Antiplasmodial activity and cytotoxicity of 10ß-aminoquinolinylethylethers of artemisinin.

Each year roughly 800 000 people die of malaria, with 95% being African children. The shortcomings of the current drugs and the emergence of P. falciparum resistance to the artemisinin class of compounds warrant the search for new classes or derivatives. In search for such compounds, a series of 10ß-amino-quinolinylethylethers of artemisinin, previously synthesized from this laboratory were screened for antimalarial activity against both the chloroquine-susceptible 3D7 and -resistant K1 strains of P. falciparum. Their cytotoxicity was also assessed against HEK 293 and HepG2 cell lines.The parasitic and mammalian cells were incubated with compounds at various concentrations for 72 h. The antimalarial activity was determined using SYBR Green I-based fluorescence. For cytotoxicity determination, cells were grown to confluence and CellTiter-Glo luminescent cell viability assay was used.All derivatives proved to be active against both strains with good selectivity towards the parasitic cells. The derivative 11 featuring 2 artemisinin moieties and an aminoethylpiperazine linker was the most active of all. It possessed 17- and 166-fold more potency than artemether against 3D7 (EC50: 9.5 vs. 166 nM) and K1 (10.9 vs. 1723.3 nM), respectively, while was found to be as potent as artesunate against both strains.Derivative 11 stands as a good candidate to be further investigated primarily in vitro in comparison with an equimolar combination of chloroquine (CQ) and artemisinin to ascertain its advantages, if any, over the combination.

Blood glutathione and cysteine concentrations in twin children.

Glutathione and cysteine are major antioxidants in blood that are associated with health and longevity. To ensure their measurement, careful attention to avoid auto-oxidation is necessary to stabilize the samples. Since no report of these compounds has been reported in children, our goal was to determine their levels of reduced and oxidized glutathione (GSH and GSSG) and cysteine (Cys and CSSC), To this end, 140 healthy children, ages 2 to 9 years from the Louisville Twin Study were studied. Blood samples were collected and analyzed for GSH, GSSG, Cys, and CSSC by our HPLC dual electrochemical method. The results showed that GSH and total GSH (GSH + GSSG) levels for monozygotic (MZ) twins were significantly higher (P < 0.001) than levels for dizygotic (DZ) twins. However, the opposite occurred for Cys and total Cys (Cys + CSSC) in that the levels were significantly higher for DZ twins than for MZ twins. (P < 0.005-0.013). In spite of this marked difference in zygosity, the within-pair correlations for twin pairs used for estimating heritability suggested that there was a major environmental influence for total GSH and total Cys. Finally. GSH levels were significantly lower for young (2-9 years) children than adults (P < 0.001).

Maternal representation of the self as parent: connections with maternal sensitivity and maternal structuring.

Maternal representations of the self as parent were assessed via the Parent Attachment and Peer Relationship Interviews (Bretherton, Biringen, Ridgeway, Maslin-Cole, & Sherman, 1989; Biringen & Bretherton, 1988) when children were 39 months of age. Maternal sensitivity and maternal structuring during mother-child interactions were assessed at 18, 24 and 39 months. The central question of this study was whether maternal representations were related to aspects of observed maternal sensitivity and maternal structuring. We found that maternal sensitivity at 18 months predicted later maternal representations of the self as parent. But beginning at 24 months and continuing to 39 months maternal structuring proved to be a more important predictor of maternal representations of the self, in particular maternal self-esteem, even after controlling for maternal sensitivity.

Genetic and environmental influences on a measure of infant attachment security.

A twin study of infant attachment security at age 24 months was conducted on archival data for a sample of 99 MZ pairs and 108 DZ pairs from the Louisville Twin Study. MZ concordance for attachment was 62.6%, which was significantly greater than the DZ concordance of 44.4%. Concordances were transformed into polychoric correlations, and LISREL was used to conduct a quantitative genetic analysis of the data. Results indicated that 25% of the variability in attachment was attributable to genetic factors, and the remaining 75% was attributable to non-shared environmental effects. No evidence was found for a contribution from shared environmental influences to attachment security. Possible concerns about the validity of twin methodology are addressed and various interpretations of the results are presented.

