Developmental dyslexia: predicting individual risk

Background: Causal theories of dyslexia suggest that it is a heritable disorder, which is the outcome of multiple risk factors. However, whether early screening for dyslexia is viable is not yet known. Methods: The study followed children at high risk of dyslexia from preschool through the early primary years assessing them from age 3 years and 6 months (T1) at approximately annual intervals on tasks tapping cognitive, language, and executive-motor skills. The children were recruited to three groups: children at family risk of dyslexia, children with concerns regarding speech, and language development at 3;06 years and controls considered to be typically developing. At 8 years, children were classified as 'dyslexic' or not. Logistic regression models were used to predict the individual risk of dyslexia and to investigate how risk factors accumulate to predict poor literacy outcomes. Results: Family-risk status was a stronger predictor of dyslexia at 8 years than low language in preschool. Additional predictors in the preschool years include letter knowledge, phonological awareness, rapid automatized naming, and executive skills. At the time of school entry, language skills become significant predictors, and motor skills add a small but significant increase to the prediction probability. We present classification accuracy using different probability cutoffs for logistic regression models and ROC curves to highlight the accumulation of risk factors at the individual level. Conclusions: Dyslexia is the outcome of multiple risk factors and children with language difficulties at school entry are at high risk. Family history of dyslexia is a predictor of literacy outcome from the preschool years. However, screening does not reach an acceptable clinical level until close to school entry when letter knowledge, phonological awareness, and RAN, rather than family risk, together provide good sensitivity and specificity as a screening battery

Genome-wide association study of receptive language ability of 12 year olds

Purpose: We have previously shown that individual differences in measures of receptive language ability at age 12 are highly heritable. The current study attempted to identify some of the genes responsible for the heritability of receptive language ability using a genome-wide association (GWA) approach. Method: We administered four internet-based measures of receptive language (vocabulary, semantics, syntax, and pragmatics) to a sample of 2329 12-year-olds for whom DNA and genome-wide genotyping were available. Nearly 700,000 single-nucleotide polymorphisms (SNPs) and one million imputed SNPs were included in a GWA analysis of receptive language composite scores. Results: No SNP associations met the demanding criterion of genome-wide significance that corrects for multiple testing across the genome (p < 5 ×10-8). The strongest SNP association did not replicate in an additional sample of 2639 12-year-olds. Conclusion: These results indicate that individual differences in receptive language ability in the general population do not reflect common genetic variants that account for >3% of the phenotypic variance. The search for genetic variants associated with language skill will require larger samples and additional methods to identify and functionally characterize the full spectrum of risk variants

Genome characteristics of primary carcinomas, local recurrences, carcinomatoses, and liver metastases from colorectal cancer patients

BACKGROUND: Colorectal cancer (CRC) is one of the most common causes of cancer-related deaths in the Western world, and despite the fact that metastases are usually the ultimate cause of deaths, the knowledge of the genetics of advanced stages of this disease is limited. In order to identify potential genetic abnormalities underlying the development of local and distant metastases in CRC patients, we have, by comparative genomic hybridization, compared the DNA copy number profiles of 10 primary carcinomas, 14 local recurrences, 7 peritoneal carcinomatoses, and 42 liver metastases from 61 CRC patients. RESULTS: The median number of aberrations among the primary carcinomas, local recurrences, carcinomatoses, and liver metastases was 10, 6, 13, and 14, respectively. Several genetic imbalances, such as gains of 7, 8q, 13q, and 20, and losses of 4q, 8p, 17p, and 18, were common in all groups. In contrast, gains of 5p and 12p were more common in the carcinomatoses than in other stages of the disease. With hierarchical cluster analysis, liver metastases could be divided into two main subgroups according to clusters of chromosome changes. CONCLUSIONS: Each stage of CRC progression is characterized by a particular genetic profile, and both carcinomatoses and liver metastases are more genetically complex than local recurrences and primary carcinomas. This is the first genome profiling of local recurrences and carcinomatoses, and gains of 5p and 12p seem to be particularly important for the spread of the CRC cells within the peritoneal cavity

Cofactor specificity motifs and the induced fit mechanism in class I ketol-acid reductoisomerases

Although most sequenced members of the industrially important ketol-acid reductoisomerase (KARI) family are class I enzymes, structural studies to date have focused primarily on the class II KARIs, which arose through domain duplication. In the present study, we present five new crystal structures of class I KARIs. These include the first structure of a KARI with a six-residue β2αB (cofactor specificity determining) loop and an NADPH phosphate-binding geometry distinct from that of the seven- and 12-residue loops. We also present the first structures of naturally occurring KARIs that utilize NADH as cofactor. These results show insertions in the specificity loops that confounded previous attempts to classify them according to loop length. Lastly, we explore the conformational changes that occur in class I KARIs upon binding of cofactor and metal ions. The class I KARI structures indicate that the active sites close upon binding NAD(P)H, similar to what is observed in the class II KARIs of rice and spinach and different from the opening of the active site observed in the class II KARI of Escherichia coli. This conformational change involves a decrease in the bending of the helix that runs between the domains and a rearrangement of the nicotinamide-binding site

Making sense of social pretense: The effect of the dyad, sex and language ability in a large observational study of children’s behaviors in a social pretend play context

