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The majority of children of mothers with epilepsy are normal, but they are at increased risk for developmental delay. Antiepileptic drugs (AEDs) appear to play a role. Our current knowledge is reviewed, including research design issues and recommendations for future research. In animals, exposure of the immature brain to some AEDs can produce widespread neuronal apoptosis and behavioral deficits. The risks of AEDs in humans are less clear, but recent studies raise concerns, especially for valproate. There is a critical need for well-designed systematic research to improve our understanding of AED effects on the fetal brain.
Animal studies have demonstrated that in utero antiepileptic drug (AED) exposure can produce behavioral as well as anatomical defects, which can occur at dosages lower than those required to produce somatic malformations [1,2]. Gestational or neonatal exposure to benzodiazepines can affect brain chemistry and behavior causing hyperactivity or learning deficits [3,4]. Despite the common use of carbamazepine in humans, very few neurobehavioral studies in animals have been conducted with this AED. In utero carbamazepine exposure did not produce hyperexcitability in primates [5]. Perinatal phenobarbital exposure in rats reduces brain weight [6]. Mice exposed prenatally to phenobarbital have neuronal deficits, reduced brain weight, and impaired development of reflexes, open-field activity, schedule-controlled behavior, spatial learning, and cate- cholamine brain levels [7–12]. Gestational or neonatal exposure to phenytoin reduces brain weight [13,14], alters neuronal membranes in the hippocampus [15], delays neurodevelopment [16], and impairs spatial learning and motor coordination [17–25]. Hyperactivity has been observed in rats and primates following prenatal exposure to phenytoin [5,23,25]. Gestational primidone in rats produces learning deficits and reduces open-field activity [26]. In utero valproate exposure can alter neuronal membranes [27], decrease brain weight in mice [28], and result in adverse neurobehavioral effects [29,30].
Teratogens interact with genotype to produce both anatomical and behavioral defects. Whether a defect occurs depends on a susceptible genotype and may involve the interaction of multiple-liability genes [31]. Proposed mechanisms underlying teratogenicity of AEDs include folate, ischemia, neuronal suppression, reactive intermediates (e.g., epoxides or free radicals), and AED-induced neuronal apoptosis [32]. The mechanisms of anatomical and behavioral teratogenesis may well differ, because it appears that the highest risk of anatomical defects is from first-trimester AED exposure, whereas the highest risk of behavioral defects appears to be from exposure during the third trimester. One of the leading hypotheses of anatomical teratogenesis involves oxidative macromolecular damage from free radicals formed as reactive intermediates of AED metabolism [33]. However, it is unclear if this mechanism contributes to AED-induced behavioral teratogenesis. Folate deficiency during pregnancy reduces neurogenesis and increases apoptosis [34], but folate nutritional status during pregnancy has not been shown to impact neurodevelopment [35]. As discussed below, there is mounting evidence that AED-induced apoptosis is the most likely candidate for the behavioral deficits. However, it is possible that one of the other noted mechanisms could contribute to triggering the apoptosis.
The immature brain is susceptible to widespread neuronal apoptosis secondary to a variety of insults including trauma, seizures, excessive oxygen, and certain drugs [36–43]. The observation that third-trimester gestational ethanol exposure can produce widespread neuronal apoptosis and neurobehavioral deficits led to the hypothesis that the adverse behavioral effects of AED exposure might bedue to asimilar mechanism[40,44]. The effect of ethanol is mediated by combined NMDA glutamate receptor blockade and GABAA receptor activation [40,45], which are receptor mechanisms affected by some AEDs. Recently, several AEDs have been tested for similar effects in a neonatal rat model. Widespread neuronal apoptosis occurs as a result of neonatal exposure to clonazepam, diazepam, phenobarbital, phenytoin, vigabatrin, or valproate [37,46]. The effect is dose dependent, occurs at therapeutically relevant blood levels, and requires only a relatively brief exposure. Further, AEDs can interact synergistically such that two AEDs, given at dosages that would not produce apoptosis when given in monotherapy, trigger the full apoptosis. This suggests that polytherapy may be more likely to result in neuronal apoptosis. The mechanism underlying the apoptosis appears to be related to reduced expression of neurotrophins and levels of protein kinases, which are important for neuronal growth and survival. Of note, the adverse effects were ameliorated by β-estradiol, which has neurotrophic effects [37,46,47]. A preliminary report found that neonatal rats dosed with carbamazepine slightly above the ED50 for anticonvulsant action developed widespread neuronal apoptosis [48]. In contrast, similar apoptotic effects were not seen at therapeutic dosages for carbamazepine, levetiracetam, lamotrigine, or topiramate in monotherapy dosages [41,49–52]. However, preliminary results suggest that carbamazepine, lamotrigine, and topiramate, but not levetiracetam, may potentiate cell death when given in combination with pro-apoptotic agents such as other AEDs. These observations raise a serious concern that certain AEDs, which are commonly used in women of child-bearing potential, could produce similar adverse effects in children exposed in utero or in the neonatal period. Additional studies are needed to examine the effects of other AEDs in this animal model, extend the studies to gestational animal models, determine if a similar mechanism occurs in humans, and delineate the factors triggering the apoptosis.
Standard IQ testing is the best method to provide data that are comparable across different ages, exposure groups, and studies, as well as to pick up cognitive impairments milder than mental deficiency. IQ tests are well standardized with age norms and are predictive of school performance. Studies reporting outcome in infants or toddlers without IQ testing usually do not add significant information on cognitive outcome. Therefore, this review focuses on the studies that report IQ (or Griffiths DQ) scores in children of women with epilepsy (WWE).
Although prenatal exposure to carbamazepine has been suggested to result in a typical pattern of minor anomalies and developmental delay [53], there is little evidence of a carbamazepine syndrome [54]. Pooled data from two prospective population-based studies [55,56] showed a 1.9% (2/105) incidence of mental deficiency in carbamazepine monotherapy-exposed children of WWE. One of the two children had West syndrome in infancy as a possible etiology.
Carbamazepine monotherapy was the most common AED exposure in two recent prospective, controlled, population-based studies [56,57] with blinded evaluation of outcome. These studies included approximately 50% of the population of children born to WWE in their catchment areas: carbamazepine monotherapy exposures numbered 35 in the former and 86 in the latter study. Blinded assessment of DQ or IQ was done at ages 2–8 using the Griffiths test [57] or at 5–11 years with the age-appropriate Wechsler scale [56]. No IQ impairment was found in the children exposed to carbamazepine monotherapy compared with nonexposed children of WWE or controls.
A retrospective population-based study [58] investigated the risk of autism spectrum disorder (ASD) in children exposed to AEDs. Participants represented 42% of the population and included 80 children exposed to carbamazepine monotherapy. The prevalence of ASD was found to be 2.5% in the children exposed to carbamazepine alone; this was not statistically significantly different from the prevalence in the general population. The study is described more in detail in Section 3d on valproate.
The largest number of children exposed to phenobarbital monotherapy in utero has been reported by Shapiro et al. [59] from a prospective controlled study. Thirty-five exposed children of WWE and 4705 children of mothers without epilepsy but with phenobarbital exposure did not differ from control children with respect to IQ measured at 4 years of age.
Cognitive effects of fetal phenobarbital exposure have also been investigated in 114 male offspring of mothers without epilepsy [60]. Demographic, socioeconomic, and medical variables (including drug treatment) were recorded prospectively, and phenobarbital exposure was determined to have occurred if maternal treatment had lasted for at least 10 days during pregnancy. Cumulative phenobarbital dosages varied from 225 to 22,500 mg. Controls were matched for potential confounders, including a variable reflecting indication for phenobarbital. The study subjects were tested in young adulthood. Men exposed to phenobarbital had IQ scores approximately 0.5 SD lower than expected. The IQ impairment was most marked after exposure in the third trimester.
Long-term cognitive effects of early postnatal phenobarbital exposure have been investigated in a randomized, placebo-controlled, blinded study [61] in which 217 toddler-aged children with febrile seizures were randomized to receive either phenobarbital 4–5 mg/kg/day or placebo. At age 7, several years after discontinuation of phenobarbital, 64% of these children were examined with the Wide Range Achievement Test (WRAT-R) and the Stanford–Binet Intelligence Scale [62]. Phenobarbital-exposed children had significantly impaired performance in WRAT-R reading scores, but not in the Stanford–Binet Scale, compared with the placebo group.
Fetal exposure to phenytoin has been suspected to cause cognitive impairment since Hanson and Smith [63] described the fetal hydantoin syndrome in five unrelated children of WWE. Four children had been exposed to 100–400 mg of phenytoin (one monotherapy, three combined with barbiturates, one also to phensuximide) and one to 300 mg of mephenytoin during the fetal period. The features of the syndrome consisted of a characteristic pattern of craniofacial abnormalities, nail and distal phalangeal hypoplasia, postnatal growth deficiency, and mental deficiency.
The incidence of the fetal hydantoin syndrome is unknown. A cohort study by Hanson et al. [64] estimated that 11% of phenytoin-exposed children showed enough unusual features to justify the diagnosis of the syndrome. In contrast, a prospective, controlled, exposure-blinded, population-based study found low intelligence (<85), an important feature of the syndrome, in only 2 of 103 phenytoin-exposed children (1.9%) [55].
Prospective data on IQ scores after prenatal phenytoin exposure have been reported from two controlled population-based studies [55,59] with blinded evaluation of outcome. The results were controlled for socioeconomic class or maternal educational level. A total of 297 children of WWE were included, which covered approximately 50–60% of the population. Two hundred five children were exposed to phenytoin, 81 of them to monotherapy. IQ assessments were done at age 4 (Stanford–Binet) or 5.5 years (age-appropriate Wechsler scale), blinded to prenatal exposure. Comparison groups included 40 nonexposed children of WWE and more than 27,000 control children of mothers without epilepsy. Phenytoin doses were not reported, but maternal phenytoin levels during pregnancy were available in the study by Gaily et al. [55]. Both studies reported lower IQ values in children of WWE compared with controls, but no significant associations were observed to phenytoin or other drug exposure.
Hanson et al. [64] reported IQ results for a different cohort from the same database as Shapiro et al. [59]. The mean IQ at age 7 of 83 children exposed to phenytoin (maximum 25% monotherapy) was five points lower than that of control children of mothers without epilepsy, controlled for socioeconomic status. However, as all children of WWE in this study were exposed to phenytoin, the independent effect of the drug cannot be estimated.
Developmental delay is one of the main features of the fetal valproate syndrome [54,65–67], which is otherwise characterized by a typical pattern of minor anomalies: trigonocephaly, bifrontal narrowing with indentation of the outer orbital ridge, medial deficiency of eyebrows, long shallow philtrum with long and thin upper lip, and broad or flat nasal bridge. Major malformations, especially neural tube and limb defects, may also occur. All studies describing the syndrome are case reports or retrospective clinic-based studies, leaving the incidence of fetal valproate syndrome unknown.
