FDQOL), Dutch Eating Behavior Questionnaire (DEBQ), and Body Mass Index (BMI). Results. The 21-item SDFI showed satisfactory internal consistency  and test-retest reliability . Three extracted subscales, SDFI-Digestion, SDFI-Appetite, and SDFI-Eating pattern, explained 56.02% of the total variance. The SDFI showed significant (P < 0.001) correlation with total symptom score of NDIK, FDRQOL-Eating status, DEBQ-External Eating scale, and BMI. The SDFI score of the Tae-Eum (50.62 ± 8.05) type was significantly (P < 0.001) larger than that of the So-Eum (43.11 ± 11.26) type. Conclusion. Current results demonstrated the reliability and validity of the SDFI and its subscales, which can be utilized as an objective instrument for diagnosis of Sasang types and assessment of the type-specific digestive function. Sasang typology is a traditional Korean personalized medicine incorporating medicinal herbs and acupuncture developed through Confucianism and clinical experience in Korea , 2. It d素證), that is, commonly observed Sasang type-specific pathophysiological symptoms regardless of health status, have been considered as pivotal information for diagnosis and intervention when the type identification based on the face or body shape could not provide confidence [Although the morphological phenotype appears to be useful and objective, there has been more emphasis on clinical observations for pathophysiological symptoms and pathological pattern identification. The type-specific original symptoms , the original symptom is regarded as the most important clinical index [太陰少陰人體形或略相彷佛難辨疑似而觀其病證則必無不辨, 人物形容仔細商量再三推移如有迷惑則參互病證明見無疑然後可以用藥最不可輕忽而一貼藥誤投重病險證一貼藥必殺人  ”““Since the Tae-Eum and So-Eum Sasang type sometimes show similar morphological shapes on face and body parts, you should consider the pathological features for the Sasang type differentiation. If you are not sure about the Sasang type differentiation of patient, you should hold the medication until the confidence from the pathological features can be achieved. You should careful with the medication even with the simple and light disease, since a single dose can cause death in severe disease patient.” .In Jae-ma Lee's book, Dong-Yi-Soo-Se-Bo-Won  , 27, as In this study, we developed the SDFI using questionnaire items from previous studies , 23, 27 The NDIK and FDQOL were widely used for examination of symptoms and quality of life changes in functional gastric diseases, and the DEBQ was commonly used for evaluation of dietary behaviors. The BMI is a numerical and physical index used to indicate digestive power and is frequently used for screening obesity. We examined the correlation of SDFI and these measures for the convergent validity and also presented significant differences between Sasang types in these digestion-related pathophysiological characteristics. This study would provide a foundation for measurement of Sasang type-specific multifaceted clinical symptoms and make possible mechanism studies on the type-specific pathophysiological symptoms. In addition, the Sasang typology inventories with acceptable validity and reliability would make the collaborative studies between Western and Eastern medicine researchers on the personalized medicine available. Participants in this study were 193 students from the School of Korean Medicine at Pusan National University, who gave written consent for conduct of the assessments. This study was approved by the Institutional Review Board (IRB) of the Pusan National University Korean Medicine Hospital (PNUKH-IRB-2012002). We administered the Questionnaire for Sasang Constitution Classification II (QSCCII) for identification of Sasang type while NDIK, FDQOL, DEBQ, BMI, and SDFI were examined for development and validation of the SDFI and its subscales. A total of 97 subjects completed the SDFI again for measurement of the test-retest reliability of the SDFI.The QSCCII, a Sasang typology-based inventory, is composed of 121 forced-choice items, including typical temperaments, body shapes, life style, and common health problems of each Sasang type. This questionnaire was developed in 1993 and revised in 1996 and has been used as an objective diagnostic tool in many studies examining the type-specific characteristics of Sasang typology , and theThe NDI is a reliable and validated disease-specific index for uninvestigated dyspepsia and functional dyspepsia, which measures symptoms and health-related quality of life. It was developed in 1999 , and theThe NDIK is composed of a symptom checklist and a disease-specific quality of life measure. In the current study, we used the symptom checklist, which includes 15 items rating common upper gastrointestinal symptoms using a 5- or 6-point Likert scale. The higher score indicates higher severity of symptoms.The FDQOL measures the quality of life of functional dyspepsia patients with the reference of Health-Related Quality of Life in 2006, and its internal consistency measured with Cronbach's alpha was 0.94 . The FDQThe DEBQ is a self-report screening instrument that measures patterns of eating behaviors . The DEBBody Mass Index (BMI) is a widely used measure