Linda Levin

Relation of DNA Methylation of 5′-CpG Island of ACSL3 to Transplacental Exposure to Airborne Polycyclic Aromatic Hydrocarbons and Childhood Asthma

In a longitudinal cohort of ∼700 children in New York City, the prevalence of asthma (>25%) is among the highest in the US. This high risk may in part be caused by transplacental exposure to traffic-related polycyclic aromatic hydrocarbons (PAHs) but biomarkers informative of PAH-asthma relationships is lacking. We here hypothesized that epigenetic marks associated with transplacental PAH exposure and/or childhood asthma risk could be identified in fetal tissues. Mothers completed personal prenatal air monitoring for PAH exposure determination. Methylation sensitive restriction fingerprinting was used to analyze umbilical cord white blood cell (UCWBC) DNA of 20 cohort children. Over 30 DNA sequences were identified whose methylation status was dependent on the level of maternal PAH exposure. Six sequences were found to be homologous to known genes having one or more 5′-CpG island(s) (5′-CGI). Of these, acyl-CoA synthetase long-chain family member 3 (ACSL3) exhibited the highest concordance between the extent of methylation of its 5′-CGI in UCWBCs and the level of gene expression in matched fetal placental tissues in the initial 20 cohort children. ACSL3 was therefore chosen for further investigation in a larger sample of 56 cohort children. Methylation of the ACSL3 5′-CGI was found to be significantly associated with maternal airborne PAH exposure exceeding 2.41 ng/m3 (OR = 13.8; p<0.001; sensitivity = 75%; specificity = 82%) and with a parental report of asthma symptoms in children prior to age 5 (OR = 3.9; p<0.05). Thus, if validated, methylated ACSL3 5′CGI in UCWBC DNA may be a surrogate endpoint for transplacental PAH exposure and/or a potential biomarker for environmentally-related asthma. This exploratory report provides a new blueprint for the discovery of epigenetic biomarkers relevant to other exposure assessments and/or investigations of exposure-disease relationships in birth cohorts. The results support the emerging theory of early origins of later life disease development.

Evolution of the mdx mouse cardiomyopathy: physiological and morphological findings

Heart failure is a major cause of death in boys with Duchenne muscular dystrophy. In order to determine if the cardiac function of the mdx mouse is similarly disturbed, we performed murine echocardiograms and left heart catheterization studies, along with morphometric analysis of cardiac fibrosis. Serial echocardiograms in mdx mice revealed the evolution from normal cardiac function in young mice to a dilated cardiomyopathy in adult mice. Very old mdx mice exhibited a widespread but patchy increase in ventricular wall fibrosis. These results show that the mdx cardiac function is more impaired than was previously thought and shares important clinical features with the cardiomyopathy of Duchenne muscular dystrophy.

IRRADIATED VOLUME AS A PREDICTOR OF BRAIN RADIONECROSIS AFTER LINEAR ACCELERATOR STEREOTACTIC RADIOSURGERY

PURPOSE To investigate the correlation between volume of brain irradiated by stereotactic radiosurgery (SRS) and the incidence of symptomatic and asymptomatic brain radionecrosis (RN). METHODS AND MATERIALS A retrospective analysis was performed of patients treated with single-fraction SRS for brain metastases at our institution. Patients with at least 6-month imaging follow-up were included and diagnosed with RN according to a combination of criteria, including appearance on serial imaging and histology. Univariate and multivariate analyses were performed to determine the predictive value of multiple variables, including volume of brain receiving a specific dose (V8 Gy-V18 Gy). RESULTS Sixty-three patients were reviewed, with a total of 173 lesions. Most patients (63%) had received previous whole-brain irradiation. Mean prescribed SRS dose was 18 Gy. Symptomatic RN was observed in 10% and asymptomatic RN in 4% of lesions treated. Multivariate regression analysis showed V8 Gy-V16 Gy to be most predictive of symptomatic RN (p < 0.0001). Threshold volumes for significant rise in RN rates occurred between the 75th and 90th percentiles, with a midpoint volume of 10.45 cm(3) for V10 Gy and 7.85 cm(3) for V12 Gy. CONCLUSIONS Analysis of patient and treatment variables revealed V8 Gy-V16 Gy to be the best predictors for RN using linear accelerator-based single-fraction SRS for brain metastases. We propose that patients with V10 Gy >10.5 cm(3) or V12 Gy >7.9 cm(3) be considered for hypofractionated rather than single-fraction treatment, to minimize the risk of symptomatic RN.

