Behavioral and brain evidence for language by ear, mouth, eye, and hand and motor skills in literacy learning.

Two studies were conducted of students with and without persisting Specific Learning Disabilities (SLDs-WL) in Grades 4 to 9 (M = 11 years, 11 months) that supported the hypotheses that CELF 4 parent ratings for listening (language by ear), speaking (language by mouth), reading (language by eye), and writing (language by hand) were correlated with both (a) normed, standardized behavioral measures of listening, speaking, reading, and writing achievement (Study 1, 94 boys and 61 girls); and (b) fMRI connectivity or DTI white matter integrity involving brain regions for primary motor functions or motor planning and control, or motor timing in a subsample of right handers who did not wear metal (Study 2, 28 boys and 16 girls). Results of these assessment studies, which have implications for planning instruction for three SLDs-WL (dysgraphia, dyslexia, and oral and written language learning disability [OWL LD]), show that more than multisensory instruction is relevant. Language by ear, by mouth, by eye, and by hand, as well as motor planning, control, and output skills and motor timing should also be considered. Research is also reviewed that supports other processes beyond multisensory input alone that should also be considered for students with SLDs-WL.

Emotional and Behavioral Correlates of Persisting Specific Learning Disabilities in Written Language during Middle Childhood and Early Adolescence.

Parents completed the Behavior Assessment System for Children-Second Edition Parent Report Scale (BASC2-PRS) while their children (94 boys, 61 girls; M=11 years-11 months) were given tests. Evidence-based profiles of multiple test scores and history (emergence and persistence) were used to assign to groups without specific learning disabilities in written language (SLDs-WL) (n= 42 control) or with SLDs-WL: (n=29 dysgraphia, n=65 dyslexia, or n=19 oral and written language learning disability [OWL LD]). Parent ratings fell in the clinical or at risk ranges for some individuals in all groups, but mean BASC2-PRS ratings showed nine significant main effects for group (n=4): Behavioral Symptoms Index, Internalizing Problems Composite, Adaptive Skills Composite, two Clinical Scales (Atypicality and Attention Problems), and four Adaptive Scales (Adaptability, Activities of Daily Living, Leadership, and Functional Communication). Each SLDs-WL group differed significantly from the control group on these nine ratings, except dysgraphia on Atypicality and dyslexia on Adaptive Composite, Adaptability, and Leadership; and each correlated with one or more hallmark impairments associated with a specific SLD-WL. In an fMRI study (without OWL LD), the dysgraphia and dyslexia groups, but not control group, showed connectivity with amygdala; BASC2 PRS Internalizing Problems Composite (internal stress) correlated with amygdala connectivity from two cortical regions involved in written word processing and production for all groups (N=40). Applications to assessing emotional and behavioral correlates of SLDs-WL for educational services and future research are discussed.

Effective Instruction for Persisting Dyslexia in Upper Grades: Adding Hope Stories and Computer Coding to Explicit Literacy Instruction.

Children in grades 4 to 6 (N=14) who despite early intervention had persisting dyslexia (impaired word reading and spelling) were assessed before and after computerized reading and writing instruction aimed at subword, word, and syntax skills shown in four prior studies to be effective for treating dyslexia. During the 12 two-hour sessions once a week after school they first completed HAWK Letters in Motion© for manuscript and cursive handwriting, HAWK Words in Motion© for phonological, orthographic, and morphological coding for word reading and spelling, and HAWK Minds in Motion© for sentence reading comprehension and written sentence composing. A reading comprehension activity in which sentences were presented one word at a time or one added word at a time was introduced. Next, to instill hope they could overcome their struggles with reading and spelling, they read and discussed stories about struggles of Buckminister Fuller who overcame early disabilities to make important contributions to society. Finally, they engaged in the new Kokopelli's World (KW)©, blocks-based online lessons, to learn computer coding in introductory programming by creating stories in sentence blocks (Tanimoto and Thompson 2016). Participants improved significantly in hallmark word decoding and spelling deficits of dyslexia, three syntax skills (oral construction, listening comprehension, and written composing), reading comprehension (with decoding as covariate), handwriting, orthographic and morphological coding, orthographic loop, and inhibition (focused attention). They answered more reading comprehension questions correctly when they had read sentences presented one word at a time (eliminating both regressions out and regressions in during saccades) than when presented one added word at a time (eliminating only regressions out during saccades). Indicators of improved self-efficacy that they could learn to read and write were observed. Reminders to pay attention and stay on task needed before adding computer coding were not needed after computer coding was added.

