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Although cigarette smoking is a clear risk factor for lung cancer, the other determinants of lung cancer risk among smokers are less clear. Tea and coffee contain catechins and flavonoids, which have been shown to exhibit anticarcinogenic properties. Conversely, caffeine may elevate cancer risk through a variety of mechanisms. The current study investigated the effects of regular consumption of black tea and coffee on lung cancer risk among 993 current and former smokers with primary incident lung cancer and 986 age-, sex-, and smoking-matched hospital controls with non-neoplastic conditions. Results indicated that lung cancer risk was not different for those with the highest black tea consumption (>or=2 cups/day) compared with nondrinkers of tea [adjusted odds ratio (aOR)=0.90; 95% confidence interval (CI)=0.66-1.24]. However, elevated lung cancer risk was observed for participants who consumed 2-3 cups of regular coffee daily (aOR=1.34; 95% CI=0.99-1.82) or >or=4 cups of regular coffee daily (aOR=1.51, 95% CI=1.11-2.05). In contrast, decaffeinated coffee drinking was associated with decreased lung cancer risk for both participants who consumed or=2 cups/day (aOR=0.64; 95% CI=0.51-0.80). These results suggest that any chemoprotective effects of phytochemicals in coffee and tea may be overshadowed by the elevated risk associated with caffeine in these beverages. [ABSTRACT FROM AUTHOR]

[2-14C]2-amino-1-methyl-phenlimidazo[4,5-b]pyridine ([14C]PhIP), a putative human carcinogenic heterocyclic amine found in well-done cooked meat, was administered orally to three colon cancer patients undergoing a partial colonectomy. Forty-eight to seventy-two hours prior to surgery, subjects received a 70-84 μg dose of 14C. Urine and blood were analyzed by HPLC for PhIP and PhIP metabolites. Metabolites were identified based on HPLC co-elution with authentic PhIP metabolite standards, mass spectral analysis and susceptibility to enzymatic cleavage. In two subjects, 90% of the administered [14CPhIP dose was eliminated in the urine, whereas in the other, only 50% of the dose was found in the urine. One subject excreted three times more radioactivity in the first 4 h than did the others. Twelve radioactive peaks associated with PhIP were detected in the urine samples. The relative amount of each metabolite varied by subject, and the amounts of each metabolite within subjects changed over time. In all three subjects the most abundant urinary metabolite was identified as 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine- N2-glucuronide (N-hydroxy-PhIP-N2-glucuronide, accounting for 47-60% of the recovered counts in 24 h. PhIP accounted for <1% of the excreted radiolabel in all three patients. Other metabolites detected in the urine at significant amounts were 4-(2-amino-1-methylimidazo[4,5-b]pyrid-6-yl)phenyl sulfate, N-hydroxy-PhIP-N3-glucuronide and PhIP-N2-glucuronide. In the plasma, N-hydroxy-PhIP-N2-glucuronide accounted for 60, 18 and 20% of the recovered plasma radioactivity at 1 h post PhIP dose in subjects 1, 2 and 3 respectively. Plasma PhIP was 56-17% of the recovered dose at 1 h post exposure. The relatively high concentration of N-hydroxy-PhIP-N2-glucuronide and the fact that it is an indicator of bioactivation make this metabolite a potential biomarker for PhIP exposure and activation. Determining the relative differences in PhIP metabolites among individuals will indicate metabolic differences that may predict individual susceptibility to carcinogenic risk from this suspected dietary carcinogen. [ABSTRACT FROM PUBLISHER]

