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Background Harmane (1-methyl-9H-pyrido[3,4-β]indole), a potent neurotoxin that has tremor-producing properties in animal models, is present in many foods; although we have demonstrated a difference in tissue harmane concentrations in ET cases vs. controls, all work to date has involved blood samples. Objectives We quantified harmane concentrations in human cerebellum, a brain region of particular pathogenic interest in essential tremor (ET), comparing ET to control brains. Methods Cerebellar cortex was snap frozen and stored at −80 °C in aliquots for biochemical analyses. Harmane concentration was assessed using high performance liquid chromatography. Results Geometric mean brain harmane concentrations (adjusted for postmortem interval [PMI] and freezer time) were higher in ET cases than controls: 1.0824 (95% confidence interval = 0.9405–1.2457) vs. 0.8037 (0.6967–0.9272), p = 0.004. Geometric mean of brain harmane concentrations (adjusting for PMI and freezer time) was highest in ET cases who reported other relatives with tremor (1.2005 [0.8712–1.6541]), intermediate in ET cases without family history (1.0312 ([0.8879–1.1976]), and both were significantly higher than controls (p = 0.02). Conclusions This study provides additional evidence of a possible etiological importance of this toxin in some cases of the human disease ET.

To promote clinical and patient oriented research, as part of the Second International ALS Conference in Tarrytown, NY, USA, seven pairs of clinicians and scientists were asked to lead discussions with meeting attendees on six major topics (one of which was discussed by two groups); each one the focus of a 90-min Breakout Session. Approximately 25 meeting attendees participated in each session. The Breakout Sessions considered six major themes: 1) Approaches to encourage clinicians to engage in more clinical research to discover the pathogenesis and cause of ALS; 2) Exploring avenues to build more effective partnerships between basic scientists and ALS physicians; 3) Increasing patient interest and commitment to participating in non-trial clinical research; 4) Brainstorming about factors that are most critical to the discovery of the pathogenesis and cause of ALS; 5) Finding ways to incorporate clinical research projects into clinical trials; and 6) Developing state-of-the-art epidemiological studies to solve the mystery of ALS. In this paper, we present the reports from each of the Breakout Sessions; and we provide a wrap-up of the entire conference.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease. The current status of the epidemiology, challenges to its study, and novel study design options are discussed in this paper. We focus on recent results from large-scale population based prospective studies, case-control studies and population based registries, risk factors, and neuropathologic fi ndings in chronic traumatic encephalomyelopathy. We identify areas of interest for future research, including time-trends in the incidence and prevalence of ALS; the meaning of lifetime risk; the phenotypic description of ALS; the defi nition of familial versus sporadic ALS, syndromic aspects of ALS; specifi c risk factors such as military service, life style factors such as smoking, the use of statins, and the presence of β -N-methylamino-L-alanine (BMAA), an excitotoxic amino acid derivative possibly produced by cyanobacteria found in almost every terrestrial and aquatic habitat; the emergence and disappearance of an endemic ALS in areas of the Pacifi c; and gene-environment interactions in the etiology of ALS. To move the epidemiology forward, we suggest using well-characterized cohorts of newly diagnosed ALS patients to identify risk and prognostic factors; storing biological material for future studies; building on the National ALS Registry as a resource of future studies; working in multidisciplinary consortia; and addressing the possible early life etiology of ALS.

Sporadic amyotrophic lateral sclerosis (ALS) is one of the most devastating neurological diseases; most patients die within 3 to 4 years after symptom onset. Oxidative stress is a disturbance in the pro-oxidative/antioxidative balance favoring the pro-oxidative state. Autopsy and laboratory studies in ALS indicate that oxidative stress plays a major role in motor neuron degeneration and astrocyte dysfunction. Oxidative stress biomarkers in cerebrospinal fluid, plasma, and urine are elevated, suggesting that abnormal oxidative stress is generated outside of the central nervous system. Our review indicates that agricultural chemicals, heavy metals, military service, professional sports, excessive physical exertion, chronic head trauma, and certain foods might be modestly associated with ALS risk, with a stronger association between risk and smoking. At the cellular level, these factors are all involved in generating oxidative stress. Experimental studies indicate that a combination of insults that induce modest oxidative stress can exert additive deleterious effects on motor neurons, suggesting that multiple exposures in real-world environments are important. As the disease progresses, nutritional deficiency, cachexia, psychological stress, and impending respiratory failure may further increase oxidative stress. Moreover, accumulating evidence suggests that ALS is possibly a systemic disease. Laboratory, pathologic, and epidemiologic evidence clearly supports the hypothesis that oxidative stress is central in the pathogenic process, particularly in genetically susceptive individuals. If we are to improve ALS treatment, well-designed biochemical and genetic epidemiological studies, combined with a multidisciplinary research approach, are needed and will provide knowledge crucial to our understanding of ALS etiology, pathophysiology, and prognosis.

The use of serum bromine concentration (SeBr) as a measure of exposure was examined in an occupational cohort. Associations with work site, department type, chemical handling, and occupation, as proxy measures of exposure, were studied. SeBr was associated with all of these measures. SeBr was also associated with various demographic characteristics (age, country of origin, and education) in men. In women, there was no association between SeBr and age, country of origin, or education. The use of SeBr as a measure of exposure is discussed. The conclusion is that the exposure to bromine can be assessed by regular monitoring of SeBr.

