Objectives: In response to an anencephaly cluster on the Texas-Mexico border, we conducted an incident matched case-control study of Neural Tube Defects (NTD). Data are presented regarding the conception residences near interstate highways and biomarkers of chemical exposures to metals, organophosphorus and organochlorine pesticides. Methods: Maternal biological samples (blood, sera, urine, and hair) were obtained at the time of NTD diagnosis for cases and a comparable time for controls with unaffected pregnancies. Conception addresses of NTD cases and matched controls were geocoded during residential visits for environmental sampling. An objective GIS subroutine was used to ascertain the distance at conception from major highways. Conditional logistic regression was used to evaluate odds ratios for distance and biological markers of chemical exposure to six dialkyl phosphate metabolites, eleven organochlorine metabolites, and three metals. Results: Infants with NTD were conceived significantly more often within 1⁄4 mile from the highways (OR=3.0, 95% CI 1.05, 8.83; p=0.041). A proximity to birthing clinic pattern was unlikely. Significant odds ratios for urinary dialkyl phosphate metabolites of organophosphorus pesticides were associated with NTD (4th quartile ORs for creatinine-adjusted Diethyl phosphate (DEP), Diethyl thiophosphate (DETP), and Diethyl dithiophosphate (DEDTP) were 3.5, 2.8, and 2.9, respectively). Serum organochlorine pesticides were also significantly associated with NTD (4th quartile ORs for lindane, dieldrin, and trans-nonachlor were 11.1, 3.8, and 9.4, respectively). There was no parallel gradient indicated for metals with the distance from the major highways. Conclusion: We invite attention to potential risks for NTD involving large-scale applications of pesticides for cropland, mosquito, and brush control on the shoulders of highways.

The choice of dopaminergic therapy in early Parkinson disease (PD) is an important clinical decision, yet factors influencing this decision have not been extensively studied. We sought to investigate the factors that may be associated with the choice of dopaminergic therapy at the NINDS Exploratory Trials in PD (NET-PD) Long-Term Study-1 (LS1). NET-PD LS1 was a clinical trial of creatine versus placebo in participants with early, mild PD on stable doses of dopaminergic therapy. Baseline data from 1616 out of the 1741 participants were evaluated using univariable and multivariable logistic or generalized logit regression analyses for available factors associated with the choice of dopaminergic therapy. The dopaminergic therapy choice was determined as: (i) therapy that subjects recalled taking 180days before the study; (ii) therapy at baseline; and (iii) the longest duration of therapy reported by participants. Younger age, higher education level, longer length of time since PD diagnosis and use of an adjunctive, non-dopaminergic or monoamine oxidase inhibitor medication were associated with more frequent use of dopamine agonist compared to levodopa or combination therapy.

Given disproportionate burden of physical inactivity among US Hispanics and emerging interests in the potential role of the built environment on physical activity, we tested the hypothesis that residing in a more walkable block group is associated with increased physical activity in a cohort of Mexican-American adults. 10,183 Mexican-American adults from Houston, TX, USA were studied. Physical activity was assessed through self-report. Geographical information systems were used to create a "walkability index" (WI). We examined the relationship between WI and physical activity using regression models. Findings for the entire study population suggested a direct association between neighborhood walkability and physical activity that approached statistical significance (High WI vs. Low WI: OR = 1.16; 95 % CI 0.95-1.40). Furthermore, participants who lived in a higher WI neighborhood were more likely to meet physical activity guidelines in 2 groups: (1) men whose recreational physical activity included walking (High WI vs. Low WI: OR = 5.43; 95 % CI 1.30-22.73) and (2) men whose only recreational physical activity was (High WI vs. Low WI: OR = 9.54; 95 % CI 1.84-49.60). Our findings suggest gender differences in the association between the built environment and physical activity in Mexican-American adults. Attempts to encourage walking among Mexican-American adults may be easier in high-walkability neighborhoods than in low-walkability neighborhoods.

