Phthalate exposure and pubertal development in a longitudinal study of US girls.

STUDY QUESTION: Does phthalate exposure during early childhood alter the timing of pubertal development in girls? SUMMARY ANSWER: Urinary concentrations of high-molecular weight phthalate (high-MWP) metabolites are associated with later pubarche. WHAT IS KNOWN ALREADY: Phthalates are anti-androgenic environmental agents known to alter early development, with possible effects on pubertal onset. STUDY DESIGN, SIZE, AND DURATION: This multi-ethnic study included 1239 girls from New York City, greater Cincinnati, and the San Francisco Bay Area who were 6-8 years old at enrollment (2004-2007) and who were followed until 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS Phthalate metabolites were measured in urine collected at enrollment from 1170 girls; concentrations ranged from <1 to >10,000 µg/l. Breast and pubic hair stages and body size were assessed one to two times annually to determine the age at transition from stage 1 to 2 for breast and pubic hair development. Associations between exposures and pubertal ages were estimated using Cox proportional hazard ratios (HR) with 95% confidence intervals (CI) and survival analyses. Associations were examined with respect to age-specific body mass-index percentile, one of the strongest predictors of pubertal onset. MAIN RESULTS AND THE ROLE OF CHANCE: Urinary concentrations of high-MWP including di(2-ethylhexyl) phthalate (ΣDEHP) metabolites were associated with later pubic hair development during 7 years of observation. The relationship was linear and was stronger among normal-weight girls. Among normal-weight girls, age at pubic hair stage 2 (PH2) was 9.5 months older for girls in the fifth compared with the first quintile of urinary ΣDEHP (medians: 510 and 59 µg/g creatinine, respectively; adjusted HR 0.70, CI 0.53-0.93, P-trend 0.005. Age at first breast development was older for fifth quintile of mono-benzyl phthalate versus first (HR 0.83, CI 0.68-1.02; P-trend 0.018). No associations were observed between low-molecular weight phthalate urinary metabolite concentrations and age at pubertal transition in adjusted analyses. LIMITATIONS, REASONS FOR CAUTION: While there is evidence that phthalate exposures are fairly consistent over time, the exposure measure in this study may not reflect an earlier, more susceptible window of exposure. We investigated alternative explanations that might arise from exposure misclassification or confounding. WIDER IMPLICATIONS OF THE FINDINGS: Phthalates are widespread, hormonally active pollutants that may alter pubertal timing. Whether exposures delay or accelerate pubertal development may depend on age at exposure as well as other factors such as obesity and exposures earlier in life. Whether exposures act independently or as part of real life mixtures may also change their effects on maturation from birth through childhood. STUDY FUNDING/COMPETING INTEREST(S): This project was supported by the US National Institutes of Health, Environmental Protection Agency, New York State Empire Clinical Research Investigator Program and the Avon Foundation. L.H.K. is employed by Kaiser Permanente. The remaining authors declare they have no actual or potential competing financial interests.

Donor-derived Trypanosoma cruzi infection in solid organ recipients in the United States, 2001-2011.

Although Trypanosoma cruzi, the parasite that causes Chagas disease, can be transmitted via organ transplantation, liver and kidney transplantation from infected donors may be feasible. We describe the outcomes of 32 transplant recipients who received organs from 14 T. cruzi seropositive donors in the United States from 2001 to 2011. Transmission was confirmed in 9 recipients from 6 donors, including 3 of 4 (75%) heart transplant recipients, 2 of 10 (20%) liver recipients and 2 of 15 (13%) kidney recipients. Recommended monitoring posttransplant consisted of regular testing by PCR, hemoculture, and serology. Thirteen recipients had no or incomplete monitoring; transmission was confirmed in five of these recipients. Four of the five recipients had symptomatic disease and all four died although death was directly related to Chagas disease in only one. Nineteen recipients had partial or complete monitoring for T. cruzi infection with weekly testing by PCR, hemoculture and serology; transmission was confirmed in 4 of 19 recipients with no cases of symptomatic disease. Our results suggest that liver and kidney transplantation from T. cruzi seropositive donors may be feasible when the recommended monitoring schedule for T. cruzi infection is followed and prompt therapy with benznidazole can be administered.