Movement Issues Identified in Movement ABC2 Checklist Parent Ratings for Students with Persisting Dysgraphia, Dyslexia, and OWL LD and Typical Literacy Learners.

Movement, which draws on motor skills and executive functions for managing them, plays an important role in literacy learning (e.g., movement of mouth during oral reading and movement of hand and fingers during writing); but relatively little research has focused on movement skills in students with specific learning disabilities as the current study did. Parents completed normed Movement Assessment Battery for Children Checklist, 2nd edition (ABC-2), ratings and their children in grades 4 to 9 (M = 11 years, 11 months; 94 boys, 61 girls) completed diagnostic assessment used to assign them to diagnostic groups: control typical language learning (N = 42), dysgraphia (impaired handwriting) (N = 29), dyslexia (impaired word decoding/reading and spelling) (N = 65), or oral and written language learning disability (OWL LD) (impaired syntax in oral and written language) (N = 19). The research aims were to (a) correlate the Movement ABC-2 parent ratings for Scale A Static/Predictable Environment (15 items) and Scale B Dynamic/Unpredictable Environment (15 items) with reading and writing achievement in total sample varying within and across different skills; and (b) compare each specific learning disability group with the control group on Movement ABC-2 parent ratings for Scale A, Scale B, and Scale C Movement-Related (Non-Motor Executive Functions, or Self-Efficacy, or Affect) (13 items). At least one Movement ABC-2 parent rating was correlated with each assessed literacy achievement skill. Each of three specific learning disability groups differed from the control group on two Scale A (static/predictable environment) items (fastens buttons and forms letters with pencil or pen) and on three Scale C items (distractibility, overactive, and underestimates own ability); but only OWL LD differed from control on Scale B (dynamic/unpredictable environment) items. Applications of findings to assessment and instruction for students ascertained for and diagnosed with persisting specific learning disabilities in literacy learning, and future research directions are discussed.

Relationships between language input and letter output modes in writing notes and summaries for students in grades 4 to 9 with persisting writing disabilities.

This study in programmatic research on technology-supported instruction first identified, through pretesting using evidence-based criteria, students with persisting specific learning disabilities (SLDs) in written language during middle childhood (grades 4-6) and early adolescence (grades 7-9). Participants then completed computerized writing instruction and posttesting. The 12 computer lessons varied output modes (letter production by stylus alternating with hunt and peck keyboarding versus by pencil with grooves alternating with touch typing on keyboard), input (read or heard source material), and task (notes or summaries). Posttesting and coded notes and summaries showed the effectiveness of computerized writing instruction on both writing tasks for multiple modes of language input and letter production output for improving letter production and related writing skills.

Evidence-Based Reading and Writing Assessment for Dyslexia in Adolescents and Young Adults.

The same working memory and reading and writing achievement phenotypes (behavioral markers of genetic variants) validated in prior research with younger children and older adults in a multi-generational family genetics study of dyslexia were used to study 81 adolescent and young adults (ages 16 to 25) from that study. Dyslexia is impaired word reading and spelling skills below the population mean and ability to use oral language to express thinking. These working memory predictor measures were given and used to predict reading and writing achievement: Coding (storing and processing) heard and spoken words (phonological coding), read and written words (orthographic coding), base words and affixes (morphological coding), and accumulating words over time (syntax coding); Cross-Code Integration (phonological loop for linking phonological name and orthographic letter codes and orthographic loop for linking orthographic letter codes and finger sequencing codes), and Supervisory Attention (focused and switching attention and self-monitoring during written word finding). Multiple regressions showed that most predictors explained individual difference in at least one reading or writing outcome, but which predictors explained unique variance beyond shared variance depended on outcome. ANOVAs confirmed that research-supported criteria for dyslexia validated for younger children and their parents could be used to diagnose which adolescents and young adults did (n=31) or did not (n=50) meet research criteria for dyslexia. Findings are discussed in reference to the heterogeneity of phenotypes (behavioral markers of genetic variables) and their application to assessment for accommodations and ongoing instruction for adolescents and young adults with dyslexia.

