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Homozygosity for the p.C282Y substitution in the HFE protein encoded by the hemochromatosis gene on chromosome 6p (HFE) is a common genetic trait that increases susceptibility to iron overload. McLaren et al. used bivariate mixture modeling to analyze the joint population distribution of transferrin saturation (TS) and serum ferritin concentration (SF) measured for participants in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. They identified four components (C1, C2, C3, and C4) with successively increasing means for TS and SF. They demonstrated that bivariate mixture modeling in TS and SF reflect the genetic locus of HFE and may isolate p.C282Y homozygotes from the general population. In the current study we used data from the another large cohort, the Australian HealthIron study of genetic and environmental modifiers of hereditary hemochromatosis, to validate the component analysis approach, to examine stability of component proportions over time and to determine if TS and SF values from an individual move between components at baseline and follow-up. Because sampling fractions from each p.C282Y / p.H63D genotype stratum are not equal, we used frequency weights based on the inverse of the probability of selection for invitation to participate. In the weighted female analytic cohorts, C4 captured most of C282Y homozygotes, and C2 was the largest component. We identified four components from the weighted male analytic cohort and C4 captured most of p.C282Y homozygotes. The bivariate mixture modeling approach suggested that the model is transferable from one white population to another, although estimated means within components may differ. [ABSTRACT FROM AUTHOR]

Background: We describe a novel strategy for power and sample size determination developed for studies utilizing investigational technologies with limited available preliminary data, specifically of imaging biomarkers. We evaluated diffuse optical spectroscopic imaging (DOSI), an experimental noninvasive imaging technique that may be capable of assessing changes in mammographic density. Because there is significant evidence that tamoxifen treatment is more effective at reducing breast cancer risk when accompanied by a reduction of breast density, we designed a study to assess the changes from baseline in DOSI imaging biomarkers that may reflect fluctuations in breast density in premenopausal women receiving tamoxifen.Method: While preliminary data demonstrate that DOSI is sensitive to mammographic density in women about to receive neoadjuvant chemotherapy for breast cancer, there is no information on DOSI in tamoxifen treatment. Since the relationship between magnetic resonance imaging (MRI) and DOSI has been established in previous studies, we developed a statistical simulation approach utilizing information from an investigation of MRI assessment of breast density in 16 women before and after treatment with tamoxifen to estimate the changes in DOSI biomarkers due to tamoxifen.Results: Three sets of 10,000 pairs of MRI breast density data with correlation coefficients of 0.5, 0.8 and 0.9 were simulated and generated and were used to simulate and generate a corresponding 5,000,000 pairs of DOSI values representing water, ctHHB, and lipid. Minimum sample sizes needed per group for specified clinically-relevant effect sizes were obtained.Conclusion: The simulation techniques we describe can be applied in studies of other experimental technologies to obtain the important preliminary data to inform the power and sample size calculations. [ABSTRACT FROM AUTHOR]

The existence of multiple inherited disorders of iron metabolism suggests genetic contributions to iron deficiency. We previously performed a genome-wide association study of iron-related single nucleotide polymorphisms (SNPs) using DNA from white men aged ≥25 y and women ≥50 y in the Hemochromatosis and Iron Overload Screening (HEIRS) Study with serum ferritin (SF) ≤12 mg/L (cases) and controls (SF >100 mg/L in men, SF >50 mg/L in women). We report a follow-up study of white, African-American, Hispanic, and Asian HEIRS participants, analyzed for association between SNPs and eight iron-related outcomes. Three chromosomal regions showed association across multiple populations, including SNPs in the TF and TMPRSS6 genes, and on chromosome 18q21. A novel SNP rs1421312 in TMPRSS6 was associated with serum iron in whites (p = 3.7×10-6) and replicated in African Americans (p = 0.0012).Twenty SNPs in the TF gene region were associated with total iron-binding capacity in whites (p<4.4×10-5); six SNPs replicated in other ethnicities (p<0.01). SNP rs10904850 in the CUBN gene on 10p13 was associated with serum iron in African Americans (P = 1.0×10-5). These results confirm known associations with iron measures and give unique evidence of their role in different ethnicities, suggesting origins in a common founder. [ABSTRACT FROM AUTHOR]

The existence of multiple inherited disorders of iron metabolism in man, rodents and other vertebrates suggests genetic contributions to iron deficiency. To identify new genomic locations associated with iron deficiency, a genome-wide association study (GWAS) was performed using DNA collected from white men aged ⩾25 y and women ⩾50 y in the Hemochromatosis and Iron Overload Screening (HEIRS) Study with serum ferritin (SF) ⩽ 12 μg/L (cases) and iron replete controls (SF>100 μg/L in men, SF>50 μg/L in women). Regression analysis was used to examine the association between case-control status (336 cases, 343 controls) and quantitative serum iron measures and 331,060 single nucleotide polymorphism (SNP) genotypes, with replication analyses performed in a sample of 71 cases and 161 controls from a population of white male and female veterans screened at a US Veterans Affairs (VA) medical center. Five SNPs identified in the GWAS met genome-wide statistical significance for association with at least one iron measure, rs2698530 on chr. 2p14; rs3811647 on chr. 3q22, a known SNP in the transferrin (TF) gene region; rs1800562 on chr. 6p22, the C282Y mutation in the HFE gene; rs7787204 on chr. 7p21; and rs987710 on chr. 22q11 (GWAS observed P<1.51610-7 for all). An association between total iron binding capacity and SNP rs3811647 in the TF gene (GWAS observed P = 7.0610-9, corrected P = 0.012) was replicated within the VA samples (observed P = 0.012). Associations with the C282Y mutation in the HFE gene also were replicated. The joint analysis of the HEIRS and VA samples revealed strong associations between rs2698530 on chr. 2p14 and iron status outcomes. These results confirm a previously-described TF polymorphism and implicate one potential new locus as a target for gene identification. [ABSTRACT FROM AUTHOR]

The article discusses a study which examined the relationship between vellus hair and melanoma incidence in order to determine the factors that may explain an increased vulnerability of children to sun exposure. Findings suggests that not only is sun exposure level an important predictor of melanoma, it was also found that areas on the body with higher numbers of vellus hair follicles have an increased vulnerability to developing melanoma.

The ornithine decarboxylase-1 (ODC1) polymorphism at position +316 affects binding by transcriptional activators and repressors and modulates the risk of metachronous colorectal adenomas, particularly in association with aspirin use. We investigated the effects of ODC1 after treatment with difluoromethylornithine (eflornithine)/sulindac or placebo. Two hundred twenty-eight colorectal adenoma patients in a randomized phase III trial were genotyped for ODC1. We used Wilcoxon rank sums tests on non-normally distributed continuous variables across two genotype groups, χ2 or Fisher exact test to assess the association between baseline categorical variables and genotype group, and log binomial regression for the primary (adenoma recurrence) and secondary outcomes (tissue polyamine response, cardiovascular toxicity, gastrointestinal toxicity, and ototoxicity). All statistical tests were two-sided. In binomial regression models with variables age, sex, race, aspirin use, treatment, and ODC1 genotype, treatment was the only statistically significant factor associated with differences in adenoma recurrence or tissue polyamine response. A statistically significant interaction was detected between ODC1 genotype and treatment with respect to adenoma recurrence (placebo group: GG, 50%, AA/GA: 34%; treatment group: GG, 11%, AA/GA, 21%; Pinteraction = .038). Excess ototoxicity was observed among ODC1 AA patients receiving treatment, but the interaction of genotype and treatment on ototoxicity was not statistically significant (P = .45). [ABSTRACT FROM PUBLISHER]

The article focuses on a study on the reasons why Asian and Pacific Islanders in the Hemochromatosis and Iron Overload Screening Study had the highest prevalence of elevated serum ferritin and transferin saturation levels. There may be a need to interpret higher TS and SF levels in persons of Asian or Pacific Island heritage compared to Whites.

