Reaching with one arm to the other: Coordinating touch, proprioception, and action during infancy.

Reaching to target locations on the body has been studied little despite its importance for adaptive behaviors such as feeding, grooming, and indicating a source of discomfort. This behavior requires multisensory integration given that it involves coordination of touch, proprioception, and sometimes vision as well as action. Here we examined the origins of this skill by investigating how infants begin to localize targets on the body and the motor strategies by which they do so. Infants (7-21 months of age) were prompted to reach to a vibrating target placed at five arm/hand locations (elbow, crook of elbow, forearm, palm, and top of hand) one by one. To manually localize the target, infants needed to reach with one arm to the other. Results suggest that coordination increases with age in the strategies that infants used to localize body targets. Most infants showed bimanual coordination and usually moved the target arm toward the reaching arm to assist reaching. Furthermore, intersensory coordination increased with age. Simultaneous movements of the two arms increased with age, as did coordination between vision and reaching. The results provide new information about the development of multisensory integration during tactile localization and how such integration is linked to action.

Differential effect of nimodipine in attenuating iron-induced toxicity in brain- and blood-brain barrier-associated cell types.

Metal homeostasis is increasingly being evaluated as a therapeutic target in stroke and neurodegenerative diseases. Metal dysregulation has been shown to lead to protein aggregation, plaque formation and neuronal death. In 2007, we first reported that voltage-gated calcium channels act as a facile conduit for the entry of free ferrous (Fe(2+)) ions into neurons. Herein, we evaluate differential iron toxicity to central nervous system cells and assess the ability of the typical L-type voltage-gated calcium channel blocker nimodipine to attenuate iron-induced toxicity. The data demonstrate that iron sulfate induces a dose-dependent decrease in cell viability in rat brain endothelial cells (RBE4; LC(50) = 150 µM), neuronal cells (Neuro-2α neuroblastoma; LC(50) = 400 µM), and in astrocytes (DI TNC1; LC(50) = 1.1 mM). Pre-treatment with nimodipine prior to iron sulfate exposure provided a significant (P < 0.05) increase in viable cell numbers for RBE4 (2.5-fold), Neuro2-α (~2-fold), and nearly abolished toxicity in primary neurons. Astrocytes were highly resistant to iron toxicity compared to the other cell types tested and nimodipine had no (P > 0.05) protective effect in these cells. The data demonstrate variable susceptibility to iron overload conditions in different cell types of the brain and suggest that typical L-type voltage-gated calcium channel blockers (here represented by nimodipine), may serve as protective agents in conditions involving iron overload, particularly in cell types highly susceptible to iron toxicity.

Diagnoses of overweight children and adolescents seen in a pediatric endocrinology clinic.

The prevalence of overweight is rising in the pediatric population. The aims of this study were to determine prevalence and diagnostic characteristics of overweight patients referred for endocrine evaluation. BMI was calculated and diagnosis codes were assigned for patients seen for endocrine evaluation. Odds ratio calculation and logistic regression were used to evaluate overweight patients. Rising odds of overweight was seen as age increased. Referring diagnoses associated with a significant (p <0.05) proportion of overweight patients included excessive growth, other pubertal disorders, and menstrual disorders. Endocrinologist diagnosis of overweight had a significantly higher proportion of overweight patients. Concordance between referring and endocrinologist diagnosis decreased as BMI category rose. A low percentage of records of overweight patients documented discussion of weight management. Certain referring diagnoses have higher proportion of overweight individuals representing clinical findings associated with being overweight. Opportunities are missed to diagnose overweight individuals as well as to begin weight management counseling.

Recurrent germline mutation in MSH2 arises frequently de novo.

INTRODUCTION: An intronic germline mutation in the MSH2 gene, A-->T at nt942+3, interferes with the exon 5 donor splicing mechanism leading to a mRNA lacking exon 5. This mutation causes typical hereditary non-polyposis colorectal cancer (HNPCC) and has been observed in numerous probands and families world wide. Recurrent mutations either arise repeatedly de novo or emanate from ancestral founding mutational events. The A-->T mutation had previously been shown to be enriched in the population of Newfoundland where most families shared a founder mutation. In contrast, in England, haplotypes failed to suggest a founder effect. If the absence of a founder effect could be proven world wide, the frequent de novo occurrence of the mutation would constitute an unexplored predisposition. METHODS: We studied 10 families from England, Italy, Hong Kong, and Japan with a battery of intragenic and flanking polymorphic single nucleotide and microsatellite markers. RESULTS: Haplotype sharing was not apparent, even within the European and Asian kindreds. Our marker panel was sufficient to detect a major mutation arising within the past several thousand generations. DISCUSSION: As a more ancient founder is implausible, we conclude that the A-->T mutation at nt942+3 of MSH2 occurs de novo with a relatively high frequency. We hypothesise that it arises as a consequence of misalignment at replication or recombination caused by a repeat of 26 adenines, of which the mutated A is the first. It is by far the most common recurrent de novo germline mutation yet to be detected in a human mismatch repair gene, accounting for 11% of all known pathogenic MSH2 mutations.

Assessment of sternal vascularity with single photon emission computed tomography after harvesting of the internal thoracic artery.