Heart transplantation in a patient with heteroresistant vancomycin-intermediate Staphylococcus aureus ventricular assist device mediastinitis and bacteremia.

Vancomycin-intermediate Staphylococcus aureus (VISA) infections are an emerging problem and antibiotic options are limited. We report the first case, to our knowledge, of heteroresistant VISA mediastinitis and bacteremia in a patient with a ventricular assist device who underwent orthotopic heart transplantation with clinical cure.

Relationship between breast cancer risk factors and mammographic breast density in the Fernald Community Cohort.

BACKGROUND: We investigated associations of known breast cancer risk factors with breast density, a well-established and very strong predictor of breast cancer risk. METHODS: This nested case-control study included breast cancer-free women, 265 with high and 860 with low breast density. Women were required to be 40-80 years old and should have a body mass index (BMI) <35 at the time of the index mammogram. Information on covariates was obtained from annual questionnaires. RESULTS: In the overall analysis, breast density was inversely associated with BMI at mammogram (P for trend<0.001), and parity (P for trend=0.02) and positively associated with alcohol consumption (ever vs never: odds ratio 2.0, 95% confidence interval 1.4-2.8). Alcohol consumption was positively associated with density, and the association was stronger in women with a family history of breast cancer (P<0.001) and in women with hormone replacement therapy (HRT) history (P<0.001). Parity was inversely associated with density in all subsets, except premenopausal women and women without a family history. The association of parity with density was stronger in women with HRT history (P<0.001). CONCLUSION: The associations of alcohol and parity with breast density appear to be in reverse direction, but stronger in women with a family history of breast cancer and women who ever used HRT.

Exendin-4 increases histone acetylase activity and reverses epigenetic modifications that silence Pdx1 in the intrauterine growth retarded rat.

AIMS/HYPOTHESIS: The abnormal intrauterine milieu of intrauterine growth retardation (IUGR) permanently alters gene expression and function of pancreatic beta cells leading to the development of diabetes in adulthood. Expression of the pancreatic homeobox transcription factor Pdx1 is permanently reduced in IUGR islets suggesting an epigenetic mechanism. Exendin-4 (Ex-4), a long-acting glucagon-like peptide-1 (GLP-1) analogue, given in the newborn period increases Pdx1 expression and prevents the development of diabetes in the IUGR rat. METHODS: IUGR was induced by bilateral uterine artery ligation in fetal life. Ex-4 was given on postnatal days 1-6 of life. Islets were isolated at 1 week and at 3-12 months. Histone modifications, PCAF, USF1 and DNA methyltransferase (Dnmt) 1 binding were assessed by chromatin immunoprecipitation (ChIP) assays and DNA methylation was quantified by pyrosequencing. RESULTS: Phosphorylation of USF1 was markedly increased in IUGR islets in Ex-4 treated animals. This resulted in increased USF1 and PCAF association at the proximal promoter of Pdx1, thereby increasing histone acetyl transferase (HAT) activity. Histone H3 acetylation and trimethylation of H3K4 were permanently increased, whereas Dnmt1 binding and subsequent DNA methylation were prevented at the proximal promoter of Pdx1 in IUGR islets. Normalisation of these epigenetic modifications reversed silencing of Pdx1 in islets of IUGR animals. CONCLUSIONS/INTERPRETATION: These studies demonstrate a novel mechanism whereby a short treatment course of Ex-4 in the newborn period permanently increases HAT activity by recruiting USF1 and PCAF to the proximal promoter of Pdx1 which restores chromatin structure at the Pdx1 promoter and prevents DNA methylation, thus preserving Pdx1 transcription.

Perfluorooctanoate and changes in anthropometric parameters with age in young girls in the Greater Cincinnati and San Francisco Bay Area.