Abstract: Repeated measurements arising from longitudinal studies occur frequently in applied research. Methods to calculate power in the context of repeated measures are available for experimental settings where the covariate of interest is a discrete treatment indicator. However, no closed form expression exists to calculate power for generalized linear models with non-zero within-cluster correlation that are common in epidemiological and observational studies in which the covariate of interest varies over time and is often measured on a continuous scale, and where the researchers control for several potential confounders. We describe a Monte Carlo simulation approach conducted to calculate power, and illustrate its application in two models frequently encountered in practice, the normal linear mixed model, and the logistic regression model, both with repeated measurements and non-zero within-cluster correlation. This approach can be used to calculate the effect on power of changing various simulation conditions controlled by the researcher, such as sample size, within-cluster correlation structure, smallest meaningful difference to detect, and distributional assumptions. [Copyright &y& Elsevier]

Abstract: Background: Levamisole (LMS) has immunomodulatory activity, stimulates the immune system of healthy, normal volunteers and has been proposed previously as a colon cancer preventive agent. Methods: Patients with a history of colonic polyps who are at increased risk of colon cancer received LMS in a placebo-controlled, double-blinded clinical trail with crossover design. Primary endpoints were immunologic and included flow cytometry of peripheral blood mononuclear cells (PBMCs), measurement of interferon-γ copy number (IGCN) in PBMCs, and an ex vivo serum immune assay. Results: No differences were seen in the expression of multiple antigens by flow cytometry pre- and post-LMS. The IGCN partitioned subjects into two distinct groups defined by a γ-distribution which had a differential response to LMS. Those with low basal IGCN had a lower percentage of CD25 expressing PBMCs and responded to low dose LMS by producing more PBMC-derived interferon-γ and increasing the expression of CD25 and two NK cell markers, CD16 and CD56. In contrast, subjects with a high basal IGCN responded to low dose LMS with a reduction in PBMC-derived interferon-γ and a decrease in the expression of CD25. Conclusions: In aggregate, these responses suggest that LMS may act as an immunostimulatory agent for one group, those with low basal IGCN, and as an immunosuppressive agent for the other. LMS may not be an optimal agent for most patients with colonic polyps and should be avoided in patients with normal immune function. IGCN may be useful as an immunologic surrogate endpoint biomarker in future cancer prevention trials with immunomodulatory agents. [Copyright &y& Elsevier]

The article discusses a randomized placebo-controlled trial that compared the effects of celecoxib and placebo in patients with 10 to 40 actinic keratoses and Fitzpatrick sun-reactive skin types I, II or III, by Elmets and colleagues, published within the issue. The trial showed that celecoxib treated and prevented the progression of lesions at the late stage of cutaneous carcinogenesis. The authors claim that the trial offered addition information on chemoprevention.

Purpose: Our preclinical studies showed that lycopene enhanced the anti‐prostate cancer efficacy of docetaxel in animal models. A phase I trial (NCT0149519) was conducted to identify an optimum dose of synthetic lycopene in combination with docetaxel (and androgen blockade [androgen deprivation therapy, ADT]), and to evaluate its effect on the safety and pharmacokinetics of docetaxel in men with metastatic prostate cancer. Methods: Subjects were treated with 21‐day cycles of 75 mg/m2 docetaxel (and ADT), plus lycopene at 30, 90 or 150 mg/day. A Bayesian model averaging continual reassessment method was used to guide dose escalation. Pharmacokinetics of docetaxel and multiple correlative studies were carried out. Results: Twenty‐four participants were enrolled, 18 in a dose escalation cohort to define the maximum tolerated dose (MTD), and six in a pharmacokinetic cohort. Docetaxel/ADT plus 150 mg/day synthetic lycopene resulted in dose‐limiting toxicity (pulmonary embolus) in one out of 12 participants with an estimated probability of.106 and thus was chosen as the MTD. Lycopene increased the AUCinf and Cmax of plasma docetaxel by 9.5% and 15.1%, respectively. Correlative studies showed dose‐related changes in circulating endothelial cells and vascular endothelial growth factor A, and reduction in insulin‐like growth factor 1R phosphorylation, associated with lycopene therapy. Conclusions: The combination of docetaxel/ADT and synthetic lycopene has low toxicity and favourable pharmacokinetics. The effects of lycopene on biomarkers provide additional support for the toxicity‐dependent MTD definition. Highlights: The maximum tolerated dose was identified as 150 mg/day of lycopene in combination with docetaxel/ADT for the treatment of metastatic prostate cancer patients.Small increases in plasma exposure to docetaxel were observed with lycopene co‐administration.Mechanistically significant effects were seen on angiogenesis and insulin‐like growth factor 1 signalling by lycopene co‐administration with docetaxel/ADT. [ABSTRACT FROM AUTHOR]

Simple Summary: The authors present a phase IIa clinical biomarker trial of colorectal cancer (CRC) survivors treated with a polyamine-inhibitory regimen (dietary arginine restriction plus daily aspirin 325 mg) as a potential future strategy for tertiary prevention of CRC (i.e., preventing colorectal adenomas and/or CRC among CRC survivors). In this study, 20 stage I-III CRC patients were treated for 12 weeks with the above-mentioned intervention, with assessments of calculated dietary arginine intake, plasma arginine levels, and rectal tissue mucosa samples assessed for polyamine levels at baseline and end-of-study. While dietary arginine intake and plasma arginine levels were significantly decreased by this intervention, rectal tissue polyamines (including tissue putrescine levels, which served as the primary study endpoint) were unaffected. After potentially curative treatment, colorectal cancer (CRC) patients remain at high risk for recurrence, second primary CRC, and high-risk adenomas. In combination with existing data, our previous findings provide a rationale for reducing tissue polyamines as tertiary prevention in non-metastatic CRC patients. The goal of this study was to demonstrate rectal tissue polyamine reduction in optimally treated stage I-III CRC patients after intervention with daily oral aspirin + dietary arginine restriction. A single-institution phase IIa clinical trial was conducted. Patients were treated with aspirin 325 mg/day and an individualized dietary regimen designed to reduce arginine intake by ≥30% over a 12-week study period. Dietary intake, endoscopy with rectal biopsies, and phlebotomy were performed pre- and post-intervention. The primary endpoint was to demonstrate ≥50% decrease in rectal tissue putrescine levels from baseline as a measure of polyamine reduction in the target tissue. Twenty eligible patients completed the study. After study intervention, mean dietary arginine intake decreased from 3.7 g/day ± 1.3 SD to 2.6 g/day ± 1.2 SD (29.7% decrease, p < 0.02 by Sign test). Mean plasma arginine levels decreased from 46.0 ng/mL ± 31.5 SD at baseline to 35 ng/mL ± 21.7 SD (p < 0.001). Rectal tissue putrescine levels were 0.90 nMol/mg-protein pre-intervention and 0.99 nMol/mg-protein post-intervention (p < 0.64, NS). No significant differences were observed for the other tissue polyamines investigated: spermidine (p < 0.13), spermine (p < 0.21), spermidine:spermine ratio (p < 0.71). Among CRC survivors, treatment with daily oral aspirin and an individualized dietary arginine restriction intervention resulted in lower calculated dietary arginine intake and plasma arginine levels but did not affect rectal tissue polyamine levels. [ABSTRACT FROM AUTHOR]

BACKGROUND: Questionnaire-based studies investigating blood donation history rely on the accurate recall of information from participants for results to be valid. This study aimed to retrieve electronic records from a national blood donation service and link them to self-reported history of donation to assess agreement between the two sources. STUDY DESIGN AND METHODS: Between 2004 and 2006, a sample of participants of northern European descent was selected from the Melbourne Collaborative Cohort Study (n = 31,192) to participate in the 'HealthIron' study (n = 1438). A total of 1052 participants completed questionnaires that included questions about blood donation history. In 2009, consenting participants' records were linked to the Australian Red Cross Blood Service (ARCBS) to provide information on blood donations made between 1980 and follow-up (2004-2006). Those who commenced blood donation before 1980 were excluded. RESULTS: A total of 718 participants were available for analysis. Of these, 394 (55%) provided signed consent, including 182 (82%) of the 227 participants who self-reported ever donating blood. The two data sources were concordant for 331 (87%) of participants, with a κ statistic of 0.74 (SE, 0.05) indicating a high level of agreement. Participants tended to overstate by a factor of 2.0 (95% confidence interval, 1.7-2.2) the number of donations they had made when compared with ARCBS records. CONCLUSION: Participants in studies assessing self-reported blood donation history are likely to correctly indicate whether or not they have ever donated blood. Quantitative estimates are potentially inaccurate and could benefit from validating a sample of records to quantify the bias. [ABSTRACT FROM AUTHOR]