At present, prospective data on IQ scores in children with prenatal valproate monotherapy exposure are available only for 26 children from two population-based, evaluator-blinded studies [56,68]. In both studies, verbal IQ was 11–13 points lower in the valproate monotherapy-exposed group than in children not exposed to AEDs or exposed to carbamazepine monotherapy. Pooled population-based data from the same studies showed that 3 of 34 (8.8%) children exposed to valproate monotherapy had mental deficiency, compared with 1 of 94 (1.1%) children of WWE who used other monotherapy during pregnancy. In both studies, maternal education level or IQ was significantly lower in the valproate group than in children of WWE exposed to other AEDs, which may have contributed to the difference.
The largest number of valproate monotherapy-exposed children reported so far (n = 41) comes from a retrospective study by Adab et al. [69]. Verbal IQ was significantly lower in the valproate group than in the unexposed and other monotherapy groups. The magnitude of the difference was approximately the same (10 points) as in the prospective studies. Maternal IQ scores were assessed, and no difference was found between valproate users and other WWE. A previous retrospective questionnaire survey in the same study population [70] reported increased educational needs in children exposed to valproate monotherapy.
Social or behavioral difficulties were reported by the parents to be present in 26 of 260 children of WWE (42% of the population) in a retrospective population-based study [58]. Review of the case records confirmed the diagnosis of an ASD by DSM-IV criteria in 12 of 26 children, 9 of whom had been exposed to valproate (5 in monotherapy). The minimum prevalence of ASD was estimated to be 1.9% in children of WWE, which was significantly higher than that of the general population. Of the 56 valproate monotherapy-exposed children, 5 (8.9%) were diagnosed with ASD.
Finally, recent preliminary results from an ongoing multicenter prospective study in the United States and United Kingdom also found lower cognitive outcomes for children exposed in utero to valproate monotherapy [71]. These preliminary results are based on cognitive assessments at 2 years of age.
Polytherapy exposure in utero carries an increased risk of malformations and lower cognitive functioning [56,72,73]. Although attempts should be made to avoid polytherapy in pregnancy, there are women whose seizures, pain, or psychiatric disorders cannot be controlled with monotherapy. Significantly impaired verbal IQ was observed in 30 children exposed to AED polytherapy compared with 107 monotherapy-exposed children in a prospective, population-based study controlling for maternal education [56]. Although not statistically significant, the lowest mean verbal IQ was observed after exposure to polytherapy including valproate (17/30); for 13 of the 17, polytherapy consisted of valproate with carbamazepine. Polytherapy exposure (23 children) was associated with impaired verbal and nonverbal IQ also in a prospective clinic-based study by Koch et al. [74], in comparison to 31 children exposed to monotherapy. The most common drugs were phenytoin and primidone. Forty-one percent of the original cohort were examined at ages 10–19. The large prospective population-based study by Shapiro et al. [59] included 107 children exposed to a combination of phenytoin and phenobarbital. Their mean IQ did not differ from that of other children of WWE. Pooled data from two prospective population-based studies [55,56] showed mental deficiency in 1 of 84 (1.2%) polytherapy-exposed children. The child had been exposed to phenytoin, carbamazepine, and alcohol.
The results of prospective population-based studies give no definite evidence that fetal exposure to phenytoin or carbamazepine impairs intelligence. Data on developmental effects of fetal valproate exposure are very limited, and confounding by genetic and environmental factors cannot be excluded. Nevertheless, the results of both prospective and retrospective studies raise concern that valproate may have a harmful effect on cognitive and, possibly, also on social development. It is not understood why verbal but not nonverbal IQ has been affected in all studies except one [68]. The data on fetal phenobarbital effects are insufficient and incongruent. Different designs, subjects, and ages at outcome measurement probably contribute to the controversy. The limited studies on polytherapy exposure suggest that combining drugs may increase the risk of harmful effects. There are no data to suggest whether some combinations would be safer or more hazardous than others. Future studies need to examine monotherapies with the most commonly used drugs, especially valproate, and evaluate frequently used combinations in situations where monotherapy is not sufficient to control maternal seizures. Future studies also need to focus on the newer AEDs as there are no published studies on cognitive effects of prenatal exposure to these AEDs.
No IQ impairment was found in two prospective population-based studies in which 14% of 189 [56] and 37% of 148 [55] children had been exposed to self-limiting generalized tonic–clonic seizures (GTCS). No episodes of status epilepticus were included. In the retrospective study by Adab et al. [69], 35% of 249 children had been exposed to GTCS, and verbal IQ was significantly reduced in those children (17% of all) who had been exposed to more than four GTCS. Although the results of cohort studies that have included mainly exposures to brief maternal GTCS are controversial, case reports have clearly documented that prolonged seizures and status epilepticus are a serious hazard for both the mother and the fetus [75].
Animal studies can control for a variety of confounding factors, examine underlying mechanisms, and provide information to guide human studies. However, interspecies differences and the lack of comparative information on pharmacokinetics and developmental outcome preclude direct extrapolation of animal results to human risks. Retrospective studies in humans may provide some insight, but are ultimately flawed because of subject selection bias and potential inaccuracy or lack of critical data. There is a compelling need for prospective, properly controlled studies in humans to establish the effects of in utero AED exposure on intellectual development. A randomized clinical trial with blind assignment of AED prior to pregnancy is not practical and raises some ethical concerns. Nevertheless, the effects of AEDs on the unborn child can be practically assessed by an appropriately designed observational study. Many prior studies have been flawed by inadequate control and statistical assessment of confounding factors, uncertain accuracy of historical and clinical information, or insufficient outcome criteria to provide delineation of subtle deficits. In recent years, several studies have provided useful information, but additional studies are needed to demonstrate the relative effects across all AEDs and to determine possible interactive effects of factors such as inheritance, psychosocial environment, and seizures during pregnancy. Future studies need to employ a prospective design beginning early in pregnancy (or, if possible, even prior to pregnancy); use adequate sample sizes (with power analysis); assess objective measures or apply blinded assessments; control for hereditary factors (e.g., genetic testing in somatic or behavioral outcome studies and formal neuropsychological evaluations of both parents in studies of cognitive/behavioral outcomes); include type, syndrome, and etiology of maternal epilepsy; and collect comprehensive data to statistically assess other possible confounding factors. Population-based studies would be required to determine actual as opposed to relative rates of poor outcomes. Inclusion and exclusion criteria may vary as a function of the goals of the specific study. The effect of potential confounding factors can be assessed statistically provided that the sample size is adequate and the pertinent data are collected. Enrollment early in pregnancy before any outcome data (e.g., ultrasound) are known should either be an inclusion criterion or this population should be targeted for separate analyses. Final results should be expressed with means and confidence intervals for continuous variables obtained from formal testing. In addition, serious affections (such as mental deficiency or significant behavioral disorders) should be clearly defined and the proportion of affected children indicated.
Heritability accounts for 30–50% of phenotypic IQ variance. IQ correlation for monozygotic twins reared together is 0.85, and for those raised apart, 0.67 [76]. Correlation for parental and child IQs is 0.42 [77]. Maternal IQ is not only a measure of inherited influences, but also has a strong association with fostering experiences. When maternal IQ is controlled, no other single environmental factor has a significant influence on child IQ in group studies [76]. Maternal education and socioeconomic status, often substituted for IQ as a control measure, correlate with the child's IQ but at a lower level. In one study that obtained both maternal IQ and education, matching groups on education was inadequate to control for the effects of maternal IQ [78,79]. Paternal IQ would be important data, as women with epilepsy may have a social disadvantage in partner choice [80]. It is also possible that maternal IQ could be affected by factors related to epilepsy and its treatment. Thus, consideration of obtaining the IQ of a first-degree maternal relative could be considered as a method to control for the effects of epilepsy and AEDs on the mother's IQ.
On a group level, obstetrical complications appear unrelated to IQ, and perinatal anoxia has a minimal correlation to IQ (r = 0.06) [76]. However, individual children could be affected by complications of pregnancy (e.g., placenta abruptio) or subsequent severe childhood illnesses. Malnutrition, as experienced in developed countries, does not have a substantial impact on intelligence, but malnutrition may affect mental and physical growth for individual children. Further, nutritional factors (e.g., folate) could possibly interact with AED exposure. Drug abuse (e.g., alcohol) during pregnancy influences development adversely. Routine childhood illnesses show no relationship to test scores, but hearing loss or more severe childhood diseases might impact development. The confluence model of family configuration (i.e., birth order, family size, and birth intervals) has not been clearly refuted, but a great deal of evidence suggests that the model is inadequate [81]. Socioeconomic status is correlated with behavioral adaptation (r = 0:4 – 0.6) [82]. A broad range of social variables are known to predispose a child to biomedical risks, the most salient of which, poverty, represents a complex accumulation of risks factors [83]. Socioeconomic status and specific home environmental factors (e.g., pressure for achievement) are related to IQ, but are not independent of family background, and may "serve as surrogate measures of parental IQ and education" [76]. Gender, ethnic origin, geographic location, maternal age, and parity are additional factors that also could potentially affect IQ scores.
Models of the epidemiology of mental retardation emphasize multiple risk factors [84]. Individuals with the same biomedical condition express different levels of cognitive deficits, demonstrating that other factors modulate the effects of the condition. Approximately 50% of patients with mental retardation have more than one risk factor, and mental retardation often reflects the cumulative or interactive effects of more than one factor [85]. Some risk factors, such as drug abuse, are embedded in a matrix of other risk factors; for example, women who abuse drugs are more likely to engage in other high-risk behaviors. Low socioeconomic status may interact with drug exposure to enhance the adverse effects. As an example, the retrospective study by Reinisch et al. [60] reviewed above found that the overall 7-point decrement in verbal IQ in men exposed in utero to phenobarbital increased to 20 points if the men were also born from an unwanted pregnancy and low socioeconomic status. In contrast to the effects of low socioeconomic status, high status may ameliorate adverse biomedical effects [86]. Thus, a variety of factors have to be monitored to assess their impact on cognitive/ behavioral outcomes.
