Parietal dysfunction during number processing in children with fetal alcohol spectrum disorders.

Number processing deficits are frequently seen in children prenatally exposed to alcohol. Although the parietal lobe, which is known to mediate several key aspects of number processing, has been shown to be structurally impaired in fetal alcohol spectrum disorders (FASD), effects on functional activity in this region during number processing have not previously been investigated. This fMRI study of 49 children examined differences in activation associated with prenatal alcohol exposure in five key parietal regions involved in number processing, using tasks involving simple addition and magnitude comparison. Despite generally similar behavioral performance, in both tasks greater prenatal alcohol exposure was related to less activation in an anterior section of the right horizontal intraparietal sulcus known to mediate mental representation and manipulation of quantity. Children with fetal alcohol syndrome and partial fetal alcohol syndrome appeared to compensate for this deficit by increased activation of the angular gyrus during the magnitude comparison task.

A tensor-based morphometry analysis of regional differences in brain volume in relation to prenatal alcohol exposure.

Reductions in brain volumes represent a neurobiological signature of fetal alcohol spectrum disorders (FASD). Less clear is how regional brain tissue reductions differ after normalizing for brain size differences linked with FASD and whether these profiles can predict the degree of prenatal exposure to alcohol. To examine associations of regional brain tissue excesses/deficits with degree of prenatal alcohol exposure and diagnosis with and without correction for overall brain volume, tensor-based morphometry (TBM) methods were applied to structural imaging data from a well-characterized, demographically homogeneous sample of children diagnosed with FASD (n = 39, 9.6-11.0 years) and controls (n = 16, 9.5-11.0 years). Degree of prenatal alcohol exposure was significantly associated with regionally pervasive brain tissue reductions in: (1) the thalamus, midbrain, and ventromedial frontal lobe, (2) the superior cerebellum and inferior occipital lobe, (3) the dorsolateral frontal cortex, and (4) the precuneus and superior parietal lobule. When overall brain size was factored out of the analysis on a subject-by-subject basis, no regions showed significant associations with alcohol exposure. FASD diagnosis was associated with a similar deformation pattern, but few of the regions survived FDR correction. In data-driven independent component analyses (ICA) regional brain tissue deformations successfully distinguished individuals based on extent of prenatal alcohol exposure and to a lesser degree, diagnosis. The greater sensitivity of the continuous measure of alcohol exposure compared with the categorical diagnosis across diverse brain regions underscores the dose dependence of these effects. The ICA results illustrate that profiles of brain tissue alterations may be a useful indicator of prenatal alcohol exposure when reliable historical data are not available and facial features are not apparent.

Alteration of infant attention and activity by polychlorinated biphenyls: unravelling critical windows of susceptibility using physiologically based pharmacokinetic modeling.

Pre- and postnatal exposure to polychlorinated biphenyls (PCBs) can impair behavioural function in animal models at doses within the range at which humans are commonly exposed. Yet, epidemiologic studies conducted in the US and Europe are inconsistent with regard to the developmental effects of lactational exposure to these chemicals. This inconsistency may be due to limitations in the current methodological approaches for assessing postnatal exposure to PCBs. Our study used a physiologically based pharmacokinetic (PBPK) model to simulate blood PCB levels during specific pre- and postnatal periods and to evaluate the relation of those levels to infant behaviour. A previously validated PBPK model was used to simulate infant blood PCB-153 levels at delivery and on a month-by-month basis during the first year of life for Inuit infants enrolled in a longitudinal birth cohort. Infant behaviour was assessed using the Behaviour Rating Scales (BRS) of the Bayley Scales of Infant Development (BSID-II) at 11 months of age and video coding of inattention and activity measured during the administration of the mental development subscale of the BSID-II. The estimated pre- and postnatal PCB exposure measures predicted significant increases in inattention and activity at 11 months. Whereas inattention was related to prenatal exposure, activity level, measured by non-elicited activity, was best predicted by postnatal exposure, with the strongest association obtained for simulated PCB levels during the 4th month of life. These findings are consistent with previous reports indicating PCB-induced behavioural alteration in attention and activity level. Simulated infant toxicokinetic profiles for the first year of life revealed windows of susceptibility during which PCBs may impair infant attention and activity.

Behavioural correlates of the P3b event-related potential in school-age children.