for body shape and body fat mass with height and weight. It is calculated as weight (kg) divided by height (m) squared (2). The previous systematic review  showed tWe conducted an extensive review of previous articles and selected 33 items which are supposed to represent type-specific characteristics in clinical settings , 23, 27.The 31 preliminary items were subjected to explorative factor analysis for examination of the possible structure of the SDFI using Principle Component Analysis and Varimax rotation with an Eigenvalue over 1.0 as the criteria. We also performed Parallel Analysis in order to obtain the right factor numbers using Monte Carlo PCA for Parallel Analysis, which estimates an average distribution of eigenvalues based on a random process that can be compared with the calculated distribution , 36. TheThe test-retest data for the reliability examination over a period of four weeks was analyzed using correlational analysis. The reliability of the SDFI and its subscales was determined using Pearson's correlational coefficients with 97 subjects.The convergent validity of the SDFI and its subscales was examined in order to confirm the construct of Sasang type-specific digestive functions by comparing the relationship with the well-established NDIK, FDQOL, DEBQ, and BMI, which measure digestive function and its subsequent physical characteristics. We used Pearson's correlational coefficients exceeding the minimum acceptable value of 0.3.Demographic differences between Sasang-type groups were tested using ANOVA for continuous variables (age and BMI) and chi-square test for categorical variables (gender). The SDFI and its subscales, NDIK, FDQOL DEBQ, and BMI, were subjected to Analysis of Variance (ANOVA) for examination of the differences between Sasang type groups and Scheffe or Dunnett's T3 was used for post hoc analysis. P values of 0.05, 0.01, and 0.001 were used for significance.The data are presented as means and standard deviations or frequency with percentage. All analyses were performed using PASW Statistics 18.0 for Windows  and Since fifteen participants did not receive their Sasang type classification based on the Questionnaire for Sasang Constitution Classification II (QSCCII), SDFI, and NDIK, FDQOL, DEBQ, and BMI were examined with the remaining 178 participants . χ2 = 8.423, df = 2, P = 0.015), while no significant  differences in age were observed between Sasang-type groups , 29.67 ± 5.13 for the SY type , and 28.63 ± 4.96 for the SE type . Significant differences in gender distribution were observed between Sasang type groups , SDFI-A , and SDFI-E . SDFI-A showed significant correlation with SDFI-E , while the SDFI-D did not show significant correlation with other subscales , FDQOL-E , DEBQ-EX , and BMI . The convergent validity of the SDFI was examined with the NDIK, FDQOL DEBQ, and BMI using Pearson's correlation analysis . SDFI shr = −0.585, P < 0.001), FDQOL , FDQOL-E , FDQOL-L , and FDQOL-Psy . SDFI-A showed significant correlation with DEBQ-EX . SDFI-E showed significant correlation with DEBQ , DEBQ-EM , DEBQ-EX , and BMI  (SDFI-D showed significant correlation with NDIK (< 0.001) .The pathophysiological features in digestive functions were measured using NDIK, FDQOL, DEBQ, and BMI in order to determine whether the SDFI showed significant differences between Sasang type groups  and to dF = 8.286, df = 2,175, P < 0.001), SDFI-D , and SDFI-E  were observed between Sasang type groups. Post hoc analysis showed that the TE type  was significantly  higher than the SE type  in SDFI, SDFI-D, and SDFI-E, respectively  between Sasang type groups, and the post hoc analysis showed that the TE type (12.31 ± 9.49) was significantly (P = 0.011) lower than the SE type (18.31 ± 13.42). There was significant difference with FDQOL  between Sasang type groups was demonstrated with ANOVA. Post hoc analysis showed that the DEBQ-R of the TE type (27.62 ± 6.35) was significantly (P = 0.046) higher than that of the SE type (24.07 ± 8.21) (The significant difference on the DEBQ-R ( ± 8.21) .F = 33.928, df = 2,171, P < 0.001) between Sasang type groups was demonstrated with ANOVA. Post hoc analysis showed that the BMI of the TE type (24.71 ± 3.07) was significantly (P < 0.001) lower than that of the SY type (21.94 ± 2.26) and the SE type (20.75 ± 2.51) (The significant difference on the BMI ( ± 2.51) .The Sasang typology is a traditional Korean personalized medicine focusing on type-specific diagnosis and intervention for safe and effective medical treatment, including acupuncture and medicinal herbs , 2. In tr = 0.886, P < 0.001). The three subscales of the SDFI measure three facets of digestive functions, namely, SDFI-D , SDFI-A , and SDFI-E , which was suggested by previous studies [The Reliability and validity examination of the 21-item SDFI demonstrated that the SDFI has three domains with acceptable internal consistency  and test-retest reliability , FDRQOL-E , and DEBQ-EX . We measured digestive function-related clinical features of each Sasang type using NDIK, FDQOL, and DEBQ and evaluated the usefulness of SDFI and its subscales by correlation analysis