In summary, future studies ideally should employ a prospective design enrolling mother/child pairs early in pregnancy. AED dosages and blood levels should be obtained in each trimester. Objective measures or blinded assessment should be used to determine results irrespective of whether the investigation is directed at somatic or behavioral outcomes. Potentially confounding factors that should be assessed and controlled depending on the study goals may include: maternal and paternal age, IQ, education, and race; socioeconomic status of household; maternal medical disorders (e.g., diabetes); maternal and family history of prior pregnancy abnormalities; maternal use of alcohol, tobacco, and other drugs (i.e., illicit, over-the-counter, and prescription) during pregnancy; maternal preconception and pregnancy nutrition, folate use, and folate/ homocysteine blood levels; epilepsy syndrome and etiology; seizure types and frequency during pregnancy; gestational age at enrollment; obstetrical complications; birth weight and head circumference; childhood diseases; and home environment during childhood, including languages spoken.
Previous studies on developmental outcome have tended to focus on intellectual functioning as the primary outcome variable and have generally ignored the use of assessment protocols that would allow for the evaluation of other domains of higher cortical functioning, such as executive functioning, language, visual–spatial and visual–motor/ constructional functioning, learning and memory, fine and gross motor skills, academic performance, adaptive functioning, and emotional/behavioral functioning.
To best determine the early developmental profiles and needs of these children, the optimal method for studying potential cognitive effects is a prospective, longitudinal design with adequate sample sizes through the age of 8. This will allow researchers to determine if various AED-exposed groups have significantly lower intellectual profiles, and to report the frequency of various learning disabilities (reading, written expression, mathematical reasoning/calculation), other neurobehavioral disorders (specific language impairment, attention deficit/hyperactivity disorder), and behavioral disorders commonly seen in childhood.
Future studies should attempt to evaluate the impact that in utero AED exposure has not only on intellectual functioning, but all aspects of higher cortical functioning as well. Please refer to Table 1, which provides a list of the major domains that should be investigated along with some suggested tests that may be used to assess each domain adequately. It is important to note that this list in not exhaustive, and inclusion/exclusion should not be considered an endorsement of any particular test. In addition, Table 2 provides a list of demographic and medical variables that can influence the outcome of studies in this area significantly. Efforts should be taken to carefully control for the potential impact of these variables.
Finally, cross-sectional studies may also be useful, as longitudinal studies take years to provide answers. Retrospective, cross-sectional studies that include samples of adolescents exposed to AEDs in utero can also provide important information about the emergence of cognitive deficits that may not appear until later in development (e.g., executive function deficits). Closer attention to factors listed in Table 2 can improve the ability to draw conclusions.
Data on older AEDs are incomplete, and there is little or no evidence of the impact of the newer AEDs, the majority which have a license as add-on therapies for partial refractory epilepsy. Future investigations are necessary to establish the cognitive/behavioral teratogenic effects of in utero exposure for all AEDs. Large cohort studies, however, are necessary and should include a sufficient number of women exposed to these newer AEDs.
Animal data demonstrate synergistic effects of polytherapy on apoptosis and suggest that risk may vary across different polytherapy combinations, but no such data are available for humans. Future studies should focus on specific polytherapy combinations in situations where monotherapy is not sufficient to control maternal seizures.
Ideally, future studies should employ a prospective design enrolling mother/child pairs early in pregnancy using sample sizes to provide adequate power. Objective measures and/or blinded assessment should be used to determine outcomes. Potentially confounding factors must be assessed and controlled as described previously. Additional specific design issues are discussed below.
A range of neuropsychological tests have been employed to investigate the neurodevelopment effects of exposure to AEDs in utero. These include the Wechsler Intelligence Scale for Children [56,68,69], Bayley's developmental scale [87], NEPSY [68], and the Griffith developmental scales [57,88]. The tests have demonstrated psychometric properties, but there is often little evidence for a rationale for their application to this research. The variation of tests also has significant implications for the generalizability of results across different studies. Further, failure to use a standardized approach restricts the use of meta-analysis.
The majority of investigations into the cognitive implications of in utero exposure to AEDs have focused on full-scale, performance (nonverbal), and verbal intellectual capabilities. Neuropsychological functioning, however, does not simply mean an assessment of intellectual functioning and, in fact, includes other processes such as language, hand/eye coordination abilities, executive functions, ability to hold concentration and apply attention to a task, creativity, and behaviors such as mood and social interaction. It is, therefore, paramount that future research comprises a comprehensive assessment of neuropsychological abilities that are investigated, as this will allow researchers to identify both expected and unexpected effects of exposure in utero.
To understand the impact of exposure in utero, it is essential that future research gathers information from control groups, of children born either to mothers with epilepsy but not taking AEDs during pregnancy, to mothers without epilepsy, and to fathers with epilepsy. The control group will allow documentation of the natural history of neuropsychological development from which various comparisons can be made. The presence of a control group will also allow for the establishment of individual variation in a nonexposed group, which may act as a reference point for the interpretation of results.
The majority of studies in the literature investigating the impact of in utero exposure to AEDs has attempted to control the hereditary aspects of intellectual functioning by taking a measure of maternal IQ or an IQ equivalent (e.g., The National Adult Reading Test). Collection of maternal IQ is usually easier than collection of paternal IQ, as the mother and the child are both enrolled into the study at the beginning from pregnancy clinics. Some mothers are no longer in contact with the father or do not wish for the father to be involved, or the father is unable or unwilling to attend. However, the nature of epilepsy causes disruption of cognitive processes and seizure activity impacts on intellectual functioning [89] as well as social interactions, which may result in a disadvantage in partner choice. Therefore, is taking a measure from the mother with epilepsy the most predictive of a child's intellectual functioning or would the IQ of the father (in most cases without epilepsy) be more reliable? Future research should focus on obtaining a more reliable assessment of IQ from both parents along with social demographic data.
Epileptic seizures result from biological dysfunction of the brain, which may in some cases be hereditary. The predisposition to abnormal activity in the brain may be contributory to the lower performance of children born to WWE. Koch et al. [74] found abnormal spike activity in children born to mothers with epilepsy. Certain types of epilepsy are considered to have higher rates of hereditary traits and the type of epilepsy is usually associated with a first drug of choice, for example, juvenile myoclonic epilepsy and valproate. This introduces bias into the investigation. To remove this bias of a family history of epilepsy, it would appear to be reasonable to consider a comparison between a group of women taking AEDs for epilepsy and a group of women taking AEDs for other conditions such as migraine and mood disorders. However, the issues of therapeutic dose ranges will need to be considered carefully.
Despite the observation of increased risk for poor outcomes in children exposed in utero to AEDs, there is considerable unexplained variability in the outcomes across children. It is likely that differences in responses to AED exposure are mediated by genetic factors. A systematic application of pharmacogenetics could provide insight in this regard. However, there are practical, methodological, and theoretical hurdles to overcome [90,91].
Beyond the influence of pharmacogenetic factors, the basic mechanisms underlying AED-induced cognitive/ behavioral teratogenesis need to be delineated. Demonstrations in animals that AEDs can induce neuronal apoptosis in the developing brain raise concern that similar adverse effects may occur in children exposed in utero or the neonatal period. Future studies should determine the effects of other AEDs in the neonatal rat model, extend the studies to gestational animal models, and determine if a similar mechanism occurs in humans. In addition, it should be determined if other mechanisms contribute by triggering the apoptosis or directly cause the AED-induced behavioral teratogenesis. Investigations of basic mechanisms not only may lead to better AED selection on an individual basis, but also could lead to preventive therapies. For example, nicotinamide can protect against ethanol-induced apoptotic neurodegeneration in the developing mouse brain [92].
It is hypothesized that differences in the development of cognitive networks account for individual differences in cognitive abilities in both normal and abnormal development [93,94]. As a consequence, the importance of using brain imaging techniques to inform on neurocognitive development is recognized. It is proposed that future research should focus on imaging of children exposed to AEDs in utero in comparison to a control group (either children of women without epilepsy or children of WWE taking no medication during pregnancy) to investigate if differences in the development of cognitive networks exist. Such knowledge would not only be of theoretical interest, but also would be of potential benefit in planning rehabilitation programs for those children with developmental problems as a result of exposure.
Functional magnetic resonance imaging (fMRI) provides a method to map the developing cognitive networks of children [95]. Additionally, the method can be used to compare two groups and could possibly highlight any neural network difference between children who were exposed to AEDs in utero and those who were not. A comparison group of children with a family history of epilepsy but who were not exposed to medication in utero would also make for an interesting investigation. However, there are methodological and interpretational challenges to this type of investigation with children [94].
Recent studies have found lower verbal IQ or language functioning in children exposed to valproate in utero [56,69]. Imaging may provide important knowledge with respect to our understanding of the neural network supporting language processing and how this might be affected by exposure to AED treatment, compared with a nonexposed group where typically language networks are established by the age of 5 [95].
Future research should be conducted to investigate to what degree both women and their physicians understand the risks of exposure to AEDs during pregnancy. There is little past research on women's understanding of the risk associated with AED treatment during pregnancy and the risk of seizures during pregnancy [96].
Animal studies clearly demonstrate that AEDs can produce neuronal apoptosis and behavioral teratogenesis in the developing brain. Children exposed in utero to AEDs are at risk for poor cognitive/behavioral outcomes. Further, the animal studies raise the possibility that neonates may also be at risk of AED-induced apoptosis. Human data are incomplete, but children exposed in utero to AEDs are at risk for poor cognitive/behavioral outcomes, and present studies raise concerns, especially with regard to valproate. Many issues remain uncertain, and there is a critical need for further research to delineate the effects of AEDs on the immature brain.
The authors thank The Epilepsy Therapy Development Project, a nonprofit organization, for supporting this review, and Jacki Gordon for providing editorial and teleconference assistance.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.

