Planum temporale morphology in children with developmental dyslexia.

The planum temporale is a highly lateralized cortical region, located within Wernicke's area, which is thought to be involved in auditory processing, phonological processing, and language. Research has linked abnormal morphology of the planum temporale to developmental dyslexia, although results have varied in large part due to methodological inconsistencies in the literature. This study examined the asymmetry of the planum temporale in 29 children who met criteria for dyslexia and 26 children whose reading was unimpaired. Leftward asymmetry of the planum temporale was found in the total sample and this leftward asymmetry was significantly reduced in children with dyslexia. This reduced leftward asymmetry in children with dyslexia was due to a planum temporale that is larger in the right hemisphere. This study lends support to the idea that planum temporale asymmetry is altered in children with developmental dyslexia.

Discovery of a novel non-steroidal GR antagonist with in vivo efficacy in the olanzapine-induced weight gain model in the rat.

We report the optimization of a series of non-steroidal GR antagonists that led to the identification of compound 7. This compound is efficacious when dosed orally in an olanzapine-induced weight gain model in rats.

Beyond phonological processing deficits in adult dyslexics: atypical FMRI activation patterns for spatial problem solving.

It is unclear the extent to which neurodevelopmental differences observed in reading disabled individuals are limited to traditional language processing areas. Some have suggested atypical processing of complex spatial problems in these individuals. Hitherto, research on this question has been limited to behavioral studies, yielding mixed results. Absence of related imaging studies is in stark contrast to the plethora examining functional neurology for verbal tasks. This study uses functional magnetic resonance imaging (fMRI) to examine how adult dyslexics perform when analyzing complex spatial material unrelated to the reading of text. We observed atypical functional neurology during spatial problem solving, which was not observed behaviorally.

The aromatase gene CYP19A1: several genetic and functional lines of evidence supporting a role in reading, speech and language.

Inspired by the localization, on 15q21.2 of the CYP19A1 gene in the linkage region of speech and language disorders, and a rare translocation in a dyslexic individual that was brought to our attention, we conducted a series of studies on the properties of CYP19A1 as a candidate gene for dyslexia and related conditions. The aromatase enzyme is a member of the cytochrome P450 super family, and it serves several key functions: it catalyzes the conversion of androgens into estrogens; during early mammalian development it controls the differentiation of specific brain areas (e.g. local estrogen synthesis in the hippocampus regulates synaptic plasticity and axonal growth); it is involved in sexual differentiation of the brain; and in songbirds and teleost fishes, it regulates vocalization. Our results suggest that variations in CYP19A1 are associated with dyslexia as a categorical trait and with quantitative measures of language and speech, such as reading, vocabulary, phonological processing and oral motor skills. Variations near the vicinity of its brain promoter region altered transcription factor binding, suggesting a regulatory role in CYP19A1 expression. CYP19A1 expression in human brain correlated with the expression of dyslexia susceptibility genes such as DYX1C1 and ROBO1. Aromatase-deficient mice displayed increased cortical neuronal density and occasional cortical heterotopias, also observed in Robo1-/- mice and human dyslexic brains, respectively. An aromatase inhibitor reduced dendritic growth in cultured rat neurons. From this broad set of evidence, we propose CYP19A1 as a candidate gene for human cognitive functions implicated in reading, speech and language.

Reading fluency: implications for the assessment of children with reading disabilities.

The current investigation explored the diagnostic utility of reading fluency measures in the identification of children with reading disabilities. Participants were 50 children referred to a university-based clinic because of suspected reading problems and/or a prior diagnosis of dyslexia, where children completed a battery of standardized intellectual, reading achievement, and processing measures. Within this clinical sample, a group of children were identified that exhibited specific deficits in their reading fluency skills with concurrent deficits in rapid naming speed and reading comprehension. This group of children would not have been identified as having a reading disability according to assessment of single word reading skills alone, suggesting that it is essential to assess reading fluency in addition to word reading because failure to do so may result in the under-identification of children with reading disabilities.

The pars triangularis in dyslexia and ADHD: A comprehensive approach.