Objective: This study aimed to 1) describe the 2-year postoperative trajectories of leg pain and overall clinical outcome after surgery for radiculopathy, 2) identify the preoperative prognostic factors that predict trajectories representing poor clinical outcomes, and 3) develop and internally validate multivariable prognostic models to assist with clinical decision-making., Methods: This retrospective cohort study included patients enrolled in the Canadian Spine Outcomes and Research Network who were diagnosed with lumbar disc pathology and radiculopathy and had undergone lumbar discectomy at one of 18 spine centers. Potential outcome predictors included preoperative demographic, health-related, and clinical prognostic factors. Clinical outcomes were 1) 2-year univariable latent trajectories of leg pain intensity (numeric pain rating scale) and 2) overall outcomes comprising multivariable trajectories showing the combined postoperative courses of leg and back pain intensity (numeric pain rating scale) together with pain-related disability (Oswestry Disability Index). Each outcome model identified a subgroup of patients classified as experiencing a poor outcome based on minimal change in their clinical status after surgery. Multivariable risk model performance and internal validity were evaluated with discrimination and calibration statistics based on bootstrap shrinkage with 500 resamplings., Results: The authors included data from 1142 patients (47.6% female). The trajectory models identified 3 subgroups based on the patients' postoperative courses of pain or disability: 88.6% of patients in the leg pain model and 71.9% in the overall outcome model experienced a good-to-excellent outcome. The models classified 11.4% (leg pain outcome) and 28.2% (overall outcome) of patients as experiencing a poor clinical outcome, which was defined as minimal improvement in pain or disability after surgery. Eleven individual demographic, health, and clinical factors predicted patients' poor leg pain and overall outcomes. The performance of the multivariable risk model for leg pain was inadequate, while the overall outcome model had acceptable discrimination, calibration, and internal validity for predicting a poor surgical outcome., Conclusions: Patients with lumbar radiculopathy experience heterogeneous postoperative trajectories of pain and disability after lumbar discectomy. Individual preoperative factors are associated with postoperative outcomes and can be combined within a multivariable risk model to predict overall patient outcome. These results may inform clinical practice but require external validation before confident clinical implementation.

Purpose: We sought to conduct a pilot investigation of the reliability and administration fidelity of a new play-based measure of social communication for infants and toddlers with an autism diagnosis., Method: Our team adapted an existing measure, the Early Communication Indicator (ECI), for use with young autistic children in clinical and research contexts. In this brief report, we detail our adaptation process including administration and scoring of the final adapted measure based on data from a two-phase pilot study with young autistic children ( N = 17)., Results: This adapted measure, the Early Communication Indicator-Autism (ECI-A), captured a range of scores for the ECI, Initiation of Joint Attention, and Directed Communication in pilot testing. Interrater reliability was moderate to strong across the scored behaviors. Finally, parents were able to administer the ECI-A with high fidelity with support from the research staff., Conclusions: This two-phase pilot study demonstrated promise for the ECI-A as a brief measure of social communication that can be administered by parents and reliably scored by trained staff with limited background in autism assessments. Validation of the ECI-A is presently underway., Supplemental Material: https://doi.org/10.23641/asha.26042077.

Older adults are the least physically active group with specific barriers to regular exercise, and online exercise programs could overcome some of those barriers. This scoping review aimed to describe the characteristics of supervised group-based synchronous online exercise programs for older adults living in the community, their feasibility, acceptability, and potential benefits. MEDLINE (Ovid), Embase, SPORTDiscus, and the Cumulative Index to Nursing and Allied Health Literature were searched until November 2022. The included studies met the following criteria: participants aged 50 years and above, a minimum of a 6-week group-based supervised and synchronous intervention, and original articles available in English. Eighteen articles were included, with 1,178 participants (67% female, average age of 71 [57-93] years), most (83%) published in the past 3 years. From the limited reported studies, delivering supervised, synchronous online exercise programs (one to three times/week, between 8 and 32 weeks) for older adults living in the community seems feasible, accepted, and can improve physical function.

Lay Abstract: Feeding problems are common among autistic children and are linked to negative health consequences. Therefore, understanding feeding problems and factors that influence these behaviors is important for developing supports for children and families. While certain sensory processing patterns are commonly associated with feeding problems, less is known about the link between sensory processing and feeding behaviors in autism, as well as how parent behaviors and feelings during mealtime differ based on child sensory preferences. This research examined two groups of young autistic children who were reported to be picky eaters by their parents: those with and those without oral hypersensitivity. Children with oral hypersensitivity had more difficulty with food acceptance and their parents reported more negative feelings around feeding their child. However, the two groups of children (oral hypersensitive and not) did not differ in their medical/oral motor symptoms, mealtime behavior, or parent use of strategies at mealtimes. This research supports the need for personalized treatment strategies based on the child's sensory preferences to support both the child and parent in managing mealtimes.