subset: commoncrawl


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...If you have the idea of what to do on a problem, you do not need to complete 10 similar problems. As such, I like to spend more time on the why than the what. If you choose me as your tutor, your math skills will improve.
New York, NYView Tutor
...Please note that unless you have already submitted a credit card number to Wyzant, I will not be able to see your phone number or email address in your initial message, and the Wyzant system will be our only available mode of contact. Thank you for your consideration. Algebra 1 is a textbook title or the name of a course, but it is not a subject.
Brooklyn, NYView Tutor
...During my time as a mathematics and test preparation tutor, I have worked extensively with ADD students of all ages from 8 to 26. Indeed, my first undergraduate thesis as a Psychology major focused specifically on the aetiology underlying ADD, then termed ADHD. My current Student with ADD is progressing nicely through his MBA at Fordham.
New York, NYView Tutor
...I believe that effective communication and a supportive environment is crucial to a good teaching/learning relationship. I don't mind questions, in fact I encourage them at any time!I see learning as a 2-way street. It is the students responsibility to stop me immediately and ask questions if he/she does not understand.
Kendall Park, NJView Tutor
...I can help you stay on track, improve your understanding of the subject, or move beyond your class level with a solid knowledge and subsequent grade improvement. Give yourself the one-on-one attention you deserve for a guaranteed success in one or all of the following key subjects:ACT Math, Alge...
Newark, NJView Tutor


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Upon trying to improve a suggested tag wiki edit (no tag wiki had previously existed for that tag) here on MSO, I was brought to a 404.
Meta Stack Exchange is where users like you discuss bugs, features, and support issues that affect the software powering all 158 Stack Exchange communities.
What is meta?
What is meta?
Here's how it works:
- Any Stack Exchange user can ask a question
- The community provides support, votes on ideas, and reports bugs
- Your voice helps shape the way Stack Exchange operates
I just experienced a bug with the same visible behavior on U&L: I improved a suggested edit to a tag wiki body which was creating the tag wiki, the suggested edit was approved while I was editing, and I was brought to a 404 page when I submitted my edit. This may or may not be the same bug given there have been changes around this part of the code. I have 20k on U&L.