The objective of this study was to design and evaluate a household-level arsenic education and well water arsenic testing intervention to increase arsenic awareness in Bangladesh. The authors randomly selected 1,000 study respondents located in 20 villages in Singair, Bangladesh. The main outcome was the change in knowledge of arsenic from baseline to follow-up 4 to 6 months after the household received the intervention. This was assessed through a pre- and postintervention quiz concerning knowledge of arsenic. Respondents were between 18 and 102 years of age, with an average age of 37 years; 99.9% were female. The knowledge of arsenic quiz scores for study participants were significantly higher at follow-up compared with baseline. The intervention was effective in increasing awareness of the safe uses of arsenic-contaminated water and dispelling the misconception that boiling water removes arsenic. At follow-up, nearly all respondents were able to correctly identify the meaning of a red (contaminated) and green (arsenic safe) well relative to arsenic (99%). The educational program also significantly increased the proportion of respondents who were able to correctly identify the health implications of arsenic exposure. However, the intervention was not effective in dispelling the misconceptions in the population that arsenicosis is contagious and that illnesses such as cholera, diarrhea, and vomiting could be caused by arsenic. Further research is needed to develop effective communication strategies to dispel these misconceptions. This study demonstrates that a household-level arsenic educational program can be used to significantly increase arsenic awareness in Bangladesh.

Essential tremor (ET) is a widespread late-life neurological disease. Genetic and environmental factors are likely to play important etiological roles. Harmane (1-methyl-9H-pyrido[3,4-b]indole) is a potent tremor-producing neurotoxin. Previously, elevated blood harmane concentrations were demonstrated in ET cases compared to controls, but these observations have all been cross-sectional, assessing each subject at only one time point. Thus, no one has ever repeat-assayed blood harmane in the same subjects twice. Whether the observed case-control difference persists at a second time point, years later, is unknown. The current goal was to reassess a sample of our ET cases and controls to determine whether blood harmane concentration remained elevated in ET at a second time point. Blood harmane concentrations were quantified by a well-established high-performance liquid chromatography method in 63 ET cases and 70 controls. A mean of approximately 6 yr elapsed between the initial and this subsequent blood harmane determination. The mean log blood harmane concentration was significantly higher in cases than controls (0.30 ± 0.61 g(-10)/ml versus 0.08 ± 0.55 g(-10)/ml), and the median value in cases was double that of controls: 0.22 g(-10)/ml versus 0.11 g(-10)/ml. The log blood harmane concentration was highest in cases with a family history of ET. Blood harmane concentration was elevated in ET cases compared to controls when reassessed at a second time point several years later, indicating what seems to be a stable association between this environmental toxin and ET.

Background Polybrominated diphenyl ethers (PBDEs) are a class of brominated flame retardants commonly used in a wide range of products. Prenatal exposure to PBDEs has been associated with adverse neurodevelopment. Our objective was to characterize predictors of exposure to PBDEs among a multi-ethnic, low-income cohort of pregnant women enrolled from highly urban communities in New York City between years 2009–2010. Methods During the first half of pregnancy we collected 316 maternal serum samples and administered an extensive questionnaire including items on demographics, diet and lifestyle. We measured 12 PBDE congeners in blood samples. Using bivariate and multivariate approaches, we regressed the most commonly detected PBDE congeners (PBDE-47, -99, -100 and -153) against potential demographic, dietary and lifestyle predictor variables. Results At least one PBDE congener was detected in each serum sample. Our analyses demonstrate unique predictor patterns for PBDE-47, -99, -100 and -153 based on demographic, lifestyle and dietary characteristics of women. Higher education and increased use of household electronics were associated with higher levels of all 4 congeners. Six characteristics were associated with PBDE-153 serum concentrations, more than for any other congener. These include maternal education, household income, body mass index, solid dairy consumption, processed meat consumption and frequent use of household electronics. Conclusions PBDE exposure in this widespread in this cohort, though levels are lower than previous assessments of US pregnant women. Lower levels may be in response to legislation restricting the production, sale and use of these compounds. In our cohort, we did not observe any individual predictor or a consistent pattern of several predictors representing a significant source of PBDE exposure. These data suggest that legislation and policy may be more effective at reducing exposure than personal lifestyle modifications.

Objective To reduce arsenic (As) exposure, we evaluated the effectiveness of training community members to perform water arsenic (WAs) testing and provide As education compared to sending representatives from outside communities to conduct these tasks. Methods We conducted a cluster based randomized controlled trial of 20 villages in Singair, Bangladesh. Fifty eligible respondents were randomly selected in each village. In 10 villages, a community member provided As education and WAs testing. In a second set of 10 villages an outside representative performed these tasks. Results Overall, 53% of respondents using As contaminated wells, relative to the Bangladesh As standard of 50 μg/L, at baseline switched after receiving the intervention. Further, when there was less than 60% arsenic contaminated wells in a village, the classification used by the Bangladeshi and UNICEF, 74% of study households in the community tester villages, and 72% of households in the outside tester villages reported switching to an As safe drinking water source . Switching was more common in the outside-tester (63%) versus community-tester villages (44%). However, after adjusting for the availability of arsenic safe drinking water sources, well switching did not differ significantly by type of As tester (Odds ratio =0.86[95% confidence interval 0.42-1.77). At follow-up, among those using As contaminated wells who switched to safe wells, average urinary As concentrations significantly decreased. Conclusion The overall intervention was effective in reducing As exposure provided there were As-safe drinking water sources available. However, there was not a significant difference observed in the ability of the community and outside testers to encourage study households to use As-safe water sources. The findings of this study suggest that As education and WAs testing programs provided by As testers, irrespective of their residence, could be used as an effective, low cost approach to reduce As exposure in many As-affected areas of Bangladesh.

Organochlorine pesticides (OCPs) are persistent endocrine disruptors. OCPs cross the placenta; this prenatal exposure has been associated with adverse pregnancy outcomes. We investigated associations between prenatal exposure to OCPs and gestational age and birth weight in 600 infants born between 1960 and 1963. The primary OCP was 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (p,p′-DDT), its primary metabolite, 1,1′-dichloro-2,2'-bis(p-chlorophenyl)ethylene(p,p′-DDE) and the contaminant, 1,1,1-trichloro-2-(p-chlorophenyl)-2-(o-chlorophenyl)-ethane (o,p′-DDT). Regression analysis indicated that for each natural log unit increase in p,p′-DDT, birth weight increased by 274 grams (95% CI 122, 425) when controlling for p,p′-DDE and o,p′-DDT. At a given level of p,p′-DDT exposure, o,p′-DDT and p,p′-DDE were associated with decreased birth weight. p,p′-DDE was negatively associated with length of gestation, controlling for p,p′-DDT and o,p′-DDT. These findings suggest opposing associations between exposure to p,p′-DDT and p,p′-DDE and birth weight. We did not find evidence to support mediation by maternal thyroid hormone status nor that the association differed by sex.