The latency and amplitude of the P3b component of event-related potentials (ERPs) have been related to behavioural performance on several attention and memory tasks in adult populations. However, the extent to which these results apply to children is unknown. This study examined the neurobehavioral correlates of the P3b component in a longitudinal sample of school-age children from Arctic Québec. Children (N=110; mean age=11.3years) were assessed on an ERP auditory oddball paradigm and a neurobehavioral evaluation targeting several aspects of cognition, including the Stewart Extended Continuous Performance Test (E-CPT), California Verbal Learning Test (CVLT), Stroop Color-Word Interference Test, and five subtests from the Wechsler Intelligence Scale for Children-Fourth edition (WISC-IV). P3b latency was positively related to reaction time measures and negatively associated with performance on the WISC-IV Digit Span Forward subtest. Amplitude of the P3b was associated with shorter completion time on the Stroop test and better delayed recognition memory performance among children who did not use semantic strategies on the CVLT. Profile analyses revealed no difference in scalp distribution of the P3b according to performance on these tests. The results are consistent with previous studies with older participants and suggest that, despite age-related differences in waveform and scalp distribution, the P3b component relates to similar neurocognitive processes in children and adults.

The relation of low-level prenatal lead exposure to behavioral indicators of attention in Inuit infants in Arctic Quebec.

The aim of this study was to investigate the association between prenatal exposure to lead (Pb) and several aspects of behavioral function during infancy through examiner ratings and behavioral coding of video recordings. The sample consisted of 169 11-month-old Inuit infants from Arctic Quebec. Umbilical cord and maternal blood samples were used to document prenatal exposure to Pb. Average blood Pb levels were 4.6 mug/dL and 5.9 mug/dL in cord and maternal samples respectively. The Behavior Rating Scales (BRS) from the Bayley Scales of Infant Development (BSID-II) were used to assess behavior. Attention was assessed through the BRS and behavioral coding of video recordings taken during the administration of the BSID-II. Whereas the examiner ratings of behaviors detected very few associations with prenatal Pb exposure, cord blood Pb concentrations were significantly related to the direct observational measures of infant attention, after adjustment for confounding variables. These data provide evidence that increasing the specificity and the precision of the behavioral assessment has considerable potential for improving our ability to detect low-to-moderate associations between neurotoxicants, such Pb and infant behavior.

Prenatal exposure of the northern Québec Inuit infants to environmental contaminants.

The Inuit population residing in Nunavik (northern Québec, Canada) relies on species from the marine food web for subsistence and is therefore exposed to high doses of environmental contaminants such as polychlorinated biphenyls and methylmercury and to a lesser extent lead. In view of the neurotoxic properties of these substances following developmental exposure, we initiated a study on infant development in this remote coastal population. Here we report the magnitude of prenatal exposure to these contaminants and to selective nutrients in Inuit mothers and their newborns who were recruited on the Hudson Bay coast. We conducted interviews during the women's pregnancies and at 1 and 11 months postpartum and collected biological samples for mercury, lead, polychlorinated biphenyls (PCBs), and chlorinated pesticides analyses as well as selenium and N-3 polyunsaturated fatty acids (n3-PUFA). Cord blood, maternal blood, and maternal hair mercury concentrations averaged 18.5 microg/L, 10.4 microg/L, and 3.7 microg/g, respectively, and are similar to those found in the Faroe Islands but lower than those documented in the Seychelles Islands and New Zealand cohorts. Concentrations of PCB congener 153 averaged 86.9, 105.3, and 131.6 microg/kg (lipids) in cord plasma, maternal plasma, and maternal milk, respectively; prenatal exposure to PCBs in the Nunavik cohort is similar to that reported in the Dutch but much lower than those in other Arctic cohorts. Levels of n3-PUFA in plasma phospholipids and selenium in blood are relatively high. The relatively low correlations observed between organochlorine and methylmercury concentrations may make it easier to identify the specific developmental deficits attributable to each toxicant. Similarly, the weak correlations noted between environmental contaminants and nutrients will facilitate the documentation of possible protective effects afforded by either n3-PUFA or selenium against neurotoxic contaminants.

Determinants of polychlorinated biphenyls and methylmercury exposure in inuit women of childbearing age.