Limited research has been conducted on the structure of the pars triangularis (PT) in dyslexia despite functional neuroimaging research finding it may play a role in phonological processing. Furthermore, research to date has not examined PT size in ADHD even though the right inferior frontal region has been implicated in the disorder. Hence, one of the purposes of this study was to examine the structure of the PT in dyslexia and ADHD. The other purposes included examining the PT in relation to overall expressive language ability and in relation to several specific linguistic functions given language functioning often is affected in both dyslexia and ADHD. Participants included 50 children: 10 with dyslexia, 15 with comorbid dyslexia/ADHD, 15 with ADHD, and 10 controls. Using a 2 (dyslexia or not) x 2 (ADHD or not) MANCOVA, findings revealed PT length and shape were comparable between those with and without dyslexia. However, children with ADHD had smaller right PT lengths than those without ADHD, and right anterior ascending ramus length was related to attention problems in the total sample. In terms of linguistic functioning, presence of an extra sulcus in the left PT was related to poor expressive language ability. In those with adequate expressive language functioning, left PT length was related to phonological awareness, phonological short-term memory and rapid automatic naming (RAN). Right PT length was related to RAN and semantic processing. Further work on PT morphology in relation to ADHD and linguistic functioning is warranted.

The relationship between cerebral hemisphere volume and receptive language functioning in dyslexia and attention-deficit hyperactivity disorder (ADHD).

Because poor comprehension has been associated with small cerebral volume and there is a high comorbidity between developmental dyslexia, attention-deficit hyperactivity disorder (ADHD), and specific language impairment, the goal of this study was to determine whether cerebral volume is reduced in dyslexia and attention-deficit hyperactivity disorder in general, as some suggest, or whether the reduction in volume corresponds to poor receptive language functioning, regardless of the diagnosis. Participants included 46 children with and without dyslexia and attention-deficit hyperactivity disorder, aged 8 to 12 years. Our results indicated that cerebral volume was comparable between those with and without dyslexia and attention-deficit hyperactivity disorder overall. However, when groups were further divided into those with and without receptive language difficulties, children with poor receptive language had smaller volumes bilaterally as hypothesized. Nonetheless, the relationship between cerebral volume and receptive language was not linear; rather, our results suggest that small volume is associated with poor receptive language only in those with the smallest volumes in both dyslexia and attention-deficit hyperactivity disorder.

A quantitative magnetic resonance imaging analysis of the cerebellar deficit hypothesis of dyslexia.

Recent evidence suggests that the primary source of dysfunction in dyslexia is the cerebellum. To examine the cerebellar deficit hypothesis of dyslexia, 20 children with dyslexia and 20 children without dyslexia were assessed using neuropsychological testing and quantitative magnetic resonance imaging. Results demonstrated that the volumes of both hemispheres and the vermis were not statistically significantly different between groups. However, children without dyslexia demonstrated greater rightward cerebellar hemisphere asymmetry. The relationship between cerebellar morphologic structure and phonological processing was assessed. For children without dyslexia, bilateral hemisphere volume moderately correlated with phonological awareness and phonological short-term memory. Hemisphere asymmetry moderately correlated with rapid naming errors, and the anterior vermis volume moderately correlated with phonological awareness. For children with dyslexia, the only statistically significant correlation was between rapid naming errors and the left hemisphere volume. Evidence suggests that atypical cerebellar morphologic structure may have a role in dyslexia for a subgroup of individuals. Although children with and without attention-deficit/hyperactivity disorder did not differ in cerebellar morphologic structure, the anterior vermis volume moderately correlated with inattention, hyperactivity, and impulsivity, while the right hemisphere volume moderately correlated with inattention and hyperactivity. Our findings provide mixed support for the cerebellar deficit hypothesis of dyslexia. Although cerebellar morphologic structure is atypical in some individuals with dyslexia, it is inconsistently related to cognitive or motor dysfunction. In our sample, cerebellar morphologic structure may be related to about one-third of cases of dyslexia. Hence, dyslexia may be best accounted for by a combination of cortical and cerebellar contributions.

Reading and the corpus callosum: an MRI family study of volume and area.

This study examines the corpus callosum in 68 readers nested in 24 families. Callosa were measured and controlled for whole brain volume, intelligence, and gender. The relation of corpus callosum size to the within-family variance of oral reading was investigated with various measurements: volume, midsagittal area, and anterior-to-posterior one-fifth area segmentations. Because this is the first known publication of MRI calculations of corpus callosum volume, some basic questions about bilateral symmetry and the efficacy of area versus volumetric measurements were explored. Results suggest that better readers within families have larger midsagittal areas at the midbody. Although reliably measured, volume did not contribute to oral reading but was highly correlated with area. Bilateral volumes of the corpus callosum were symmetric.

Right hemisphere brain morphology, attention-deficit hyperactivity disorder (ADHD) subtype, and social comprehension.