Background Polychlorinated biphenyls (PCBs), known endocrine disruptors, were banned in 1979 but persist in the environment. Previous studies are inconsistent regarding prenatal exposure to PCBs and pregnancy outcomes. We investigated associations between prenatal exposure to PCBs and gestational length and birth weight. Methods In a sample of 600 infants (born between 1960 and 1963) randomly selected from Child Health and Development Studies participants followed through adolescence we measured 11 PCB congeners in maternal post partum sera (within three days of delivery). Length of gestation was computed from the reported first day of the last menstrual period (LMP) and delivery date. Linear regression was used to estimate associations between PCB exposure and gestational age and birth weight, adjusting for potential confounders. PCBs were grouped according to hypothesized biological action (1b (sum of weak phenobarbital inducers), 2b (sum of limited dioxin activity), and 3 (sum of CYP1A and CYP2b inducers)) or degree of ortho- substitution (mono, di, tri). Secondary analyses examined associations between total PCB exposure and exposure to individual congeners. Results Each unit increase in mono-ortho substituted PCBs was associated with a 0.30 week decrease (95% confidence interval (CI) -0.59, -0.016), corresponding to a 2.1 (95% CI −4.13, -0.11) day decrease in length of gestation. Similar associations were estimated for di-ortho substituted PCBs, (1.4 day decrease; (95% CI −2.9, 0.1)) and group 3 PCBs (0.84 day decrease; (95% CI −1.8, 0.11). We found similar associations in congener specific analyses and for the sum of congeners. Conclusions Our study provides new evidence that PCB exposure shortens length of gestation in humans. This may have public health implications for population exposures.

Background and Aims: An emerging body of evidence indicates that early-life arsenic (As) exposure may influence the trajectory of health outcomes later in life; however, the mechanisms underlying t...

Background and Aims: Epidemiologic evidence suggests that effects of prenatal phthalate exposure on child executive function and behavior are sexually dimorphic. We reported (ISEE 2010) adverse ass...

Background and Aims: Prenatal exposure to environmentally relevant levels of PBDEs may impair normal brain development by interfering with adequate maternal thyroid function, which is essential to ...

Background and Aims: Several reports indicate that drinking water arsenic (WAs) and manganese (WMn) are associated with children’s intellectual function. Very little is known, however, about possib...

Recently, epidemiologic studies of developmental neurotoxicology have been challenged to increase focus on co-exposure to multiple toxicants. Earlier reports, including our own work in Bangladesh, have demonstrated independent associations between neurobehavioral function and exposure to both arsenic (As) and manganese (Mn) in school-aged children. Our earlier studies, however, were not designed to examine possible interactive effects of exposure to both As and Mn. To allow investigation of possible synergistic impact of simultaneous exposures, we recruited a new sample of 299 8-11 year old children, stratified by design on As (above and below 10 μg/L) and Mn (above and below 500 μg/L) concentrations of household wells. When adjusted only for each other, both As and Mn in whole blood (BAs; BMn) were significantly negatively related to most WISC-IV subscale scores. With further adjustment for socio-demographic features and ferritin, BMn remained significantly associated with reduced Perceptual Reasoning and Working Memory scores; associations for BAs, and for other subscales, were expectably negative, significantly for Verbal Comprehension. Urinary As (per gram creatinine) was significantly negatively associated with Verbal Comprehension scores, even with adjustment for BMn and other contributors. Mn by As interactions were not significant in adjusted or unadjusted models (all p's>0.25). Findings are consistent with other reports documenting adverse impact of both As and Mn exposure on child developmental outcomes, although associations appear muted at these relatively low exposure levels.

Long-term exposure to high concentrations of lead results in renal dysfunction. During a prospective study of environmental lead and pregnancy outcomes in 1502 women residing in two towns in Yugoslavia, we explored whether moderate exposure to lead results in increased rates of proteinuria. The geometric mean blood lead concentrations (BPb) were 17.1 and 5.1 micrograms/dl in the smelter and nonexposed towns, respectively. Increases in BPb were associated with increased odds ratios for both trace and > or = 1+ proteinuria, measured using a urinary dipstick. Comparing the women in the upper 10th percentile of exposure to those in the lowest 10th percentile, the adjusted odds ratio for > or = 1+ proteinuria was 4.5 (95% CI 1.5, 13.6). Similarly, the adjusted odds ratio for trace proteinuria was 2.3 (95% CI 1.3, 4.1). Similar to other studies showing associations between chronic exposure to lead and renal dysfunction, our data suggest that long-term exposure to environmental lead may be associated with proteinuria. Images Figure 1. Figure 2.

For a prospective study of lead exposure, iron status, and infant development, we recruited infants living in a smelter town and a non-lead-exposed town in Kosovo, Yugoslavia. Among 392 infants assessed at age 2 years, the mean Mental Development Index (MDI), Bayley Scales of Infant Development, was 105.2. At age 2 years, geometric mean blood lead concentrations were 35.5 and 8.4 micrograms/dl, respectively, among infants from the exposed and nonexposed towns. After controlling for variables associated with MDI, we found significant independent associations for both blood lead and hemoglobin concentrations. For example, a rise in blood lead concentration at age 2 years from 10 to 30 micrograms/dl was associated with an estimated 2.5 point decrement in MDI (p = 0.03); statistically nonsignificant decrements were associated with blood lead levels measured at birth and at 6, 12, and 18 months of age. A decrease in hemoglobin concentration at 18 months of age from 12 to 10 gm/dl was associated with an estimated 3.4 point decrement in MDI (p = 0.02); the latter association was present in both towns, suggesting that it was due to iron deficiency anemia independent of lead exposure. The findings suggest that the brain is vulnerable to the effects of both lead exposure and anemia before 2 years of age. On a global basis, the developmental consequences of anemia may exceed those of lead exposure.