Background: Acute pancreatitis (AP) is a frequent cause of hospitalization with long-term health consequences, including type 3c diabetes mellitus (DM). The incidence and risk factors for new-onset morbidities after AP need to be clarified to inform a personalized medicine approach., Methods: Using a longitudinal electronic healthcare record-linkage analysis, all patients admitted to hospital in Scotland with a first episode of AP between 1 April 2009 and 31 March 2012 and followed for a minimum of 5 years after their index AP admission were identified. All new-onset morbidity with specific focus on type 3c DM were analysed and, using time-split multiple regression., Results: A total of 2047 patients were included. AP requiring critical care was followed by 2 years of heightened risk (HR 5.24) of developing type 3c DM, increased risk of new-onset cardiac disease (HR 1.61), and renal disease (HR 2.96). The additional risk conferred by critical care AP had a negative interaction with time, whereas additional risk associated with male sex and a non-gallstone aetiology was long lasting., Conclusion: Based on these findings, a personalized approach to include type 3c DM screening for a minimum of 2 years for individuals who required critical care when hospitalized with AP is recommended., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd.)

Background: The proportion of births via cesarean section (CS) varies worldwide and in many countries exceeds WHO-recommended rates. Long-term health outcomes for children born by CS are poorly understood, but limited data suggest that CS is associated with increased infection-related hospitalisation. We investigated the relationship between mode of birth and childhood infection-related hospitalisation in high-income countries with varying CS rates., Methods and Findings: We conducted a multicountry population-based cohort study of all recorded singleton live births from January 1, 1996 to December 31, 2015 using record-linked birth and hospitalisation data from Denmark, Scotland, England, and Australia (New South Wales and Western Australia). Birth years within the date range varied by site, but data were available from at least 2001 to 2010 for each site. Mode of birth was categorised as vaginal or CS (emergency/elective). Infection-related hospitalisations (overall and by clinical type) occurring after the birth-related discharge date were identified in children until 5 years of age by primary/secondary International Classification of Diseases, 10th Revision (ICD-10) diagnosis codes. Analysis used Cox regression models, adjusting for maternal factors, birth parameters, and socioeconomic status, with results pooled using meta-analysis. In total, 7,174,787 live recorded births were included. Of these, 1,681,966 (23%, range by jurisdiction 17%-29%) were by CS, of which 727,755 (43%, range 38%-57%) were elective. A total of 1,502,537 offspring (21%) had at least 1 infection-related hospitalisation. Compared to vaginally born children, risk of infection was greater among CS-born children (hazard ratio (HR) from random effects model, HR 1.10, 95% confidence interval (CI) 1.09-1.12, p < 0.001). The risk was higher following both elective (HR 1.13, 95% CI 1.12-1.13, p < 0.001) and emergency CS (HR 1.09, 95% CI 1.06-1.12, p < 0.001). Increased risks persisted to 5 years and were highest for respiratory, gastrointestinal, and viral infections. Findings were comparable in prespecified subanalyses of children born to mothers at low obstetric risk and unchanged in sensitivity analyses. Limitations include site-specific and longitudinal variations in clinical practice and in the definition and availability of some data. Data on postnatal factors were not available., Conclusions: In this study, we observed a consistent association between birth by CS and infection-related hospitalisation in early childhood. Notwithstanding the limitations of observational data, the associations may reflect differences in early microbial exposure by mode of birth, which should be investigated by mechanistic studies. If our findings are confirmed, they could inform efforts to reduce elective CS rates that are not clinically indicated., Competing Interests: The authors have declared that no competing interests exist.

Children with Autism Spectrum Disorder (ASD) often display atypical sensory reactivity within the first years of life, prior to a diagnosis. This study examined sensory reactivity patterns at 14 months, changes from 14 to 23 months, and later ASD severity at 3 to 5 years of age in children (n = 87) at elevated likelihood of ASD. Results indicated that observed hyporeactivity at 14 months and increases from 14 to 23 months were related to higher ASD severity during the preschool years. Parent report of hyperreactivity at 14 months was associated with higher ASD severity in the RRB domain during the preschool years. Early hypo and hyperreactivity may predict later severity of ASD and aid in subtyping and developing individualized treatments.