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How complex can it be? He's cute, has a great body and solid voice. You can pretty much rule the world with that simple recipe 😉
The 23-year-old singer graces the cover of OUT magazine's June/July 2016 issue, to promote the June 10 release of his new album, Last Year Was Complicated. Photographer Doug Inglish snaps the youngest Jonas brother in designer threads from Dior Homme and Louis Vuitton to name a couple.
Check out more pics below. If you have a thing for armpits, definitely proceed.
Or should I say doesn't talk. Troye Sivan sidesteps the topic of his relationship status when asked by the publication. "I feel like I share everything about myself, like everything. That's the one thing – I should keep something to myself," he states in OUT magazine's May 2016 issue.
It's great to see the 20-year-old breakout YouTube star getting some much-deserved attention. All that hard work on the talk show circuit, including stops on The Ellen DeGeneres Show and Tonight Show, is paying off. His sensational single, "Youth," is just outside the Billboard Hot 100 Top 20. I feel a Top 10 breakthrough isn't that far ahead.
Check out more pics snapped by Kai Z Feng below, along with quotes from the accompanying interview.
For its 'Love Issue,' OUT magazine looked to Tom Daley and Dustin Lance Black to grace the cover. With their upcoming nuptials on the horizon and coordinating pajamas, the two are perfect as the annual issue's coverboys.
The 21-year-old Olympic diver and his 41-year-old screenwriter fiance open up about their romance to the publication. They cover everything from what happened on their first date (I'm assuming an edited PG version) all the way to Black proposing to Daley.
Check out more pics snapped by Harry Borden below, along with learning more details of their whirlwind romance.
"We literally spent three or four hours talking about the crap that we'd been through…. It was one of the first times that I felt, 'Oh my God, this isn't just a thing where I am attracted to someone. This is someone that I've connected with on a whole new level.'"
All I have to say to any of these striking blokes is… invade away!!! Seriously, each and every one of them is stunning to say the least.
To show off the hottest looks this fall, OUT magazine enlisted photographer Mariano Vivanco to snap some of Britain's top male models. The likes of Paul Sculfor, Matt Trethe, Oliver Cheshire, Jacey Elthalion, Remy Clerima, Will Chalker, Tidiou M'Baye, Allen Taylor, Oliver Smiles, Rob Knighton and Harry Goodwins show off threads by Louis Vuitton, Gucci, Dior Homme and Burberry to name a few. Check out the stylish editorial found in the latest issue of OUT below.
Eddie Redmayne plays transgender pioneer Lili Elbe in The Danish Girl due out November 27. Elbe née Einar Mogens Wegener was one of the first people to undergo sex reassignment surgery. Redmayne reunited with his Les Miserables director Tom Hooper for the film.
The 33-year-old Oscar winner talks about the challenging role with OUT magazine. He discusses the advice he received from the trans community for his preparation and also shares thoughts on gender and Caitlyn Jenner. Check out more pics below snapped by John Balsom featured in the publication's September 2015 Fall Preview issue.
On What The Role Taught Him About Gender
"That it's fluid, I suppose. And also that it needn't be labeled. My greatest ignorance when I started was that gender and sexuality were related. And that's one of the key things I want to hammer home to the world: You can be gay or straight, trans man or woman, and those two things are not necessarily aligned."
Seeing Walter Savage nearly nude is nothing new. I've been following the American model on Instagram for some time now. The sexy stud brings his sexy assets to the pages of OUT magazine. He poses for an extremely sizzling spread for the glossy.
Photographer Greg Vaughan captures Savage in all his hairy glory. If you like your men with a bit of fur, you'll appreciate what the Soul Artist Management stunner brings to the table as he models pieces from Lacoste, Dior Homme, Versace, Louis Vuitton and more.
Check out more pics below from the editorial titled "The Exhibitionist."
Sometimes changing one's look can alienate one's fans. That's not the case with Adam Lambert's less eccentric look. Almost universally, his less-is-more approach has been embraced by his army of Glamberts.
"I just generally grew out of that old look and enjoyed new ones—it's as simple as that. There's also a point where I was working really hard to achieve a look that I was really into, and it was really fun and I wanted to stand out and be crazy and be weird and make a statement with the stuff I was wearing. I look back on some of those red carpet looks, and I'm like, What were you thinking?"
The 33-year-old singer also opens up about coming out publicly in 2009 in the latest issue of OUT Magazine. Read his thoughts on that below, along with checking out more pics snapped by Jack Waterlot.
Earlier this year, Kit Harington received backlash after he stated it was 'demeaning' to be called a hunk. Life must be hard to be so good looking and be seen as a sexual object constantly… NOT!!! I'd like to have that burden in life 😉
The 28-year-old Game of Thrones actor stands by his comments and defends them in an interview with OUT Magazine. Check out his thoughts below, along with more pics snapped by Nino Munoz. I don't want to offend him, but he looks fantastic in the editorial, even with clothes on.


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Revision Rhinoplasty
Revision Rhinoplasty WORTH IT RATING* DETAILS
in the last 24 months
in the last 12 months
over all time
Unhappy with your nose job? Revision rhinoplasty might be of interest. This kind of surgery sends a doctor back in to correct any aesthetic and/or functional issues with your nose. LEARN MORE ›
Choosing a doctor? Ask 20 essential questions
- Average Price: $9,475
Reviews from the Community
Seeking Revision Rhinoplasty (Who Should I Consider?) - California
It's crazy to think that I'm even considering doing this again. I've been back and fourth deciding between doctors and just when I feel like I've picked the right one then I hear about a new revision doctor making this such a difficult decision. All I know is that I never want to do this again... READ MORE
27, Male. 3 Previous Rhinoplasties. Hate my Nose. Trouble Breathing, Want a 4th Surgery to Finally Sort It out - Manchester
Hello all, I am hoping for a lot of help and opinions here from fellow patients and surgeons. My story is a long one but one that I have not shared and want to so that I can finally get it resolved. I'm a 27 year old Male from Manchester in the United Kingdom. I had my first Rhinoplasty in... READ MORE
Trying to Decide if I Want to Go Through with a Revision - Houston, TX
Eeek! I'm so glad I found this site and I love reading everyone else's stories. I had rhinoplasty when I graduated college in 2006. I hated my old nose, it was super wide and had a bump. My healing process didn't go quite as expected and I became obsessed with these stupid massaging exercises... READ MORE
I Hate my Nose ! - Glendale, CA
When you have gotten bullied and made fun of did to your nose you are never going to be satisfied with it. Ever since I had memory I remember people always made fun of how big and bumpy my nose was. Then to top things off when I was about 10 years old I broke it :( there came a point to where I... READ MORE
Disastrous Revision Rhinoplasty - New York, NY
Let me give you an idea of what an horrendous revision Rhinoplasty (actually two by the same doctor...) has done to me. Sorry its a bit long but its in detail. Please read it, particularly if you are considering this doctor. I went to see Dr Minas Constantinides in May 2013 on the advice of a... READ MORE
Revised Nose Job - Denver, CO
My ENT Specialist ruined my sinuses and my nose. I had to have revised nose job because of her mistakes and had to have my sinus pockets fixed after her mess up. I decided that I could not live with her mess and decided to look for two expert surgeons. That is where Dr. Cote came in along with... READ MORE
Revision Rhinoplasty by Dr Warwick Nettle = 5 stars
Dr Warwick Nettle is the best plastic and reconstructive surgeon I have come across. He is not only an extremely nice and humble man but the quality of his work is absolutely amazing. He has great bedside manner, is extremely caring (he even called me the day after surgery to check up on me) and... READ MORE
Revision Rhinoplasty 33/female – New York, NY
I have never written a review for anything before, and I never imagined THIS would be what I'd be reviewing. But I really have to give credit where it's due, and Dr. Slupchynskyj deserves it. This board and the people who share their experiences here have been a great resource for me, so I... READ MORE
Revision Rhinoplasty, Chin Implant, Neck Lift, Buccal Fat Removal Review - Los Angeles, CA
Im 32 years old male who had 2 previous Rhinoplasties one done in 1999 and the other 2001. My first Rhino was horrible all I needed was hump and tip reduction the surgeon ruined my nose he made it very saddle wide piggy nose. I Had to wait year and half so I can fix it. My second rhinoplasty was... READ MORE
Revision Rhinoplasty Gone South - Saint Louis, MO
Had a rhinoplasty and six months later revision. Primary improved the tip and bridge greatly. However transition from nose to forehead was quite awkward. Asked the doctor about the issue and agreed to revise. Procedure was to focus on that top part of nose referred to as nasion and radix... READ MORE
Rhinoplasty Revision- Dr. Darrow in Boston
Gallico is a fine artist, uses Photoshop to envision his changes, and created the whole plastic surgery department at Mass General. My mother says many people in the hospital go to him and love his work. However, upon my 2nd consultation a year out from the first time we spoke of a revision, I... READ MORE
18 Years Old - West Orange, NJ
I had a rhinoplasty procedure prior. It was from another doctor. I was horrified by the results and did a lot of research. After days of research, i found Dr. Joseph. I booked a consultation appointment and right after the appointment, i had full confidence in Dr. Joseph and I knew that he was... READ MORE
Dr Eric M. Joseph Saved my Nose, Third Nose Job! - West Orange, NJ
Ok, this a lot to read, but you need to hear it if you've lost hope in finding a rhinoplasty revision doctor. I started my nose trial and error's by getting a bump removed by Dr. Fodero, in Livingston, NJ. For background, I wasn't blessed in the nose department. People said it wasn't that bad,... READ MORE
My Dream Nose, Every Penny's Worth It - Philippines
My recent nose was done by dr. Alonzo silicone L shape, worst decision of my life ! The implant is like floating at my bridge that made it sway left and right even with the slightest touch and it's really not properly aligned. I will share this story at a different post. From a girl who has... READ MORE
Bad Revision Rhinoplasty By A Park Avenue Doctor - New York, NY
Dr. Guida is a nice person but his surgical skills regarding a complex surgery such as mine was not good. I've requested a full refund from him but he's declined so now I'll be taking him to court. He did what I thought was a revision rhino where I had a rib graft cartilage removed from another... READ MORE
Can I Get a Revision Rhino? and Not Mess Up Whats Left of Me? - Seattle, WA
Hello! so about two years ago I got a rhinoplasty done (with general anast) i had a broken tilted assymetric nose, now two years later i still have difficulity breathing! cant go a day without nasal spray and i think the splints on the sides of my nose are forming bumps... :( i dont have much... READ MORE
Revision Rhinoplasty/ Nose Surgery/ to Make the Tip of the Nose Longer? Munich, DE
Hi everyone ? ?First i need to say my english is not the best :I ?I had 2 nose surgery once 10 years ago other 2 years, ?I have like kind of thick nose skin, ?I was happy with my first one, my problem was it looked so upturned and wasn't straight anyway 2 years ago i decided to undergo another... READ MORE
Just Had Revision Surgery with Dr. Richard Davis- Waiting to See my Results!!! - Miramar, FL
I have had three previous surgeries with Dr. Kenneth Brown in Clearwater. He does an amazing job at breast augmentation but clearly not rhinoplasty. He left my nose crocked and collapsed to one side with uneven nostrils as well as other damage. I couldn't breathe and it was a mess. After... READ MORE
The Best Surgeon for a Revision Rhinoplasty - Wayne, NJ
After my nose surgery 18 years ago, I have been on the hunt for someone to correct my first surgery that I was not happy with. I consulted with many plastic surgeons in NYC until I found someone that I not only felt comfortable with but who did an amazing job! Dr. Jeffrey Wise is a sculptor and... READ MORE
Yes, We Are Doing This! Finally. (The Other Sister-revision Journey)
This post is long overdue. My sister has been posting about our joint rhinoplasties, primarily about her 1st rhinoplasty experience with Dr. Grigoryants (post is under Yes. We Are Doing This! Finally). I am now sharing my experience as a revision rhino with Dr. Grigoryants. There was no... READ MORE


