The Pediatrician and Disaster Preparedness

Recent natural disasters and events of terrorism and war have heightened society's recognition of the need for emergency preparedness. In addition to the unique pediatric issues involved in general emergency preparedness, several additional issues related to terrorism preparedness must be considered, including the unique vulnerabilities of children to various agents as well as the limited availability of age- and weight-appropriate antidotes and treatments. Although children may respond more rapidly to therapeutic intervention, they are at the same time more susceptible to various agents and conditions and more likely to deteriorate if not monitored carefully.The challenge of dealing with the threat of terrorism, natural disasters, and public health emergencies in the United States is daunting not only for disaster planners but also for our medical system and health professionals of all types, including pediatricians. As part of the network of health responders, pediatricians need to be able to answer concerns of patients and families, recognize signs of possible exposure to a weapon of terror, understand first-line response to such attacks, and sufficiently participate in disaster planning to ensure that the unique needs of children are addressed satisfactorily in the overall process. Pediatricians play a central role in disaster and terrorism preparedness with families, children, and their communities. This applies not only to the general pediatrician but also to the pediatric medical subspecialist and pediatric surgical specialist. Families view pediatricians as their expert resource, and most of them expect the pediatrician to be knowledgeable in areas of concern. Providing expert guidance entails educating families in anticipation of events and responding to questions during and after actual events. It is essential that pediatricians educate themselves regarding these issues of emergency preparedness. For pediatricians, some information is currently available on virtually all of these issues in recently produced printed materials, at special conferences, in broadcasts of various types, and on the Internet. However, selecting appropriate, accurate sources of information and determining how much information is sufficient remain difficult challenges. Similarly, guidance is needed with respect to developing relevant curricula for medical students and postdoctoral clinical trainees

Hormone receptor status of a first primary breast cancer predicts contralateral breast cancer risk in the WECARE study population

Abstract Background Previous population-based studies have described first primary breast cancer tumor characteristics and their association with contralateral breast cancer (CBC) risk. However, information on influential covariates such as treatment, family history of breast cancer, and BRCA1/2 mutation carrier status was not available. In a large, population-based, case-control study, we evaluated whether tumor characteristics of the first primary breast cancer are associated with risk of developing second primary asynchronous CBC, overall and in subgroups of interest, including among BRCA1/2 mutation non-carriers, women who are not treated with tamoxifen, and women without a breast cancer family history. Methods The Women’s Environmental Cancer and Radiation Epidemiology Study is a population-based case-control study of 1521 CBC cases and 2212 individually-matched controls with unilateral breast cancer. Detailed information about breast cancer risk factors, treatment for and characteristics of first tumors, including estrogen receptor (ER) and progesterone receptor (PR) status, was obtained by telephone interview and medical record abstraction. Multivariable risk ratios (RRs) and 95% confidence intervals (CIs) were estimated in conditional logistic regression models, adjusting for demographics, treatment, and personal medical and family history. A subset of women was screened for BRCA1/2 mutations. Results Lobular histology of the first tumor was associated with a 30% increase in CBC risk (95% CI 1.0–1.6). Compared to women with ER+/PR+ first tumors, those with ER-/PR- tumors had increased risk of CBC (RR = 1.4, 95% CI 1.1–1.7). Notably, women with ER-/PR- first tumors were more likely to develop CBC with the ER-/PR- phenotype (RR = 5.4, 95% CI 3.0–9.5), and risk remained elevated in multiple subgroups: BRCA1/2 mutation non-carriers, women younger than 45 years of age, women without a breast cancer family history, and women who were not treated with tamoxifen. Conclusions Having a hormone receptor negative first primary breast cancer is associated with increased risk of CBC. Women with ER-/PR- primary tumors were more likely to develop ER-/PR- CBC, even after excluding BRCA1/2 mutation carriers. Hormone receptor status, which is routinely evaluated in breast tumors, may be used clinically to determine treatment protocols and identify patients who may benefit from increased surveillance for CBC

The association of mammographic density with risk of contralateral breast cancer and change in density with treatment in the WECARE study.