Background: The male bias in autism spectrum disorder (ASD) diagnoses is well documented. As a result, less is known about the female ASD phenotype. Recent research suggests that conclusions drawn from predominantly male samples may not accurately capture female behavior. In this study, we explore potential sex differences in attention to social stimuli, which is generally reported to be diminished in ASD. Population-based sex differences in attention to faces have been reported, such that typically developing (TD) females attend more to social stimuli (including faces) from infancy through adulthood than TD males. It is yet unknown whether population-based sex differences in the face domain are preserved in ASD., Methods: A dynamic, naturalistic infrared eye-tracking paradigm measured attention to social stimuli (faces) in 74 school-aged males and females with ASD (male N  = 23; female N  = 19) and without ASD (male N  = 16; female N  = 16). Two kinds of video stimuli were presented that varied in social content: rich social scenes (dyadic play between two children) and lean social scenes (parallel play by two children)., Results: Results revealed a significant 3-way interaction between sex, diagnosis, and condition after controlling for chronological and mental age. ASD females attended more to faces than ASD males in the socially lean condition. This effect was not found in the typically developing (TD) group. ASD males attended less to faces regardless of social context; however, ASD females only attended significantly less to faces compared to TD females in the socially rich condition. TD males and ASD females did not differ in their attention to faces in either condition., Conclusions: This study has implications for how the field understands core social deficits in children with ASD, which should ideally be benchmarked against same-sex peers (male and female). Social attention in ASD females fell on a continuum-greater than their ASD male peers, but not as great as TD females. Overall, their social attention mirrored that of TD males. Improved understanding of the female social phenotype in ASD will enhance early screening and diagnostic efforts and will guide the development of sex-sensitive experimental paradigms and social interventions., Competing Interests: Competing interestsThe authors declare that they have no competing interests.

Objective: Primary hyperparathyroidism (PHPT) is functionally characterized by an inappropriately raised secretion of parathyroid hormone, leading to raised serum calcium levels. Some patients are referred for parathyroidectomy, and some are managed conservatively. The aim of the audit was to compare the mortality outcomes between the two groups. Methods: We retrospectively identified a cohort of inpatients with a main or secondary diagnosis of PHPT between 1986 and 2010 and followed them up to the end of 2011. The risk of mortality in PHPT patients compared to the background general population was estimated by calculating standardized mortality ratios (SMRs), adjusting for age, sex, and person-years at risk. Mortality in surgically treated patients was compared to conservatively treated patients using Cox regression, taking account of the Charlson Comorbidity Index. Results: A total of 2,589 patients (77.9% females) were diagnosed with PHPT in Scotland over this period. Of patients diagnosed with PHPT, 41.6% (1,077/2,589) had died by the end of 2011. The SMR was 1.58 (95% confidence interval [CI], 1.48 to 1.67). A total of 54.8% of the patients underwent surgery (SMR, 1.30; 95% CI, 1.18 to 1.43), while the rest were treated "conservatively" (SMR, 1.88; 95% CI, 1.73 to 2.03) ( P <.001). When other significant variables including the Charlson Comorbidity Index were taken into account in the final model, the hazard ratio for the "conservatively" managed group was reduced to 1.49 (95% CI, 1.30 to 1.70; P <.0001). Conclusion: Our study confirmed that inpatients diagnosed with PHPT have increased mortality. The risk of mortality was lower in those treated surgically compared with patients treated conservatively. Abbreviations: CI = confidence interval; HR = hazard ratio; PHPT = primary hyperparathyroidism; PTX = parathyroidectomy; SMR = standard mortality ratio; SMR01 = Scottish Morbidity Records.