The psychostimulants considered the gold standard in the treatment of attention deficit hyperactivity disorder, one of the most common childhood disorders, are also finding their way into the hands of healthy young adults as brain augmentation to improve cognitive performance. The possible long-term effects of psychostimulant exposure in adolescence are considered controversial, and thus, the objective of this study was to investigate whether the chronic exposure to the psychostimulant amphetamine affects the behavioral diurnal rhythm activity patterns of female adolescent Wistar-Kyoto (WKY) rat. The hypothesis of this study is that change in diurnal rhythm activity pattern is an indicator for the long-term effect of the treatment. Twenty-four rats were divided into two groups, control (N = 12) and experimental (N = 12), and kept in a 12:12-h light/dark cycle in an open-field cage. After 5–7 days of acclimation, 11 days of consecutive non-stop behavioral recordings began. On experimental day 1 (ED1), all groups were given an injection of saline. On ED2 to ED7, the experimental group was injected with 0.6 mg/kg amphetamine followed by 3 days of washout from ED8 to ED10, and amphetamine re-challenge on ED11 similar to ED2. The locomotor movements were counted by the computerized animal activity monitoring system, and the cosinor statistical test analysis was used to fit a 24-h curve of the control recording to the activity pattern after treatment. The horizontal activity, total distance, number of stereotypy, vertical activity, and stereotypical movements were analyzed to find out whether the diurnal rhythm activity patterns were altered. Data obtained using these locomotor indices of diurnal rhythm activity pattern suggest that amphetamine treatment significantly modulates the locomotor diurnal rhythm activity pattern of female WKY adolescent rats.

A prospective, multicenter phase I trial was undertaken by the North American Clinical Trials Network (NACTN) to investigate the pharmacokinetics and safety of, as well as obtain pilot data on, the effects of riluzole on neurological outcome in acute spinal cord injury (SCI). Thirty-six patients, with ASIA impairment grades A-C (28 cervical and 8 thoracic) were enrolled at 6 NACTN sites between April 2010 and June 2011. Patients received 50 mg of riluzole PO/NG twice-daily, within 12 h of SCI, for 14 days. Peak and trough plasma concentrations were quantified on days 3 and 14. Peak plasma concentration (Cmax) and systemic exposure to riluzole varied significantly between patients. On the same dose basis, Cmax did not reach levels comparable to those in patients with amyotrophic lateral sclerosis. Riluzole plasma levels were significantly higher on day 3 than on day 14, resulting from a lower clearance and a smaller volume of distribution on day 3. Rates of medical complications, adverse events, and progression of neurological status were evaluated by comparison with matched patients in the NACTN SCI Registry. Medical complications in riluzole-treated patients occurred with incidences similar to those in patients in the comparison group. Mild-to-moderate increase in liver enzyme and bilirubin levels were found in 14-70% of patients for different enzymes. Three patients had borderline severe elevations of enzymes. No patient had elevated bilirubin on day 14 of administration of riluzole. There were no serious adverse events related to riluzole and no deaths. The mean motor score of 24 cervical injury riluzole-treated patients gained 31.2 points from admission to 90 days, compared to 15.7 points for 26 registry patients, a 15.5-point difference (p=0.021). Patients with cervical injuries treated with riluzole had more-robust conversions of impairment grades to higher grades than the comparison group.

Cocaine is one of well-known drugs of abuse, and many children experience early exposure to cocaine. Because of an immature neuronal system in adolescents, they may react differently to repeated cocaine administration compared to adults. Most of the published papers report the effect of cocaine on adult male rats and this paper focused on the effects of cocaine on the 24 h locomotor activity rhythm patterns activity of adolescent Sprague Dawley (SD) female rats. Changes in the locomotor activity rhythm patterns could indicate that cocaine elicits long-term changes in the clock genes of the body that regulate different physiological processes. The objective of this study was to investigate whether cocaine in adolescent female rats modulated their daily activity pattern. Animals were divided into control (saline), 3.0, 7.5, 15.0 mg/kg cocaine groups. On experimental day 1 (ED 1), all groups were given saline injection. From ED 2 to ED 7, either saline or cocaine (3.0, 7.5, or 15.0 mg/kg) was given daily. ED 8 to ED 10 were the washout days, where no injection was given. On ED 11, the animals were injected with saline or with the same dose of cocaine as they were treated on ED 2 to ED 7. Each animal's locomotor activities was recorded nonstop following saline or cocaine injection for 11 consecutive days using the open field assay. In conclusion, it was observed that all three groups receiving repeated cocaine administration (3.0, 7.5, and 15.0 mg/kg) displayed significantly altered locomotor activity rhythm patterns.