The objectives of this study were to to identify maternal characteristics associated with traditional food consumption and to examine food items associated with polychlorinated biphenyls (PCBs) and mercury body burden in pregnant Inuit women from Northern Québec. We interviewed women from three communities at mid-pregnancy and at 1 and 11 months postpartum. We measured PCBs, Hg, and selenium in maternal blood; Hg was also measured in maternal hair. The women reported eating significant amounts of fish, beluga muktuk/fat, seal meat, and seal fat. Although consumption of fish and seal was associated with lower socioeconomic status, consumption of beluga whale was uniform across strata. Fish and seal meat consumption was associated with increased Hg concentrations in hair. Traditional food intake during pregnancy was unrelated to PCB body burden, which is more a function of lifetime consumption. This study corroborated previous findings relating marine mammal and fish consumption to increased Hg and selenium body burden. Despite widespread knowledge regarding the presence of these contaminants in traditional foods, a large proportion of Inuit women increased their consumption of these foods during pregnancy, primarily because of pregnancy-related changes in food preferences and the belief that these foods are beneficial during pregnancy.

Prognostic factors and response to fludarabine therapy in patients with Waldenström macroglobulinemia: results of United States intergroup trial (Southwest Oncology Group S9003).

Current information on Waldenström macroglobulinemia (WM) is based on retrospective or single-institution studies of patients requiring therapy. Between 1992 and 1998, 231 patients with WM were enrolled in a prospective observational multicenter clinical trial. Of these, 182 patients with symptomatic or progressive disease were treated with 4 to 8 cycles of therapy with a purine nucleoside analogue, fludarabine (FAMP; 30 mg/m(2) of body-surface area daily for 5 days every 28 days). A serum beta2-microglobulin (beta2M) level below 3 mg/L and a hemoglobin level of at least 120 g/L (12 g/dL) at presentation predicted a lower likelihood of requiring therapy. The overall rate of response to FAMP therapy was 36% (95% confidence interval, 29%-44%), with 2% complete remissions. Patients who were 70 years old or older had a substantially lower likelihood of response (odds ratio, 0.34; P =.004) than younger patients. On multivariate analysis, a serum beta2M level of 3 mg/L or higher, hemoglobin level below 120 g/L, and serum IgM level below 40 g/L [4 g/dL] were significant adverse prognostic factors for survival. We developed a simple staging system for WM by using these variables and identified 4 distinct subsets of patients with estimated 5-year overall survival rates of 87%, 64%, 53%, and 22%, and 5-year progression-free survival rates of 83%, 55%, 33%, and 12%. Prognosis in WM is highly variable and serum beta2M was the dominant predictor of a need for therapy and of survival. FAMP has activity against WM. Our staging system may provide guidance for a risk-based approach to the treatment of WM.

Contending with contradictory data in a risk assessment context: the case of methylmercury.

Two large sample, prospective longitudinal studies one in the Seychelles Islands in the Indian Ocean, the other in the Faroes Islands in the North Sea were conducted during the 1990s to examine the effects of prenatal methylmercury exposure on intellectual function in childhood. The Faroes study found evidence linking this exposure to adverse outcome, but the Seychelles study did not. A peer review workshop held in Raleigh, NC, in 1998 concluded that the inconsistencies between the Faroes and Seychelles findings could be explained by differences in study design and sources of exposure. The US Environmental Protection Agency contracted with the National Academy of Sciences (NAS) to convene an expert panel to provide guidance for a new risk assessment for methylmercury. The NAS panel reviewed the Faroes and Seychelles studies in light of data from a smaller New Zealand study and other data not available to the Raleigh reviewers. These additional data provided evidence of adverse effects in studies whose design and source of exposure were similar to that in the Seychelles, leading the NAS panel to conclude that the weight of the evidence supported the Faroes findings. A power analysis, conducted by computing standardized regression coefficients for the three studies, indicated that many of the Faroes findings were so subtle that the power to detect them in the Seychelles study, despite its large sample size, was only about 50%. Because prospective epidemiological studies are often hampered by limited control over confounding and other factors, including unmeasured between cohort differences in genetic vulnerability and nutritional adequacy, inferences about toxicity often depend heavily on a qualitative assessment of the weight of the evidence from multiple studies.

The influence of maternal drinking and drug use on the quality of the home environment of school-aged children.