Introduction: Severe acute pancreatitis (AP) requiring critical care admission (ccAP) impacts negatively on long-term survival., Objective: To document organ-specific new morbidity and identify risk factors associated with premature mortality after an episode of ccAP., Design: Cohort study., Setting: Electronic healthcare registries in Scotland., Participants: The ccAP cohort included 1471 patients admitted to critical care with AP between 1 January 2008 and 31 December 2010 followed up until 31 December 2014. The population cohort included 3450 individuals from the general population of Scotland frequency-matched for age, sex and social deprivation., Methods: Record linkage of routinely collected electronic health data with population matching., Primary and Secondary Outcome Measures: Patient demographics, comorbidity (Charlson Comorbidity Index), acute physiology, organ support and other critical care data were linked to records of mortality (death certificate data) and new-onset morbidity. Kaplan-Meier and Cox regression analyses were used to identify risk factors associated with mortality., Results: 310 patients with AP died during the index admission. Outcomes were not ascertained for five patients, and the deprivation quintile was not known for six patients. 340 of 1150 patients in the resulting postdischarge ccAP cohort died during the follow-up period. Greater comorbidity measured by the Charlson score, prior to ccAP, negatively influenced survival in the hospital and after discharge. The odds of developing new-onset diabetes mellitus after ccAP compared with the general population were 10.70 (95% CI 5.74 to 19.94). A new diagnosis of myocardial infarction, stroke, heart failure, liver disease, peptic ulcer, renal failure, cancer, peripheral vascular disease and lung disease was more frequent in the ccAP cohort than in the general population., Conclusions: The persistent deleterious impact of severe AP on long-term outcome and survival is multifactorial in origin, influenced by pre-existing patient characteristics and acute episode features. Further mechanistic and epidemiological investigation is warranted., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY. Published by BMJ.)

Recent studies suggest that circumscribed interests (CI) in females with Autism Spectrum Disorder (ASD) may align more closely with interests reported in typical female development than those typically reported for ASD males. We used eye-tracking to quantify attention to arrays containing combinations of male, female and neutral images in elementary-aged males and females with and without ASD. A number of condition × sex effects emerged, with both groups attending to images that corresponded with interests typically associated with their biological sex. Diagnostic effects reported in similar studies were not replicated in our modified design. Our findings of more typical attention patterns to gender-typical images in ASD females is consistent with evidence of sex differences in CI and inconsistent with the "Extreme Male Brain" theory of ASD.

Background/objectives: Advances in cancer management have resulted in improved survival rates, particularly in children and young adults. However, treatment may adversely affect reproductive outcomes among female cancer survivors. The objective of this study was to investigate their risk of adverse perinatal outcomes compared to the general population., Design/methods: We performed a population-based analysis, including all female cancer survivors diagnosed before the age of 40 years between 1981 and 2012. Pregnancy and perinatal complications were identified through linkage of the Scottish Cancer Registry with hospital discharge records based on the Community Health Index (CHI) database. We compared 1,629 female cancer survivors with a first ever singleton pregnancy after diagnosis, with controls matched on age, deprivation quintile, and year of cancer diagnosis selected from the general population (n = 8,899). Relative risks and 95%-confidence intervals of perinatal risks were calculated using log-binomial regression., Results: Survivors were more likely to give birth before 37 weeks of gestation (relative risk (RR]) 1.32, 95%-CI 1.10-1.59), but did not show an increased risk of low birth weight (<2.5kg: RR 1.15, 95%-CI 0.94-1.39), and were less likely to give birth to offspring small for gestational age (RR 0.81, 95%-CI 0.68-0.98). Operative delivery and postpartum haemorrhage were more common but approached rates in controls with more recent diagnosis. The risk of congenital abnormalities was not increased (RR 1.01, 95%-CI 0.85-1.20)., Conclusion: Cancer survivors have an increased risk of premature delivery and postpartum haemorrhage, but their offspring are not at increased risk for low birth weight or congenital abnormalities. In recent decades there has been a normalisation of delivery method in cancer survivors, nevertheless careful management remains appropriate particularly for those diagnosed in childhood., Competing Interests: The authors have declared that no competing interests exist.