The North American Clinical Trials Network (NACTN) for the Treatment of Spinal Cord Injury is a consortium of 10 neurosurgery departments, a data management center, and a pharmacological center. The NACTN was established with the goal of bringing recent molecular and cell-based discoveries in neuroprotection and regeneration from the laboratory into clinical trials that optimize meaningful data outcomes and maximum safety to patients. The requirements of planning and executing clinical trials in spinal cord injury (SCI) and the steps that the NACTN has taken to address these requirements are discussed and illustrated in articles in this issue of the Journal of Neurosurgery: Spine. The progress that the NACTN has made in meeting these goals can be summarized as organizing a network of hospitals capable of enrolling a sufficient number of patients for conducting Phase I and II trials; creating a Data Management Center and a database of the natural history of recovery after SCI (at the time of this writing 485 patients were enrolled in the database); creating a database of the incidence and severity of complications that occur during acute and subacute treatment after SCI; developing a Pharmacological Center capable of performing pharmacokinetic and pharmacodynamic studies of therapeutic drugs; completing enrollment of 36 patients in NACTN's first clinical trial, a Phase I study of riluzole, a neuroprotective drug; and performing pharmacokinetic and pharmacodynamic studies of riluzole in acute SCI.

OBJECT:The aim of this multicenter, prospective study was to determine the spectrum, incidence, and severity of complications during the initial hospitalization of patients with spinal cord injury.METHODS:The study was conducted at 9 university-affiliated hospitals that comprise the clinical centers of the North American Clinical Trials Network (NACTN) for Treatment of Spinal Cord Injury. The study population comprised 315 patients admitted to NACTN clinical centers between June 25, 2005, and November 2, 2010, who had American Spinal Injury Association (ASIA) Impairment Scale grades of A-D and were 18 years of age or older. Patients were managed according to a standardized protocol.RESULTS:The study population was 79% male with a median age of 44 years. The leading causes of injury were falls (37%) and motor vehicle accidents (28%). The distribution of initial ASIA grades were A (40%), B (16%), C (15%), and D (29%). Fifty-eight percent of patients sustained 1 or more severe, moderate, or mild complications. Complications were associated with more severe ASIA grade: 84% of patients with Grade A and 25% of patients with Grade D had at least 1 complication. Seventy-eight percent of complications occurred within 14 days of injury. The most frequent types of severe and moderate complications were respiratory failure, pneumonia, pleural effusion, anemia, cardiac dysrhythmia, and severe bradycardia. The mortality rate was 3.5% and was associated with increased age and preexisting morbidity.CONCLUSIONS:Knowledge of the type, frequency, time of occurrence, and severity of specific complications that occur after spinal cord injury can aid in their early detection, treatment, and prevention. The data are of importance in evaluating and selecting therapy for clinical trials.