BACKGROUND: Although many studies have examined the development of children of male alcoholics, few studies have considered substance use by the female caregiver. This study evaluated the relationship between substance use by female caregivers and factors that affect the child-rearing environment. METHODS: A total of 480 inner-city African-American women were recruited during pregnancy for a longitudinal study of the effects of prenatal alcohol use and substance use by caregivers on the development of their children. All women were screened for alcohol consumption at their first prenatal visit to a large urban maternity hospital. Those who averaged seven or more drinks per week (0.5 oz absolute alcohol per day) at the time of conception were invited to participate in the study, as was a 5% random sample of lighter drinkers and abstainers. At the 7.5-year follow-up assessment, the quantity and frequency of alcohol consumption and drug use, as well as several measures of the child-rearing environment, were assessed for 231 of the caregivers. RESULTS: Current alcohol use was uncorrelated with standard demographic factors, such as socioeconomic status, but was related to poorer family functioning, lower quality of parental intellectual stimulation, and higher levels of domestic violence. There were independent effects of illicit drug use on family environment, domestic violence, and caregiver depression. History of drinking during pregnancy, however, was not related to the current child-rearing environment. Poorer parental functioning generally was found only among the caregivers who currently drank both heavily (six or more drinks/occasion) and frequently (three or more days/week). After controlling for lifetime alcohol problems, current drinking still predicted a less cohesive and organized family environment and higher levels of domestic violence. CONCLUSIONS: Current heavy, frequent drinking in this relatively homogenous, economically disadvantaged sample was unrelated to demographics and seemed to have an important negative impact on the quality of the child-rearing environment, whereas drinking during pregnancy was unrelated to the current child-rearing environment.

A phase II trial of etoposide, leucovorin, 5-FU, and interferon alpha 2b (ELFI) + G-CSF for patients with pancreatic adenocarcinoma: a Southwest Oncology Group study (SWOG 9413).

BACKGROUND: Chemotherapeutic treatments using combinations of etoposide, leucovorin and 5-FU (ELF) have shown activity in the treatment of gastrointestinal malignancies. Interferon alpha 2b is known to have antiproliferative effects on several cell lines and has well documented in vitro evidence of synergism with 5-FU. It was postulated that the combination of ELF and interferon alpha 2b would improve response rates and survival in patients with pancreas cancer. METHODS: Fifty-five eligible patients with locally-advanced or metastatic pancreatic adenocarcinoma received a regimen consisting of: i.v. leucovorin at 300 mg/m2/day on Days 1-3 (of 28-day cycle), i.v. etoposide at 80 mg/m2/day on Days 1-3, i.v. 5-FU at 500 mg/m2/day on Days 1-3, subcutaneous interferon alpha 2b at 3 million units TIW, and subcutaneous G-CSF at 5 microg/kg/day on Days 4-14 (or until WBC exceeds 10,000/microl). Patients with no evidence of disease progression continued on treatment for a total of 6 cycles. RESULTS: Complete response was demonstrated in 1 patient, partial response in 5 patients (11% confirmed response rate). The median survival was 5 months, and the six-month survival rate was 40%. Ten patients completed all 6 cycles of treatment. Toxicity-related dose delays and reductions were necessary for most patients. CONCLUSIONS: Although the combination of ELF and interferon alpha 2b (ELFI) has modest activity in pancreatic cancer, it is a toxic and complex regimen that is not superior to other currently available approaches for the chemotherapeutic management of pancreatic cancer. ELFI cannot be recommended as a standard therapy.

A phase II trial of topotecan in esophageal carcinoma: a Southwest Oncology Group study (SWOG 9339).

BACKGROUND: Chemotherapeutic treatments containing topoisomerase I inhibitors have shown antitumor activity against a number of solid tumors. Responses have been seen in Phase I trials using topotecan in ovarian, lung, and esophageal cancer. A phase II trial using continuous infusion topotecan was completed to assess activity in esophagus cancer. METHODS: Forty-five eligible patients with locally-advanced or metastatic squamous cell carcinoma or adenocarcinoma of the esophagus received a regimen consisting of 24-hour continuous infusion topotecan at 1.5 mg/m2/day on Days 1, 8, 15, 22 (of 42-day cycle). Patients continued on treatment until evidence of disease progression or unacceptable toxicity. RESULTS: Partial response was demonstrated in 1 patient (2% confirmed response rate). Thirty-six patients progressed during the first cycle of treatment. The median survival was 3 months, and the median progression-free survival was 1 month. Toxicity was mild with only one Grade 4 toxicity reported. CONCLUSIONS: This phase II trial indicates no significant anti-neoplastic activity for topotecan administered in the dose and schedule to patients with squamous cell or adenocarcinoma of the esophagus.

Transforming family planning programmes: towards a framework for advancing the reproductive rights agenda.