The Efficacy of a Clinic-Based Behavioral Nutrition Intervention Emphasizing a DASH-Type Diet for Adolescents with Elevated Blood Pressure

OBJECTIVE To examine the efficacy of a 3-month clinic-based behavioral nutrition intervention emphasizing a diet high in fruits, vegetables, and low fat dairy (DASH intervention) versus routine outpatient hospital-based nutrition care (RC) on diet and blood pressure (BP) in adolescents with elevated BP. STUDY DESIGN Fifty-seven adolescents with a clinical diagnosis of prehypertension or hypertension (systolic BP or diastolic BP, 90(th) to 99(th) percentile) were randomly assigned to DASH or RC. SBP, DBP, 3-day diet recall, weight, and height were assessed at pretreatment, post-treatment, and 3 months later (follow-up). RESULTS In completer analysis, DASH versus RC had a greater decrease in SBP z scores from baseline to post-treatment (P < 0.01) and a trend for a greater decrease in SBP z scores from baseline through follow-up (P = .07). DBP z scores changed similarly for conditions from baseline through follow-up. Relative to RC, DASH had a greater increase in intake of fruits (P < .001), potassium and magnesium (P < .01), and a greater decrease in total fat (P < .05) from baseline to post-treatment. From baseline through follow-up, DASH versus RC had a greater increase in low fat dairy (P < .001). CONCLUSIONS The DASH intervention proved more effective than RC in improving SBP and diet quality in adolescents with elevated BP.

A Comparison of Proximity and Land Use Regression Traffic Exposure Models and Wheezing in Infants

Background We previously reported an association between infant wheezing and residence < 100 m from stop-and-go bus and truck traffic. The use of a proximity model, however, may lead to exposure misclassification. Objective Results obtained from a land use regression (LUR) model of exposure to truck and bus traffic are compared with those obtained with a proximity model. The estimates derived from the LUR model were then related to infant wheezing. Methods We derived a marker of diesel combustion—elemental carbon attributable to traffic sources (ECAT)—from ambient monitoring results of particulate matter with aerodynamic diameter < 2.5 μm. We developed a multiple regression model with ECAT as the outcome variable. Variables included in the model were locations of major roads, bus routes, truck traffic count, and elevation. Model parameter estimates were applied to estimate individual ECAT levels at infants’ homes. Results The levels of estimated ECAT at the monitoring stations ranged from 0.20 to 1.02 μg/m3. A LUR model of exposure with a coefficient of determination (R2) of 0.75 was applied to infants’ homes. The mean (± SD) ambient exposure of ECAT for infants previously categorized as unexposed, exposed to stop-and-go traffic, or exposed to moving traffic was 0.32 ± 0.06, 0.42 ± 0.14, and 0.49 ± 0.14 μg/m3, respectively. Levels of ECAT from 0.30 to 0.90 μg/m3 were significantly associated with infant wheezing. Conclusions The LUR model resulted in a range of ECAT individually derived for all infants’ homes that may reduce the exposure misclassification that can arise from a proximity model.