OBJECT:Pulmonary complications are the most common acute systemic adverse events following spinal cord injury (SCI), and contribute to morbidity, mortality, and increased length of hospital stay (LOS). Identification of factors associated with pulmonary complications would be of value in prevention and acute care management. Predictors of pulmonary complications after SCI and their effect on neurological recovery were prospectively studied between 2005 and 2009 at the 9 hospitals in the North American Clinical Trials Network (NACTN).METHODS:The authors sought to address 2 specific aims: 1) define and analyze the predictors of moderate and severe pulmonary complications following SCI; and 2) investigate whether pulmonary complications negatively affected the American Spinal Injury Association (ASIA) Impairment Scale conversion rate of patients with SCI. The NACTN registry of the demographic data, neurological findings, imaging studies, and acute hospitalization duration of patients with SCI was used to analyze the incidence and severity of pulmonary complications in 109 patients with early MR imaging and long-term follow-up (mean 9.5 months). Univariate and Bayesian logistic regression analyses were used to analyze the data.RESULTS:In this study, 86 patients were male, and the mean age was 43 years. The causes of injury were motor vehicle accidents and falls in 80 patients. The SCI segmental level was in the cervical, thoracic, and conus medullaris regions in 87, 14, and 8 patients, respectively. Sixty-four patients were neurologically motor complete at the time of admission. The authors encountered 87 complications in 51 patients: ventilator-dependent respiratory failure (26); pneumonia (25); pleural effusion (17); acute lung injury (6); lobar collapse (4); pneumothorax (4); pulmonary embolism (2); hemothorax (2), and mucus plug (1). Univariate analysis indicated associations between pulmonary complications and younger age, sports injuries, ASIA Impairment Scale grade, ascending neurological level, and lesion length on the MRI studies at admission. Bayesian logistic regression indicated a significant relationship between pulmonary complications and ASIA Impairment Scale Grades A (p = 0.0002) and B (p = 0.04) at admission. Pulmonary complications did not affect long-term conversion of ASIA Impairment Scale grades.CONCLUSIONS:The ASIA Impairment Scale grade was the fundamental clinical entity predicting pulmonary complications. Although pulmonary complications significantly increased LOS, they did not increase mortality rates and did not adversely affect the rate of conversion to a better ASIA Impairment Scale grade in patients with SCI. Maximum canal compromise, maximum spinal cord compression, and Acute Physiology and Chronic Health Evaluation-II score had no relationship to pulmonary complications.

Objective . The objectives of the study were to detect high-risk areas and to examine how racial and ethnic status affect the geographic distribution of female breast cancer mortality in Texas. Analyses were based on county-level data for the years from 2000 to 2008. Materials and Methods . Breast cancer mortality data were obtained from the Texas Cancer Registry, and the Spatial Scan Statistics method was used to run Purely Spatial Analyses using the Discrete Poisson, Bernoulli, and Multinomial models. Results and Conclusions . Highest rates of female breast cancer mortality in Texas have shifted over time from southeastern areas towards northern and eastern areas, and breast cancer mortality at the county level is distributed heterogeneously based on racial/ethnic status. Non-Hispanic blacks were at highest risk in the northeastern region and lowest risk in the southern region, while Hispanics were at highest risk in the southern region along the border with Mexico and lowest risk in the northeastern region.

OBJECTIVE:Low levels of safety climate and training have been associated with higher occurrence of occupational-related health outcomes; workplace violence and verbal abuse could be considered an early indicator of escalating psychological workplace violence. We examined whether low level of safety factors were associated with a higher prevalence of verbal abuse at the workplace.METHODS:We used data from a cross-sectional survey administered among a stratified random sample of 1,000 employees from 10 of the 29 public hospitals in Costa Rica. Odds ratios (OR) and 95% confidence intervals (95%CI) were calculated using survey logistic regression models to estimate the association between safety factors and verbal abuse from the following sources: administrators, supervisors, patients, patients' relatives and coworkers.RESULTS:There was a high prevalence of verbal abuse among the healthcare workforce from both external (i.e., patients and patients' relatives) and internal workplace sources (i.e., coworkers, supervisors and administrators). A low level of safety climate was associated with verbal abuse from all sources with associations ranging from verbal abuse from administrators (OR=6.07; 95%CI: 2.05-17.92) to verbal abuse from patients (OR=2.24; 95%CI: 1.23-4.09).CONCLUSION:These results highlight the need to address organizational characteristics of the workplace that may increase the risk of verbal abuse for the future development of prevention interventions in this setting.