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The Marie Souza Team - Top Selling on Cape Cod
Cape Cod Real Estate Services
Hopefully you had a Title 5 contingency in the offer and PS. This way if the sellers have not installed and had it inspected by the date specified in t ... more
I've specialized in REOs with this changing market and various loose ends need to be addressed with each asset. Hang in there if it is the proeprty yo ... more


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I have installed WoL, size 14 GB, when I buy HotS I'm afraid that might grow up to 30 GB, which is too much. Since I'm not going to play campaign, is there an option to install online multiplayer only?
Nope, unfortunately you cannot pick and choose. However, HotS was less than 5GB for me, you should be fine.
EDIT: I did digital download, IDK if a physical copy is bigger/smaller.


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1200 Reviews
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I have relied on Appliance Factory Parts for parts in the past and have been satisifed with thier ability to ship quickly and acurately.
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We are a USA business based in Denver, Colorado and we stand fully behind our products and service


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My husband just asked me what they eat, and I don't have a clue, so I'm off to look them up on the web. Such a delicate paw, Jean, and so lost in thought in this beautiful photo. Your collection really is a triumph. I had no idea they would be this endearing, until I came across your two galleries. Wonderful stuff!
Very best wishes to you, sue
Wow, they eat just about everything, don't they? Very diverse little creatures!
The web is wonderful, it took me all of 20 seconds to find that out. I would still be searching for my book on mammals in the old days :D
cheers, Jean, sue
Sue, yes, they eat all sorts of things. I give them some sunflower seeds. Occassionally left overs from the catfood. I think because they are so adaptable and can eat so many different things, that has helped them spread and be successful. There was a documentary once that I found fascinating and wished I'd saved a copy.
People really get irritated with raccoons because they are crafty and find ways to get into the garbage left by humans. If and when they get into the garbage, they take it out and spread it thoroughly. It is such a mess to clean up and a rude awakening in the mornings. Not a good way to start a day. But long ago, I learned how to secure the lids on the garbage containers.
A remarkable collection you've got there! Thanks for sharing.
Best regards from Belgium - Hans
Hans Sterkendries, Thank you so much. I am very glad to share the raccoons, my neighbors who live in the woods around my house.
Greetings to you in Belgium!
are all fantastic photo!!!
Rafl, thank you. I just realized that this photo has a Look Around! My first!
A raccoon Look Around! One of Panoramio's best. :)
now that is cool! you had better get them a nice trout this spring to eat, they deserve it!
Tell me please Jean, what is a LOOK AROUND?
I watched a documentary some years ago where a family of raccoons were living in a roof space at some USA family home. I remember it being hilariously funny. I cant recall what became of them.
As you say Jean, they are so adaptable.
It's a fine photo, love it.
OH yes, it's a great look around, isn't it? If you posted enough photos of the progress of a sneeze, you might get a look around which would function like one of those old flip along books, which are like a film! I often become frustrated with Lookarounds of places as they don't 'look around far enough, and there's only a variation of a few degrees in the shots, rather than actually as if you were turning around, which is what i expected them to be like, but in your raccoons, it's really good to be able to instantly flip from one to another. Well done Jean and well done Google earth!
Very best wishes to you, Jean, really the best look around I've come across so far!
Sue, I sometimes feel that way too about the Look Arounds. This one really surprised me because it really looks like you change from one to the other. I would wish that I could congratulate the person behind this nice piece of ... whatever it is! Really cool stuff! I'm just amazed... and tickled pink!
I do ask some silly questions forgive me. now I know what it is. Well done Jean, it LOOKS great.
I got a little confused there! It seems we were all typing at the same moment!
Now that is the oddest experience for me in Panoramio yet!
Jessica G., thank you for that fine compliment! I still think of your winter chickadee!
Don, now I wouldn't want to spoil them, maybe after the economy strengthens! ha ha
and Don, that is one of the best things I have ever seen, that Klaus Herr is super fantastic! I have been in there before and had so much fun 'walking' up the hill to the bridge and tried to get into the vehicle but it was locked. I flung out my arms and spun around until I got dizzy. It is a great link!! Thanks!
Jim, there was a TV story showing a really funny raccoon pet living in a house here in America a few months ago. Someone even pointed it out to me on u-tube but I don't remember the proper names to find it again. It showed the pet raccoon living inside and apparantly had been fine until he got to adulthood then he started making holes in the walls. He had destroyed the kitchen cabinets too. But he was perfectly tame, just unruly and wouldn't stop making the holes. The homeowner was so totally in love with the critter. He was cute on TV! Just so you know... The raccoons in my photos are wild and only come to visit.
Sue, somehow I was able to see your comment before I saw the ones above it! My view counters are not working, I'm not getting ANY Panoramio emails whereas only recently I at least got a tiny few. I wonder what is UP! Or down. Things are not always ducky, are they?
Jim, thanks for figuring that out!
Thanks everyone!
Thank you Jazz, and I will be back to see you tomorrow. I have to go now.
Whow! Voted! Jean that´s great! you have your own "Look arrond". Congratulations! Klaus
Yes! Klaus, I was so excited when I discovered it! I think the one responsible for creating the 'look around' did a wonderful job, good work. I was so surprised and never imagined that a look around could come from such pictures. Really cool! Thanks for your lovely comment!
:))) Great capture
Thank you very much, Dario.M.
Photo taken in Ellijay, NC 28734, USA


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170 Reviews
This was the first time I made a Blueberry pie. I made it for my dad for Father's Day (since it is his favorite). I used fresh blueberries and the pillsbury crust. I read the reviews before and added a Tsp of Cornstarch to the Flour Mix. I also did the egg wash on the bottom crust and top crust. After I had all the berries added to the flour mix, I did squish them a little bit so it was still almost all whole berries, but some of the squished berries mixed well to make a great filling. I saw that Alton Brown squished about half his berries first so I tried squishing some of mine. I would probably make this pie exactly the same again. My dad sent me a text message on Father's Day evening thanking me for the wonderful pie and said he had devoured a fourth of the pie before he had even realized what had happened. :-) Also, the vanilla ice cream is a must in my opinion. :-)
This was my first time making (or eating) a blueberry pie. My husband had requested it, after seeing blueberry pie on TV, so I tried this recipe, and it came out great.

I forgot the butter, so when I checked the pie at ~30 minutes, I brushed some melted butter on the top of the lattice crust (aiming to get some blobs in the lattice holes), before popping it back in the oven. After reading some of the reviews, I decided to let it bake a little longer (about 50 minutes).