Background: We report our experience of selecting tag SNPs in 35 genes involved in iron metabolism in a cohort study seeking to discover genetic modifiers of hereditary hemochromatosis. Methods: We combined our own and publicly available resequencing data with HapMap to maximise our coverage to select 384 SNPs in candidate genes suitable for typing on the Illumina platform. Results: Validation/design scores above 0.6 were not strongly correlated with SNP performance as estimated by Gentrain score. We contrasted results from two tag SNP selection algorithms, LDselect and Tagger. Varying r² from 0.5 to 1.0 produced a near linear correlation with the number of tag SNPs required. We examined the pattern of linkage disequilibrium of three levels of resequencing coverage for the transferrin gene and found HapMap phase 1 tag SNPs capture 45% of the ≥ 3% MAF SNPs found in SeattleSNPs where there is nearly complete resequencing. Resequencing can reveal adjacent SNPs (within 60 bp) which may affect assay performance. We report the number of SNPs present within the region of six of our larger candidate genes, for different versions of stock genotyping assays. Conclusion: A candidate gene approach should seek to maximise coverage, and this can be improved by adding to HapMap data any available sequencing data. Tag SNP software must be fast and flexible to data changes, since tag SNP selection involves iteration as investigators seek to satisfy the competing demands of coverage within and between populations, and typability on the technology platform chosen. [ABSTRACT FROM AUTHOR]

Background: Few cross-sectional studies report iron deficiency (ID) prevalence in women of different race/ethnicity and ages in US or Canada. Materials and methods: We evaluated screening observations on women who participated between 2001–2003 in a cross-sectional, primary care-based sample of adults ages ≥25 y whose observations were complete: race/ethnicity; age; transferrin saturation; serum ferritin; and HFE p.C282Y and p.H63D alleles. We defined ID using a stringent criterion: combined transferrin saturation <10% and serum ferritin <33.7 pmol/L (<15 μg/L). We compared ID prevalence in women of different race/ethnicity subgrouped by age and determined associations of p.C282Y and p.H63D to ID overall, and to ID in women ages 25–44 y with or without self-reported pregnancy. Results: These 62,685 women included 27,079 whites, 17,272 blacks, 8,566 Hispanics, 7,615 Asians, 449 Pacific Islanders, 441 Native Americans, and 1,263 participants of other race/ethnicity. Proportions of women with ID were higher in Hispanics and blacks than whites and Asians. Prevalence of ID was significantly greater in women ages 25–54 y of all race/ethnicity groups than women ages ≥55 y of corresponding race/ethnicity. In women ages ≥55 y, ID prevalence did not differ significantly across race/ethnicity. p.C282Y and p.H63D prevalence did not differ significantly in women with or without ID, regardless of race/ethnicity, age subgroup, or pregnancy. Conclusions: ID prevalence was greater in Hispanic and black than white and Asian women ages 25–54 y. p.C282Y and p.H63D prevalence did not differ significantly in women with or without ID, regardless of race/ethnicity, age subgroup, or pregnancy. [ABSTRACT FROM AUTHOR]

The incidences of both T1D and T2D are increasing in the U.S., and CVD is the leading cause of death among both cohorts. Despite differences in the underlying pathophysiology of T1D and T2D, CVD prevention approaches for T1D have been widely extrapolated from T2D studies. A few prior studies have compared CVD incidence and mortality rates between patients with T1D and T2D; however, a comparison of CVD risk factors between T1D and T2D within the same study cohort, as a measure of differences in progression to CVD events, has not been done. We thus compared CVD risk factors between patients with T1D and T2D, among U.S. adults (≥age 20) with self-reported diabetes from NHANES 1999-2016. First, we classified diabetes cases (n=5347) into T1D (n=230) and T2D (n=4677) using a treatment-based approach we developed, regardless of age at diagnosis (n=440 excluded as unassigned). Next, we compared the demographics, classical CVD risk factors and diabetes-related risk factors by diabetes type using bivariate analysis, and stepwise model selection. The final model comprised race, age, education, diabetes duration, triglycerides, CKD, BMI, and HbA1c [Table]. The similarity between the final model and the bivariate association results, suggests that differences in CVD risk factors between T1D and T2D are mainly due to the underlying pathophysiology and cannot merely be explained by demographic and diabetes-related differences between the two types. Disclosure: M. Mosslemi: None. H.L. Park: None. C.E. McLaren: None. N.D. Wong: Advisory Panel; Self; Novartis Pharmaceuticals Corporation. Consultant; Self; Akcea Therapeutics, AstraZeneca. Research Support; Self; Amarin Corporation, Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc. [ABSTRACT FROM AUTHOR]

Relatively few imaging and sensing technologies are employed to study human lactation physiology. In particular, human mammary development during pregnancy as well as mammary involution after lactation have been poorly described, despite their importance for breast cancer diagnosis and treatment during these phases. Our case study shows the potential of diffuse optical spectroscopic imaging (DOSI) to uniquely study the spatiotemporal changes in mammary tissue composition during the involution of the lactating breast toward its pre-pregnant state. At nine time intervals over a period of eight months after the cessation of breastfeeding, we reconstructed 2-D maps of mammary water content, lipid content, total hemoglobin (THb) concentration, oxygen saturation (StO2), and tissue optical scattering. Mammary lipid content in the nonareolar region showed a significant relative increase of 59%, whereas water content and THb concentration showed a significant relative decrease of 50% and 48%, respectively. Significant changes were also found in StO2 and tissue optical scattering. Our findings are consistent with the gradual replacement of fibroglandular tissue by adipose tissue and vascular regression during mammary involution. Moreover, our data provide unique insight into the dynamics of breast tissue composition and demonstrate the effectiveness of DOSI as a technique to study human lactation physiology. [ABSTRACT FROM AUTHOR]

Objective: To quantitatively measure tissue composition and hemodynamics during resuscitative endovascular balloon occlusion of the aorta (REBOA) in two tissue compartments using non-invasive two-channel broadband diffuse optical spectroscopy (DOS).Methods: Tissue concentrations of oxy- and deoxyhemoglobin (HbO2 and HbR), water, and lipid were measured in a porcine model (n = 10) of massive hemorrhage (65% total blood volume over 1 h) and 30-min REBOA superior and inferior to the aortic balloon.Results: After hemorrhage, hemoglobin oxygen saturation (StO2 = HbO2/[HbO2 + HbR]) at both sites decreased significantly (-29.9% and -42.3%, respectively). The DOS measurements correlated with mean arterial pressure (MAP) (R2 = 0.79, R2 = 0.88), stroke volume (SV) (R2 = 0.68, R2 = 0.88), and heart rate (HR) (R2 = 0.72, R2 = 0.88). During REBOA, inferior StO2 continued to decline while superior StO2 peaked 12 min after REBOA before decreasing again. Inferior DOS parameters did not associate with MAP, SV, or HR during REBOA.Conclusions: Dual-channel regional tissue DOS measurements can be used to non-invasively track the formation of hemodynamically distinct tissue compartments during hemorrhage and REBOA. Conventional systemic measures MAP, HR, and SV are uncorrelated with tissue status in inferior (downstream) sites. Multi-compartment DOS may provide a more complete picture of the efficacy of REBOA and similar resuscitation procedures. [ABSTRACT FROM AUTHOR]