This paper tests the hypothesis that exposure to lead during pregnancy is associated with reduced intrauterine growth and an increase in preterm delivery. The sample comprises women, recruited at mid-pregnancy, residing in Titova Mitrovica, a lead smelter town, or in Pristina, a non-exposed town 25 miles away. Both towns are in the province of Kosovo, Yugoslavia. Mean blood lead concentrations (BPb's) at mid-pregnancy were 0.92 mumol/L (+/- 0.38, N = 401) in the exposed town and 0.27 mumol/L (+/- 0.09, N = 506) in the comparison town. No differences were found between towns for either birthweight or length of gestation. Mean birthweight was 3308 (+/- 566) grams in Titova Mitrovica and 3361 (+/- 525) grams in Pristina. Mean length of gestation was 274 (+/- 18.8) days in Titova Mitrovica and 275 (+/- 15.6) days in Pristina. After adjustment for the effects of potential confounders, no significant relationships were found between maternal BPb measured at mid-pregnancy, at delivery or in the umbilical cord and either birthweight, length of gestation, or preterm delivery (less than 37 weeks). We conclude that exposure to environmental lead does not impair fetal growth or influence length of gestation.

Background Arsenic methylation relies on folate-dependent one-carbon metabolism and facilitates urinary As elimination. Clinical manifestations of As toxicity vary considerably among individuals and populations, and poor methylation capacity is thought to confer greater susceptibility. Objective After determining that folate deficiency, hyperhomocysteinemia, and low urinary creatinine are associated with reduced As methylation, and that As exposure is associated with increased genomic methylation of leukocyte DNA, we asked whether these factors are associated with As-induced skin lesion risk among Bangladeshi adults. Methods We conducted a nested case–control study of 274 cases who developed lesions 2 years after recruitment, and 274 controls matched to cases for sex, age, and water As. Results The odds ratios and 95% confidence intervals (CIs) for development of skin lesions for participants who had low folate (< 9 nmol/L), hyperhomocysteinemia (men, > 11.4 μmol/L; women, > 10.4 μmol/L), or hypomethylated leukocyte DNA at recruitment (< median) were 1.8 (95% CI, 1.1–2.9), 1.7 (95% CI, 1.1–2.6), and 1.8 (95% CI, 1.2–2.8), respectively. Compared with the subjects in the first quartile, those in the third and fourth quartiles for urinary creatinine had a 0.4-fold decrease in the odds of skin lesions (p < 0.01). Conclusions These results suggest that folate deficiency, hyperhomocysteinemia, and low urinary creatinine, each associated with decreased As methylation, are risk factors for As-induced skin lesions. The increased DNA methylation associated with As exposure previously observed, and confirmed among controls in this study, may be an adaptive change because hypomethylation of leukocyte DNA is associated with increased risk for skin lesions.

We aimed to investigate oxidative stress biomarkers in a cross-sectional pilot study of 50 participants with sporadic ALS (SALS) compared to 46 control subjects. We measured urinary 8-oxodeoxyguanosine (8-oxodG), urinary 15-F(2t)-isoprostane (IsoP), and plasma protein carbonyl by ELISA methods. We also determined if ELISA measurement of 8-oxodG could be validated against measures from high-pressure liquid chromatography coupled with electrochemical detection, the current standard method. We found that 8-oxodG and IsoP levels adjusted for creatinine were significantly elevated in SALS participants. These differences persisted after age and gender were controlled in regression analyses. These markers are highly and positively correlated with each other. 8-oxodG measured by the two techniques from the same urine sample were positively correlated (p

A recent Lancet series highlighted enormous loss to young children's developmental potential in developing countries, from exposure to sociocultural and health risks. The possibility that nutritional deficiencies might exacerbate the adverse impact of environmental exposures to developmental toxicants such as heavy metals and pesticides has not been explored. While both arsenic and manganese exposures have known neurotoxicity in adults, systematic investigation in young children has only recently begun. Five hundred and ninety 6- and 10-year-old Bangladeshi children participated in three overlapping studies. Well-water arsenic and manganese were measured from home wells; urine and blood samples were provided; and sociodemographic and household characteristics obtained. For new analyses, 'stunting' was defined as 2 or more standard deviations below the Centers for Disease Control and Prevention gender-specific height-for-age norms. Developmental assessments employed culturally adapted variants of the WISC-III (age 10) or WPPSI-III (age 6). In prior analyses, after adjusting for social factors, well-water arsenic and manganese were both significantly associated with poorer developmental scores at age 10; associations for water arsenic at 6 years were significant, but attenuated. Negative associations with metal exposures held up in newer analyses, and stunting was significantly associated with lower intellectual functioning in analyses considering either metal. There were no significant stunting-by-metal interactions. Developmental risks often co-occur. Millions in South Asia are exposed to naturally occurring arsenic and manganese through household wells. Stunting affects more than 25% of young children in developing countries. The combined neurocognitive loss from both risks, although rarely jointly studied, represents a substantial loss of global potential.