It was *almost* too sweet, but that is probably because I'm not used to eating a lot of sugar. The sweetness was mellowed out perfectly by the vanilla ice cream. I might use slightly less sugar next time, but other than that, this pie was perfect. My husband was 100% pleased.
didn't get a picture, it was all gone! ;)
- Margarine? That's vegetable oil on a pie. Ick.
- Someone didn't think lemon juice was appropriate. The acid (of lemon) and pectin (of fruit) react with sugar and will thicken (set).
- Tapioca flour is better than all-purpose. It's grain free (for you non gluten folks), is smoother in texture and binds better.
- I've never understood the infatuation with (read: overuse of) cinnamon. It can compete with the blueberry flavor. Maybe a teeny hint. Nutmeg is a softer complement.
- Egg yolk vs. whole egg for glazing crust.
- Make your own flaky crust and make sure you have a little bit of vinegar in it. You can also swap some water with blueberry, apple or orange juice. Certain liquors can be used as well.
- 35 minutes is definitely not long enough. You need the blueberry mixture to get hot enough for the pectin, etc. to set. Cook at the bottom of the oven to avoid burning the crust too early.
This recipe was a hit! I am not a huge fan of blueberries but this pie was delicious! Will definitely make this again.
I just realized I didn't rate this recipe yet. I had never made a blueberry pie before because I really "didn't" like it but my sons do. I've made it 3 times now and I'm a convert. This one is so easy to make that even I can do it. I did the unthinkable and used premade frozen crusts that come in their own tinfoil pans. This turned out to be a good thing. I took the advise of others and coated the bottom crust with the beaten egg and added 2 tablespoons of corn starch to the dry ingredients and berries. The cooking time I increased as well to 50 min. After 30 minutes I used the tinfoil plate to cover the pie to keep it from getting to brown instead of tinfoil around the edges. That worked so well as the crust came out nice and brown and not crumbly with the pie well cooked. For the best results let it cool then chill in the refridgerater before cutting. Awesome recipe Bev :>)
Thank you Bev! I'm new to pie-making and never even liked blueberry, but this was a huge hit for the dads on Father's Day. The sugary top to the pie crust and the whole, bursting-berries were raved over by all. Now I love blueberry pie, I'll have to make this all the time!
Making this recipe for the second time today. First time, my mom said she didn't like blueberry pie.Now, she;s the one wanting me to make another one!
Other than adjusting the bake time to 50 minutes, this recipe is AH-mazing. This is the first time I ever made a blueberry pie, and my boyfriend loved it!!
This pie was fantastic. I left out the butter and lemon juice because I see no point for those ingredients in pie. 35 minutes is not long enough to cook this pie. Change time to 50 minutes and it will cook up right.


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Stormwater Treatment: A Look at Various Methods, Hydrodynamic Separators
Since the passing of the Clean Water Act, the industry has made great strides in improving the quality of point source discharges to the environment. As treatment technologies continue to improve, non-point source pollution becomes a more significant contributor to environmental degradation.
Revisiting the Selection of Stainless Steel in Water and Wastewater Treatment Environments: Part 3
Based on the City of Hollywood's experience, the use of 316L stainless steel should be evaluated carefully due to the potential for problems in the erection and construction of water treatment facilities that will be in contact with high chloride water and/or other corrosive chemistries. As with many membrane facilities, much of the stainless steel is exposed (not buried), which subjected it to atmospheric as well as water quality problems. Therefore, unless the quality control of the raw and reject water (chemical, physical and microbial) can be assured, 316L stainless steel may not be the appropriate material for engineers to specify.
Materials Selection
The Great Activated Carbon Dilemma
Drinking water treatment professionals have long held fast to the belief that granular activated carbon (GAC) based on bituminous coal provides the best performance for their demanding application. That's why, when an article in 1999 cited evidence that a lignite-based GAC outperformed a bituminous-based carbon, industry experts were surprised and more than a bit skeptical.
Fresno Discovers Big Difference Between Reagglomerated Carbon and Direct Activated Carbons
Ultraviolet Dechlorination Technology
At the Procter & Gamble manufacturing plant in Greensboro, N.C., an Aquionics ultraviolet (UV) dechlorination unit was installed before two banks of reverse osmosis (RO) membranes. Trials that ran soon after the UV system's installation showed a dramatic reduction in the RO membrane wash frequency—down from an average of eight cleanings per month to only two per month.
Reverse Osmosis Membranes Maintenance Costs Reduced
Evaluating Activated Carbons
challenges are emerging in the industry that require new methods and product
developments. This article discusses additional test methods for the AC
ASTM, AWWA and EPA Standard Methods and New Test Methods for AC
Packaged Treatment Plant Treats Tough Water Supplies Consistently, Economically
Since the 1960s, municipalities and industries have used packaged water treatment plants to successfully and economically treat small water supplies. These packaged plants have offered a smaller footprint, lower capital cost and easy operation.
Growing Awareness of POU
The future of safe drinking water lies squarely in the hands of the point-of-use (POU) water purification industry. Growing awareness among decision-makers and consumers is the force behind the increasing importance of the POU industry.
Membranes: Fouling & Cleaning
Membrane technology offers the possibility of managing total water resources. The spiral wound membrane element configuration is the most widely used due to its high packing density and relatively low price. This article will describe some technological advances in the area of innovative new membranes and application concepts for spiral wound membrane elements.
Using Advanced Adsorptive Media for Arsenic Treatment
On November 26, 2001, the new arsenic standard was signed into law—lowering the acceptable level for the contaminant from 50 parts per billion (ppb) to 10 ppb. Approximately 4,100 municipal water systems serving nearly 13 million people nationwide are affected by the law and are required to meet compliance by January 2006. According to the U.S. Environmental Protection Agency (EPA), 97 percent of these systems are small systems serving fewer than 10,000 people each. The economic impact on these small systems is likely to be large. However, there currently are options available to small municipalities that may be more affordable than central treatment.
New POU Technologies May Be the Answer for Small Municipalities Facing High Costs
Project Compares Brackish Water Desalination Technologies – Part 2
Part one of this article appeared in the February issue and described how nanofiltration, reverse osmosis and electrodialysis reversal are being run side-by-side at the Brackish Water Demonstration Facility in California.
One Year Performance Comparisons


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Blighted by drought and famine, ongoing border conflicts and claims of political oppression, that is the side of Ethiopia we hear most about.
However, you might be surprised to know it is one of the world's fastest growing economies.
Little wonder that it is fast attracting the attention of foreign investors, long nervous about putting their money in Africa.
Charlotte Ashton reports.


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Minnetonka Laredo Wedge Sandal
Compare at $60.00
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Item # 295779
Slide into a versatile leather platform sandal that will last you season after season! Comfortable and stylish, the Minnetonka Laredo thong sandal is a must-have wedge for summer!
- Leather upper
- Decorative metal ornament details with stone accents
- Instep strap with inside elastic insert for stretch fit
- Comfort cushioned microfiber lined footbed
- 1" platform, 1¾" molded wedge heel
- Synthetic sole
- Imported
- View more Minnetonka
By: Ahron
Location: Los Angeles
June 16, 2016
Not comfortabl
"The sandals has a cushion so I essumed they will be comfortable. Somehow it designed in a way that it is not comfortable to walk with, and it fall off the foot. I use them only if I know that I won't walk a lot. Very desepointing :("
By: Ripley25
Location: Ohio
May 29, 2016
Great Fit
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I'm attempting to convert some of my WPF skills to Silverlight, and have run into a slightly odd problem in the test mini-app I've been working on. In WPF, I got used to using DataTriggers within a style to set up control properties based on properties of the bound data. I discovered that some assemblies related to Blend allow you to do something like this in Silverlight, and I came up with something like this, in which I've got the following namespaces declared:
<DataTemplate x:Key="testItemTemplate">
<StackPanel Orientation="Horizontal">
<TextBox Text="{Binding Name, Mode=TwoWay}" x:Name="thing"/>
<ia:DataTrigger Binding="{Binding Name}" Value="ReddenMe" Comparison="Equal">
<ia:ChangePropertyAction TargetName="thing" PropertyName="Foreground" Value="Red">
In this example, I've got a data object implementing INotifyPropertyChanged and raising the PropertyChanged event as usual for the Name property. I get the expected behaviour if I change the value of the textbox and lose focus, but if the initial value of the textbox is set to ReddenMe (which for this contrived example I'm using as the trigger for the text to be red), the text doesn't go red. Does anybody know what's going on here? For DataTriggers in WPF, the trigger would be fired immediately for any data.
I realise that I could use a Converter here, but I can think of situations where I'd want to use triggers, and I wonder if there's anything I could do to make this work.