HSV type 1 (HSV-1) is a prevalent human pathogen that infects >3.72 billion individuals worldwide and can cause potentially blinding recurrent corneal herpetic disease. HSV-1 establishes latency within sensory neurons of trigeminal ganglia (TG), and TGresident CD8+ T cells play a critical role in preventing its reactivation. The repertoire, phenotype, and function of protective CD8+ T cells are unknown. Bolstering the apparent feeble numbers of CD8+ T cells in TG remains a challenge for immunotherapeutic strategies. In this study, a comprehensive panel of 467 HLA-A*0201-restricted CD8+ T cell epitopes was predicted from the entire HSV-1 genome. CD8+ T cell responses to these genome-wide epitopes were compared in HSV-1-seropositive symptomatic individuals (with a history of numerous episodes of recurrent herpetic disease) and asymptomatic (ASYMP) individuals (who are infected but never experienced any recurrent herpetic disease). Frequent polyfunctional HSV-specific IFN-γ+CD107a/b+CD44high CD62LlowCD8+ effector memory T cells were detected in ASYMP individuals and were primarily directed against three "ASYMP" epitopes. In contrast, symptomatic individuals have more monofunctional CD44highCD62LhighCD8+ central memory T cells. Furthermore, therapeutic immunization with an innovative prime/pull vaccine, based on priming with multiple ASYMP epitopes (prime) and neurotropic TG delivery of the T cell-attracting chemokine CXCL10 (pull), boosted the number and function of CD44highCD62LlowCD8+ effector memory T cells and CD103highCD8+ tissue-resident T cells in TG of latently infected HLA-A*0201-transgenic mice and reduced recurrent ocular herpes following UV-B-induced reactivation. These findings have profound implications in the development of T cell-based immunotherapeutic strategies to treat blinding recurrent herpes infection and disease. [ABSTRACT FROM AUTHOR]

Background and Aim Women who are homozygous for the p.C282Y mutation in the HFE gene are at much lower risk of iron overload-related disease than p.C282Y homozygous men, presumably because of the iron-depleting effects of menstruation and pregnancy. We used data from a population cohort study to model the impact of menstruation cessation at menopause on serum ferritin (SF) levels in female p.C282Y homozygotes, with p.C282Y/p.H63D simple or compound heterozygotes and those with neither p.C282Y nor p.H63D mutations ( HFE wild types) as comparison groups. Methods A sample of the Melbourne Collaborative Cohort Study was selected for the 'HealthIron' study ( n = 1438) including all HFE p.C282Y homozygotes plus a random sample stratified by HFE-genotype (p.C282Y and p.H63D). The relationship between the natural logarithm of SF and time since menopause was examined using linear mixed models incorporating spline smoothing. Results For p.C282Y homozygotes, SF increased by a factor of 3.6 (95% CI (1.8, 7.0), P < 0.001) during the first 10 years postmenopause, after which SF continued to increase but at less than half the previous rate. In contrast, SF profiles for other HFE genotype groups increase more gradually and did not show a distinction between premenopausal and postmenopausal SF levels. Only p.C282Y homozygotes had predicted SF exceeding 200 μg/L postmenopause, but the projected SF did not increase the risk of iron overload-related disease. Conclusions These data provide the first documented evidence that physiological blood loss is a major factor in determining the marked gender difference in expression of p.C282Y homozygosity. [ABSTRACT FROM AUTHOR]

Background GNPAT p.D519G positivity is significantly increased in HFE p.C282Y homozygotes with markedly increased iron stores. We sought to determine associations of p.D519G and iron-related variables with iron stores in p.C282Y homozygotes. Methods We defined markedly increased iron stores as serum ferritin > 2247 pmol/L (> 1000 μg/L) and either hepatic iron > 236 μmol/g dry weight or iron > 10 g by induction phlebotomy (men and women). We defined normal or mildly elevated iron stores as serum ferritin < 674.1 pmol/L (< 300 μg/L) or either age ≥ 40 y with iron ≤ 2.5 g iron by induction phlebotomy or age ≥ 50 y with ≤ 3.0 g iron by induction phlebotomy (men only). We compared participant subgroups using univariate methods. Using multivariable logistic regression, we evaluated associations of markedly increased iron stores with these variables: age; iron supplement use (dichotomous); whole blood units donated; erythrocyte units received as transfusion; daily alcohol consumption, g; and p.D519G positivity (heterozygosity or homozygosity). Results The mean age of 56 participants (94.6% men) was 55 ± 10 (SD) y; 41 had markedly increased iron stores. Prevalences of swollen/tender 2nd/3rd metacarpophalangeal joints and elevated aspartate or alanine aminotransferase were significantly greater in participants with markedly increased iron stores. Only participants with markedly increased iron stores had cirrhosis. In multivariable analyses, p.D519G positivity was the only exposure variable significantly associated with markedly increased iron stores (odds ratio 9.9, 95% CI [1.6, 60.3], p = 0.0126). Conclusions GNPAT p.D519G is strongly associated with markedly increased iron stores in p.C282Y homozygotes after correction for age, iron-related variables, and alcohol consumption. [ABSTRACT FROM AUTHOR]

Both familial and sporadic porphyria cutanea tarda (PCT) are iron dependent diseases. Symptoms of PCT resolve when iron stores are depleted by phlebotomy, and a sequence variant of HFE (C282Y, c.843G>A, rs1800562) that enhances iron aborption by reducing hepcidin expression is a risk factor for PCT. Recently, a polymorphic variant (D519G, c.1556A>G, rs11558492) of glyceronephosphate O-acyltransferase (GNPAT) was shown to be enriched in male patients with type I hereditary hemochromatosis (HFE C282Y homozygotes) who presented with a high iron phenotype, suggesting that GNPAT D519G, like HFE C282Y, is a modifier of iron homeostasis that favors iron absorption. To challenge this hypothesis, we investigated the frequency of GNPAT D519G in patients with both familial and sporadic PCT. Patients were screened for GNPAT D519G and allelic variants of HFE (both C282Y and H63D). Nucleotide sequencing of uroporphyrinogen decarboxylase (URO-D) identified mutant alleles. Patients with low erythrocyte URO-D activity or a damaging URO-D variant were classified as familial PCT (fPCT) and those with wild-type URO-D were classified as sporadic PCT (sPCT). GNPAT D519G was significantly enriched in the fPCT patient population (p = 0.0014) but not in the sPCT population (p = 0.4477). Both HFE C282Y and H63D (c.187C>G, rs1799945) were enriched in both PCT patient populations (p<0.0001) but showed no greater association with fPCT than with sPCT. Conclusion: GNPAT D519G is a risk factor for fPCT, but not for sPCT. [ABSTRACT FROM AUTHOR]

Young patients with dense breasts have a relatively low-positive biopsy rate for breast cancer (~1 in 7). South Korean women have higher breast density than Westerners. We investigated the benefit of using a functional and metabolic imaging technique, diffuse optical spectroscopic imaging (DOSI), to help the standard of care imaging tools to distinguish benign from malignant lesions in premenopausal Korean women. DOSI uses near-infrared light to measure breast tissue composition by quantifying tissue concentrations of water (ctH2O), bulk lipid (ctLipid), deoxygenated (ctHHb), and oxygenated (ctHbO2) hemoglobin. DOSI spectral signatures specific to abnormal tissue and absent in healthy tissue were also used to form a malignancy index. This study included 19 premenopausal subjects (average age 41±9), corresponding to 11 benign and 10 malignant lesions. Elevated lesion to normal ratio of ctH2O, ctHHb, ctHbO2, total hemoglobin (THb = ctHHb þ ctHbO2), and tissue optical index (ctHHb × ctH2O/ctLipid) were observed in the malignant lesions compared to the benign lesions (p < 0.02). THb and malignancy index were the two best single predictors of malignancy, with >90% sensitivity and specificity. Malignant lesions showed significantly higher metabolism and perfusion than benign lesions. DOSI spectral features showed high discriminatory power for distinguishing malignant and benign lesions in dense breasts of the Korean population. [ABSTRACT FROM AUTHOR]