BACKGROUND: Mammographic density (MD) is an established predictor of risk of a first breast cancer, but the relationship of MD to contralateral breast cancer (CBC) risk is not clear, including the roles of age, mammogram timing, and change with treatment. Multivariable prediction models for CBC risk are needed and MD could contribute to these. METHODS: We conducted a case-control study of MD and CBC risk in phase II of the WECARE study where cases had a CBC diagnosed ≥ 2 years after first diagnosis at age <55 years and controls had unilateral breast cancer (UBC) with similar follow-up time. We retrieved film mammograms of the unaffected breast from two time points, prior to/at the time of the first diagnosis (253 CBC cases, 269 UBC controls) and ≥ 6 months up to 48 months following the first diagnosis (333 CBC cases, 377 UBC controls). Mammograms were digitized and percent MD (%MD) was measured using the thresholding program Cumulus. Odds ratios (OR) and 95% confidence intervals (CI) for association between %MD and CBC, adjusted for age, treatment, and other factors related to CBC, were estimated using logistic regression. Linear regression was used to estimate the association between treatment modality and change in %MD in 467 women with mammograms at both time points. RESULTS: For %MD assessed following diagnosis, there was a statistically significant trend of increasing CBC with increasing %MD (p = 0.03). Lower density (<25%) was associated with reduced risk of CBC compared to 25 to < 50% density (OR 0.69, 95% CI 0.49, 0.98). Similar, but weaker, associations were noted for %MD measurements prior to/at diagnosis. The relationship appeared strongest in women aged < 45 years and non-existent in women aged 50 to 54 years. A decrease of ≥ 10% in %MD between first and second mammogram was associated marginally with reduced risk of CBC (OR 0.63, 95% CI 0.40, 1.01) compared to change of <10%. Both tamoxifen and chemotherapy were associated with statistically significant 3% decreases in %MD (p < 0.01). CONCLUSIONS: Post-diagnosis measures of %MD may be useful to include in CBC risk prediction models with consideration of age at diagnosis. Chemotherapy is associated with reductions in %MD, similar to tamoxifen

Breast Cancer Family History and Contralateral Breast Cancer Risk in Young Women: An Update From the Women's Environmental Cancer and Radiation Epidemiology Study.

Purpose The Women's Environmental Cancer and Radiation Epidemiology (WECARE) study demonstrated the importance of breast cancer family history on contralateral breast cancer (CBC) risk, even for noncarriers of deleterious BRCA1/2 mutations. With the completion of WECARE II, updated risk estimates are reported. Additional analyses that exclude women negative for deleterious mutations in ATM, CHEK2*1100delC, and PALB2 were performed. Patients and Methods The WECARE Study is a population-based case-control study that compared 1,521 CBC cases with 2,212 individually matched unilateral breast cancer (UBC) controls. Participants were younger than age 55 years when diagnosed with a first invasive breast cancer between 1985 and 2008. Women were interviewed about breast cancer risk factors, including family history. A subset of women was screened for deleterious mutations in BRCA1/2, ATM, CHEK2*1100delC, and PALB2. Rate ratios (RRs) were estimated using multivariable conditional logistic regression. Cumulative absolute risks (ARs) were estimated by combining RRs from the WECARE Study and population-based SEER*Stat cancer incidence data. Results Women with any first-degree relative with breast cancer had a 10-year AR of 8.1% for CBC (95% CI, 6.7% to 9.8%). Risks also were increased if the relative was diagnosed at an age younger than 40 years (10-year AR, 13.5%; 95% CI, 8.8% to 20.8%) or with CBC (10-year AR, 14.1%; 95% CI, 9.5% to 20.7%). These risks are comparable with those seen in BRCA1/2 deleterious mutation carriers (10-year AR, 18.4%; 95% CI, 16.0% to 21.3%). In the subset of women who tested negative for deleterious mutations in BRCA1/2, ATM, CHEK2*1100delC, and PALB2, estimates were unchanged. Adjustment for known breast cancer single-nucleotide polymorphisms did not affect estimates. Conclusion Breast cancer family history confers a high CBC risk, even after excluding women with deleterious mutations. Clinicians are urged to use detailed family histories to guide treatment and future screening decisions for young women with breast cancer

A case-control study of the joint effect of reproductive factors and radiation treatment for first breast cancer and risk of contralateral breast cancer in the WECARE study.

OBJECTIVE: To examined the impact of reproductive factors on the relationship between radiation treatment (RT) for a first breast cancer and risk of contralateral breast cancer (CBC). METHODS: The Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study is a multi-center, population-based case-control study where cases are women with asynchronous CBC (N = 1521) and controls are women with unilateral breast cancer (N = 2211). Rate ratios (RR) and 95% confidence intervals (CI) were estimated using conditional logistic regression to assess the independent and joint effects of RT (ever/never and location-specific stray radiation dose to the contralateral breast [0, >0-<1Gy, ≥1Gy]) and reproductive factors (e.g., parity). RESULTS: Nulliparous women treated with RT (≥1Gy dose) were at increased risk of CBC compared with nulliparous women not treated with RT, although this relationship did not reach statistical significance (RR = 1.34, 95% CI 0.87, 2.07). Women treated with RT who had an interval pregnancy (i.e., pregnancy after first diagnosis and before second diagnosis [in cases]/reference date [in controls]) had an increased risk of CBC compared with those who had an interval pregnancy with no RT (RR = 4.60, 95% CI 1.16, 18.28). This was most apparent for women with higher radiation doses to the contralateral breast. CONCLUSION: Among young female survivors of breast cancer, we found some evidence suggesting that having an interval pregnancy could increase a woman's risk of CBC following RT for a first breast cancer. While sampling variability precludes strong interpretations, these findings suggest a role for pregnancy and hormonal factors in radiation-associated CBC

Quantification of Retrograde Axonal Transport in the Rat Optic Nerve by Fluorogold Spectrometry