Study Question: What is the impact of cancer in females aged ≤39 years on subsequent chance of pregnancy?, Summary Answer: Cancer survivors achieved fewer pregnancies across all cancer types, and the chance of achieving a first pregnancy was also lower., What Is Known Already: The diagnosis and treatment of cancer in young females may be associated with reduced fertility but the true pregnancy deficit in a population is unknown., Study Design, Size, Duration: We performed a retrospective cohort study relating first incident cancer diagnosed between 1981 and 2012 to subsequent pregnancy in all female patients in Scotland aged 39 years or less at cancer diagnosis (n = 23 201). Pregnancies were included up to end of 2014. Females from the exposed group not pregnant before cancer diagnosis (n = 10 271) were compared with general population controls matched for age, deprivation quintile and year of diagnosis., Participants/materials, Setting, Methods: Scottish Cancer Registry records were linked to hospital discharge records to calculate standardized incidence ratios (SIR) for pregnancy, standardized for age and year of diagnosis. Linkage to death records was also performed. We also selected women from the exposed group who had not been pregnant prior to their cancer diagnosis who were compared with a matched control group from the general population. Additional analyses were performed for breast cancer, Hodgkin lymphoma, leukaemia, cervical cancer and brain/CNS cancers., Main Results and the Role of Chance: Cancer survivors achieved fewer pregnancies: SIR 0.62 (95% CI: 0.60, 0.63). Reduced SIR was observed for all cancer types. The chance of achieving a first pregnancy was also lower, adjusted hazard ratio = 0.57 (95% CI: 0.53, 0.61) for women >5 years after diagnosis, with marked reductions in women with breast, cervical and brain/CNS tumours, and leukaemia. The effect was reduced with more recent treatment period overall and in cervical cancer, breast cancer and Hodgkin lymphoma, but was unchanged for leukaemia or brain/CNS cancers. The proportion of pregnancies that ended in termination was lower after a cancer diagnosis, and the proportion ending in live birth was higher (78.7 vs 75.6%, CI of difference: 1.1, 5.0)., Limitations, Reasons for Caution: Details of treatments received were not available, so the impact of specific treatment regimens on fertility could not be assessed. Limited duration of follow-up was available for women diagnosed in the most recent time period., Wider Implications of the Findings: This analysis provides population-based quantification by cancer type of the effect of cancer and its treatment on subsequent pregnancy across the reproductive age range, and how this has changed in recent decades. The demonstration of a reduced chance of pregnancy across all cancer types and the changing impact in some but not other common cancers highlights the need for appropriate fertility counselling of all females of reproductive age at diagnosis., Study Funding/competing Interest(s): This study was funded by NHS Lothian Cancer and Leukaemia Endowments Fund. Part of this work was undertaken in the MRC Centre for Reproductive Health which is funded by the MRC Centre grant MR/N022556/1. RAA has participated in Advisory Boards and/or received speaker's fees from Beckman Coulter, IBSA, Merck and Roche Diagnostics. He has received research support from Roche Diagnostics, Ansh labs and Ferring. The other authors have no conflicts to declare.

Recent work suggests sensory seeking predicts later social symptomatology through reduced social orienting in infants who are at high-risk for autism spectrum disorder (ASD) based on their status as younger siblings of children diagnosed with ASD. We drew on extant longitudinal data from a community sample of at-risk infants who were identified at 12 months using the First Year Inventory, and followed to 3-5 years. We replicate findings of Damiano et al. (in this issue) that a) high-risk infants who go on to be diagnosed with ASD show heightened sensory seeking in the second year of life relative to those who do not receive a diagnosis, and b) increased sensory seeking indirectly relates to later social symptomatology via reduced social orienting. We extend previous findings to show that sensory seeking has more clinical utility later in the second year of life (20-24 months) than earlier (13-15 months). Further, this study suggests that diminished attention disengagement at 12-15 months may precede and predict increased sensory seeking at 20-24 months. Findings add support for the notion that sensory features produce cascading effects on social development in infants at risk for ASD, and suggest that reduced attention disengagement early in life may set off this cascade., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To measure the increasing incidence of primary hyperparathyroidism (PHPT) in Scotland, to determine the relationship between PHPT and deprivation, and to investigate the relationship between parathyroidectomy (PTX) and social deprivation., Methods: We retrospectively identified a cohort of patients diagnosed with PHPT between 1986 and 2013 from the Scottish Morbidity Records (SMR01) database. The diagnosis of PHPT was made in accordance with the International Classification of Diseases code., Results: Between the years 1986 and 2013, 4002 patients were diagnosed with PHPT. There was a significant increase in the incidence of PHPT in this period (p < 0.0001), an association between the incidence of PHPT and deprivation (p < 0.0001) plus an association between a lower rate of PTX and deprivation (p < 0.001)., Conclusion: The increase in incidence of PHPT may be due to a combination of increased awareness of PHPT, easier diagnosis, and an ageing population. The lower rate of PTX in relation to deprivation may reflect comorbidities, age, and uncertainty about the long-term benefits of PTX in asymptomatic patients.