Purpose: This study investigated the impact of arms/hands and body position on the measurement of breast density using MRI. Methods: Noncontrast-enhanced T 1-weighted images were acquired from 32 healthy women. Each subject received four MR scans using different experimental settings, including a high resolution hands-up, a low resolution hands-up, a high resolution hands-down, and finally, another high resolution hands-up after repositioning. The breast segmentation was performed using a fully automatic chest template-based method. The breast volume (BV), fibroglandular tissue volume (FV), and percent density (PD) measured from the four MR scan settings were analyzed. Results: A high correlation of BV, FV, and PD between any pair of the four MR scans was noted (r > 0.98 for all). Using the generalized estimating equation method, a statistically significant difference in mean BV among four settings was noted (left breast, score test p = 0.0056; right breast, score test p = 0.0016), adjusted for age and body mass index. Despite differences in BV, there were no statistically significant differences in the mean PDs among the four settings (p > 0.10 for left and right breasts). Using Bland-Altman plots, the smallest mean difference/bias and standard deviations for BV, FV, and PD were noted when comparing hands-up high vs low resolution when the breast positions were exactly the same. Conclusions: The authors' study showed that BV, FV, and PD measurements from MRI of different positions were highly correlated. BV may vary with positions but the measured PD did not differ significantly between positions. The study suggested that the percent density analyzed from MRI studies acquired using different arms/hands and body positions from multiple centers can be combined for analysis. [ABSTRACT FROM AUTHOR]

Background and Aim The risk of hemochromatosis-related morbidity for HFE simple heterozygosity for either the C282 Y or H63 D substitutions in the HFE protein was assessed using a prospective community-based cohort study. Methods HFE genotypes were measured for 31 192 persons of northern European descent, aged between 40 and 69 years when recruited to the Melbourne Collaborative Cohort Study, and subjects were followed for an average of 12 years. For a random sample of 1438 participants stratified according to HFE genotype, two sets of biochemical iron indices performed 12 years apart and, at follow-up only, the presence/absence of six disease features associated with hereditary hemochromatosis were obtained. Summary data for 257 (139 female) C282 Y simple heterozygotes and 123 (74 female) H63 D simple heterozygotes were compared with 330 (181 female) controls with neither HFE mutation. Results At baseline, mean transferrin saturation ( TS) (95% confidence interval) and prevalence of TS > 55% were 35.14% (33.25, 37.04) and 3/112 (3%), 33.03% (29.9, 36.15) and 0/39 (0%), and 29.67% (27.93, 31.4) and 3/135 (2%) for C282 Y, H63 D and wild-type male participants, respectively. At follow-up, mean TS levels remained similar to baseline levels for both men and women irrespective of simple heterozygosity for either mutation. No HFE C282 Y or H63 D simple heterozygotes had documented iron overload (based on hepatic iron measures or serum ferritin greater than 1000 mg/ L at baseline with documented therapeutic venesection). Conclusion No documented iron overload was observed for HFE simple heterozygotes for either C282 Y or H63 D, and morbidity for both HFE simple heterozygote groups was similar to that of HFE wild-type participants. [ABSTRACT FROM AUTHOR]

It is difficult to construct a control group for trials of adjuvant therapy (Rx) of prostate cancer after radical prostatectomy (RP) due to ethical issues and patient acceptance. We utilized 8 curve-fitting models to estimate the time to 60%, 65%, … 95% chance of progression free survival (PFS) based on the data derived from Kattan post-RP nomogram. The 8 models were systematically applied to a training set of 153 post-RP cases without adjuvant Rx to develop 8 subsets of cases (reference case sets) whose observed PFS times were most accurately predicted by each model. To prepare a virtual control group for a single-arm adjuvant Rx trial, we first select the optimal model for the trial cases based on the minimum weighted Euclidean distance between the trial case set and the reference case set in terms of clinical features, and then compare the virtual PFS times calculated by the optimum model with the observed PFSs of the trial cases by the logrank test. The method was validated using an independent dataset of 155 post-RP patients without adjuvant Rx. We then applied the method to patients on a Phase II trial of adjuvant chemo-hormonal Rx post RP, which indicated that the adjuvant Rx is highly effective in prolonging PFS after RP in patients at high risk for prostate cancer recurrence. The method can accurately generate control groups for single-arm, post-RP adjuvant Rx trials for prostate cancer, facilitating development of new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Gallbladder cancer is a rare malignancy, which often goes undiagnosed until advanced stages of disease and is associated with poor prognosis. The only potentially curative treatment is surgical resection. This retrospective study aims to investigate the validity of the revised 7th edition American Joint Committee on Cancer staging criteria and determine prognostic factors. Forty-two patients with confirmed gallbladder cancer who underwent attempted curative resection from 1999 to 2012 at the University of California, Irvine Medical Center were reviewed. Survival probability was determined using the Kaplan-Meier method. Ten patients underwent laparos-copy, were deemed unresectable, and no further surgical intervention was performed. R0 surgical resection, which included radical portal lymphadenectomy, liver segment IVb/V resection, with or without bile duct resection, was performed in the remaining 32 patients. N2 nodes were resected if positive on frozen section. Overall survival probability for Stage I to II patients was 100 per cent. Overall survival probability for Stage III patients was 80 per cent (95% confidence interval [CI], 61 to 99%) and 39.3 per cent (95% CI, 28 to 78%) for Stage IV patients. This study demonstrates that 7th edition clinical stage, T stage, and liver involvement are statistically significant predictors of prognosis. These data also demonstrate a benefit to extended resection in patients even with Stage III and IV disease. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to determine locoregional control (LRC), disease-free survival (DFS), and toxicity of high-dose-rate interstitial brachytherapy (HDR-ISBT) in the treatment of locally advanced cervical cancer. Methods and Materials: Between March 1996 and May 2009, 116 patients with cervical cancer were treated. Of these, 106 (91%) patients had advanced disease (International Federation of Gynecology and Obstetrics stage IIB-IVA). Ten patients had stage IB, 48 had stage II, 51 had stage III, and 7 had stage IVA disease. All patients were treated with a combination of external beam radiation therapy (EBRT) to the pelvis (5040 cGy) and 2 applications of HDR-ISBT to a dose of 3600 cGy to the implanted volume. Sixty-one percent of patients also received interstitial hyperthermia, and 94 (81%) patients received chemotherapy. Results: Clinical LRC was achieved in 99 (85.3%) patients. Three-year DFS rates were 59%, 67%, 71%, and 57% for patients with stage IB, II, III, and IVA disease, respectively. The 5-year DFS and overall survival rates for the entire group were 60% and 44%, respectively. Acute and late toxicities were within acceptable limits. Conclusions: Locally advanced cervical cancer patients for whom intracavitary BT is unsuitable can achieve excellent LRC and OS with a combination of EBRT and HDR-ISBT. [Copyright &y& Elsevier]

Angiogenesis, the formation of blood vessels, is necessary for a tumor to grow, but when angiogenesis first appears in the progression of breast ductal carcinomas is unknown. To determine when this occurs, the authors examined microvessel density (MVD) by CD31 and CD105 immunostaining in normal ducts, 32 cases of usual hyperplasia, 19 cases of atypical hyperplasia, and 29 cases of ductal carcinoma in situ (DCIS). Simple hyperplasia had a 22-fold greater MVD than normal ducts (P < .0001). An increase during the progression of ductal changes was highly significant (P < .0001). To determine a possible mechanism, immunohistochemistry for vascular endothelial growth factor (VEGF) was evaluated. VEGF staining intensity of ductal epithelium increased during the progression from normal to hyperplastic to DCIS. This study shows that the first significant increase in angiogenesis occurs very early in the evolution of ductal proliferations as ductal cells become hyperplastic. [ABSTRACT FROM PUBLISHER]