Social comprehension involves empathy for others' experiences and appropriate responses to nonverbal cues. Previous research using magnetic resonance imaging (MRI) has suggested a relationship between brain morphology and psychiatric syndromes, such as attention-deficit hyperactivity disorder (ADHD), that typically entail social difficulties. The right hemisphere, specifically, has been associated with social skill deficits, and numerous studies have also associated ADHD with social skill deficits. No studies, however, have examined the association of ADHD subtype with both social comprehension and right-hemisphere morphology. Fifty-nine children (6-12 years old) underwent MRI, from which the right hemisphere was classified into four morphologic subtypes. Children were also grouped by ADHD subtype or clinical control status. From Behavior Assessment System for Children (BASC) items, a social comprehension subscale was constructed. Analyses revealed significant differences in social comprehension based on ADHD subtype. Differences in social comprehension based on ADHD status were especially pronounced in children with atypical right-hemisphere morphology. Thus, the diagnosis of ADHD might be associated with underlying risk in the area of social comprehension, especially for children with atypical right-hemisphere morphology.

Highly enantioselective synthesis of glycidic amides using camphor-derived sulfonium salts. Mechanism and applications in synthesis.

The reactions of a range of amide-stabilized sulfur ylides derived from readily available camphor-derived sulfonium salts for the synthesis of glycidic amides have been studied. Primary, secondary, and tertiary amides were tested, and it was found that the highest enantioselectivities were observed with tertiary amides, which provided glycidic amides in good to excellent yields, exclusive trans selectivity, and excellent enantioselectivities. The reaction was general for aromatic aldehydes, but aliphatic aldehydes gave more variable enantioselectivities. The epoxy amides could be converted cleanly into epoxy ketones by treatment with organolithium reagents. We were also able to effect selective ring opening of the epoxy amides with a variety of nucleophiles, followed by hydrolysis of the amide to yield the corresponding carboxylic acid. This methodology was applied to the total synthesis of the target compound SK&F 104353. A combination of crossover experiments and theoretical calculations has revealed that the rate- and selectivity-determining step is ring closure, not betaine formation as was the case for phenyl-stabilized ylides.

Brain morphology and neuropsychological profiles in a family displaying dyslexia and superior nonverbal intelligence.

Behavioral research suggests that individuals with dyslexia may have exceptional skills in nonverbal cognitive processes, while genetic studies have noted that giftedness, high IQ and/or special talents tend to run in families. Taken together, these results suggest that persons within families (particularly offspring) may share similar cortical systems supporting those functions. Postmortem and in vivo imaging studies have linked dyslexia to abnormalities in the structures associated with the parietal operculum (PO) (e.g., planum temporale, supramarginal gyrus, and angular gyrus). In this paper we present data on a single family showing a link between dyslexia, superior nonverbal IQ and atypical PO presentation. We consider the psychometric and neurological patterns of this family as a tentative etiological test of the putative dyslexia-talent association.

Testing the double-deficit hypothesis in an adult sample.

The double-deficit hypothesis of dyslexia posits that reading deficits are more severe in individuals with weaknesses in phonological awareness and rapid naming than in individuals with deficits in only one of these reading composite skills. In this study, the hypothesis was tested in an adult sample as a model of reading achievement. Participants were parents of children referred for evaluation of reading difficulties. Approximately half of all participants reported difficulty learning to read in childhood and a small subset demonstrated ongoing weaknesses in reading. Structural equation modeling results suggest that the double-deficit hypothesis is an accurate model for understanding adult reading achievement. Better reading achievement was associated with better phonological awareness and faster rapid automatized naming in adults. Posthoc analyses indicated that individuals with double deficits had significantly lower reading achievement than individuals with single deficits or no deficits.

Synthesis and protein degradation capacity of photoactivated enediynes.

[structure: see text] The viability of proteins as targets of thermally and photoactivated enediynes has been confirmed at the molecular level. Model studies using a labeled substrate confirmed the efficacy of atom transfer from diyl radicals produced from enediynes to form captodatively stabilized carbon centered aminoacyl radicals, which then undergo either fragmentation or dimerization. To exploit this finding, a family of enediynes was developed using an intramolecular coupling strategy. Derivatives were prepared and used to target specific proteins, showing good correlation between affinity and photoinduced protein degrading activity. The findings have potential applications in the design of artificial chemical proteases and add to our understanding of the mechanism of action of the clinically important enediyne antitumor antibiotics.