OBJECTIVE: This study prospectively evaluates the effect on sternal vascularity of harvesting the left internal thoracic artery. METHODS: Twenty-four consecutive patients undergoing primary coronary artery bypass grafting were studied. One patient's procedure was altered during the operation, and he was eliminated from the study. The patients were prospectively randomized to receive a skeletonized internal thoracic artery (group I, n = 11) or a pedicled internal thoracic artery (group II, n = 12) graft. Each patient underwent a preoperative technetium 99 methylene diphosphonate bone scan using single photon emission computed tomography. The ratio of the mean counts per pixel on the left side of the sternum was compared with the mean counts per pixel on the right side. Postoperatively, all patients had a second scan, and sternal uptake was compared with the preoperative uptake. RESULTS: No significant differences in preoperative and operative variables were observed between the groups. A statistically significant reduction in blood flow to the left side of the sternum was shown postoperatively in group II compared with group I (0.61 +/- 0.11 vs 0.85 +/- 0.09; P <.001). Multivariable logistic regression analysis of preoperative and operative variables revealed only a pedicled left internal thoracic artery to be associated with a 20% or more reduction in left-to-right sternal activity ratio (odds ratio, 100; 70% confidence limits, 22-465; P =.002). CONCLUSION: A pedicled left internal thoracic artery graft to the left anterior descending artery reduces blood flow to the left side of the sternum during the acute postoperative period. This does not occur when the left internal thoracic artery is skeletonized.

IgM rheumatoid factor and the inhibition of covalent binding of C4b to IgG in immune complexes.

Work by other investigators has shown that IgM-rheumatoid factors (IgM-RF's) can impede complement-mediated inhibition of immune precipitation. We examined the binding of complement component C4b to radiolabelled IgG in model immune complexes and demonstrate that IgM-RF's are capable of reducing the covalent binding of C4b to 125I-IgG in the complexes. Reduced binding to IgG, however, may not be accompanied by binding of C4b to IgM-RF's within the complex, as we also demonstrate that IgM-RF's are relatively poor at C4b capture compared with normal IgM.

99mTc-MDP bone SPECT for the evaluation of sternal ischaemia following internal mammary artery dissection.

Coronary artery bypass grafting (CABG) is one of the most frequently performed operations in the United States. The use of internal mammary artery (IMA) grafting has been identified as increasing the risk of sternal wound infections and mediastinitis. The purpose of our study was to prospectively evaluate the effect of different techniques of left internal mammary artery (LIMA) harvesting on sternal vascularity. Thirty-three patients undergoing primary coronary artery bypass grafting were studied. The patients were divided into groups that received a skeletonized IMA (group I, n=11), a pedicled IMA (group II, n=12), or a semiskeletonized IMA (group III, n=10) graft. Each patient underwent a preoperative 99mTc-methylene diphosphonate bone scan using single photon emission computed tomography (SPECT). The ratio of the mean counts/pixel for each side of the sternum was obtained. Post-operatively, all patients had a repeat bone SPECT. Ratios of unilateral sternal uptakes were compared to the preoperative study. A univariable analysis of post-operative to pre-operative ratios revealed statistically significant reduction in vascularity to the left side of the sternum post-operatively in group II compared with groups I and III (0.68 0.12 vs 0.99 0.24 and 0.93 0.09; P<0.01). There was no difference between groups I and III (P=1). Multivariable analysis revealed only the type of harvesting to be associated with post-operative reduction in left to right sternal activity ratio (P<0.02). Pairwise comparisons revealed that differences are due to pedicled type of harvesting (group II vs group I, P=0.03; II vs III, P=0.001; and I vs III, P=0.115). A pedicled IMA graft causes acute post-operative sternal ischaemia. This does not occur when the IMA is skeletonized or semiskeletonized. Hence, it may be prudent to minimize dissection during mobilization of the IMA to decrease the likelihood of post-operative sternal complications.

NGP1-01, a multi-targeted polycyclic cage amine, attenuates brain endothelial cell death in iron overload conditions.

Development and progression of neurodegenerative disorders have, amongst other potential causes, been attributed to a disruption of iron regulatory mechanisms and iron accumulation. Excess extracellular iron may enter cells via nontraditional routes such as voltage-gated calcium channels and N-methyl-d-aspartate (NMDA) receptors leading to intracellular oxidative damage and ultimately mitochondrial failure. Nimodipine, an L-type calcium channel blocker has been shown to reduce iron-induced toxicity in neuronal and brain endothelial cells. Our current study investigates NGP1-01, a multimodal drug acting as an antagonist at both the NMDA receptor and the L-type calcium channel. Our previous studies support NGP1-01 as a promising neuroprotective agent in diseases involving calcium-related excitotoxicity. We demonstrate here that NGP1-01 (1 and 10µM) pretreatment abrogates the effects of iron overload in brain endothelial cells protecting cellular viability. Both concentrations of NGP1-01 were found to attenuate iron-induced reduction in cellular viability to a similar extent, and were statistically significant. To further verify the mechanism, the L-type calcium channel agonist FPL 64176 was administered to promote iron uptake. Addition of NGP1-01 dose-dependently reduced FPL 64176 stimulated uptake of iron. These data support further evaluation of NGP1-01 as a neuroprotective agent, not only in diseases associated with excitotoxicity, but also in those of iron overload.