in clinical use as convergent validity . The SDFr = 0.59) and FDQOL (r = −0.43). The NDIK [As for the SDFI subscales, the SDFI-D measures digestive functions and upper gastrointestinal symptoms and showed significant correlation coefficients with NDIK . The SDFI-A showed significant correlation with DEBQ-EX (r = 0.48), and the SDFI-E showed significant correlation with DEBQ, DEBQ-EM, and DEBQ-EX as 0.48, 0.44, and 0.49, respectively. The DEBQ [The SDFI-A and SDFI-E measure the pattern of eating, such as appetite, volume, and speed of the meal, and these two subscales have significant correlation coefficients (The DEBQ  measuresr = 0.299) and SDFI-E (r = 0.310), and BMI of the TE type was significantly higher than that of other Sasang types, which was repeatedly reported in previous studies [In this study, BMI was used as a representative physical measure indicating digestive power and obesity. BMI showed significant correlation with SDFI r = 0.99 and SD studies , 7. Thes studies . As for  studies , nonulce studies , and gas studies , which w studies . We analyzed the significant differences between Sasang types in NDIK, FDQOL, and DEBQ to determine the characteristics of the TE Sasang type groups compared with others. The TE type showed a low NDIK score, which measures the frequency of upper gastrointestinal symptoms. The TE also showed a significantly lower score than the SE type on FDQOL, which measures how much the quality of life was worsened by digestive disease. The TE type showed a significantly higher DEBQ-R score, which represents periodic overeating due to the suppressed desire for the food itself. These results are similar to those of previous clinical studies on Sasang type-specific gastrointestinal features , 23, 27.In this study, we developed the SDFI as a clinical index for measurement of Sasang type-specific pathophysiological symptoms, which are regarded as the most important clinical features in Sasang typology practice. Objective measures of the type-specific symptoms would be useful for making Sasang type differentiation and type-specific symptom based-disease diagnosis and intervention more reliable. For example, the location of the pathogen and severity of disease can be identified with the status of digestion in the SE and SY types , 42 and In previous studies, the Sasang Personality Questionnaire (SPQ)  showed SStudy considering the relation between these indexes would also be a foundation for innovative clinical studies in traditional medicine. A close relationship of gastrointestinal problems with psychosocial factors, including depression, anxiety, and stress, has recently been reported . The SE This study has several limitations that may affect generalizability of the results. First, the subjects were relatively young, healthy persons, and this may dampen the influence of living habits and show minor chronic digestive symptoms. Conduct of studies using clinical samples with gastrointestinal disease, metabolic syndrome , diabete Second, because the SDFI and other instruments used in this study are self-report questionnaire and may have the influence of response bias, the clinical validity should be confirmed again using other objective measures of gut hormones , triglycThe SDFI would be useful for the Sasang type and pattern identification since the SDFI has theoretical background, subscale construct, and questionnaire items based on an extensive review of previous clinical studies  and has


Graves’ disease (GD) is the most common cause of thyrotoxicosis and often involves the orbits. Graves’ ophthalmopathy (GO), also known as Thyroid Eye Disease (TED), can be clinically significant and advance to sight-threatening stages. Our knowledge of the immunogenetic pathophysiology of GO is rapidly expanding. The present review is an attempt to summarize the current state of knowledge on the immunogenetics of GO. First we briefly review the epidemiology and clinical importance of GO, and then we describe in detail the macromolecular pathogenesis and finally immunogenetics of GO. Discrepancies between the results from various reports and the limitations of the available data are discussed. In particular, there is a scarcity of data from non-Asian populations. While several studies have demonstrated significant associations between polymorphisms in certain genes , there is a need for studies that investigate the relationship between polymorphisms and both serum and local concentrations of the resulting proteins. A complete understanding of GO susceptibility and pathogenesis has not been yet possible due to a number of important knowledge gaps that need to be filled by future research. AntibodSeveral risk factors have been identified for GD. Genetic susceptibility is an important concept. The disease tends to run in families (concordance rate of 20%-40% in monozygotic twins and greater than 10% in siblings) and has a predilection to women  . InfectiThe onset of GD in up to 30% of women is within a year after pregnancy . AlthougThe literature on GD is extensive. The focus of our attention in this article is on a specific complication of GD, namely