PURPOSE: Disturbed axonal transport is an important pathogenic factor in many neurodegenerative diseases, such as glaucoma, an eye disease characterised by progressive atrophy of the optic nerve. Quantification of retrograde axonal transport in the optic nerve usually requires labour intensive histochemical techniques or expensive equipment for in vivo imaging. Here, we report on a robust alternative method using Fluorogold (FG) as tracer, which is spectrometrically quantified in retinal tissue lysate. METHODS: To determine parameters reflecting the relative FG content of a sample FG was dissolved in retinal lysates at different concentrations and spectra were obtained. For validation in vivo FG was injected uni- or bilaterally into the superior colliculus (SC) of Sprague Dawley rats. The retinal lysate was analysed after 3, 5 and 7 days to determine the time course of FG accumulation in the retina (n = 15). In subsequent experiments axona transport was impaired by optic nerve crush (n = 3), laser-induced ocular hypertension (n = 5) or colchicine treatment to the SC (n = 10). RESULTS: Spectrometry at 370 nm excitation revealed two emission peaks at 430 and 610 nm. We devised a formula to calculate the relative FG content (c(FG)), from the emission spectrum. c(FG) is proportional to the real FG concentration as it corrects for variations of retinal protein concentration in the lysate. After SC injection, c(FG) monotonously increases with time (p = 0.002). Optic nerve axonal damage caused a significant decrease of c(FG) (crush p = 0.029; hypertension p = 0.025; colchicine p = 0.006). Lysates are amenable to subsequent protein analysis. CONCLUSIONS: Spectrometrical FG detection in retinal lysates allows for quantitative assessment of retrograde axonal transport using standard laboratory equipment. It is faster than histochemical techniques and may also complement morphological in vivo analyses

CYP2D6 phenotype, tamoxifen, and risk of contralateral breast cancer in the WECARE Study.

BACKGROUND: Tamoxifen treatment greatly reduces a woman's risk of developing a second primary breast cancer. There is, however, substantial variability in treatment response, some of which may be attributed to germline genetic variation. CYP2D6 is a key enzyme in the metabolism of tamoxifen to its active metabolites, and variants in this gene have been associated with reduced tamoxifen metabolism. The impact of variation on risk of contralateral breast cancer (CBC) is unknown. METHODS: Germline DNA from 1514 CBC cases and 2203 unilateral breast cancer controls was genotyped for seven single nucleotide polymorphisms, one three-nucleotide insertion-deletion, and a full gene deletion. Each variant has an expected impact on enzyme activity, which in combination allows for the classification of women as extensive, intermediate, and poor metabolizers (EM, IM, and PM respectively). Each woman was assigned one of six possible diplotypes and a corresponding CYP2D6 activity score (AS): EM/EM (AS = 2), EM/IM (AS = 1.5), EM/PM (AS = 1), IM/IM (AS = 0.75), IM/PM (AS = 0.5), and PM/PM (AS = 0). We also collapsed categories of the AS to generate an overall phenotype (EM, AS ≥ 1; IM, AS = 0.5-0.75; PM, AS = 0). Rate ratios (RRs) and 95% confidence intervals (CIs) for the association between tamoxifen treatment and risk of CBC in our study population were estimated using conditional logistic regression, stratified by AS. RESULTS: Among women with AS ≥ 1 (i.e., EM), tamoxifen treatment was associated with a 20-55% reduced RR of CBC (AS = 2, RR = - 0.81, 95% CI 0.62-1.06; AS = 1.5, RR = 0.45, 95% CI 0.30-0.68; and AS = 1, RR = 0.55, 95% CI 0.40-0.74). Among women with no EM alleles and at least one PM allele (i.e., IM and PM), tamoxifen did not appear to impact the RR of CBC in this population (AS = 0.5, RR = 1.08, 95% CI 0.59-1.96; and AS = 0, RR = 1.17, 95% CI 0.58-2.35) (p for homogeneity = - 0.02). CONCLUSION: This study suggests that the CYP2D6 phenotype may contribute to some of the observed variability in the impact of tamoxifen treatment for a first breast cancer on risk of developing CBC

Using Population Genetic Theory and DNA Sequences for Species Detection and Identification in Asexual Organisms

It is widely agreed that species are fundamental units of biology, but there is little agreement on a definition of species or on an operational criterion for delimiting species that is applicable to all organisms.We focus on asexual eukaryotes as the simplest case for investigating species and speciation. We describe a model of speciation in asexual organisms based on basic principles of population and evolutionary genetics. The resulting species are independently evolving populations as described by the evolutionary species concept or the general lineage species concept. Based on this model, we describe a procedure for using gene sequences from small samples of individuals to assign them to the same or different species. Using this method of species delimitation, we demonstrate the existence of species as independent evolutionary units in seven groups of invertebrates, fungi, and protists that reproduce asexually most or all of the time.This wide evolutionary sampling establishes the general existence of species and speciation in asexual organisms. The method is well suited for measuring species diversity when phenotypic data are insufficient to distinguish species, or are not available, as in DNA barcoding and environmental sequencing. We argue that it is also widely applicable to sexual organisms