Catalase is an endogenous antioxidant enzyme that neutralizes hydrogen peroxide and is induced by oxidative challenge. A -262C --> T polymorphism in the promoter region of the gene (CAT) is associated with risk of several conditions related to oxidative stress. We sought to determine the functional effects of the CAT polymorphism on enzyme activity in erythrocytes and the potential modifying effects of demographic and lifestyle factors on genotype/phenotype relationships, using specimens and data from controls from breast and prostate cancer studies in Arkansas (n = 420). There was a dose-response reduction in catalase activity by genotype, with geometric means of 115.4 units/mg hemoglobin for those with CC genotypes, 82.1 units/mg for those with CT genotypes, and 73.5 units/mg for those with TT genotypes. Associations were only observed among Caucasians (P < 0.0001), with no effects among African Americans (P = 0.91), and were stronger among women than men, although numbers in stratified analyses were small. Differences in catalase activity by genotype were most pronounced among those in the highest tertiles of consumption of fruits and vegetables (-35%, P = 0.003), with weaker relationships among those who were lower consumers (-21.8%, P = 0.16). Among those with CC genotypes, there was no change in activity by consumption, but there were notable decreases in activity by tertiles of consumption for those with at least one T allele. These data indicate that the CAT -262C --> T polymorphism predicts a portion of catalase phenotype, which may be limited to Caucasians. Associations between genotype and phenotype were modified by dietary factors, illustrating the biochemical complexity of studies of genetic polymorphisms and disease risk.

Regular use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been hypothesized to be associated with reduced risk of hematologic cancer, although previous results have been inconsistent. The current study investigated the effects of aspirin or acetaminophen use on adult acute leukemia risk among 169 individuals with leukemia and 676 age and sex matched hospital controls with non-neoplastic conditions who completed a comprehensive epidemiologic questionnaire. Results indicate that regular aspirin use may be associated with a modest decrease in leukemia risk [adjusted odds ratio (aOR), 0.84; 95% confidence interval (CI), 0.59-1.21]. In contrast, ever using acetaminophen was associated with elevated leukemia risk (aOR, 1.53; 95% CI, 1.03-2.26). Results did not differ between men and women. Other studies have demonstrated that acetaminophen is associated with transient decreases in DNA repair, and lymphocytes may be particularly susceptible to DNA damage, suggesting a mechanism for the elevated acute leukemia risk observed among acetaminophen users.

Observed weak or null associations between fruit and vegetable intake and breast cancer risk could be due to heterogeneity in endogenous antioxidant capabilities. The authors evaluated potential relations between a functional polymorphism in catalase, an antioxidant enzyme, and breast cancer risk, particularly in relation to fruit and vegetable intake and supplement use. Women (1,008 cases and 1,056 controls) in the Long Island Breast Cancer Study Project (1996-1997) were interviewed, completed a food frequency questionnaire, and provided blood for genotyping. The high-activity catalase CC genotype was associated with an overall 17% reduction in risk of breast cancer compared with having at least one variant T allele (odds ratio = 0.83, 95% confidence interval: 0.69, 1.00). Vegetable and, particularly, fruit consumption contributed to the decreased risk associated with the catalase CC genotype. Associations were more pronounced among women who did not use vitamin supplements, with a significant multiplicative interaction (p(interaction) = 0.02) for the CC genotype and high fruit intake (odds ratio = 0.59, 95% confidence interval: 0.38, 0.89), and there was no association among supplement users. These results indicate the importance of diet, rather than supplement use, in concert with endogenous antioxidant capabilities, in the reduction of breast cancer risk. CC genotypes were prevalent in approximately 64% of controls; thus, the preventive potential for fruit consumption has widespread implications.