The development of detour ability during infancy.

3 longitudinal studies were conducted to examine the generalization of detour ability across motor responses and barrier types and the relationship between the development of object permanence and detour ability. In Experiment 1, 12 8-month-olds were tested every 3 weeks for 4 months on 4 different detour problems and Stage 4 and 6 object permanence tasks. In the detour problems, infants had to reach or move around a transparent or opaque barrier to obtain an object. The results indicated that infants made reaching detours before corresponding locomotor ones and generally made detours around opaque barriers before transparent ones. Infants also solved the Stage 4 task before the detour problems but failed to solve the Stage 6 task before testing ended. The results of Experiments 2 and 3 suggested that the difference in reaching and locomotor detour performance was not an artifact of barrier length or the infant's position relative to the barrier. The overall results are discussed in relation to issues of developmental synchrony and Piaget's theory of infant spatial development.

A perception--action perspective on tool use development.

In this essay I argue for a new wave of research on tool use development. Advances in the literature on perception-action development hold important clues for how tool use unfolds in children. These advances suggest that tool use may be a more continuous developmental achievement than has been previously believed. On this view, tool use is rooted in the perception-action routines that infants employ to gain information about their environments. Although tools alter the properties of effector systems, children use tools to explore and change their environments, building on efforts that originate in infancy. Based on this approach, new research directions are suggested, including efforts designed to investigate the processes by which children detect and relate affordances between objects, coordinate spatial frames of reference, and incorporate early-appearing action patterns into instrumental behaviors.

Developmental biodynamics: brain, body, behavior connections.

This special section, Developmental Biodynamics: Brain, Body, Behavior Connections, celebrates a renewed and revitalized interest in the study of motor development. The renewed interest has been sparked by advances in the neurosciences, biomechanics, and behavioral sciences and, importantly, in the attempts to integrate theories and findings across these disciplines. In this introduction to the special section, we consider the contributions that have led to a reinvigorated field of motor development and to its new interdisciplinary look. We highlight the papers in the special section by discussing how they illustrate related advances across research in the neurosciences, biomechanics, and behavioral sciences and how progress across these domains has come to define and characterize the emerging field of developmental biodynamics.

Using writing instruments: invariances in young children and adults.

In 2 studies, developmental changes in variability associated with handwriting were investigated. In Study 1, variability in grip patterns and pen positioning relative to a flat surface were examined in 3- and 5-year-olds and adults. The results indicated that between 3 and 5 years of age there is a reduction in the number of grips that individual children routinely use and a reduction in variability associated with pen-surface positioning. In Study 2, the 3-year-old children who participated in Study 1 were tested 6 months later. In comparison to young 3-year-old children, older 3-year-olds use an adult grip pattern more often and are less variable in pen-surface positioning, although the use of multiple grip patterns is still common. The findings from both studies are considered in relation to prior research that emphasized modal patterns of motor development and newer work that uses developmental changes in variability to understand the acquisition of motor skill.

The development of anticipatory hand orientation during infancy.

The development of infants' prehensile adjustments regarding the orientation of objects was investigated. Five- and nine-month-olds (N = 16 per group) were presented with horizontally and vertically oriented dowels to determine at what point during the reach, hand orientation approximated that of the dowel. Nine-month-olds rotated their hands appropriately, early in the course of the reach, i.e., before tactual contact of the dowel, whereas five-month-olds did so mostly after tactual contact. Analyses of the effects of trials within the experimental session indicated that this age difference was not associated with practice or fatigue effects. The results are discussed in relation to the development of visual control of prehensile behavior.

C4B deficiency is not associated with meningitis or bacteremia with encapsulated bacteria.

The two isotypes of the fourth complement component are C4A and C4B. C4B forms ester bonds more efficiently than C4A and so, in theory, is more likely than C4A to bind to polysaccharide capsules of encapsulated bacteria. Two studies have reported homozygous C4B deficiency in patients with meningitis or bacteremia caused by encapsulated organisms. In the present study the association between C4B deficiency and these disorders was evaluated in four groups: patients with bacteremia, those with meningitis, those who developed Haemophilus influenzae type b (Hib) disease after Hib polysaccharide vaccination, and patients less than 1 year old with meningitis. Healthy adults served as controls. Of the 257 patients, 2.3% had homozygous C4B deficiency compared with 3.7% of 349 controls. According to these data, there is no increase in homozygous C4B deficiency among patients with bacteremia or meningitis caused by encapsulated bacteria.

Peptidomimetic inhibitors of protein farnesyltransferase show potent antimalarial activity.

Malaria continues to represent a very serious health problem in the tropics. The current methods of clinical treatment are showing deficiencies due to the increased incidence of resistance in the parasite. In the present paper we report the design, synthesis, and evaluation of potential antimalarial agents against a novel target, protein farnesyltransferase. We show that the most potent compounds are active against Plasmodium falciparum in vitro at submicromolar concentrations.