Essential tremor (ET) is a widespread late-life neurological disease. Genetic and environmental factors likely play an etiological role. Harmane (1-methyl-9H-pyrido[3,4- b ]indole) is a potent tremor-producing neurotoxin. In 2002, we demonstrated elevated blood harmane concentrations in an initial sample of 100 ET cases compared to 100 controls. Between 2002 and 2007, we assembled a new and larger sample of ET cases and controls. We now attempt to replicate our previous findings. Cases and controls were frequency-matched on age, gender, and race. Blood harmane concentrations were quantified by high-performance liquid chromatography. Subjects comprised 150 ET cases and 135 controls (mean age 65.3 ± 15.5 vs. 65.5 ± 14.2 years, p = 0.94). Mean log blood harmane concentration was ∼50% higher in cases than controls (0.50 ± 0.54 g −10 /ml vs. 0.35 ± 0.62 g −10 /ml, p = 0.038). In a logistic regression analysis, log blood harmane concentration was associated with ET (OR adjusted 1.56, 95% CI 1.01–2.42, p = 0.04), and odds of ET was 1.90 (95% CI 1.07–3.39, p = 0.029) in the highest versus lowest log blood harmane tertile. Log blood harmane was highest in ET cases with familial ET (0.53 ± 0.57 g −10 /ml), intermediate in cases with sporadic ET (0.43 ± 0.45 g −10 /ml) and lowest in controls (0.35 ± 0.62 g −10 /ml) (test for trend, p = 0.026). Blood harmane appears to be elevated in ET. The higher concentrations in familial ET suggests that the mechanism may involve genetic factors.

We are prospectively examining the relation between environmental lead exposure and pregnancy outcome in cohorts of women exposed to a wide range of air lead concentrations. Titova Mitrovica, Yugoslavia, is the site of a large lead smelter, refinery, and battery factory. At midpregnancy, 602 women in T. Mitrovica and 900 women in Pristina, a non-lead-exposed control town, were interviewed. Blood was obtained for blood lead (PbB), hemoglobin, erythrocyte protoporphyrin, and serum ferritin measurements. Women were seen again at delivery, at which time maternal and umbilical cord blood samples were obtained. While many demographic and social characteristics were similar across the two towns, women in Pristina were more likely to report employment outside the home, cigarette smoking, and alcohol use during pregnancy. As expected, PbB levels were substantially higher in the smelter town. At midpregnancy, PbB geometric means were 17.1 micrograms/dL in T. Mitrovica and 5.1 micrograms/dL in Pristina; 86% of the pregnant women in T. Mitrovica, compared to 3.4% of those in Pristina, had PbB levels greater than 10 micrograms/dL. Within T. Mitrovica, distance between the home and the smelter was the most important predictor of PbB at mid-pregnancy and delivery. Husband's employment in the lead industry was associated with a significant increase in maternal PbB levels independent of place of residence. Higher maternal serum ferritin concentrations were associated with lower PbB levels, suggesting that dietary iron inhibits lead absorption. Overall, the placenta was a poor barrier to lead; the relationship between maternal PbB and umbilical cord PbB was linear across a wide range of PbB levels.

Initial examination of the surgery experience of participants in a large employer-sponsored second opinion program revealed minimal savings in medical resource costs. But closer examination of relative savings for specific procedure categories showed that the greatest savings are for high-cost procedures: hysterectomy, prostatectomy, back surgery, and hip replacement. Furthermore, a nonconfirming second opinion does not dissuade patients from some procedures. Decisions about which procedures to include in a mandatory program should consider volume, costs, and effects of nonconfirmation, as well as the advantages of a mandatory second opinion for skeptical patients, or for patients for whom a controversial procedure has been recommended.

Background: Studies in cell culture and animal models indicate that arsenic exposure induces modifications in DNA methylation, including genome-wide DNA hypomethylation. It is not known whether arsenic exposure influences genomic DNA methylation in human populations chronically exposed to arsenic-contaminated drinking water. Objective: The objective of this study was to determine whether arsenic is associated with genomic hypomethylation of peripheral blood leukocyte (PBL) DNA in Bangladeshi adults who are chronically exposed to arsenic. We also investigated whether arsenic-induced alterations in DNA methylation may be influenced by folate nutritional status. Design: PBL DNA methylation and concentrations of plasma folate, plasma arsenic, and urinary arsenic were assessed in 294 adults in Araihazar, Bangladesh. Genomic PBL DNA methylation was measured by using a [ 3 H]-methyl incorporation assay. Results: Urinary arsenic, plasma arsenic, and plasma folate were positively associated with the methylation of PBL DNA (P = 0.009, 0.03, and 0.03, respectively). Stratification of participants by folate nutritional status [

Background/Aim: Harmane [1-methyl-9H-pyrido(3,4-b)indole] is a tremor-producing neurotoxin. Blood harmane concentrations are elevated in essential tremor (ET) patients for unclear reasons. Potential mechanisms include increased dietary harmane intake (especially through well-cooked meat) or genetic-metabolic factors. We tested the hypothesis that meat consumption and level of meat doneness are higher in ET cases than in controls. Methods: Detailed data were collected using the Lawrence Livermore National Laboratory Meat Questionnaire. Results: Total current meat consumption was greater in men with than without ET (135.3 ± 71.1 vs. 110.6 ± 80.4 g/day, p = 0.03) but not in women with versus without ET (80.6 ± 50.0 vs. 79.3 ± 51.0 g/day, p = 0.76). In an adjusted logistic regression analysis in males, higher total current meat consumption was associated with ET (OR = 1.006, p = 0.04, i.e., with 10 additional g/day of meat, odds of ET increased by 6%). Male cases had higher odds of being in the highest than lowest quartile of total current meat consumption (adjusted OR = 21.36, p = 0.001). Meat doneness level was similar in cases and controls. Conclusion: This study provides evidence of a dietary difference between male ET cases and male controls. The etiological ramifications of these results warrant additional investigation.

Prenatal and early-life exposure to lead is hypothesized to have a range of adverse effects on childhood health. Drawing on data collected from a population-based prospective cohort study of a highly exposed town and a low exposed town in Kosovo, Yugoslavia we assessed whether elevated maternal blood lead (BPb) concentrations during pregnancy were associated with reduced childhood measures of attained height and BMI or growth rate, and whether the associations, if any, were mediated by maternal thyroid hormone concentration at mid-pregnancy. There was no association between blood lead levels and height or BMI in either town. However, increased maternal thyroid hormone was unexpectedly associated with reduced attained childhood height, and growth rate of height from 6.5 to 10 years, in the low-exposure town. We examine potential reasons for this unexpected inverse association.