The role of the corpus callosum in interhemispheric transfer of information: excitation or inhibition?

The corpus callosum is the major neural pathway that connects homologous cortical areas of the two cerebral hemispheres. The nature of how that interhemispheric connection is manifested is the topic of this review; specifically, does the corpus callosum serve to communicate an inhibitory or excitatory influence on the contralateral hemisphere? Several studies take the position that the corpus callosum provides the pathway through which a hemisphere or cortical area can inhibit the other hemisphere or homologous cortical area in order to facilitate optimal functional capacity. Other studies suggest that the corpus callosum integrates information across cerebral hemispheres and thus serves an excitatory function in interhemispheric communication. This review examines these two contrasting theories of interhemispheric communication. Studies of callosotomies, callosal agenesis, language disorders, theories of lateralization and hemispheric asymmetry, and comparative research are critically considered. The available research, no matter how limited, primarily supports the notion that the corpus callosum serves a predominantly excitatory function. There is evidence, however, to support both theories and the possibility remains that the corpus callosum can serve both an inhibitory and excitatory influence on the contralateral hemisphere.

Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the cannabinoid CB(1) and CB(2) receptors: steric and electronic effects of naphthoyl substituents. New highly selective CB(2) receptor agonists.

In an effort to improve indole-based CB(2) cannabinoid receptor ligands and also to develop SAR for both the CB(1) and CB(2) receptors, 47 indole derivatives were prepared and their CB(1) and CB(2) receptor affinities were determined. The indole derivatives include 1-propyl- and 1-pentyl-3-(1-naphthoyl)indoles both with and without a 2-methyl substituent. Naphthoyl substituents include 4- and 7-alkyl groups as well as 2-, 4-, 6-, 7-methoxy and 4-ethoxy groups. The effects of these substituents on receptor affinities are discussed and structure-activity relationships are presented. In the course of this work three new highly selective CB(2) receptor agonists were identified, 1-propyl-3-(4-methyl-1-naphthoylindole (JWH-120), 1-propyl-2-methyl-3-(6-methoxy-1-naphthoylindole (JWH-151), and 1-pentyl-3-(2-methoxy-1-naphthoylindole (JWH-267). GTPgammaS assays indicated that JWH-151 is a full agonist at CB(2), while JWH-120 and JWH-267 are partial agonists. Molecular modeling and receptor docking studies were carried out on a set of 3-(4-propyl-1-naphthoyl)indoles, a set of 3-(6-methoxy-1-naphthoyl)indoles and the pair of N-pentyl-3-(2-methoxy-1-naphthoyl)indoles. Docking studies indicated that the CB(1) receptor affinities of these compounds were consistent with their aromatic stacking interactions in the aromatic microdomain of the CB(1) receptor.

What ever happened to developmental Gerstmann's syndrome? Links to other pediatric, genetic, and neurodevelopmental syndromes.

Developmental Gerstmann's syndrome is a neurodevelopmental disorder infrequently described in the literature. The limited literature might result from controversy surrounding developmental Gerstmann's syndrome as a "true syndrome." Developmental Gerstmann's syndrome requires a tetrad of symptoms: left-right confusion, finger agnosia, dyscalculia, and dysgraphia, with constructional dyspraxia often included as a fifth symptom. The etiology of developmental Gerstmann's syndrome is unknown, but several hypotheses have been proposed, and none have been conclusively confirmed. Based on the paucity of recent research on developmental Gerstmann's syndrome, individuals who meet the criteria for the disorder could be given other diagnoses. A clustering of neuropsychologic features across other seemingly related disorders suggests that the conceptualization of the tetrad of symptoms traditionally associated with developmental Gerstmann's syndrome more appropriately reflects soft signs that are commonly associated with a number of other neurodevelopmental disorders. Thus, although developmental Gerstmann's syndrome is of historical interest to neurodevelopmental specialists, there appears to be no basis for considering this disorder as a unique syndrome.

The relationship between perisylvian morphology and verbal short-term memory functioning in children with neurodevelopmental disorders.

Although children with neurodevelopmental disorders frequently present with reduced short-term memory functioning, the relationship between perisylvian morphology and verbal short-term memory functioning has received limited attention. Thus, examining this relationship in children with neurodevelopmental disorders was the focus of this exploratory study. Results suggested leftward asymmetry in the temporal bank of the planum temporale is related to better coding and storage of semantic material. In contrast, parietal bank morphology is related to coding and storage of phonological material, and presence of an extra gyrus in the parietal region is associated with reduced phonological working memory. Data also supported a relationship between pars triangularis morphology and verbal short-term memory functioning, but this is not material-specific.