Graves’ ophthalmopathy (GO) or Thyroid Eye Disease (TED). First we briefly review the epidemiology and clinical importance of GO, and then we will describe in detail the macromolecular pathogenesis and finally immunogenetics of GO. 2The GD process is not limited to the thyroid gland. In a subset of patients GD also involves the pretibial skin and the orbit, the latter known as GO or TED . OrbitalThe degree of eye involvement among GD patients varies considerably from very mild cases with tenuous changes only detected on imaging, to more severe sight-threatening forms with optic nerve compression . ClinicaA number of scoring systems has been developed to define the severity of GO, among which the NOSPECS and Clinical Activity Score (CAS) systems have been widely used in research and practice. The NOSPECS system (1977) uses a 7 class scheme from 0 (no signs or symptoms) to 6 (sight loss) . ClassesSimilar to other autoimmune conditions, GO has a multifactorial etiology; genetic and environmental factors interact in concert and trigger a deviant process that presents self-antigens as non-self . Risk fa3via the T-cell receptor (TCR). Activated T-cells recruit B-cells through CD40-CD154 ligation. B-cells differentiate into plasma cells via interferon γ (INF- γ) and interleukin 2 (IL-2), activated T-cells recognize THSR on the orbital fibroblasts, and hence a site-specific immune response is initiated  are discussed in separate sections. A summary of the relevant studies is provided in Table 4.11). Considering that GO is an autoimmune condition, any imbalance between the production of pro- and anti-inflammatory cytokines can alter the downstream cascade of reactions and trigger the autoimmune response -60. TherCytokines released predominantly by leukocytes infiltrating the retro-orbital tissues are likely to play a key role in the cascade of the autoimmune reactions in the orbit . AlthougAmong several cytokines studied, the role of polymorphisms in the cytokines of the IL-1 family and TNF-α in genetic susceptibility to GO seems to be the strongest. The TNF gene codes for TNF-α, a key proinflammatory cytokine that has also been the target of a new therapy for GO . A groupIn a study from Japan, eight different alleles named as IFN-γ*1 to IFN-γ*8 were identified, among which IFN-γ*3 and IFN-γ*5 were associated with GO . A studyThe major members of the IL-1 superfamily are IL-1α, IL-1β, and the IL-1 receptor antagonist (IL-1RA). IL-1α and -β are pro-inflammatory cytokines and the IL-1RA competes for receptor binding with IL-1α and IL-1β . There a1.A summary of other cytokines with significant associations with GO is provided in Table 4.2et al. [The CTLA-4 gene encodes for a negative regulator of the T-cell immune response and seems to be an immunogenetic associate of several autoimmune diseases -84. The et al.  argued a4.3HLA gene polymrphisms are one of the susceptibility factors proposed for GO. There are two types of HLA molecules: class I  and class II . HLA molecules are encoded by a cluster of genes forming a complex on chromosome 6 (MHC) . HLA claA major limitation in studying autoimmune associations of different HLA alleles is the strong linkage disequilibrium between HLA alleles and alleles of undefined neighboring loci which may exert the primary effect , 100. Th4.4GO was recently reported to be associated with polymorphisms in the gene for intracellular adhesion molecule-1 (ICAM-1), which plays a major role in leukocyte circulation and migration , as well5We provide an exhaustive review of the available studies on the immunogentics of GO. Several important patterns arise from this review. First, more than half of the studies are from Asian populations. Considering that ethnicity may play an important role in the immunogenetics of autoimmune conditions, the results from one ethnicity cannot be extended to the other ethnicities in a straightforward manner. There is a scarcity of data from Caucasian populations and a complete lack of data from Africa. Studies from these ethnicities would be illuminating. Second, the three most frequently reported associations with GO are for CTLA-4, HLA-DRB-1, and TNF-α. The interplay between these three factors might be a significant determinant of GO susceptibility and pathogenesis. However, particular caution should be practiced when considering HLA genes. These genes, as described above, tend to be in linkage disequilibrium with neighboring genes, which might also be important players in GO pathogenesis. Finally, association studies like those reviewed here only serve as a start point for further studies. No causal relationships can be extracted from a mere association. One of the best ways to enrich the results of the observed associations is by functional studies that investigate the relationship between a given polymorphism and serum level of the resulting protein. For GO, however, one also needs to know the relationship between the polymorphisms of interest and local  concentrations of the resulting protein. Very little attention has been paid to this point, a fact which has limited our understanding of the disease pathogenesis.