Background Manganese is a common natural contaminant of groundwater in Bangladesh. In this cross-sectional study we assessed the association between water manganese and all-cause infant mortality in the offspring of female participants in the Health Effects of Arsenic Longitudinal Study Cohort. Methods In 2001, drinking water samples were collected, a history of well use was obtained, and a history of birth outcomes was ascertained. To avoid misclassification of exposure, women were included only if they had been drinking from the same well for most of their childbearing years (marriage years – well years ≤ 2). Of a total of 26,002 births (among 6,537 mothers), 3,837 children were born to women with this profile. The current analysis was based on the portion of these infants (n = 3,824) with recorded exposure and outcome status, 335 of whom died before reaching 1 year of age. Results Infants exposed to water manganese greater than or equal to the 2003 World Health Organization standard of 0.4 mg/L had an elevated mortality risk during the first year of life compared with unexposed infants [odds ratio (OR) = 1.8; 95% confidence interval (CI), 1.2–2.6]. Adjustment for water arsenic, indicators of social class, and other variables did not appreciably alter these results. When the population was restricted to infants born to recently married parents (marriage year 1991 or after), this elevation was more pronounced (OR = 3.4; 95% CI, 1.5–7.9). Conclusions These preliminary findings indicate a possible association between manganese exposure and infant mortality. However, given the methodologic limitations of this study, the association needs to be confirmed through future work.

Populations in South and East Asia and many other regions of the world are chronically exposed to arsenic-contaminated drinking water. To various degrees ingested inorganic arsenic (InAs) is methylated to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) via folate-dependent one-carbon metabolism; impaired methylation is associated with adverse health outcomes. Consequently folate nutritional status may influence arsenic methylation and toxicity. The objective of this study was to test the hypothesis that folic acid supplementation of arsenic-exposed adults would increase arsenic methylation. Two hundred adults in a rural region of Bangladesh previously found to have low plasma concentrations of folate (= 9 nmol/L) were enrolled in a randomized double-blind placebo-controlled folic acid-supplementation trial. Plasma concentrations of folate and homocysteine and urinary concentrations of arsenic metabolites were analyzed at baseline and after 12 wk of supplementation with folic acid at a dose of 400 µg/d or placebo. The increase in the proportion of total urinary arsenic excreted as DMA in the folic acid group (72% before and 79% after supplementation) was significantly (P < 0.0001) greater than that in the placebo group as was the reduction in the proportions of total urinary arsenic excreted as MMA (13% and 10% respectively; P < 0.0001) and as InAs (15% and 11% respectively; P < 0.001). These data indicate that folic acid supplementation to participants with low plasma folate enhances arsenic methylation. Because persons whose urine contains low proportions of DMA and high proportions of MMA and InAs have been reported to be at greater risk of skin and bladder cancers and peripheral vascular disease these results suggest that folic acid supplementation may reduce the risk of arsenic-related health outcomes. (authors)

We recently reported an adverse association between drinking water arsenic and cognitive function in 10-year-old children living in Bangladesh (Wasserman et al. 2004), where approximately 30–40 million people (British Geological Survey and Bangladesh Department of Public Health Engineering 2001) are chronically exposed to naturally elevated levels of arsenic in groundwater pumped from approximately half the total of approximately 10 million tube wells in the country. That finding supplements reports of neurologic sequelae of acute and chronic exposure in adults (Bolla-Wilson and Bleecker 1987; Morton and Caron 2003; Morton and Dunnette 1994; Pershagen et al. 1981; Schoolmeester and White 1980). Two other studies have examined children’s intellectual function, in a small sample of children from a Mexican lead smelter area (Calderon et al. 2001) and from Taiwanese children in regions with and without elevated As in well water (Tsai et al. 2003). Both reported negative associations with As exposure, although the domains of vulnerable intellectual function differed across investigations. In a related investigation (Wasserman et al. 2006), we recently observed poorer intellectual functioning, primarily in visual motor skills, in 10-year-olds from a region in Bangladesh where household well water concentrations were variable in manganese but extremely low in As. These findings were consistent with other investigations of motor function in children exposed to high levels of Mn (e.g., Takser et al. 2003). We sought to expand these findings on children’s intellectual function to a younger age group, drawing once again on children of adults participating in our prospective study of the health effects of As in Araihazar, Bangladesh. Wells in the study site, a 25-km2 region located approximately 30 km east of Dhaka, are characterized by a wide range of As concentrations in drinking water, with 75% exceeding the World Health Organization (WHO) As standard of 10 μg/L, and 53% exceeding the Bangladesh standard of 50 μg/L (van Geen et al. 2003a). We report here the results of a cross-sectional investigation of intellectual function in 301 6-year-old children.

Background: -Carboline alkaloids (e.g., harmane) are highly tremorogenic chemicals. Animal protein (meat) is the major dietary source of these alkaloids. The authors previously demonstrated that blood harmane concentrations were elevated in patients with essential tremor (ET) vs controls. Whether this difference is due to greater animal protein consumption by patients or their failure to metabolize harmane is unknown. Objective: The aim of this study was to determine whether patients with ET and controls differ with regard to 1) daily animal protein consumption and 2) the correlation between animal protein consumption and blood harmane concentration. Methods: Data on current diet were collected with a semiquantitative food frequency questionnaire and daily calories and consumption of animal protein and other food types was calculated. Blood harmane concentrations were log-transformed (logHA). Results: The mean logHA was higher in 106 patients than 161 controls (0.61 0.67 vs 0.43 0.72 g 10 /mL, p 0.035). Patients and controls consumed similar amounts of animal protein (50.2 19.6 vs 49.4 19.1 g/day, p 0.74) and other food types (animal fat, carbohydrates, vegetable fat) and had similar caloric intakes. In controls, logHA was correlated with daily consumption of animal protein (r 0.24, p 0.003); in patients, there was no such correlation (r 0.003, p 0.98). Conclusions: The similarity between patients and controls in daily animal protein consumption and the absence of the normal correlation between daily animal protein consumption and logHA in patients suggests that another factor (e.g., a metabolic defect) may be increasing blood harmane concentration in patients. NEUROLOGY 2005;65:391-396