Preliminary results from a twin study of infant--caregiver attachment.

Two pilot studies were conducted. First, the validity of a measure of infant-caregiver attachment for twins was assessed. Sixteen twin pairs from the Louisville Twin Study (LTS) were assessed in the Strange Situation (SS) at ages 19 or 25 months. Concordance between the LTS procedure and the SS procedure for assessing attachment was 78.1%, significantly greater than chance. Second, twin similarity for attachment as measured by the LTS procedure was assessed. Videotapes of 34 MZ pairs and 26 DZ pairs at ages 18 and 24 months were rated in terms of attachment behavior. MZ concordance for attachment was 67.6%, significantly greater than the DZ concordance rate of 38.5%. Results are discussed in the context of current debate in attachment theory.

Evidence for genetic influence on both cross-situation and situation-specific components of behavior.

An assumption often made in the study of personality and in social psychology is that methods variance and situation-specific effects, as key components of measured behavioral variance, are environmental effects. The results of the present research refute that assumption. Nine measures-3 aspects of temperament measured in each of 3 ways-were obtained at age 24 months for twin sibships participating in the Louisville Twin Study. This report describes a new model that captures the unique information potentially available in such data, by combining multitrait-multimethod and twin-family analytic designs. The results indicated significant genetic influence on methods-situations components of variance along with genetic influence on traits. The findings support heuristics that include both situation-specific patterns of behavior and cross-situational consistencies.

Eye color changes past early childhood. The Louisville Twin Study.

OBJECTIVE: To determine whether eye color changes after 6 years of age. DESIGN: Longitudinal data on eye color were obtained from the Louisville Twin Study, Louisville, Ky. Twins (n = 1513 [individuals]) were assessed at least once and most twins (n = 1386) were examined on 2 or more occasions. Parents of twins were also examined at the study inception, 128 of whom were assessed again from February 1989 to October 1993. MAIN OUTCOME MEASURE: Eye color was assessed at each examination by matching the iridial coloration of the subject to 1 of 15 painted glass eye anterior segments, similar to those in artificial eyes, mounted on a circular disk. The spectrum ranged from light blue (1) to dark brown (15). RESULTS: Among whites (n = 1359), the eye color of 3.8% to 8.6% of the sample twins became 2 U or more darker or 2 U or more lighter during 3- to 9-year intervals between 6 years of age and adulthood (> 18 years, < 24 years). Among identical (monozygotic) twin pairs, there was a high degree of concordance in eye color (r = 0.98 [P < .001]), while in fraternal (dizygotic) twin pairs, the concordance was less pronounced (r = 0.49) and decreased with age (r = 0.07). Among the sample of the mothers of twins, 9% had irides that lightened by 2 U or more during the follow-up period. CONCLUSION: Most individuals achieve stable eye color by 6 years of age. However, a subpopulation of 10% to 15% of white subjects have changes in eye color throughout adolescence and adulthood in the eye color range that can be expected to reflect changes in iridial melanin content or distribution. These data also suggest that such changes in eye color, or the propensity to such changes, may be genetically determined.

Quantitative genetic analysis of injury liability in infants and toddlers.

A threshold model of latent liability was applied to infant and toddler twin data on total count of injuries sustained during the interval from birth to 36 months of age. A quantitative genetic analysis of estimated twin correlations in injury liability indicated strong genetic dominance effects, but no additive genetic variance was detected. Because interpretations involving overdominance have little research support, the results may be due to low order epistasis or other interaction effects. Boys had more injuries than girls, but this effect was found only for groups whose parents were prompted and questioned in detail about their children's injuries. Activity and impulsivity are two behavioral predictors of childhood injury, and the results are discussed in relation to animal research on infant and adult activity levels, and impulsivity in adult humans. Genetic epidemiological approaches to childhood injury should aid in targeting higher risk children for preventive intervention.

Left ventricular boundary detection from spatio-temporal volumetric computed tomography images.