A new protocol for the in situ generation of aromatic, heteroaromatic, and unsaturated diazo compounds and its application in catalytic and asymmetric epoxidation of carbonyl compounds. Extensive studies to map out scope and limitations, and rationalization of diastereo- and enantioselectivities.

A variety of metalated tosylhydrazone salts derived from benzaldehyde have been prepared and were reacted with benzaldehyde in the presence of tetrahydrothiophene (THT) (20 mol %) and Rh(2)(OAc)(4) (1 mol %) to give stilbene oxide. Of the lithium, sodium, and potassium salts tested, the sodium salt was found to give the highest yield and selectivity. This study was extended to a wide variety of aromatic, heteroaromatic, aliphatic, alpha,beta-unsaturated, and acetylenic aldehydes and to ketones. On the whole, high yields of epoxides with moderate to very high diastereoselectivities were observed. A broad range of tosylhydrazone salts derived from aromatic, heteroaromatic, and alpha,beta-unsaturated aldehydes was also examined using the same protocol in reactions with benzaldehyde, and again, good yields and high diastereoselectivities were observed in most cases. Thus, a general process for the in situ generation of diazo compounds from tosylhydrazone sodium salts has been established and applied in sulfur-ylide mediated epoxidation reactions. The chiral, camphor-derived, [2.2.1] bicyclic sulfide 7 was employed (at 5-20 mol % loading) to render the above processes asymmetric with a range of carbonyl compounds and tosylhydrazone sodium salts. Benzaldehyde tosylhydrazone sodium salt gave enantioselectivities of 91 +/- 3% ee and high levels of diastereoselectivity with a range of aldehydes. However, tosylhydrazone salts derived from a range of carbonyl compounds gave more variable selectivities. Although those salts derived from electron-rich or neutral aldehydes gave high enantioselectivities, those derived from electron-deficient or hindered aromatic aldehydes gave somewhat reduced enantioselectivities. Using alpha,beta-unsaturated hydrazones, chiral sulfide 7 gave epoxides with high diastereoselectivities, but only moderate yields were achieved (12-56%) with varying degrees of enantioselectivity. A study of solvent effects showed that, while the impact on enantioselectivity was small, the efficiency of diazo compound generation was influenced, and CH(3)CN and 1,4-dioxane emerged as the optimum solvents. A general rationalization of the factors that influence both relative and absolute stereochemistry for all of the different substrates is provided. Reversibility in formation of the betaine intermediate is an important issue in the control of diastereoselectivity. Hence, where low diastereocontrol was observed, the results have been rationalized in terms of the factors that contribute to the reduced reversion of the syn betaine back to the original starting materials. The enantioselectivity is governed by ylide conformation, facial selectivity in the ylide reaction, and, again, the degree of reversibility in betaine formation. From experimental evidence and calculations, it has been shown that sulfide 7 gives almost complete control of facial selectivity, and, hence, it is the ylide conformation and degree of reversibility that are responsible for the enantioselectivity observed. A simple test has been developed to ascertain whether the reduced enantioselectivity observed in particular cases is due to poor control in ylide conformation or due to partial reversibility in the formation of the betaine.

Transcranial Doppler ultrasonography and neurocognitive functioning in children with sickle cell disease.

OBJECTIVE: We examined the relationship between cerebral blood flow velocity, measured by transcranial Doppler (TCD) ultrasonography, and neurocognitive functioning. METHODS: Participants were 60 children who had sickle cell disease (HbSS) and had no documented history of stroke. Children were classified according to Stroke Prevention Trial in Sickle Cell Anemia criteria (normal, conditional, and abnormal), and their performance was compared on measures of intellectual abilities, academic achievement, sustained attention/concentration, executive function, and parent and teacher ratings of executive function. RESULTS: Children with abnormal TCD values performed more poorly than children with conditional TCD values on measures of verbal intelligence and executive function. Children with conditional TCD values performed more poorly than children with normal TCD values on measures of sustained attention/concentration and executive function. TCD values also were a significant predictor of auditory working memory in exploratory analyses. CONCLUSIONS: Our findings support the hypothesis that neurocognitive functions subserved by the frontal systems (eg, sustained attention/concentration and executive function) seem to be the most useful indices of progressive cerebrovasculopathy in children with HbSS disease.