BACKGROUND Indian Asian men residing in the United Kingdom have a higher prevalence of hyperhomocysteinemia than do their European counterparts. This has been largely attributed to dietary deficiencies in cobalamin associated with vegetarianism among these Indian Asians. OBJECTIVE We aimed to ascertain the prevalence of folate and cobalamin deficiencies and hyperhomocysteinemia in Bangladesh. DESIGN Plasma concentrations of homocysteine, folate, and cobalamin and urinary concentrations of creatinine were assessed in 1650 adults in Bangladesh. RESULTS The prevalence of hyperhomocysteinemia (men: >11.4 micromol/L; women: >10.4 micromol/L) was markedly (P < 0.0001) greater among men (63%; x +/- SD: 15.3 +/- 9.5 micromol/L) than among women (26%; 9.5 +/- 4.7 micromol/L). Folate was lower (9.8 +/- 6.5 and 12.3 +/- 7.6 nmol/L, respectively), whereas cobalamin was higher (281 +/- 115 and 256 +/- 118 pmol/L, respectively) (P < 0.0001 for both) among men than among women. Folate explained 15% and cobalamin explained 5% of the variation in homocysteine concentrations. For men, folate (P = 0.005) and cobalamin (P = 0.03) were positively correlated with urinary creatinine. Smoking (P < 0.0003) and betelnut use (P < 0.0002) were independent negative predictors of folate. CONCLUSIONS Bangladeshi men have a high prevalence of hyperhomocysteinemia, which is more closely associated with folate than with cobalamin, although other factors, eg, smoking and betelnut use, may also contribute to its cause. The positive correlations between urinary creatinine and plasma folate and cobalamin were unanticipated and could suggest that, in marginal nutrition, these vitamins may be limiting for creatine biosynthesis.

Motor signs in essential tremor (ET) are varied. Patients may have limb tremors, including postural, kinetic (e.g. writing, pouring), and rest tremors, head tremor, voice tremor, or chin tremor. Factor analysis allows one to determine whether these signs fall into a smaller number of discrete domains. Such an analysis has not been performed on a group of ET cases. ET cases (n = 168) were recruited from the Neurological Institute of New York and a videotaped examination was performed. A factor analysis was performed on 17 motor items. Four distinct factors emerged, explaining 68.7% of the total variance. These were factor I (action tremor in the dominant arm), factor II (action tremor in the nondominant arm), factor III (tremor at rest) and factor IV (chin tremor, head tremor, and voice tremor). The demonstration of these four factors will be of potential use for pathological and genetic studies as well as interventional studies, as will be discussed.

Occupational exposures to manganese and organic solvents cause parkinsonism as well as prominent action tremor, resembling essential tremor (ET), yet their association with ET has not been studied. These chemicals cause cerebellar pathology. Cerebellar changes have been linked with ET. Using lifetime occupational histories, the authors demonstrated that occupational exposures were similar in cases and controls, which does not support an etiologic link between occupational exposures to these chemicals and ET.

There are several reasons to study caffeine, coffee, and ethanol intake in essential tremor (ET) patients. ET patients also might modify their use of these beverages because of their effects on tremor. Intake of caffeine, coffee, and ethanol has not been quantified in a group of ET patients. Our objective is to use a semiquantitative food frequency questionnaire to compare current daily intake of coffee, caffeine, and ethanol in ET patients and controls. A total of 130 ET cases were patients at the Neurological Institute of New York, and 175 controls were ascertained by random digit dialing. Caffeine (in milligrams) and ethanol (in grams) intake were calculated from a semiquantitative food-frequency questionnaire. Mean daily caffeine intake in patients was 138.4 versus 246.6 mg in controls; medians were 101.1 versus 175.5 mg (P < 0.001). Mean daily ethanol intake in patients was 8.2 versus 6.2 gm in controls; medians were 2.4 versus 1.9 gm (P = 0.89). Cases drank less coffee than controls, but drank similar amounts of tea, soft drinks, fruit juices, and milk. Daily caffeine intake was not correlated with tremor severity or duration. ET patients consumed less caffeine than did controls, which is likely to be a dietary modification in response to tremor. The observation that caffeine consumption was not correlated with tremor severity raises the additional possibility that lower caffeine consumption in ET patients may not exclusively be a response to tremor. A prospective study is needed to explore whether decreased caffeine consumption is a risk factor for ET.

In this study, the authors investigated the associations between socioeconomic status and exposures to polychlorinated biphenyls (PCBs) and dichlorodiphenyldichloroethylene (DDE) in a cohort of inner-city African-American pregnant women. Data for this study were derived from the Columbia Presbyterian Medical Center subcohort of the National Collaborative Perinatal Project. African-American women from whom venous blood had been collected during their third trimester of pregnancy during the time period between 1960 and 1965 were included in the current study (n = 152). Prenatal samples were assayed for PCB and DDE concentrations. The authors used linear-regression analysis to explore the association between socioeconomic indicators and PCB and DDE concentrations. Mean concentrations of the 4 most abundant congeners (i.e., PCB4) and total DDE were 3.9 microg/l and 37.2 microg/l, respectively. In adjusted analyses, income was associated significantly with an increase in serum concentrations of PCBs, whereas education was not. Neither income nor education was associated with concentrations of DDE. The authors concluded that maternal socioeconomic indicators may influence the effects of exposure to PCBs among African-American pregnant women.