In the immediate period after traumatic spinal cord injury (SCI) a variety of secondary injury mechanisms combine to gradually expand the initial lesion size, potentially leading to diminished neurological outcomes at long-term follow-up. Riluzole, a benzothiazole drug, which has neuroprotective properties based on sodium channel blockade and mitigation of glutamatergic toxicity, is currently an approved drug that attenuates the extent of neuronal degeneration in patients with amyotrophic lateral sclerosis. Moreover, several preclinical SCI studies have associated riluzole administration with improved functional outcomes and increased neural tissue preservation. Based on these findings, riluzole has attracted considerable interest as a potential neuroprotective drug for the treatment of SCI. Currently, a Phase I trial evaluating the safety and pharmacokinetic profile of riluzole in human SCI patients is being conducted by the North American Clinical Trials Network (NACTN) for Treatment of Spinal Cord Injury. The current review summarizes the existing preclinical and clinical literature on riluzole, provides a detailed description of the Phase I trial, and suggests potential opportunities for future investigation. Clinical trial registration no.: NCT00876889.

Diurnal rhythms influence many of the physiological processes that act to maintain homeostasis of the body in response to different environmental changes. Thus, disturbances in diurnal rhythms can lead to various physiological complications. Repeated exposure to psychostimulants may cause long-term effects by disturbing diurnal rhythms. The aim of the present study is to use the open field assay to determine whether repeated exposure to the psychostimulant methylphenidate (MPD) changes diurnal locomotor activity patterns of female adult Sprague-Dawley (SD) rats. As much as 31 female adult SD rats were divided into four groups. On experimental day (ED) 1, all groups were given an injection of saline. On ED 2-7, animals were injected once a day with either saline, or 0.6 mg/kg MPD, or 2.5 mg/kg MPD, or 10 mg/kg MPD depending on the group. On ED 8-10, no injections were given (washout period). On ED 11, animals were treated as they were on ED 2-7. Locomotor movements were recorded using a computerized animal activity monitoring system. The horizontal activity (HA), total distance traveled (TDT), and number of stereotypies (NOS) were analyzed by cosine curve statistical analysis (CCSA) test. The HA and TDT diurnal rhythm activity patterns of ED 2, 7, 8, and 11 were significantly different (p < 0.05) from the control recording of ED 1 according to the CCSA test. The observation obtained in this study suggests that repeated administration of MPD (all doses tested) is able to change diurnal locomotor patterns, which indicates that chronic MPD treatment exerts long-term effects.

Background: Laboratory evidence is presented of significant associations between reduced maternal serum folate and vitamin B12 levels and neural tube birth defects (NTD) compared to referents. Methods: This was an incident case-control study. Cases of neural tube defects (including anencephaly and open spina bifida) diagnosed in residents within 100 miles of the US-Mexico border from January 1993 to October 2000 were eligible. Most cases were diagnosed in utero upon visits to clinics, obstetrical or genetic expert offices. Cases identified upon hospital admission or at delivery were also eligible. Cases identified after discharge were not. Controls were matched on geographic region, maternal age, race/ethnicity, gestational age, and type of health insurance (including none). Results: Three hundred eighty-two border area residents (107 cases and 275 individually matched controls) provided biological specimens. Median folate concentrations for case mothers were 36% lower than controls (9.8 ng/mL vs. 15 ng/mL). Maternal serum folate concentrations in quartiles above 9.5 ng/mL indicated significantly reduced risk (OR = 0.4, OR = 0.3, and OR = 0.2). Likewise, the risk for NTD decreased (OR = 0.4, OR = 0.3, and OR = 0.2) in quartiles of sera B12 concentrations above 246 pg/mL. Conclusions: Physician attention is invited to significantly lower concentrations of serum folate and vitamin B12 in women with NTD-affected pregnancies. This study assayed sera samples from women while still pregnant or immediately after delivery. The confounding effect of reduced folate and B12 levels with other biological and chemical exposures will be addressed in subsequent communications.