Recent international agreements call for the transformation of family planning programmes from a focus on demographic goals to the promotion of health and rights objectives. But the practical implications of this agenda for current and future programmes remain unclear. Public health resources are devoted to preventing illness and reducing the prevalence and incidence of disease across a population. Human rights methodologies focus on protecting the rights of individuals, and on the right to health and health care. Both of these approaches need to be re-thought and reconciled on a practical level to promote rights-based health programmes. Applying a rights framework to reproductive health programmes means, among other things, focusing as much on the process as on the outcome, incorporating efforts to address the gender and power dimensions of reproductive and sexual decision-making into every level of programme, and focusing on building a sense of entitlement among both the seekers and the providers of services. It also means moving beyond a focus only on the technical quality of clinic-based services to incorporate the ethos of a rights perspective at every level. Political, institutional, and technical barriers to the realisation of the reproductive health and rights agenda include national level politics, lack of capacity within civil society, and lack of transparency of institutional actors.

Neurobehavioral effects of prenatal alcohol exposure at 26 months.

Effects of prenatal alcohol exposure on the Bayley Scales of Infant Development were evaluated at 13 and 26 months and on three language measures at 26 months, in 92 economically disadvantaged, African American toddlers. After consideration of 17 potential confounders, a significant alcohol-related deficit in the Mental Development Index (MDI) was seen at 13 months as was a tendency for poorer Psychomotor Development Index (PDI) performance. The PDI deficit continued to be evident at 26 months. When the 26-month MDI was factor analyzed, four factors emerged: Linguistic Representation, Spatial Fine Motor, Other Fine Motor, and Relational Representation. As in a previous study of these children at 13 months of age, Spatial Fine Motor deficits were specifically associated with prenatal alcohol exposure. These findings appear consistent with reports relating prenatal alcohol exposure to poorer spatial visualization and spatial memory in adolescence. No effects of prenatal exposure were detected on language. Maternal postpartum drinking was associated with decreased language intelligibility.

Breastfeeding effects on intelligence quotient in 4- and 11-year-old children.

OBJECTIVE: A study of preterm children found an IQ advantage among those who were breastfed as infants after controlling for maternal social class and educational status. However, this advantage needs to be examined in light of other maternal characteristics, such as maternal IQ and parenting skills, which were not measured in that study and which have been found to be related to breastfeeding. METHODOLOGY: IQ was assessed in 323 children at 4 years of age on the McCarthy Scales of Children's Abilities and the Peabody Picture Vocabulary Test-Revised and in 280 children on the Wechsler Intelligence Test for Children-Revised at 11 years of age. RESULTS: Children who were breastfed in infancy had significantly higher scores on IQ tests at both ages, even after adjusting for social class and education, confirming the earlier findings and extending them to a predominantly full-term sample. However, the effect of breastfeeding was no longer significant after adjusting for maternal IQ assessed on the Peabody Picture Vocabulary Test-Revised and for parenting skills assessed on the Home Observation for Measurement of the Environment. Significant relations between breastfeeding and Woodcock Reading Achievement scores at 11 years were also reduced to nonsignificant levels after the inclusion of maternal IQ and the Home Observation for Measurement of the Environment. CONCLUSIONS: These findings suggest that the observed advantage of breastfeeding on IQ is related to genetic and socioenvironmental factors rather than to the nutritional benefits of breastfeeding on neurodevelopment. They should not be interpreted as detracting from the medical benefits associated with breastfeeding.

Drinking moderately and pregnancy. Effects on child development.

Children exposed to moderate levels of alcohol during pregnancy show growth deficits and intellectual and behavioral problems similar to, although less severe than, those found in children with fetal alcohol syndrome. Research has begun to examine the extent to which these problems affect the child's ability to function on a day-to-day basis at school and with peers. Findings indicate that "moderate" drinking has much more impact on child development when the mother consumes several drinks in a single day than when she drinks the same quantity in doses of one to two drinks per day over several days.

Bacillus sphaericus inhibits hatching of phlebotomine sand fly eggs.

The effect of Bacillus sphaericus, at various concentrations, on hatching of phlebotomine sand fly eggs was examined using laboratory bioassays. Aqueous suspensions of B. sphaericus, strain 2362, inhibited hatching of eggs of Phlebotomus duboscqi and Sergentomyia schwetzi by 95% at concentrations as low as 0.05 and 0.11 mg/cm2, respectively. In contrast, B. sphaericus did not affect the ability of pupae to emerge as adults.