METHODS: We conducted a study of per- and polyfluoroalkyl substance biomarkers, including PFOA, in girls from Greater Cincinnati (CIN, N = 353) and the San Francisco Bay Area (SFBA, N = 351). PFOA was measured in the baseline serum sample collected in 2004-2007 of 704 girls at age 6-8 years. Mixed effects models were used to derive the effect of PFOA on BMI, waist-to-height and waist-to-hip ratios over increasing age in this longitudinal cohort. RESULTS: Median PFOA serum concentrations were 7.3 (CIN) and 5.8 (SFBA) ng/mL, above the U.S. population median for children 12-19 years in 2005-2006 (3.8 ng/mL). Log-transformed serum PFOA had a strong inverse association with BMIz in the CIN girls (p = 0.0002) and the combined two-site data (p = 0.0008); the joint inverse effect of PFOA and Age*PFOA weakened at age at 10-11 years. However, in the SFBA group alone, the relationship was not significant (p = 0.1641) with no evidence of changing effect with age. The effect of PFOA on waist:height ratio was similar to BMIz at both sites, but we did not find a significant effect of PFOA on waist:hip ratio in either the CIN or SFBA girls. CONCLUSIONS: PFOA is associated with decreased BMI and waist:height ratio in young girls, but the strength of the relationship decreases with age. Site heterogeneity may be due to greater early life exposure in Cincinnati. DISCLAIMER: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Use of trade names is for identification only and does not imply endorsement by the CDC, the Public Health Service, or the US Department of Health and Human Services.

Employment status as a confounder when assessing occupational exposures and spontaneous abortion.

Studies of occupational exposure and spontaneous abortion may use pregnancies during which the mother was unemployed as part or all of the unexposed comparison group. Any type of maternal employment, however, may be a risk factor for spontaneous abortion, and potential confounder in occupational reproductive studies. This study evaluates the effect of employment in a cohort of pregnancies of 1535 women. Employed pregnancies had a significantly higher rate of spontaneous abortion (14.5%) than unemployed pregnancies (11.7%) (RR = 1.23, 95% CI = 1.02, 1.49). Gravidity acted as an effect modifier, as the employment effect was seen only in multigravidous pregnancies (RR = 1.38, 95% CI = 1.11, 1.72) and not primigravidous pregnancies (RR = 0.96). The effect persisted when an independent sample of one randomly selected pregnancy per woman was used for the analysis (RR = 1.27, 95% CI = 0.90, 1.79). The data were examined for confounding by other factors which could explain the excess in spontaneous abortion among employed pregnancies. The employment effect persisted with adjustment for other risk factors including maternal age, education, income, maternal diabetes, race, alcohol usage and smoking, and prior pregnancy ending in induced abortion. Stratifying by prior pregnancy loss eliminated the employment effect among those with prior loss (RR = 1.03) but enhanced the effect among those multigravidous without the risk factor (RR = 1.50, 95% CI = 1.15, 1.97). Selection bias, also, was explored as a possible explanation of this employment effect, but could not be substantiated. Assessment of a true exposure effect requires consideration of a potential employment effect either in the design or analysis.

Sources of variability in the human lymphocyte micronucleus assay: a population-based study.

The cytokinesis block method was used to examine the intraclass correlation coefficient of the human lymphocyte micronucleus assay, sources of variability, and practical issues regarding the number of samples per subject. Twenty samples of 100 binucleate cells from a single phlebotomy per subject were analyzed (n = 112), using methods to evaluate variance components. The results showed marked intraindividual (sampling error) variation greater than interindividual variation, and no between-group contribution to the total variance. The intraclass correlation was 41.6%, indicating that slightly greater than half of the total variation in micronucleus outcomes was due to error variance (i.e., 58.4%). After adjusting for age, the intraclass correlation coefficient decreased trivially from 41.6% to 39.8%. There was a strong differential gender effect, favoring a greater micronuclei frequency in women. In conclusion, the data suggest that most of the variability in our data set for the micronucleus assay was due to sampling error; a strong differential gender effect favoring females was also verified. Equally important, in terms of practical applications, our analysis of the appropriate number of samples per subject revealed that scoring greater than 1,000 cells (10 determinations per subject) yielded no substantial improvement in statistical sensitivity, compared to the traditional 20 determinations. We suggest that more attention should be directed toward improving the assay's utility, while reducing sampling error.