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IMDb > Juan de la Cosa (Character)
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Juan de la Cosa (Character)
from Christopher Columbus (1949)
The content of this page was created by users. It has not been screened or verified by IMDb staff.
Alternate Names:
De La Cosa / Juan De la Cosa
FilmographyEdit Credits
There may be more credits available for this character. To edit the credits displayed or to add more credits to this character's filmography, click the Edit Credits link.
- Vespucci (2017) Played by Jason Croot (as Juan De la Cosa)
- Christopher Columbus: The Discovery (1992) Played by Glyn Grain (as De La Cosa)
- Cristóbal Colón, de oficio... descubridor (1982) Played by Alberto Fernández
- Dawn of America (1951) Played by Antonio Casas
... aka "Alba de América" - Spain (original title)
- Christopher Columbus (1949) Played by Niall MacGinnis
Additional Details
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Exhibitors sought for SNAME tech conference
A limited number of tabletop exhibit and sponsorship opportunities are available at the 13th International Conference on Fast Sea Transportation.
Marine industry technology news ranges from engine and other product debuts to reports of executive promotions and interviews with CEOs.
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Boating Industry magazine announced its list of the top 50 products of the year.
Simrad Yachting today unveiled its closely guarded Halo Pulse Compression Radar product, which it calls "the world's first high-performance solid-state, open-array radar system with pulse compression technology."
For the first time in more than a decade, the World Maritime Technology Conference will be held Nov. 3-7 at the Rhode Island Convention Center in Providence.
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Skip to comments.Dusty Rhodes, A Death in the Family
Posted on 01/28/2005 6:39:57 PM PST by Congressman Billybob
With great sorrow, but also with great joy, I attended the funeral this week of Dusty Rhodes in Highlands, North Carolina.
Dusty was born in Georgia, but was working in the coal fields of western Kentucky when World War II broke out. He went into the service, did his duty. After the war, his new skills earned him a job with the telephone company. One of his first assignments brought him to Highlands, to install the new rotary phone service. There were several young women who handled all the calls on this small, operator-driven system. Dustys efforts put them out of work. One of them was Manila Reese.
Dusty and Manila met, took a shine to each other, and got married. They settled down to raise a family. They built the small building to house Rhodes Superette, which has provided a good living to three generations of that family. But there is much, much more to the extraordinary life of this gentle man as Pastor Robinson called him at the services at the First Baptist Church.
Dusty was a lay preacher at his Church. He taught Sunday School. More than that, he lived his faith every day of the week. I knew Dusty personally for 56 years. I never heard him say a harsh word about anyone else. I never heard anyone else say that THEY heard Dusty say a harsh word. He was, as I said to his children, Kitty and Dusty, Jr., family to all of us.
One in five of all the residents of this small town were crowded into the Church for the services. Had the services waited until school was over for the day, attendance would have been far higher. This was a man who was a kind and thoughtful friend to everyone he ever met, with no exceptions.
Ill tell two stories I know about him that describe this man, and that were not in his obituary nor in the eulogies delivered at the service.
The first is highly personal. When my son died at college, 14 years ago, Dusty showed up at my mothers house in Highlands with a platter of food. No one had called him. He just heard, as he heard everything in this town, that we had a family tragedy, and he responded as Southerners often do, with the sacrament of food.
The second story happened many times. Rhodes Superette always closed fairly early at night, so the family could go home for their suppers together. It was, of course, closed on Sundays, though much business was lost by that choice. Though his business wasnt open at night, the tourists who come to Highlands in three seasons of the year could still count on him.
People coming up from Atlanta drive right by the Superette. Those whod met Dusty could call him and say what they needed when they arrived late Friday. The groceries would be bagged and labeled, sitting behind the store. Folks could pick them up on the way into town, and come by to pay later in the weekend, or have the price put on their tab. (Yes, the Superette is an old-fashioned type of store, where next to the cash register is a flip-file with customer cards in it. The total of your purchase goes on the ledger, and you sign for it.)
Why did I use the word joy concerning the services for Dusty? Because that was his nature. The title for the Church bulletin for him is, Homegoing Celebration for Dusty Rhodes. Because of his deep faith, which he lived out every day, he was a joyful man. And he passed on that joy as best he could to everyone who crossed his path. No matter who you were, regardless of age, occupation, race, creed, color, or national origin.
Pastor Robinson preached up a storm about that very aspect. He read the three references in the New Testament to Barnabas, whose name means he who encourages. And he said that those passages applied every bit to this fine man who was a mainstay of this community from when he chose to marry and settle down here, in the Blue Ridge Mountains of North Carolina.
There is a passage I ran across before Dusty died. I cannot imagine a better epitaph for a man who will live on in the hearts and minds of thousands of people of all ages and walks of life, who had the privilege of knowing him.
The best portion of a good man's life is the little, nameless, unremembered acts of kindness and love. --William Wordsworth
About the Author: John Armor is a First Amendment attorney and author who lives in the Blue Ridge Mountains of North Carolina. firstname.lastname@example.com
John / Billybob
Dusty Rhodes died!!!???? I had no idea :(
Sorry for the loss of your friend. This lovely tribute says a lot about him AND you.
Our local oldies DJ goes by the name "Dusty Rhodes."
John, thanks for your touching tribute to a wonderful human being.
My God be with you and Dusty's family, now and forever.
That being said, I offer my condolences to you Congressman on the loss of your dear friend. May he Rest in Peace.
Sorry about your friend Congressman
My mistake. I meant no disrespect.
RIP to your friend, Congressman. His kind is becoming scarce.
I never spoke with him, but I recall reading some of his posts. One that stands out was his generous donation to FR during a long past FReepathon. He put the FReepathon over the top. God bless him and his family and friends he leaves behind.
Condolences to the family and friends. Sorry to hear of the loss of this good man.
I knew a 'Dusty Rhodes' as a kid too,, he just had a different name in my old hometown.
He ran a Cliff's Little Supermarket for 40 some years or so .. thru good times and bad, he was always there to help folks out in the community if he could.
Wordsworth: "You know, every act of kindness is a little bit of
love we leave behind."
Absolutely beautiful and touching. Thank you for your kind words for this dear man.
I wondered if this was our Dusty Rhodes, the ex wrestler. I just saw one of the commercials he does for a local car dealer this evening.
I remodeled a drug store in Highlands back in the seventies.
It took several days and every morning I would get to the job site a few minutes before the lady who ran the store.
Outside the store was a makeshift shelf and every morning there was a pile of change on the shelf. Curiosity got the best of me and I finally asked the owner why it was there.
She said locals would walk by in the morning and get a newspaper from the stack dropped off by truck and simply
leave the money on the shelf.
That was also back when land was cheap in those hills.
I lived in Charlotte at the time where no quarter was safe
just laying there.
Funny how we all know of one or two special people like your friend. They are the sweetness that makes life bearable.
Congressmam...beautiful eulogy.
Dusty Rhodes?
Bah, humbug.
And God Bless.
My condolences on the loss of your good friend. A finer eulogy, no man could ever hope for.
You must have been a worthy child of God.
How I love the religious heritage of America. The understanding, the vision, and the faith that are behind those simple words from the church bulletin speak volumes about a people who whose lives were simply too big to contain.
Where they were met by oppression in the lands of their origin they sought freedom. That freedom has been passed to us to use in whatever way may please us.
Another generation labors on, in seemingly small ways, to build living monuments within their daily lives; monuments that honor a God who cannot be contained; a God who frees his spirit within his mortal children and gives them the freedom to honor that spirit, or not, in whatever way they choose.
I wish the people of the world could see that America is defined, not by headlines, but by it's people; people in cities and in hamlets; people working in jobs that are great or small; people living lives that are monuments; people whose spirit simply cannot be contained.
My sincere condolences to you and all who were close to Dusty Rhodes of Highlands, North Carolina.
I've only known a very few men that could fit his style and they were wonderful too.
Thank you for your time and memories, Sir.
I appreciate vignettes like this, about authentic Americans. Must say, though, at first I thought it was about the dratted pinch-hitter for the NY Giants who cost the Indians the 1954 World Series.
You made him sound wonderful. I wish I had known him.
As you point out, they are not somber occasions of despair, bereft of hope - although, naturally, there is present some sadness of parting. Rather, the reality is a genuine peace and comfort for the family and friends. Those who know the Lord only expect separation from their loved one for a short time, and then a joyful reunion in Heaven. They are celebrations of a life of love and the recognition of a mere passing on to another, more wonderful phase and one which shall be shortly joined.
Great eulogy, John. You are right in saying the strength of this people lies in the persons of those like Dusty Rhodes - not in recognition of fame, money, power or the fleeting things of this world. It lies in the faithful lives of "little" men and women like him who dwell all over this great and blessed land living out lives of faith, service and love.
1 Corinthians 15:51-58; 1 Thessalonians 4:13-18
Condolences to Dusty's Family and Friends.
Seems almost every Rhodes family has a Dusty. Besides this Gentleman and Dusty Rhodes the Wrestler, There was a Country Music Family on the Air in Memphis Tenn, back in the Fifties with a Dusty.
Great article, John.
Yes, we are over here also. As the temperature goes down tonight it will get even worse. I suspect you are set for a few days of isolation. You'll probably get it!
My condolences and prayers.. he sounds like he was a fine fellow and someone I would have been proud to know.
"And the dead in Christ shall rise FIRST!"
Never met the man, but that doesn't lessen my interest. He sounds like the sort of man I'd like to, but probably never, be. Thanks for posting.
Dusty Rhodes, the wrestler, real name is Virgil Runnels.
That's what I thought.
No, this isn't the same wrestler we are thinking about. This is just a regular guy. I heard the wrestler Dusty Rhodes is aged and started some sort of business years ago.
Is this the same Dusty working as a Sergeant At Arms in the state House?
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