High environmental relative moldiness index during infancy as a predictor of asthma at 7 years of age

BACKGROUND Mold exposures may contribute to the development of asthma, but previous studies have lacked a standardized approach to quantifying exposures. OBJECTIVE To determine whether mold exposures at the ages of 1 and/or 7 years were associated with asthma at the age of 7 years. METHODS This study followed up a high-risk birth cohort from infancy to 7 years of age. Mold was assessed by a DNA-based analysis for the 36 molds that make up the Environmental Relative Moldiness Index (ERMI) at the ages of 1 and 7 years. At the age of 7 years, children were evaluated for allergic sensitization and asthma based on symptom history, spirometry, exhaled nitric oxide, and airway reversibility. A questionnaire was administered to the parent regarding the childs asthma symptoms and other potential cofactors. RESULTS At the age of 7 years, 31 of 176 children (18%) were found to be asthmatic. Children living in a high ERMI value (≥5.2) home at 1 year of age had more than twice the risk of developing asthma than those in low ERMI value homes (<5.2) (adjusted odds ratio [aOR], 2.6; 95% confidence interval [CI], 1.10-6.26). Of the other covariates, only parental asthma (aOR, 4.0; 95% CI, 1.69-9.62) and allergic sensitization to house dust mite (aOR, 4.1; 95% CI, 1.55-11.07) were risk factors for asthma development. In contrast, air-conditioning at home reduced the risk of asthma development (aOR, 0.3; 95% CI, 0.14-0.83). A high ERMI value at 7 years of age was not associated with asthma at 7 years of age. CONCLUSIONS Early exposure to molds as measured by ERMI at 1 year of age, but not 7 years of age, significantly increased the risk for asthma at 7 years of age.

House dust (1-3)-β-D-glucan and wheezing in infants

Background:  (1–3)‐β‐d‐glucan is a fungal cell wall component, suspected to cause respiratory symptoms in adults. However, very little is known on the possible health effects of (1–3)‐β‐d‐glucan during infancy. We examined the association between (1–3)‐β‐d‐glucan exposure and the prevalence of allergen sensitization and wheezing during the first year of life in a birth cohort of 574 infants born to atopic parents. Endotoxin exposure was included as a possible confounder.

Exposure to Traffic-related Particles and Endotoxin during Infancy Is Associated with Wheezing at Age 3 Years

RATIONALE Murine models demonstrate a synergistic production of reactive oxygen species on coexposure to diesel exhaust particles and endotoxin. OBJECTIVES It was hypothesized that coexposure to traffic-related particles and endotoxin would have an additive effect on persistent wheezing during early childhood. METHODS Persistent wheezing at age 36 months was assessed in the Cincinnati Childhood Allergy and Air Pollution Study, a high-risk birth cohort. A time-weighted average exposure to traffic-related particles was determined by applying a land-use regression model to the homes, day cares, and other locations where children spent time from birth through age 36 months. Indoor levels of endotoxin were measured from dust samples collected before age 12 months. The relationship between dichotomized (or=75th percentile) traffic-related particle and endotoxin exposure and persistent wheezing, controlling for potential covariates, was examined. MEASUREMENTS AND MAIN RESULTS Persistent wheezing at age 36 months was significantly associated with exposure to increased levels of traffic-related particles before age 12 months (OR = 1.75; 95% confidence interval, 1.07-2.87). Coexposure to endotoxin had a synergistic effect with traffic exposure on persistent wheeze (OR = 5.85; 95% confidence interval, 1.89-18.13) after adjustment for significant covariates. CONCLUSIONS The association between traffic-related particle exposure and persistent wheezing at age 36 months is modified by exposure to endotoxin. This finding supports prior toxicological studies demonstrating a synergistic production of reactive oxygen species after coexposure to diesel exhaust particles and endotoxin. The effect of early versus later exposure to traffic-related particles, however, remains to be studied because of the high correlation between exposure throughout the first 3 years of life.

Estrogen receptor β2 and β5 are associated with poor prognosis in prostate cancer, and promote cancer cell migration and invasion