Published studies investigating the association between genetic polymorphism -884C/T (rs763110) of the FAS ligand (FASL) promoter and cancer risk reported inconclusive results. To derive a more precise estimation of the relationship, we performed an updated meta-analysis of all eligible studies.heterogeneity<0.001; TT+TC vs. CC: OR = 0.85, 95%CI = 0.77–0.94; Pheterogeneity<0.001). Stratified analysis revealed that there was a statistically reduced cancer risk in Asians  and in patients with cancers of head and neck  and ovarian cancer . Meta-regression showed that ethnicity (p = 0.029) and genotyping method (p = 0.043) but not cancer types (p = 0.772), sample size (p = 0.518), or source of controls (p = 0.826) were the source of heterogeneity in heterozygote comparison.We carried out a meta-analysis, including 47 studies with 19,810 cases and 23,485 controls, to confirm a more conclusive association between the FASL rs763110 polymorphism and cancer susceptibility. Overall, significantly reduced cancer risk was associated with the variant -884T when all studies were pooled (TC vs. CC: OR = 0.83, 95%CI = 0.75–0.92; POur results suggest that the FASL polymorphism rs763110 is associated with a significantly reduced risk of cancer, especially in Asian populations. FASL gene is an important one of them, which situated on chromosome 1q23 with four exons. Though it is highly polymorphic, but the polymorphism C to T substitution at position -844 in the promoter region has been studied extensively In the past decade, numerous studies have suggested that the FASL -844C/T polymorphism is associated with many types of cancers PubMed and China National Knowledge Infrastructure (CNKI) were searched comprehensively using the terms relating to the FASL gene  in combination with words related to cancer  and polymorphism or variation. Last search was updated on May 29, 2013.In order to minimize potential publication bias, there were no language and other restrictions. Furthermore, citations in the retrieved articles were manually examined to identify additional relevant studies. Only the most recent or complete study was used if more than one of the same patient populations was applied in several publications.The major inclusion criteria were: (1) case-control or nested case-control studies; (2) investigating the association between the FASL rs763110 polymorphism and cancer risk; (3) cancers diagnosed by histopathology; (4) sufficient data for calculating an odds ratio (OR) with 95% confidence intervals (CIs). Accordingly, case-only studies, reviews and repeated papers were excluded.Data were independently extracted by two reviewers (Xu and Zhou) and checked by the other authors. The following information was abstracted: name of the first author, year of publication, country where the study was conducted, genotyping method, ethnicity, cancer types, source of controls, age, gender, number of cases and controls, genotype frequency in cases and controls and Hardy-Winberg equilibrium (HWE). Different ethnicities were classified as Caucasian, Asian, and African. All eligible studies were defined as hospital-based (HB) or population-based (PB) according to the source of controls. In case of discrepancies, a consensus on each item was reached among the authors.For the controls of each study, Hardy-Winberg equilibrium (HWE) was evaluated using the goodness-of-fit chi-square test and a p<0.05 was considered with a significant selective bias After careful retrieve and selection, 44 articles  or recessive model .heterogeneity<0.001, heterogeneity<0.001). In Caucasians and Africans, however, no significant association was found in each comparison.In the sub-group analyses by ethnicity, significant reduced risks were found for T carriers among Asians , but not for studies using Taqman assay.The results of the sub-group