This paper presents a new automatic technique for left ventricle boundary detection from a set of three-dimensional (3D) computed tomography (CT) volumetric cardiac images. The goals of this paper are to incorporate the temporal information into LV boundary detection, to link the shape modeling and LV boundary detection together, and to provide a compact representation of recovered LV boundaries to cardiac imaging. The proposed technique introduces spatio-temporal boundary detection and iterative model-based boundary refinement to left ventricular boundary extraction. The proposed technique has been applied to two sets of four-dimensional (4D) computed tomography images. Experimental results are compared with the manually edited images.

Heredity and environment in phoneme articulation: hereditary and environmental contributions to articulation proficiency.

Large twin samples and recent applications of multiple regression techniques to behavioral genetics methodology makes possible evaluation of genetic and environmental contributions to the articulation proficiency of individual phonemes. Factor analysis of the articulation scores from 256 MZ and DZ twins and 124 of their non-twin siblings (all children ranged from 2; 11 to 9; 8 years) were conducted to reduce a 50-item articulation test to a more manageable set of five articulation factors. The twins' factor scores were then analyzed using multiple regression procedures to determine the extent to which the individual factors resulted from genetic and/or environmental influences. The /r/ and /[symbol: see text], t[symbol: see text], d[symbol: see text]/ factors were found to have strong genetic components, while the /l, j, w/ factor was found to be strongly influenced by environmental sources of variation.

Insulin-like growth factor-I comparisons in healthy twin children.

Insulin-like growth factor-I (IGF-I) levels in plasma were measured in healthy twin children. The within-pair correlation for 43 monozygotic pairs was r = 0.91 (P < or = 0.0001), an association significantly higher than that for same sex dizygotic pairs (r = 0.40; P < or = 0.06). The high correlation for monozygotic twins indicated a marked genetic influence on IGF-I levels. After correction for age and sex, the correlation between IGF-I level and height was r = 0.38 (P < or = 0.0001). These findings provide clear evidence that IGF-I levels correlate with height, a growth characteristic known to be genetically controlled.

Health consequences of behaviors: injury as a model.

Injury is the third leading cause of death in the United States and the leading cause for children, adolescents, and young adults. Injury results from multiple factors and so may its prevention. The first and simplest approach toward preventing injuries has been to innovatively and aggressively apply a traditional public health model. Strategically, the goal has been to remove harmful agents of injury and to make the environment safer. Tactics such as public information, product regulation, legislative action, and the like have been credited with reductions in mortality and morbidity. To expand our understanding and our prevention strategies across multiple injuries, other scientific knowledge bases and intervention models from fields such as psychology and child development are being used to study childhood injury. These approaches show that in addition to environmental determinants, psychosocial factors involving both the care giver and the child are related to injury. The research programs described here illustrate the advantage of investigating psychosocial factors at both molar and molecular levels. General characteristics of mothers and children related to injury help define families at risk, as well as suggesting vehicles for intervention. Behavioral factors influencing risk perception highlight the etiology of increased risk in adolescence. Injury episodes, even slight, as well as "near injuries" and dangerous and risky behavior can be quantified and analyzed by retrospective ("postmortem") approaches yielding data on commonly occurring consequences (and the lack thereof) for minor injury. Finally, approaches that simulate dangerous situations can identify interaction patterns that result in childhood injury. Based on such research, we are coming to view injuries as the result of patterns of behaviors that develop and persist over time, and as such these patterns can be detected and, one hopes, altered before a serious medical event occurs. The role of the pediatrician after injury occurs is clear. With regard to prevention of injuries, pediatricians' roles are being defined by those individuals who have begun to investigate causes, educate families, and advocate for regulation and prevention. However, like the causes and methods for prevention, the disciplines involved in the study and prevention of injury are multiple. Such a multidisciplinary approach that considers multiple factors, theories, models, and interventions to prevent injury may be the approach that is as simple as possible.

Classification of chromatic visual evoked potentials with the aid of a neural net.

Twelve normal subjects, and six color blind (three protanopes and three deuteranopes) individuals were used in this study. Visual evoked potentials (50-150 msec post-stimulus) were recorded in response to three stimuli: (a) three horizontal, achromatic bars alternating in luminosity between bright and dim, (b) bars alternating between blue and red, and (c) bars alternating between green and red. The resulting waveforms were normalized in amplitude and submitted to a commercial neural net program for classification. The network correctly identified 24 of the 36 normal responses. (2) The network was also asked to distinguish between the responses of normal and color blind individuals. Based upon the blue/red response, the network correctly classed 12 of 18 responses, and based upon the green/red response correctly classified 14 of 18 (including all 6 color blinds). (3) These results are statistically highly significant and suggest that the VEP elicited by chromatic stimulation is substantially different from that elicited by achromatic stimuli.