Estrogens play a pivotal role in the development and progression of prostate cancer (PCa). Their actions are mediated by estrogen receptors (ERs), particularly ERβ in the prostate epithelium. With the discovery of ERβ isoforms, data from previous studies that focused principally on the wild-type ERβ (ERβ1) may not be adequate in explaining the still controversial role of ERβ(s) in prostate carcinogenesis. In this study, using newly generated isoform-specific antibodies, immunohistochemistry (IHC) was performed on a tumor microarray comprised of 144 specimens. IHC results were correlated with pathological and clinical follow-up data to delineate the distinct roles of ERβ1, ERβ2, and ERβ5 in PCa. ERβ2 was commonly found in the cytoplasm and was the most abundant isoform followed by ERβ1 localized predominantly in the nucleus, and ERβ5 was primarily located in the cytoplasm. Logistic regression analyses demonstrated that nuclear ERβ2 (nERβ2) is an independent prognostic marker for prostate specific antigen (PSA) failure and postoperative metastasis (POM). In a Kaplan–Meier analysis, the combined expression of both nERβ2 and cytoplasmic ERβ5 identified a group of patients with the shortest POM-free survival. Cox proportional hazard models revealed that nERβ2 predicted shorter time to POM. In concordance with IHC data, stable, ectopic expression of ERβ2 or ERβ5 enhanced PCa cell invasiveness but only PCa cells expressing ERβ5 exhibited augmented cell migration. This is the first study to uncover a metastasis-promoting role of ERβ2 and ERβ5 in PCa, and show that the two isoforms, singularly and conjointly, have prognostic values for PCa progression. These findings may aid future clinical management of PCa.

Spinal deformity: a new classification derived from neutral upright spinal alignment measurements in asymptomatic juvenile, adolescent, adult, and geriatric individuals.

OBJECTIVE: To evaluate the role of stereotactic radiosurgery (SRS) in the management of recurrent or residual intracranial hemangioblastomas, we assessed tumor control, survival, and complications in 32 consecutive patients. METHODS: We retrospectively reviewed records of 32 consecutive hemangioblastoma patients (74 intracranial tumors) who underwent gamma knife SRS. The median patient age was 43.8 years (range, 21.3-79.4 yr). Thirty-one patients had undergone previous surgical resections. Nineteen patients had sporadic lesions (22 tumors), and 13 patients had von Hippel-Lindau disease-associated hemangioblastomas (52 tumors). The median SRS target volume was 0.72 mL (range, 0.08-16.6 mL), and the median marginal dose was 16.0 Gy (range, 11-20 Gy). RESULTS: At a median of 50.1 months (range, 6.0-165.4 mo), seven patients had died from disease progression, and one patient had died secondary to heart failure. The overall survival after radiosurgery was 100%, 94.4%, and 68.7% at 1, 3, and 7 years, respectively. Follow-up imaging studies demonstrated tumor control in 68 tumors (91.9%). The progression-free survival after SRS at 1, 3, and 5 years was 96.9%, 95.0%, and 89.9%, respectively. Factors associated with an improved progression-free survival included von Hippel-Lindau disease-associated hemangioblastoma, solid tumor, lower tumor volume, and greater marginal dose. CONCLUSION: SRS is an important tool in the management of hemangioblastomas and is associated with a high tumor control rate and a low risk of adverse radiation effects.OBJECTIVEIn this literature review, the authors analyze data from previously published studies that evaluated neutral upright spinal alignment (NUSA) from the occiput to the pelvis in asymptomatic individuals. Based on the data for NUSA in asymptomatic volunteers, a new classification is proposed for spinal deformity. METHODSA review of the English literature was conducted to identify studies evaluating NUSA from the occiput to the pelvis in asymptomatic juvenile, adolescent, adult, and geriatric volunteers. From the literature review, 17 angles and displacements were selected to depict neutral upright coronal and axial spinal alignment, and 21 angles and displacements were selected to depict neutral upright sagittal spinal alignment. Pooled estimates of the mean and variance were calculated for the angles and displacements from the articles that met inclusion criteria. A new classification of spinal deformity was then developed based on age-dependent NUSA; spinal abnormality; deformity curve location, pattern, magnitude, and flexibility; and global spinal alignment. RESULTSDespite a wide variation in the regional curves from the occiput to the pelvis in asymptomatic volunteers, global spinal alignment is maintained in a narrow range for preservation of horizontal gaze and balance of the spine over the pelvis and femoral heads. CONCLUSIONA new classification of spinal deformity is proposed that provides a structure for defining deformity of all patient ages and spinal abnormalities.