Purpose: The purpose of this study was to evaluate the age- and race-dependence of the breast fibroglandular tissue density based on three-dimensional breast MRI. Methods: The normal breasts of 321 consecutive patients including Caucasians, Asians, and Hispanics were studied. The subjects were separated into three age groups: Younger than 45, between 45 and 55, and older than 55. Computer algorithms based on body landmarks were used to segment the breast, and fuzzy c-means algorithm was used to segment the fibroglandular tissue. Linear regression analysis was applied to compare mean differences among different age groups and race/ethnicity groups. The obtained parameters were not normally distributed, and the transformed data, natural log (ln) for the fibroglandular tissue volume, and the square root for the percent density were used for statistical analysis. Results: On the average, the transformed fibroglandular tissue volume and percent density decreased significantly with age. Racial differences in mean transformed percent density were found among women older than 45, but not among women younger than 45. Mean percent density was higher in Asians compared to Caucasians and Hispanics; the difference remained significant after adjustment for age, but not significant after adjusted for both age and breast volume. There was no significant difference in the density between the Caucasians and the Hispanics. Conclusions: The results analyzed using the MRI-based method show age- and race-dependence, which is consistent with literature using mammography-based methods. [ABSTRACT FROM AUTHOR]

Abstract: We sought to determine if TNF promoter variants could explain iron phenotype heterogeneity in adults with previous HFE genotyping. HEIRS Study participants genotyped for C282Y and H63D were designated as high transferrin saturation (TS) and/or serum ferritin (SF) (high TS/SF), low TS/SF, or controls. We grouped 191 C282Y homozygotes as high TS/SF, low TS/SF, or controls, and 594 other participants by race/ethnicity as high TS/SF or controls. Using denaturing high-performance liquid chromatography (DHPLC), we screened the TNF promoter region in each participant. We performed multiple regression analyses in C282Y homozygotes using age, sex, HEIRS Study Field Center, and positivity for TNF −308G→A and −238G→A to determine if these attributes predicted ln TS or ln SF. DHPLC analyses were successful in 99.3% of 791 participants and detected 9 different variants; TNF −308G→A and −238G→A were the most prevalent. Most subjects positive for variants were heterozygous. The phenotype frequencies of each variant did not differ significantly (p <0.05) across subgroups of C282Y homozygotes, or across white, black, Hispanic, and Asian non-C282Y homozygotes subgrouped as high TS/SF phenotypes and controls. TNF −308G→A positivity was a significant predictor of initial screening ln TS but not ln SF; TNF −238G→A predicted neither ln TS nor ln SF. We conclude that TNF promoter variants have little, if any, effect on initial screening SF values in adults with or without C282Y homozygosity. We cannot exclude a possible association of homozygosity for TNF promoter variants on TS and SF values. [Copyright &y& Elsevier]

The article presents the study which examines the impact of parent behaviors on children's coping and distress when conducting anesthesia induction in the U.S. It cites the anesthetic method wherein the Revised Preoperative Child-Adult Medical Procedure Interaction Scale is used in coding the behavior of anesthesiologist, nurse and parent, and the distress and coping of children. The result shows that behaviors such as empathy and reassurance have been reinterpreted by the anesthesiologists to be related to more distress. On the other hand, specific behaviors like talking about nonmedical topics and using humor have been found to be related to more coping in children who underwent painful medical procedures.

There is emerging evidence that there are genetic modifiers of iron indices for HFE gene mutation carriers at risk of hereditary hemochromatosis. A random sample, stratified by HFE genotype, of 863 from a cohort of 31 192 people of northern European descent provided blood samples for genotyping of 476 single nucleotide polymorphisms (SNPs) in 44 genes involved in iron metabolism. Single SNP association testing, using linear regression models adjusted for sex, menopause and HFE genotype, was conducted for four continuously distributed outcomes: serum ferritin (log transformed), transferrin saturation, serum transferrin, and serum iron. The SNP rs884409 in CYBRD1 is a novel modifier specific to HFE C282Y homozygotes. Median unadjusted serum ferritin concentration decreased from 1194 μg/l ( N = 27) to 387 μg/l ( N = 16) for male C282Y homozygotes and from 357 μg/l ( N = 42) to 69 μg/l ( N = 12) for females, comparing those with no copies to those with one copy of rs884409. Functional testing of this CYBRD1 promoter polymorphism using a heterologous expression assay resulted in a 30% decrease in basal promoter activity relative to the common genotype ( P = 0·004). This putative genetic modifier of iron overload expression accounts for 11% (95% CI 0·4%, 22·6%) of the variance in serum ferritin levels of C282Y homozygotes. [ABSTRACT FROM AUTHOR]

Abstract: Heme carrier protein 1 (HCP1) has been identified as a possible heme carrier by in vitro analysis. To determine the association of mutations within the HCP1 gene with iron phenotypes, we examined the entire coding region of the HCP1 gene in 788 US and Canadian participants selected from the Hemochromatosis and Iron Overload Screening (HEIRS) Study using denaturing high-performance liquid chromatography. We sequenced the exon and flanking intronic regions if variants were detected. We tested 298 non-C282Y homozygotes from four racial/ethnic backgrounds (White, Black, Asian, and Hispanic) selected because they had high serum ferritin (SF) and transferrin saturations (TS). As controls, we chose 300 other random participants of the same racial/ethnic backgrounds from the same geographic locations. From the 333 HEIRS Study C282Y homozygotes, we selected 75 based on high SF and TS, 75 based on low SF and TS; and 75 were selected randomly as controls. Thirty-five of the randomly selected C282Y homozygotes were also included in the high and the low SF and TS groups due to numerical limitations. We identified eight different HCP1 genetic variants; each occurred in a heterozygous state. Except one, each was found in a single HEIRS Study participant. Thus, HCP1 variants are infrequent in the populations that we tested. Five HEIRS Study participants had non-synonymous, coding region HCP1 variants. Each of these five had TS above the 84th gender- and ethnic/racial group-specific percentile (TS percentiles: 84.7, 91.3, 97.9, 99.5, and 99.9). [Copyright &y& Elsevier]

Background: Most persons who are homozygous for C282Y, the HFE allele most commonly asssociated with hereditary hemochromatosis, have elevated levels of serum ferritin and transferrin saturation. Diseases related to iron overload develop in some C282Y homozygotes, but the extent of the risk is controversial. Methods: We assessed HFE mutations in 31,192 persons of northern European descent between the ages of 40 and 69 years who participated in the Melbourne Collaborative Cohort Study and were followed for an average of 12 years. In a random sample of 1438 subjects stratified according to HFE genotype, including all 203 C282Y homozygotes (of whom 108 were women and 95 were men), we obtained clinical and biochemical data, including two sets of iron measurements performed 12 years apart. Disease related to iron overload was defined as documented iron overload and one or more of the following conditions: cirrhosis, liver fibrosis, hepatocellular carcinoma, elevated aminotransferase levels, physician-diagnosed symptomatic hemochromatosis, and arthropathy of the second and third metacarpophalangeal joints. Results: The proportion of C282Y homozygotes with documented iron-overload–related disease was 28.4% (95% confidence interval [CI], 18.8 to 40.2) for men and 1.2% (95% CI, 0.03 to 6.5) for women. Only one non-C282Y homozygote (a compound heterozygote) had documented iron-overload–related disease. Male C282Y homozygotes with a serum ferritin level of 1000 μg per liter or more were more likely to report fatigue, use of arthritis medicine, and a history of liver disease than were men who had the wild-type gene. Conclusions: In persons who are homozygous for the C282Y mutation, iron-overload–related disease developed in a substantial proportion of men but in a small proportion of women. N Engl J Med 2008;358:221-30. [ABSTRACT FROM AUTHOR]

The article presents a study which assesses the extent of insurance and employment problems associated with population screening involving 101,168 primary care patients from the U.S. and Canada for iron phenotypes and hemochromatosis gene (HFE) genotypes associates with hemochromatosis. A clinical examination was offered to 2,253 participants who were identified to be at risk, while 1,154 of these participants who responded to initial questionnaire concerning psychosocial issues were surveyed after one year. From these 1,154 participants, only 0.4% had verified problems with insurance or employment that they think were related to hereditary hemochromatosis and iron overload.