Educating medical students about musculoskeletal problems. Are community needs reflected in the curricula of Canadian medical schools?

BACKGROUND: Musculoskeletal problems are a common reason why patients present for medical treatment. The purpose of the present study was to review the curricula of Canadian medical schools to determine whether they prepare their students for the demands of practice with respect to musculoskeletal problems. METHODS: The amount of time spent on musculoskeletal education at each of Canada's medical schools was reviewed by surveying the directors (or equivalents) of all sixteen undergraduate musculoskeletal programs. With use of data from this survey and the Association of American Medical Colleges' guide to curricula, the percentage of the total curriculum devoted to musculoskeletal education was determined. The prevalence of disorders related to the musculoskeletal system among patients of primary care physicians was determined on an international basis by reviewing the literature and on a local basis by surveying all primary care physicians affiliated with the University of British Columbia's Department of Family Medicine. RESULTS: The curriculum analysis revealed that, on the average, medical schools in Canada devoted 2.26% (range, 0.61% to 4.81%) of their curriculum time to musculoskeletal education. The questionnaires completed by the directors of the undergraduate programs indicated widespread dissatisfaction with the musculoskeletal education process and, specifically, with the amount of time devoted to musculoskeletal education. Our literature review and survey of local family physicians revealed that between 13.7% and 27.8% of North American patients presenting to a primary care physician have a chief symptom that is directly related to the musculoskeletal system. CONCLUSION: There is a marked discrepancy between the musculoskeletal knowledge and skill requirements of a primary care physician and the time devoted to musculoskeletal education in Canadian medical schools.

Do persons living near a uranium processing site have evidence of increased somatic cell gene mutations? A first study.

The objective of this study was to examine if individuals living near a uranium processing site have greater mutagenic damage, as measured by three mutagenicity assays, compared with subjects unexposed to any nuclear facilities. The design was a cross-sectional exploratory analysis of 112 subjects; 56 volunteer residents were from within a 5-mile radius of the Fernald Uranium Processing site and 56 'control' subjects were from a geographically separate area unexposed to any known uranium emissions. The groups were constrained to be similar in age and sex composition. The main outcome measures were three human somatic gene mutation assays consisting of the HPRT T-lymphocyte cloning assay to measure 6-thioguanine resistant lymphocytes; the glycophorin A assay to detect the loss of expression of the M or N allele; and the micronucleus assay as a marker of chromosomal damage. The results showed no statistically significant or quantitatively important differences between groups for all three mutagenicity assays; only the unselected cloning efficiency was statistically significantly different between groups (0.42 +/- 0.16 for the Fernald versus 0.35 +/- 0.12 for the comparison groups). In both groups, age was significantly related to HPRT mutant frequency, with a 1.25% rate of increase in mutant frequencies for each 1-year gain of age in the Fernald group and a 1.12% rate of increase in mutant frequencies for each 1-year gain of age in the comparison group. For the micronucleus data, females had a greater mean micronucleus frequency than males. In addition, smokers had an increased mean ln (natural logarithm) HPRT mutant frequency (3.06 +/- 0.14 for current smokers compared with a mean of 2.72 +/- 0.05 for non-current (i.e. never plus former) smokers). Our results are consistent with the previously reported association between sex type and micronucleus frequency, the known relationship between age and T-lymphocyte cloning efficiency and age and HPRT mutant frequency, and verify the wide inter-subject variability for the latter. Finally, we conclude that at a population level, the relationships between current cigarette use and HPRT mutant frequency, and sex type and micronucleus frequency, are stronger than is the association between geographic proximity to a uranium processing site and mutagenic abnormalities.