analyses by sample size, source of control and genotyping method were shown in supplemental information .Begg’s funnel plot and Egger’s test were performed to assess the publication bias. The figure of the funnel plot did not show any evidence of obvious asymmetry (p = 0.430 for TC vs. CC) . Then, tA total of 47 eligible studies, including 19,810 cases and 23,485 controls were identified and analyzed in this meta-analysis. We demonstrated that the FASL -844T allele was associated with a statistically reduced risk of cancer. This significant association was found in Asians but not for Caucasians or Africans. With all published data, this finding might be plausible.All controls in the studies involved were mainly cancer-free. The distribution of genotype in the control group was consistent with the Hardy-Weinberg equilibrium in all studies except for two studies shown in . When exThe FAS/FASL signaling system plays an important role in the cell apoptosis pathway, including regulation of immune system, maintaining immune-privileged ability and performing other regulatory functions With newly added studies, we carried out sub-group analyses. When stratified by ethnics, we found a significant association in Asians, but not for Caucasians or Africans, which may suggest that ethnic variation of genetic background would be modified by environmental factors In the sub-group analysis by cancer type, no significant association was found except for heterozygote and dominant model comparison of ovarian cancer and cancers of head and neck shown in . In our Attention should be paid to the relatively large heterogeneity in our results. Meta-regression was performed for heterozygote model according to ethnicity, cancer type, source of control, genotyping method and sample size. We found the sources of heterogeneity were mainly from ethnicity (p = 0.029) and genotyping method (p = 0.043). In addition, through sub-group analysis by ethnicity, we found that I-squared for the Asian, Caucasian and African studies was 80.9%, 0.0% and 19.3%, respectively . Then weSome limitation should be noted in this meta-analysis. Firstly, the controls were not uniformly defined and some studies included inpatient with benign disease which may contribute to the FASL gene mutation and development of various cancers. Secondly, due to limited individual data, we did not conduct a more precise analysis on other covariates such as age, gender, and environmental factors. Thirdly, the heterogeneity is difficult to exclude, in that it is influenced by complicated factors, such as age, sex, genetic diversities, different lifestyle, and clinical characteristics.Despite these limitations, our meta-analysis had significantly higher statistical power than the previous study that analyzed the association between the FASL -844C/T rs763110 polymorphism and cancer risk, since the cancer patients involved in our meta-analysis were twice as many as the previous one. We also analyzed the rs763110 polymorphism in various populations, including Africans. Cancer types in our study were more multifarious and a significant association was also found in cancers of head and neck and ovarian cancer though the sample size was relatively small.In conclusion, this meta-analysis suggests that the FASL-844C/T rs763110 polymorphism is associated with a significantly reduced risk of cancer, especially in Asian populations. To verify these results, large scale case-control studies with detailed individual information are needed.Checklist S1PRISMA checklist.(DOC)Click here for additional data file.File S1Subgroup analysis by sample size, source of control and genotyping method of ORs with a random-effects model for associations between FASL rs763110 polymorphism and cancer risk under heterozygote comparison (TC vs. CC).(DOCX)Click here for additional data file.