Pretend play with peers is purportedly an important driver of social development in the preschool period, however, fundamental questions regarding the features of children’s pretend play with a peer, and the effect of the dyad for pretend play, have been overlooked. The current study undertook detailed behavioral coding of social pretend play in 134 pairs of 5-year-old children (54% boys) in order to address three main aims: (i) describe the duration and proportion of children engaging in key social pretend play behaviors, namely, calls for attention, negotiation (comprising role assignment and joint proposals) and enactment of pretend play, (ii) examine the effect of the dyad in influencing the occurrence of different social pretend play behaviors, and (iii) assess the independent and combined effect of individual child characteristics (i.e., language ability and sex) that may influence social pretend play behaviors beyond the influence of the dyad. Results demonstrated the overwhelming effect of the dyad in shaping children’s social pretend play behaviors, with language ability and sex explaining relatively little of the total variability in play behaviors. Results are discussed considering the contribution that this type of study can make to theories of associations between children’s social development and social pretend play.LEGO Foundatio

Field demonstration of simultaneous wind and temperaturemeasurements from 5to50 km with a Na double-edge magneto-optic filter in a multi-frequency Doppler lidar

We report the first (to our knowledge) field demonstration of simultaneous wind and temperature measurements with a Na double-edge magneto-optic filter implemented in the receiver of a three-frequency Na Doppler lidar. Reliable winds and temperatures were obtained in the altitude range of 10-45 km with 1 km resolution and 60 min integration under the conditions of 0.4 W lidar power and 75 cm telescope aperture. This edge filter with a multi-frequency lidar concept can be applied to other direct-detection Doppler lidars for profiling both wind and temperature simultaneously from the lower to the upper atmosphere

The pharmacokinetics of the interstitial space in humans

BACKGROUND: The pharmacokinetics of extracellular solutes is determined by the blood-tissue exchange kinetics and the volume of distribution in the interstitial space in the different organs. This information can be used to develop a general physiologically based pharmacokinetic (PBPK) model applicable to most extracellular solutes. METHODS: The human pharmacokinetic literature was surveyed to tabulate the steady state and equilibrium volume of distribution of the solutes mannitol, EDTA, morphine-6-glucuronide, morphine-3-glucuronide, inulin and β-lactam antibiotics with a range of protein binding (amoxicillin, piperacillin, cefatrizine, ceforanide, flucloxacillin, dicloxacillin). A PBPK data set was developed for extracellular solutes based on the literature for interstitial organ volumes. The program PKQuest was used to generate the PBPK model predictions. The pharmacokinetics of the protein (albumin) bound β-lactam antibiotics were characterized by two parameters: 1) the free fraction of the solute in plasma; 2) the interstitial albumin concentration. A new approach to estimating the capillary permeability is described, based on the pharmacokinetics of the highly protein bound antibiotics. RESULTS: About 42% of the total body water is extracellular. There is a large variation in the organ distribution of this water – varying from about 13% of total tissue water for skeletal muscle, up to 70% for skin and connective tissue. The weakly bound antibiotics have flow limited capillary-tissue exchange kinetics. The highly protein bound antibiotics have a significant capillary permeability limitation. The experimental pharmacokinetics of the 11 solutes is well described using the new PBPK data set and PKQuest. CONCLUSIONS: Only one adjustable parameter (systemic clearance) is required to completely characterize the PBPK for these extracellular solutes. Knowledge of just this systemic clearance allows one to predict the complete time course of the absolute drug concentrations in the major organs. PKQuest is freely available

Lexicality and frequency in specific language impairment: accuracy and error data from two nonword repetition tests

Purpose: Deficits in phonological working memory and deficits in phonological processing have both been considered potential explanatory factors in Specific Language Impairment (SLI). Manipulations of the lexicality and phonotactic frequency of nonwords enable contrasting predictions to be derived from these hypotheses. Method: 18 typically developing (TD) children and 18 children with SLI completed an assessment battery that included tests of language ability, non-verbal intelligence, and two nonword repetition tests that varied in lexicality and frequency. Results: Repetition accuracy showed that children with SLI were unimpaired for short and simple high lexicality nonwords, whereas clear impairments were shown for all low lexicality nonwords. For low lexicality nonwords, greater repetition accuracy was seen for nonwords constructed from high over low frequency phoneme sequences. Children with SLI made the same proportion of errors that substituted a nonsense syllable for a lexical item as TD children, and this was stable across nonword length. Conclusions: The data show support for a phonological processing deficit in children with SLI, where long-term lexical and sub-lexical phonological knowledge mediate the interpretation of nonwords. However, the data also suggest that while phonological processing may provide a key explanation of SLI, a full account is likely to be multi-faceted

A New Method for Isolation of Interstitial Fluid from Human Solid Tumors Applied to Proteomic Analysis of Ovarian Carcinoma Tissue

Major efforts have been invested in the identification of cancer biomarkers in plasma, but the extraordinary dynamic range in protein composition, and the dilution of disease specific proteins make discovery in plasma challenging. Focus is shifting towards using proximal fluids for biomarker discovery, but methods to verify the isolated sample's origin are missing. We therefore aimed to develop a technique to search for potential candidate proteins in the proximal proteome, i.e. in the tumor interstitial fluid, since the biomarkers are likely to be excreted or derive from the tumor microenvironment. Since tumor interstitial fluid is not readily accessible, we applied a centrifugation method developed in experimental animals and asked whether interstitial fluid from human tissue could be isolated, using ovarian carcinoma as a model. Exposure of extirpated tissue to 106 g enabled tumor fluid isolation. The fluid was verified as interstitial by an isolated fluid:plasma ratio not significantly different from 1.0 for both creatinine and Na+, two substances predominantly present in interstitial fluid. The isolated fluid had a colloid osmotic pressure 79% of that in plasma, suggesting that there was some sieving of proteins at the capillary wall. Using a proteomic approach we detected 769 proteins in the isolated interstitial fluid, sixfold higher than in patient plasma. We conclude that the isolated fluid represents undiluted interstitial fluid and thus a subproteome with high concentration of locally secreted proteins that may be detected in plasma for diagnostic, therapeutic and prognostic monitoring by targeted methods