Intercorrelations and sources of variability in three mutagenicity assays: a population-based study.

The purpose of this study was to evaluate the intercorrelation between three genetic assays in 112 subjects. The group was pooled from two originally separate but homogeneous subgroups of 56 persons each. Procedures included assays for hprt mutant frequencies, micronuclei in human lymphocytes, and mutations at the glycophorin A (gpa) loci. We found no statistically significant or biologically important intercorrelations among the three biomarkers. We did, however, observe significant correlations between log(e) hprt mutant frequency and cloning efficiency (inverse correlation for these 2 variables), age and log(e) hprt mutant frequency, an inverse relationship between cloning efficiency and age, and an important differential sex effect favoring a greater micronuclei frequency in females than males. No significant correlations between the covariates of interest and glycophorin A variant frequencies NN or NO were observed. Using multivariable linear regression, age was found to account for the majority of the variability in hprt mutant frequency (greater than sex and/or smoking); for micronuclei data, only sex contributed a statistically significant and biologically important proportion to the total variation. We conclude that despite observing no significant intercorrelations between the three assays performed simultaneously from the same individuals in a large population database, a significant correlation between age and hprt mutant frequency and an inverse association between cloning efficiency and hprt do exist; furthermore, we verified the strong differential sex-specific effect on micronucleus frequencies.

Cluster analysis applied to building-related illness.

Identifying remediable causes of occupant symptoms in building-related illness is frequently difficult. This is particularly true when the building-wide prevalence of symptoms is comparable to that reported in non-problem buildings. This analysis applied an epidemiological approach to an assessment of a problem building, allowing investigators to visually identify an area of apparent increased symptom density. A cluster analysis approach permitted biostatistical confirmation of the visual cluster. Building-related symptom reporting was statistically significantly associated with a prior physician diagnosis of dust and/or mold allergy. The likely etiology of building occupant symptoms was identified within the region implicated by the cluster analysis. This approach may be useful to focus building evaluations on both the likely physical source and general characteristics of suspect etiologic agents.

Fractures of the tarsal bones.

Fractures involving the midtarsal bones are relatively uncommon. The morbidity associated with these injuries can be significant, however. Accurate diagnosis and appropriate treatment can help restore midfoot function and decrease the incidence of chronic pain. Treatment should preserve the function of the talonavicular joint, maintain the relative length of the medial and lateral columns, and protect the ligaments and soft tissues until adequate healing has occurred.

Role of the nurse counsellor in managing patients with the hyperventilation syndrome.

A hyperventilation clinic was established specifically to deal with patients referred from the accident and emergency department with the hyperventilation syndrome. This was run by a staff nurse, who counselled the patients and taught abdominal breathing techniques and relaxation. In 30 patients so managed, 63% said their symptoms were much better or had completely gone and in only 6% was there no improvement; 43% had previously had more than one attendance at the A&E department, but following treatment only 2 patients represented during 5 months of follow up. The use of a nurse counsellor seems to be a simple and effective approach to managing these patients and considerably reduces both casualty and outpatient physician time.

Disseminated intravascular coagulation complicating Epstein-Barr virus infection in a cardiac transplant recipient: a case report.

Viral infections are particularly common after cardiac transplantation. Herein we have presented a case of Epstein-Barr infection that presented as a viral syndrome with respiratory symptoms, but was complicated by multiorgan failure and disseminated intravascular coagulation. Transplant physicians should be aware of this unique complication of an otherwise self-limited infection.

Tumor lysis syndrome occurring after the administration of rituximab for posttransplant lymphoproliferative disorder.

Tumor lysis syndrome (TLS) may occur after the administration of rituximab for lymphoproliferative disorders. We describe the case of a heart transplant recipient who developed TLS after a single dose of rituximab for the treatment of posttransplant lymphoproliferative disorder. Because rituximab is being used more frequently, it is important for transplant physicians to be aware of this potential complication particularly after administering the first dose.