Quantitative genetic analysis of longitudinal trends in height: preliminary results from the Louisville Twin Study.

A preliminary series of quantitative genetic models was applied to a subset of longitudinal height data, spanning birth to maturity, gathered from twin families in the Louisville Twin Study. Descriptive Cholesky factor parameterization was found to give more satisfactory results than did a system of constraints based on a model of developmental transmission of a time-constant and time-specific factors. The results from application of two autosomal sex-limitation models are contrasted with those from a model specifying both autosomal and sex-chromosomal patterns of inheritance. The latter model was more conducive to parameter reduction. Although these models do not constitute conclusive tests of autosomal sex-limitation versus sex-linkage, the more parsimonious model is consistent with previous research suggesting a stature locus on the long arm of the Y chromosome. Heritability of height is estimated at about 90% or greater from 6 years of age on. Substantial and fairly constant longitudinal genetic correlations are found from 3 years of age on. Shared environmental effects unrelated to parental height were seen for birth length, corrected for gestational age, to height at 3 years of age, but these are not satisfactorily differentiated from possible twin effects in the present sample. The genetic consequences of assortative mating are emphasized since failure to take assortment into account can lead to overestimation of shared environmental effects and under-estimation of genetic effects. The results indicate that about 20% of within-gender variability for mature height can be attributed to the genetic consequences of assortment, even though the phenotypic marital correlation of 0.22 is quite modest. The importance of testing the assumption of multivariate normality underlying the application of the method of maximum-likelihood is also highlighted.

Assessment of infant mental development: toward a broader perspective.

The limitations on predictions of intelligence provided by single-point neonatal and infant assessments continue to hamper efforts to certify the clinical outcome of children at risk. Although new methods of clinical assessment show promise of offsetting these limitations, each method alone has not markedly improved predictions. From a developmental perspective, a strategy for assessment should include a broad range of measures combined empirically to form a developmental risk registry. The strategy takes into account evolving changes, as well as levels of competencies of the infant, and considers these within the evolving environmental context of the family.

Children's behavioral inhibition over age and across situations: genetic similarity for a trait during change.

Ratings of behaviors pertaining to inhibition were observed for 130 twins participating in a longitudinal study. Ratings were available for four ages (12, 18, 24, and 30 months) and from three sources at each age: direct observations obtained in a laboratory setting, direct observations obtained in conjunction with infant mental testing, and a temperament measure from a questionnaire completed by parents. For the individual twins, the age-to-age correlations were in the moderate range (.26 to .64). The situation-to-situation correlations were generally in the same range (.17 to .64). When the twins were recombined into twin pairs, within-pair (intraclass) correlations indicated that monozygotic (MZ) twins were more concordant than dizygotic (DZ) twins for each of the behaviors at each of the ages. Also, the MZ twins were more concordant for the direction and degree of behavioral change from age to age or from situation to situation. These data provide additional evidence for the biological influence on behavioral inhibition, a characteristic that has been studied in temperament and personality research. The results suggest that the trait of behavioral inhibition and a change in the trait are genetically conditioned. In addition, it is suggested that the concept of trait be expanded to include the person-centered biological regulation of change.

Developmental research of twin's temperament.

In the Louisville Twin Study, pairs of 3- and 4-year-old twins were provided with standardized competitive or cooperative tasks in a laboratory setting. Some tasks required a pair of twins to share toys; other fostered a more competitive engagement between the twins. Behavioral ratings identified temperament and social components at both ages, and between the two ages, there were transformations in the links between the components. Parental ratings of the twins' temperament at the same ages were moderately correlated with the laboratory observations, but the pattern of the relations changed from one age to the next. The combined sets of measures were subjected to twin analyses for 43 pairs of twins. The results are discussed in terms of the similarity of MZ and DZ pairs for the dimensions of temperament and the transformations of temperament.