Although semen analysis is routinely used to evaluate the male partner in infertile couples, sperm measurements that discriminate between fertile and infertile men are not well defined.We evaluated two semen specimens from each of the male partners in 765 infertile couples and 696 fertile couples at nine sites. The female partners in the infertile couples had normal results on fertility evaluation. The sperm concentration and motility were determined at the sites; semen smears were stained at the sites and shipped to a central laboratory for an assessment of morphologic features of sperm with the use of strict criteria. We used classification-and-regression-tree analysis to estimate threshold values for subfertility and fertility with respect to the sperm concentration, motility, and morphology. We also used an analysis of receiver-operating-characteristic curves to assess the relative value of these sperm measurements in discriminating between fertile and infertile men.The subfertile ranges were a sperm concentration of less than 13.5 x 10(6) per milliliter, less than 32 percent of sperm with motility, and less than 9 percent with normal morphologic features. The fertile ranges were a concentration of more than 48.0 x 10(6) per milliliter, greater than 63 percent motility, and greater than 12 percent normal morphologic features. Values between these ranges indicated indeterminate fertility. There was extensive overlap between the fertile and the infertile men within both the subfertile and the fertile ranges for all three measurements. Although each of the sperm measurements helped to distinguish between fertile and infertile men, none was a powerful discriminator. The percentage of sperm with normal morphologic features had the greatest discriminatory power.Threshold values for sperm concentration, motility, and morphology can be used to classify men as subfertile, of indeterminate fertility, or fertile. None of the measures, however, are diagnostic of infertility.

The Yugoslavia Prospective Study of environmental lead exposure has studied the associations between exposure to lead and pregnancy outcomes; childhood neuropsychological, behavioral, and physical development; and hematologic, renal, and cardiovascular function. The cohort comprises 577 children born to women recruited at midpregnancy in two towns in Kosovo, Yugoslavia; one town is the site of a lead smelter, refinery, and battery plant and the other is 25 miles away and relatively unexposed. A sample of these children has been followed at 6-month intervals through 7.5 years of age. Blood lead concentrations ranged from 1 to 70 microg/dl. Exposure to lead was not associated with adverse pregnancy outcomes. Exposure was associated with modest decrements in intelligence, small increases in blood pressure, higher risks of proteinuria, small increases in behavior problems, and perturbed hematopoiesis. Only at low level exposures (i.e.

This analysis compares the rates of spontaneous abortion among women living in the vicinity of a lead smelter with those of women living in a town where blood lead levels were low. Data derive from the obstetric histories of both groups of women obtained while seeking prenatal care for a later pregnancy. A total of 639 women (304 exposed, 335 unexposed) had at least one previous pregnancy and lived at the same address since their first pregnancy. The geometric mean blood lead concentrations in the sample at the time of the interviews were 0.77 mumol/L in the exposed town and 0.25 mumol/L in the unexposed town. The rates of spontaneous abortions in first pregnancies were similar, with 16.4 percent of women in the exposed town and 14.0 percent in the unexposed town reporting loss. The adjusted odds ratio relating town of residence to spontaneous abortion was 1.1 (95% CI = 0.9, 1.4). This analysis represents the first systematic attempt to seek an association between environmental lead exposure and spontaneous abortion. As such, the failure to find a positive association strongly suggests that at the levels of exposure represented in our sample, such an association does not exist.

For a prospective study of lead exposure and early development, we recruited pregnant women from a lead smelter town and from an unexposed town in Yugoslavia and followed their children through 7 years of age. In this paper we consider associations between lifetime lead exposure, estimated by the area under the blood lead (BPb) versus time curve (AUC7), and intelligence, with particular concern for identifying lead's behavioral signature. The Wechsler Intelligence Scales for Children-Version III (WISC-III) was administered to 309 7-year-old children, 261 of whom had complete data on intelligence, blood lead, and relevant sociodemographic covariates (i.e., Home Observation for the Measurement of the Environment (HOME), birth weight, gender, sibship size, and maternal age, ethnicity, intelligence, and education). These showed anticipated associations with 7-year intelligence, explaining 41-4% of the variance in Full Scale, Performance, and Verbal IQ. Before covariate adjustment, AUC7 was unrelated to intelligence; after adjustment, AUC7 explained a significant 2.8%-4.2% of the variance in IQ. After adjustment, a change in lifetime BPb from 10 to 30 micro/dl related to an estimated decrease of 4.3 Full Scale IQ points; estimated decreases for Verbal and Performance IQ were 3.4 and 4.5 points, respectively. AUC7 was significantly and negatively related to three WISC-III factor scores: Freedom from Distractibility, Perceptual Organization, and Verbal Comprehension; the association with Perceptual Organization was the strongest. Consistent with previous studies, the IQ/lead association is small relative to more powerful social factors. Findings offer support for lead's behavioral signature; perceptual-motor skills are significantly more sensitive to lead exposure than are the language-related aspects of intelligence. Images Figure 1. A Figure 1. B Figure 1. C Figure 1. D Figure 2.

Interventions may need to begin before pregnancy The prevalence of overweight and obesity in women of childbearing age and in pregnant women has steadily increased over the past 20 years.1 2 Maternal obesity is associated with a variety of adverse outcomes for the mother, such as increased mortality, pre-eclampsia, and gestational diabetes. It is also associated with adverse outcomes for the child at birth (such as large for gestational age babies and fetal distress) and in later life (such as increased risk of later obesity, metabolic disorders including insulin resistance and dyslipidemia, hypertension, asthma, and behavioral problems).3 The linked paper by Reynolds and colleagues (doi:10.1136/bmj.f4539) is the first to describe associations between maternal obesity and risk of cardiovascular morbidity and mortality in mid-life.4 What are the possible …

We examined associations between blood lead concentration (BPb) and blood pressure in 282 children age 5.5 years, residing in an exposed or unexposed town in Kosovo, Yugoslavia. Mean BPb in the exposed town was 37.3 micrograms per dl (standard deviation = 12.0 micrograms per dl) and in the unexposed town was 8.7 micrograms per dl (standard deviation = 2.8 micrograms per dl). After adjustment, a 10 micrograms per dl increase in BPb was associated with a 0.5 (95% CL = -0.2, 1.3) mmHg increase in systolic and a 0.4 (95%, CL = -0.1, 0.9) mmHg increase in diastolic blood pressure. These associations, although compatible with no relation, are similar to those observed in adults; and the data are most consistent with a small association between BPb and blood pressure.