Fat embolism syndrome in isolated femoral fractures: does timing of nailing influence incidence?

In a consecutive series of 274 patients with isolated femoral shaft fractures 11 patients (4%) developed fat embolism syndrome. There were no cases of fat embolism syndrome in patients over the age of 35 years. Of the remaining patients, 60 operated on within 10 h of injury did not develop fat embolism. This left 109 patients who had nailing performed more than 10 h after injury of whom eleven (10%) developed fat embolism syndrome (p < 0.027). Patients under the age of 35 years with isolated femoral fractures should have nailing performed as early as possible after injury to minimize fat embolism syndrome.

Sick building syndrome. Medical evaluation of two work forces.

Sick building syndrome, characterized by upper respiratory irritative and central nervous system symptoms, is poorly understood. Building ventilation problems are frequent, although causative agent(s) are unknown. Few studies have addressed clinical characterization of symptomatic building occupants. Employees from two sites underwent standardized evaluation including medical history, physical examination and screening neurologic and neuropsychologic testing while acutely symptomatic. Both symptomatic and asymptomatic individuals were evaluated when one of the sites was evacuated. Baseline evaluation results for this group were available for comparison. Symptoms of both work forces mirrored those reported in the literature. General medical examination abnormalities were few and minor, while neurologic and neuropsychologic examinations documented mental status, cerebellar, and neurobehavioral deficits. There were statistically significant changes from baseline. Abnormalities were self-limited. Controlled evaluations of symptomatic sick building occupants should be performed to verify these findings.

MR assessment of posttraumatic flexion contracture of the elbow.

Preoperative assessment of posttraumatic flexion contracture of the elbow includes plain radiographs and tomograms, which are difficult to obtain in the coronal plane due to the contracture. We conducted this study to determine the usefulness of MR imaging in the work-up of these patients. Twelve patients with flexion contracture of the elbow were studied. In addition to standard spin-echo sequences, a sagittally acquired spoiled gradient-recalled echo 3D data set of the flexed elbow was obtained and reformatted coronally using a curved plane of reconstruction. The MR findings were compared to the plain films, tomograms and surgical results. MRI allowed identification of loose bodies that were sometimes poorly visualized, or not seen, on plain films, and demonstrated degenerative changes equally as well as tomograms. MR showed soft tissue abnormalities including capsular and collateral ligament thickening. Curvilinear reconstructions were helpful in the assessment of collateral ligaments in patients with severe contractures. We conclude that MR is useful in the evaluation of elbow flexion contractures, particularly in assessing soft tissue causes.

Terfenadine increases the QT interval in isolated guinea pig heart.

Torsades de pointes ventricular tachycardia (VT) has been reported in patients taking the nonsedating antihistamine, terfenadine. We performed electrophysiologic studies of 14 isolated guinea pig hearts using the Langendorff technique to assess whether terfenadine exerted actions that could be responsible for inducing the arrhythmia. Twelve hearts were perfused with an oxygenated Tyrode's solution containing a 2-microM preparation of either racemic, R-, or S-terfenadine. QT interval (QT), monophasic action potential duration (APD), and ventricular effective refractory periods (ERP) were measured at a fixed range of cycle lengths (CL). At 400-ms CL, both isomers and racemate prolonged QT and APD by 8% and ERP was increased by 14%. Infusion of vehicle, dimethyl sulfoxide (DMSO), alone in two hearts caused a slight decrease in QT and APD, suggesting that the direct effect of terfenadine on QT may have been underestimated. One-way analysis of variance (ANOVA) showed no statistical difference in effect on QT, APD, or ERP for the three forms of terfenadine (p < 0.05). These results support the conclusion that terfenadine induces torsades de pointes because of direct actions in delaying cardiac repolarization. The lack of stereospecificity in this action indicates that chirally pure formulations are not likely to have greater safety than the racemate.