Abstract: The ferroportin (FPN1) Q248H polymorphism has been associated with increased serum ferritin (SF) levels in sub-Saharan Africans and in African Americans (AA). AA participants of the HEIRS Study who did not have HFE C282Y or H63D who had elevated initial screening SF (≥300 μg/L in men and ≥200 μg/L in women) (defined as cases) were frequency-matched to AA participants with normal SF (defined as controls) to investigate the association of the Q248H with elevated SF. 10.4% of cases and 6.7% of controls were Q248H heterozygotes (P =0.257). Q248H homozygosity was observed in 0.5% of the cases and none of the controls. The frequency of Q248H was higher among men with elevated SF than among control men (P =0.047); corresponding differences were not observed among women. This appeared to be unrelated to self-reports of a previous diagnosis of liver disease. Men with elevated SF were three times more likely than women with elevated SF to have Q248H (P =0.012). There were no significant differences in Q248H frequencies in men and women control participants. We conclude that the frequency of the FPN1 Q248H polymorphism is greater in AA men with elevated SF than in those with normal SF. [Copyright &y& Elsevier]

Background: and Methods We tested the usefulness of measuring the hepatic iron concentration to evaluate total body iron stores in patients who had been cured of thalassemia major by bone marrow transplantation and who were undergoing phlebotomy treatment to remove excess iron. Results: We began treatment with phlebotomy a mean (±SD) of 4.3±2.7 years after transplantation in 48 patients without hepatic cirrhosis. In the group of 25 patients with liver-biopsy samples that were at least 1.0 mg in dry weight, there was a significant correlation between the decrease in the hepatic iron concentration and total body iron stores (r=0.98, P<0.001). Assuming that the hepatic iron concentration is reduced to zero with complete removal of body iron stores during phlebotomy, the amount of total body iron stores (in milligrams per kilogram of body weight) is equivalent to 10.6 times the hepatic iron concentration (in milligrams per gram of liver, dry weight). With the use of this equation, we could reliably estimate total body iron stores as high as 250 mg per kilogram of body weight, with a standard error of less than 7.9. Conclusions: The hepatic iron concentration is a reliable indicator of total body iron stores in patients with thalassemia major. In patients with transfusion-related iron overload, repeated determinations of the hepatic iron concentration can provide a quantitative means of measuring the long-term iron balance. (N Engl J Med 2000;343:327-31.) [ABSTRACT FROM AUTHOR]

Exposure to particulate matter (PM) air pollution has been shown to exacerbate children's asthma, but the exposure sources and temporal characteristics are still under study. Children's exposure to PM is likely to involve both combustion-related ambient PM and PM related to a child's activity in various indoor and outdoor microenvironments. Among 19 children with asthma, 9–17 years of age, we examined the relationship of temporal changes in percent predicted forced expiratory volume in 1 sec (FEV1) to personal continuous PM exposure and to 24-hr average gravimetric PM mass measured at home and central sites. Subjects were followed for 2 weeks during either the fall of 1999 or the spring of 2000, in a southern California region affected by transported air pollution. FEV1 was measured by subjects in the morning, afternoon, and evening. Exposure measurements included continuous PM using a passive nephelometer carried by subjects; indoor, outdoor home, and central-site 24-hr gravimetric PM2.5 (PM of aerodynamic diameter < 2.5 pm) and PM10; and central-site hourly PM10, nitrogen dioxide, and ozone. Data were analyzed with linear mixed models controlling for within-subject autocorrelation, FEV1 maneuver time, and exposure period. We found inverse associations of FEV1 with increasing PM exposure during the 24 hr before the FEV1 maneuver and with increasing multiday PM averages. Deficits in percent predicted FEV1 (95% confidence interval) for given PM interquartile ranges measured during the preceding 2g-hr were as follows: 128 μg/m3 1-hr maximum personal PM, -6.0% (-10.5 to -1.4); 30 μg/m3 24-hr average personal PM, -5.9% (-10.8 to -1.0); 6.7 μg/m3 indoor home PM2.5, -1.6% (-2.8 to -0.4); 16 μg/m3 indoor home PM10, -2.1% (-3.7 to -0.g); 7.1 μg/m3 outdoor home PM2.5, -1.1% (-2.4 to 0.1); and 7.5 μg/m3 central-site PM2.5, -0.7% (-1.9 to 0.4). Stronger associations were found for multiday moving averages of PM for both personal and stationary-site PM. Stronger associations with personal PM were found in boys allergic to indoor allergens. FEV1 was weakly associated with NO2 but not with O3. Results suggest mixed respiratory effects of PM in asthmatic children from both ambient background exposures and personal exposures in various microenvironments. [ABSTRACT FROM AUTHOR]

Objective. The initial clinical response to platinum is a major determinant of outcome for patients with ovarian cancer. This retrospective study was undertaken to correlate the response and survival of newly diagnosed advanced ovarian cancer patients who received platinum-based therapy with in vitro drug response to cisplatin or carboplatin measured as percentage cell inhibition (PCI) in the in vitro Extreme Drug Resistance (EDR) assay.Methods. Outcomes for newly diagnosed ovarian cancer patients with tumor specimens submitted in a serial fashion for the EDR assay were studied. EDR assay results for cisplatin and carboplatin were correlated with clinical outcome for 79 evaluable chemotherapy naı¨ve cases who presented with advanced (stages IIC, III, and IV) ovarian cancer. Stage IV and suboptimally debulked stage IIIc accounted for 16 cases, while 63 cases were optimally debulked Stage III/IIc. All patients were treated with platinum-based combination chemotherapy at a single institution. In vitro results for patient tumors were classified as low drug resistance (PCI > median), intermediate drug resistance [PCI between the median and 1 standard deviation (SD) below the median], or extreme drug resistance (PCI more than 1 SD below the median). For the purpose of this analysis, in vitro EDR to either cisplatin or carboplatin was considered to represent extreme resistance to platinum (EDRP), while the absence of EDR to either cisplatin or carboplatin was considered to represent low resistance to platinum (LDRP). Patients demonstrating relative in vitro resistance to paclitaxel and non-cross-resistance to cyclophosphamide and/or doxorubicin received cyclophosphamide plus platinum (CP); cyclophosphamide, doxorubicin, and platinum (CAP); or platinum alone in place of paclitaxel plus platinum (TP). Progression-free survival (PFS) and overall survival (OS) were correlated with EDR assay results.Results. Median PFS was 6 months for the 17 cases exhibiting EDRP, compared to 24 months for the 62 cases exhibiting LDRP in vitro [relative risk (RR) 3.78, confidence intervals (CI) 1.82–7.83], adjusted for stage, debulking status, in vitro response to 3-OH-cyclophosphamide, and histological grade. Estimated overall 5-year survival was 19% for patients with tumors showing EDRP, compared to 68% for patients with tumors showing LDRP (RR 2.32, CI 1.06–5.07). Patients treated with CP (n = 20) showed no significant difference in OS compared to patients treated with TP (n = 54), CAP (n = 4), or cisplatin (n = 1) alone. In vitro platinum response remained an independent predictor of PFS and OS in multivariate analyses adjusted for CP versus TP, CAP, or platinum administration, and adjusted for debulking status. Median PFS for all 79 patients was 22 months, with an estimated 5-year survival of 57%.Conclusions. Patients with tumors demonstrating in vitro EDR to platinum were at significantly increased risk for progression and death when treated with standard platinum-based regimens. Such patients may therefore benefit from entry onto trials with novel agents or combinations. [Copyright &y& Elsevier]

Examines strengths of pollutant associations with asthma symptoms between subgroups of asthmatic children who were on versus not on regularly scheduled anti-inflammatory medications. Strength of pollutant associations during respiratory infections in subjects not on anti- inflammatory medications; Divergence of exposure-response relationships by anti-inflammatory medication use.