Dietary factors appear to be involved in the high incidence of prostate cancer in "Westernized" countries, implicating dietary carcinogens such as heterocyclic amines (HAs) in the initiation of prostate carcinogenesis. We examined 24 human prostate samples with respect to their potential for activation and detoxification of HAs and the presence of DNA adducts formed in vivo. Cytochromes P450 1B1, 3A4 and 3A5 were expressed at low levels (<0.1-6.2 pmol/mg microsomal protein). N-Acetyltransferase (NAT) activities, using p-aminobenzoic acid (NAT1) and sulfamethazine (NAT2) as substrates, were <5-5,500 and <5-43 pmol/min/mg cytosolic protein, respectively. Glutathione S-transferases (GSTs) P1, M2 and M3 were expressed at 0.038-1.284, 0.005-0.126 and 0.010-0.270 microg/mg cytosolic protein, respectively; GSTM1 was expressed in all GSTM1-positive samples (0.012-0.291 microg/mg cytosolic protein); and GSTA1 was expressed at low levels (<0.01-0.11 microg/mg cytosolic protein). Binding of N-hydroxy-PhIP to DNA in vitro occurred primarily by an AcCoA-dependent process (<1-54 pmol/mg/DNA), PAPS- and ATP-dependent binding being <1-7 pmol/mg DNA. In vivo, putative PhIP- or 4-aminobiphenyl-DNA adducts were found in 4 samples (0.4-0.8 adducts/10(8) bases); putative hydrophobic adducts were found in 6 samples (8-64 adducts/10(8) bases). Thus, the prostate appears to have low potential for N-hydroxylation of HAs but greater potential for activation of N-hydroxy HAs to genotoxic N-acetoxy esters. The prostate has potential for GSTP1-dependent detoxification of ATP-activated N-hydroxy-PhIP but little potential for detoxification of N-acetoxy-PhIP by GSTA1. However, there were no significant correlations between expression/activities and DNA adducts formed in vitro or in vivo, DNA adducts in vivo possibly reflecting carcinogen exposure., (Copyright (c) 2005 Wiley-Liss, Inc.)

SULT1A1 is a phase II detoxification enzyme involved in the biotransformation of a wide variety of endogenous and exogenous phenolic compounds. Human platelet SULT1A1 enzymatic activity shows marked inter-individual variability and a common coding polymorphism, SULT1A1*1/*2, has been described that accounts for a proportion of this variability. We examined the 5'-flanking region of the SULT1A1 gene to determine if genetic variability in this portion of the gene influenced enzymatic activity. Direct sequencing revealed five common genetic polymorphisms (-624G>C, -396G>A, -358A>C, -341C>G and -294T>C) that were present at different allele frequencies in Caucasian, African-American and Chinese groups. Platelet SULT1A1 enzymatic activity was significantly correlated with individual promoter region polymorphisms and the associations were different between African-Americans and Caucasians. Haplotypes were constructed and platelet enzymatic activity according to haplotype was examined. The haplotypes were also significantly correlated with activity; haplotypes GAACT and GGACT (accounting for 13% and 5% of inter-individual variability in platelet activity, respectively) were important in Caucasians while haplotypes GAACC, GAACT and GGACC (accounting for 8%, 5% and 4% of variability) were significantly associated with activity in African-Americans. The coding region polymorphism, SULT1A1*1/*2 was in linkage disequilibrium with the promoter region polymorphisms and showed no effect on activity when examined in the context of the 5'-flanking region polymorphisms. These studies indicate that variation in the promoter region of the SULT1A1 gene exerts a significant influence on enzymatic activity.