Methylphenidate (MPD), or Ritalin, is a psychostimulant that is prescribed for an extended period of time to children and adolescents with attention deficit hyperactivity disorder. Adolescence is a time of critical brain maturation and development, and the drug exposure during this time could lead to lasting changes in the brain that endure into the adulthood. Circadian rhythms are 24 h rhythms of physiological processes that are synchronized by the master-clock, the suprachiasmatic nucleus, to keep the body stable in a changing environment. The aim of present study is to observe the effect of repeated MPD exposure on the locomotor diurnal rhythm activity patterns of female adolescent Sprague-Dawley (SD) rats using the open field assay. 31 female adolescent SD rats were divided into four groups: control, 0.6 mg/kg, 2.5 mg/kg, and 10 mg/kg MPD group. On experimental day 1, all groups were given an injection of saline. On experimental days 2-7, animals were injected once a day with either saline, 0.6 mg/kg, 2.5 mg/kg, or 10 mg/kg MPD, and experimental days 8-10 were the washout period. A re-challenge injection was given to each animal on experimental day 11 with the similar dose as the experimental days 2-7. The locomotor movements were counted by the computerized animal activity monitoring system. The data were analyzed statistically to find out whether the diurnal rhythm activity patterns were altered. The obtained data showed that repeated administrations of 2.5 mg/kg and 10 mg/kg MPD were able to change the locomotor diurnal rhythm patterns, which suggests that these MPD doses exerts long-term effects.

BACKGROUND:We collected sample data on radon concentrations concurrently in the air, water, and soil in the northern part of the Texas-Mexico border (both sides) popularly known as Paso Del Norte.METHODS:These field data were used to statistically correlate relative contributions of yard soil, tap water, location, and house features to concentrations of radon indoors.RESULTS:Indoor air radon concentrations in some homes were up to nine-fold the limit recommended by the US Environmental Protection Agency (USEPA). Concentrations of radon in tap water were up to nearly three-fold the recommended limit. Apartments and manufactured homes had generally greater concentrations of indoor radon. Statistically significant associations were indicated between indoor radon air levels and radon in the soil (P < 0.001); radon in the water and radium in water (P = 0.016); radon air levels and apartment living (P = 0.010); and mobile homes vs. wood, brick, and stucco construction (P = 0.016).CONCLUSION:Radon soil gas, apartment living, and the aluminum plank wall environment of mobile homes were associated with elevated indoor radon in the homes studied. Physician's attention is invited to the potential nontrivial risk from radon, as it becomes trapped inside enclosed structures. This article is intended to serve as a resource for primary care physicians who want to better understand the distribution and contributing factors for indoor radon. The Surgeon General recommends every US home be tested for radon as of January 13, 2005.

Objectives: This study estimated the prevalence of chronic back pain among migrant farmworker family members and identified associated work and non-work variables. Methods: Migrant farmworkers (n = 390 from 267 families) from Starr County, Texas were interviewed in their home once a year for 2 years. The original survey included items measuring demographics, smoking, sleep, farm work, and chronic back pain. For this cross-sectional analysis, multi-level logistic regression was used to identify associated work and other variables associated with chronic back pain while accounting for intraclass correlations due to repeated measures and multiple family members. Results: The prevalence of chronic back pain during the last migration season ranged from 9.5% among the youngest children to 33.3% among mothers. Variables significantly associated with chronic back pain were age (odds ratio [ OR], 1.03, per year increase), depressive symptoms while migrating (OR, 8.72), fewer than 8 hours of sleep at home in Starr County (OR, 2.26), fairly bad/very bad quality of sleep while migrating (OR, 3.25), sorting crops at work (OR, 0.18), and working tree crops (OR, 11.72). Conclusion: The role of work exposures, depressive symptoms, and sleep in chronic back pain among farmworkers warrants further examination. Refinements in outcome and exposure assessments are also needed given the lack of a standardized case definition and the variety of tasks and crops involved in farm work in the United States.