Background: Deferiprone is an orally active iron-chelation agent that is being evaluated as a treatment for iron overload in thalassemia major. Studies in an animal model showed that prolonged treatment is associated with a decline in the effectiveness of deferiprone and exacerbation of hepatic fibrosis. Methods: Hepatic iron stores were determined yearly by chemical analysis of liver-biopsy specimens, magnetic susceptometry, or both. Three hepatopathologists who were unaware of the patients' clinical status, the time at which the specimens were obtained, and the iron content of the specimens examined 72 biopsy specimens from 19 patients treated with deferiprone for more than one year. For comparison, 48 liver-biopsy specimens obtained from 20 patients treated with parenteral deferoxamine for more than one year were similarly reviewed. Results: Of the 19 patients treated with deferiprone, 18 had received the drug continuously for a mean (±SE) of 4.6±0.3 years. At the final analysis, 7 of the 18 had hepatic iron concentrations of at least 80 μmol per gram of liver, wet weight (the value above which there is an increased risk of cardiac disease and early death in patients with thalassemia major). Of 19 patients in whom multiple biopsies were performed over a period of more than one year, 14 could be evaluated for progression of hepatic fibrosis; of the 20 deferoxamine-treated patients, 12 could be evaluated for progression. Five deferiprone-treated patients had progression of fibrosis, as compared with none of those given deferoxamine (P=0.04). By the life-table method, we estimated that the median time to progression of fibrosis was 3.2 years in deferiprone-treated patients. After adjustment for the initial hepatic iron concentration, the estimated odds of progression of fibrosis increased by a factor of 5.8 (95 percent confidence interval, 1.1 to 29.6) with each additional year of deferiprone treatment. Conclusions: Deferiprone does not adequately control body iron burden in patients with thalassemia and may worsen hepatic fibrosis. (N Engl J Med 1998;339:417-23.) [ABSTRACT FROM AUTHOR]

Glyceronephosphate O-acyltransferase (GNPAT) p.D519G (rs11558492) was identified as a genetic modifier correlated with more severe iron overload in hemochromatosis through whole-exome sequencing of HFE p.C282Y homozygotes with extreme iron phenotypes. We studied the prevalence of p.D519G in HFE p.C282Y/p.H63D compound heterozygotes, a genotype associated with iron overload in some patients. Cases were Australian participants with elevated serum ferritin (SF) levels ≥300μg/L (males) and ≥200μg/L (females); subjects whose SF levels were below these cut-offs were designated as controls. Samples were genotyped for GNPAT p.D519G. We compared the allele frequency of the present subjects, with/without elevated SF, to p.D519G frequency in public datasets. GNPAT p.D519G was more prevalent in our cohort of p.C282Y/p.H63D compound heterozygotes with elevated SF (37%) than European public datasets: 1000G 21%, gnomAD 20% and ESP 21%. We conclude that GNPAT p.D519G is associated with elevated SF in Australian HFE p.C282Y/p.H63D compound heterozygotes. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: We sought to determine the prevalence of elevated measures of iron status in African Americans and whether the combination of serum ferritin concentration >200 μg/L for women or >300 μg/L for men and transferrin saturation in the highest quartile represents increased likelihood of mutation of HFE, self-reported iron overload or self-reported liver disease. Subjects and Methods: A cross-sectional observational study of 27,224 African Americans ≥25 years of age recruited in a primary care setting was conducted as part of the multi-center, multi-ethnic Hemochromatosis and Iron Overload Screening (HEIRS) Study. Measurements included serum ferritin concentration, transferrin saturation, testing for HFE C282Y and H63D, and self-reported iron overload and liver disease. Results: Serum ferritin concentration >200 μg/L for women or >300 μg/L for men occurred in 5263 (19.3%) of African Americans, while serum ferritin concentration in this range with highest-quartile transferrin saturation (>29% women; >35% men) occurred in 1837 (6.7%). Adjusted odds of HFE mutation (1.76 women, 1.67 men), self-reported iron overload (1.97 women, 2.88 men), or self-reported liver disease (5.18 women, 3.73 men) were greater with elevated serum ferritin concentration and highest-quartile transferrin saturation than with nonelevated serum ferritin concentration (each P <.05). Conclusions: Serum ferritin concentration >200 μg/L for women or >300 μg/L for men in combination with transferrin saturation >29% for women or >35% for men occurs in approximately 7% of adult African American primary care patients. Patients with this combination of iron test results should be evaluated for increased body iron stores or liver disease. [Copyright &y& Elsevier]

Background: Iron overload and hemochromatosis are common, treatable conditions. HFE genotypes, levels of serum ferritin, transferrin saturation values, and self-reported medical history were studied in a multiethnic primary care population. Methods: Participants were recruited from primary care practices and blood-drawing laboratories. Blood samples were tested for transferrin saturation, serum ferritin, and C282Y and H63D mutations of the HFE gene. Before genetic screening, participants were asked whether they had a history of medical conditions related to iron overload. Results: Of the 99,711 participants, 299 were homozygous for the C282Y mutation. The estimated prevalence of C282Y homozygotes was higher in non-Hispanic whites (0.44 percent) than in Native Americans (0.11 percent), Hispanics (0.027 percent), blacks (0.014 percent), Pacific Islanders (0.012 percent), or Asians (0.000039 percent). Among participants who were homozygous for the C282Y mutation but in whom iron overload had not been diagnosed (227 participants), serum ferritin levels were greater than 300 μg per liter in 78 of 89 men (88 percent) and greater than 200 μg per liter in 79 of 138 women (57 percent). Pacific Islanders and Asians had the highest geometric mean levels of serum ferritin and mean transferrin saturation despite having the lowest prevalence of C282Y homozygotes. There were 364 participants in whom iron overload had not been diagnosed (29 C282Y homozygotes) who had a serum ferritin level greater than 1000 μg per liter. Among men, C282Y homozygotes and compound heterozygotes were more likely to report a history of liver disease than were participants without HFE mutations. Conclusions: The C282Y mutation is most common in whites, and most C282Y homozygotes have elevations in serum ferritin levels and transferrin saturation. The C282Y mutation does not account for high mean serum ferritin levels and transferrin saturation values in nonwhites. N Engl J Med 2005;352:1769-78. [ABSTRACT FROM AUTHOR]

Background: To determine whether deferoxamine prevents the complications of transfusional iron overload in thalassemia major, we evaluated 59 patients (30 were female and 29 male; age range, 7 to 31 years) periodically for 4 to 10 years or until death. Methods: At each follow-up visit, we performed a detailed clinical and laboratory evaluation and measured hepatic iron stores with a noninvasive magnetic device. Results: The body iron burden as assessed by magnetic measurement of hepatic iron stores was closely correlated (R = 0.89, P<0.001) with the ratio of cumulative transfusional iron load to cumulative deferoxamine use (expressed in millimoles of iron per kilogram of body weight, in relation to grams of deferoxamine per kilogram, transformed into the natural logarithm). Each increase of one unit in the natural logarithm of the ratio (transfusional iron load to deferoxamine use) was associated with an increased risk of impaired glucose tolerance (relative risk, 19.3; 95 percent confidence interval, 4.8 to 77.4), diabetes mellitus (relative risk, 9.2; 95 percent confidence interval, 1.8 to 47.7), cardiac disease (relative risk, 9.9; 95 percent confidence interval, 1.9 to 51.2), and death (relative risk, 12.6; 95 percent confidence interval, 2.4 to 65.4). All nine deaths during the study occurred among the 23 patients who had begun chelation therapy later and used less deferoxamine in relation to their transfusional iron load (P<0.001). Conclusions: The early use of deferoxamine in an amount proportional to the transfusional iron load reduces the body iron burden and helps protect against diabetes mellitus, cardiac disease, and early death in patients with thalassemia major. (N Engl J Med 1994;331:567-73.) [ABSTRACT FROM AUTHOR]