NAT2 polymorphisms as risk factors for various types of cancer. Colorectal adenomas are recognized as a pre-neoplastic lesion. A growing body of research documenting the association of NAT2 polymorphisms with the risk of colorectal adenomas has yielded conflicting results. The aim of the present study was to derive a more precise estimation of this association. Meta-analyses assessing the association of NAT2 variants with colorectal adenomas were conducted and subgroup analyses on smoking status and the source of the controls were also performed. Eligible studies were identified for the period before March 2012. A total of seven case-control studies, including 3,197 cases and 4,681 controls, were selected following extensive searching and screening. In the overall data, no associations between NAT2 polymorphisms and colorectal adenomas were observed . However, in the subgroup analysis concerning smoking status, slow acetylator variants were revealed to be correlated with increased colorectal adenoma risk in individuals who have smoked . In conclusion, the data of the present study suggested that NAT2 polymorphisms may be a risk factor for colorectal adenomas in individuals who have a history of smoking.Previous studies have implicated  Colorectal cancer is one of the most common malignancies worldwide, particularly in Western populations, and is thought to be correlated with colorectal adenoma, a type of pre-neoplastic lesion. The mechanisms of colon adenoma genesis are still unclear.Evidence indicates that certain epidemiological factors, including cigarette smoking, alcohol use and meat consumption, may contribute to the risk of colorectal adenomas ,2. MoreoCYP1A1 and GSTM1, respectively  gene encodes a phase II enzyme that plays an essential role in the metabolism of aromatic heterocyclic amines and hydrazines via N- and O-acetylation  studies should be observational (case-control or cohort); iii) studies must present the sample size, odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) and genetic distributions or information that may aid the interpretation of the results. After extensive searching, all studies were reviewed in accordance with the criteria defined above for further analysis.The following criteria were used for the literature selection: i) studies should be concerned with the association of Data were extracted and entered into a database by two reviewers independently. In the case of conflicting evaluations, agreement was reached following discussion. If a consensus could not be reached, a third reviewer was consulted to resolve the dispute and a final decision was then made according to the majority decision. Carriers of at least one of the high-activity alleles were identified as rapid acetylators and individuals carrying two low-activity alleles were classified as slow acetylators, as stated in the primary literature.NAT2 polymorphisms and colorectal adenoma risk was estimated for each study. To detect possible sample size biases, the OR and corresponding 95% CI of each study were plotted against the number of participants. A Chi-square-based Q statistic test was performed to assess heterogeneity. If the result of the heterogeneity test was P>0.1, ORs were pooled according to the fixed-effects model (Mantel-Haenszel). Otherwise, the random-effects model (DerSimonian and Laird) was used. The significance of the pooled ORs was determined using a Z-test.The OR of the Publication bias was assessed by visual inspection of funnel plots  in whichet al  are presented in We established a database of the extracted information from each study. The relevant information is shown in As shown in NAT2 polymorphisms and colorectal adenoma risk , suggesting that NAT2 polymorphisms may have little association with colorectal adenoma risk  or the population-based group fluoranthene, may have a reduced detoxification ability, thus resulting in an increased risk of colon adenoma as well as cancer. However, only two of the studies provided sufficient data concerning smoking status for subgroup analysis. Biases may be noted due to the limited number of selected studies and sample sizes. Therefore, these results should be interpreted with care.A previous meta-analysis suggested that smoking affected the formation and aggressiveness of colon adenomas . Another variant , in the  protein  and cataxylation . Polymorcer risk . IndividSubgroup analyses of the source of the controls also failed to reveal significant associations in studies using hospital- or population-based controls. Since hospital-based controls may not always truly represent the general population, particularly when the controls have any disease-related conditions relevant to the studied genotypes, inherent selection biases may exist. Further well-designed studies, including population-based controls with strict matching criteria, are required to reduce such possible biases.Inter-study heterogeneity was observed in this study. Thus, the random-effects model was used. Subgroup analyses were then conducted. As expected, the heterogeneities of the subgroups were reduced or removed. The data suggested that the source of the controls and smoking status may partly contribute to the heterogeneities. Additionally, other factors, including age, gender, ethnicity and the prevalence of lifestyle factors, may also generate heterogeneities.Publication bias is an important factor that should be considered in a meta-analysis. In the present study, a funnel plot and Egger’s test were used to assess publication biases. The results indicated that publication biases exerted little effect on the overall results, suggesting that the meta-analysis was robust and credible.Certain limitations may be included in this study. Firstly, in this meta-analysis, the majority of published studies and papers written in English were searched. However, it is possible that some related published or unpublished studies that may have met the inclusion criteria were missed. Thus, it is inevitable that publication biases may exist in the results. Secondly, all the studies concerned mixed ethnicities, with the exception of one study by Tiemersma  involvinNAT2 genetic variations with the overall risk of colorectal adenoma were revealed, statistically significant findings were noted in individuals with a history of smoking, suggesting that NAT2 genetic variations may modify the colorectal adenoma risk of smokers. Further investigations are required to confirm this conclusion.In conclusion, although no significant associations of