Geospatial tools were used to evaluate radioactivity in drinking water and an association with cleft birth defects. From the use of a space-time clustering program (SaTScan), a significantly increased relative risk of 3.0 (95% CI, 1.8-4.3) for cleft births in northwest Harris County was previously reported for the period from 1990 through 1994. This cluster occurred in an area containing water wells with alpha radiation that exceeded allowed standards. New data for a decade later (from 1999 through 2002) from the recently formed Texas Birth Defects Registry and concurrent data for radium in tap water from the Texas Commission on Environmental Quality made it possible to conduct a follow-up investigation. Rates of cleft birth defects were again significantly (P<.001) greater both in ZIP codes and census tracts with elevated radium concentration in drinking water. Adjustment for sex of newborn, maternal age, race, and educational achievement did not remove this association. A persistent pattern in two separate study periods makes the reported association more robust and noteworthy for the attention of Texas physicians. Introduction Orofacial cleft birth defects are some of the more common congenital anomalies.1 The incidence varies among investigations (depending on the data sources and the inclusion or noninclusion of stillbirth and abortions with the live birth totals). In Texas, during the period from 1999 through 2002, a total of 851 babies were born with cleft palate alone and 1563 with cleft lip, with or without cleft palate.2 Cleft palate alone had a rate of 5.87 per 10,000 births (95% CI, 5.47-6.26) and cleft lip had a rate of about 10.78 per 10,000 births (95% CI, 10.25-11.31). The causes of cleft palate and cleft lip have not been firmly established. Current theory holds that cleft formation is a heterogeneous process; thus, defects are likely to result from a variety of causes, including genetic influences and environmental insults3-19 Several studies have reported that exposures to radiation involve teratogenic risks.20-26 Exposure of animals to radium, in the phase of organogenesis comparable to that in humans, has been shown to result in abnormal and incomplete embryonic development.22,23,27 Ritenouer22 found that maternal exposure to gamma radiation in pregnancy resulted in preimplantation death, growth retardation, and central nervous system defects. Brent28 reported growth retardation, microcephaly, and mental retardation in the offspring of women who were treated with therapeutic radiation for medical reasons before knowing they were pregnant. Studies of atomic bomb survivors in Hiroshima and Nagasaki, Japan, indicated that the risk of malformations was greatest between 8 to 15 weeks of gestation.27,29 The major defect in children born after the A-bomb was decreased size and shape of the cranium.30 Domestic exposure to radiation has also been implicated in the development of birth defects, including cleft defects. An epidemiological study conducted in the 1950s in New York31 found an elevated rate of malformations, specifically cleft malformations, in areas underlain Spatial Distribution of Orofacial Cleft Defect Births in Harris County, Tex... http://texasmedicalassociation.com/Template.aspx?id=7287 1 of 10 5/13/2010 9:09 AM by uranium-bearing igneous rocks. More recently, studies in the former East Germany reported a 9.4% increase in the rates of cleft malformations subsequent to the meltdown of the Chernobyl reactor in 1986.7,32 In all, both ionizing and nonionizing radiation have been shown to impair animal and human reproductive capacity.33,34 Uranium-bearing formations occur in Texas and Mexico and coincide geographically with the recharge area of the Gulf Coast ground water aquifer. While these radioactive deposits exist at depth, they could be brought to the surface in connection with human activities. Among others, the presence of uranium → radium → radon isotopes could be anticipated in the production water and wastewater associated with hydrocarbon exploration.35-37 In the late 1980s and 1990s, urban development began spilling rapidly into northwest Harris County, Texas. Some of the previous land uses might not have been fully compatible with this urban advance and the development of groundwater wells. During the 1980s and early 1990s, elevated concentrations of radium-226 and radon-222 were reported in several wells in northwest Harris County, Texas, by Cech and coinvestigators.38-43 Radium concentrations, up to 22 pCi/L, were found in the tap water near a major hydrocarbon exploration field. Radon concentrations, as great as 2,000 pCi/L, were also detected in the same area. That elevated domestic level radiation continues to be an issue in Harris County is evident from a 2003 monograph by the National Resources Defense Council, which stated that the average radon levels in the Harris County public water supplies are twice the proposed national standard of 300 pCi/L44 While radon is not routinely monitored in the public water supplies, the US Environmental Protection Agency (USEPA) has established 5 pCi/L as the maximum contaminant level (MCL) for radium (combined Ra-226 and Ra-228 isotopes).45 In this regard, the Texas Commission on Environmental Quality (TCEQ) registered that during the period from 1999 through 2002 as many as 18 different public water supply systems in Harris County were still in violation of this combined MCL.46 In the same part of Harris County, our earlier study reported a cluster of significantly greater-than-expected orofacial cleft defect births for the period from 1990 through 1994 (with the relative risk = 3.0, P=.043).47 Twenty-two babies were born in this period with cleft defect, against the expected seven, in an area of 4 square miles. In that study, Geographic Information System (GIS) methods were used to map home addresses of cleft births and all births in Harris County according to the data from the Bureau of Vital Statistics. Those data were analyzed by using the space-time clustering program SaTScan,48 developed by the National Cancer Institute. The distribution was compared with historical data on radium and radon in the water collected by the first author. Methods The Texas Birth Defects Registry, which became operational in the 1994s, has data from 1999 through 2002. This new (and presumably better verified) data set made it possible to reexamine the spatial distribution of cleft defects for consistency of an association with concurrent new data on distribution of waterborne radium. The present study population consisted of births nearly one decade later than our earlier study. Concurrent new data on radium concentrations in household water supplies from 1999 through 2002 were obtained from TCEQ. Data on the reference population of all births in Harris County were obtained from the Texas Center for Health Statistics. Fetal experience in the first trimester is the key to the formation of orofacial cleft birth defects. To take into account this developmental stage vulnerability and to maintain temporality for the hypothesized exposureeffect relationship, the radium distribution record was restricted to observations made from January 1, 1999, through June 30, 2002, and orofacial cleft birth defect records were restricted to births between July 1, 1999, and December 31, 2002. The locations of public water supply wells were geocoded and mapped by latitude and longitude with MapInfo software.49 Combined radium (Ra-226 and Ra-228) concentrations in community well water in Harris County, Texas, were mapped (Figure 1). A contour map of radium concentrations was constructed by using SURFER50 (step not shown) and overlaid with maps of Harris County ZIP codes and census tracts. These geographic polygons were dichotomized as low radium (<3 pCi/L) and elevated radium (≥3 pCi/L). The MCL for combined total radium is 5 pCi/L. However, the threshold of 3 pCi/L was used to classify zip codes and census tracts for radium exposure, because radium found in Harris County is primarily in the form of Ra-226, which makes up roughly 60% of the total combined radium concentrations. The same rationale and the same threshold concentrations were used in the earlier studies.47 Census tracts and ZIP codes corresponding to the exposure dichotomy were identified and mapped by using Spatial Distribution of Orofacial Cleft Defect Births in Harris County, Tex... http://texasmedicalassociation.com/Template.aspx?id=7287 2 of 10 5/13/2010 9:09 AM MapInfo shape files for the year 2000 (Figure 2, a and b). Residential addresses of orofacial cleft defect births were geocoded by using MapMarker software.51 ZIP codes stated in the address and the ZIP codes generated from geocoding were verified for consistency by using MapMarker and the Postmaster General's address database system.52 Most (98.4%) of the addresses could be accurately geocoded to a point location; the remaining small proportion (1.6%) could not be accurately geocoded due to missing or incomplete address information. The geocoded addresses were mapped with MapInfo. The SaTScan software48 was used to investigate spatial clustering of cases, and multivariate models were used to adjust cleft birth rates for demographic covariates. A longitude and latitude grid for Harris County that was constructed contained square "blocks" measuring 0.01 degrees (approximately 0.6 miles) on each side. This allowed us to count the number of cases vs noncases within each "block." The "block" rates were modeled by using a Bernoulli clustering algorithm, which progressively grouped "blocks" with elevated rates adjusting for the inhomogeneity of the background population. Case enumeration of orofacial cleft defect births was aggregated for the 4-year period of this study, and rates by ZIP codes and census tracts per 10,000 live births were calculated by using total live births by ZIP codes and census tracts as denominators, respectively. Maps dis