A randomized 2×2 factorial trial, part 1: single-dose rabbit antithymocyte globulin induction may improve renal transplantation outcomes.

BACKGROUND: We conducted a randomized and unblinded 2 × 2 sequential-factorial trial, composed of an induction arm (part 1) comparing single-dose (SD) versus divided-dose rabbit antithymocyte globulin (rATG), and a maintenance arm (part 2) comparing tacrolimus minimization versus withdrawal. We report the long-term safety and efficacy of SD-rATG induction in the context of early steroid withdrawal and tacrolimus minimization or withdrawal. METHODS: Patients (n=180) received 6 mg/kg rATG, SD or four alternate-day doses (1.5 mg/kg/dose), with early steroid withdrawal and tacrolimus or sirolimus maintenance. After 6 months targeted maintenance levels were tacrolimus, 2 to 4 ng/mL and sirolimus, 4 to 6 ng/mL or, if calcineurin inhibitor-withdrawn, sirolimus 8 to 12 ng/mL with mycophenolate mofetil 2 g two times per day. Primary endpoints were renal function (abbreviated modification of diet in renal disease) and chronic graft histopathology (Banff). Secondary endpoints included patient survival, graft survival, biopsy-proven rejection, and infectious or noninfectious complications. RESULTS: Follow-up averaged longer than 4 years. Tacrolimus or sirolimus and mycophenolate mofetil exposure was identical between groups. The SD-rATG associated with improved renal function (2-36 months; P<0.001) in deceased donor recipients. The SD-rATG associated with quicker lymphocyte, CD4 T cell, and CD4-CD8 recovery and fewer infections. Cox multivariate hazard modeling showed divided-dose-rATG (P=0.019), deceased donor (P=0.003), serious infection (P=0.0.018), and lower lymphocyte count (P=0.001) associated with increased mortality. Patients with all four covariates showed a 27-fold increased likelihood of death (P=0.00002). Chronic graft histopathology, rejection rates, and death-censored graft survival were not significantly different between groups. CONCLUSION: The SD-rATG induction improves the 3-year renal function in recipients of deceased donor kidneys. This benefit, along with possibly improved patient survival and fewer infections suggest that how rATG is administered may impact its efficacy and safety.

Single-dose rATG induction at renal transplantation: superior renal function and glucoregulation with less hypomagnesemia.

BACKGROUND: Rabbit anti-thymocyte globulin (rATG) induction reduces reperfusion injury and improves renal function in kidney recipients by means of properties unrelated to T-cell lysis. Here, we analyze intensive rATG induction (single dose, rATG(S) , vs. divided dose, rATG(D) ) for improved renal function and protection against hyperglycemia. METHODS: Patients without diabetes (n = 98 of 180) in a prospective randomized trial of intensive rATG induction were followed for six months for the major secondary composite end point of impaired glucose regulation (hyperglycemia and new-onset diabetes after transplantation, NODAT). Prospectively collected data included fasting blood glucose and HbA(1c). Serum Mg(++) was routinely collected and retrospectively analyzed. RESULTS: Induction with rATG(S) produced less impaired glucose regulation (p = 0.05), delayed NODAT development (p = 0.02), less hyperglycemia (p = 0.02), better renal function (p = 0.04), and less hypomagnesemia (p = 0.02), a factor associated with a lower incidence of NODAT. Generalized linear modeling confirmed that rATG(S) protects against a synergistic interaction between tacrolimus and sirolimus that otherwise increased hypomagnesemia (p = 0.008) and hyperglycemia (p = 0.03). CONCLUSIONS: rATG(S) initiated before renal reperfusion improved early renal function and reduced impaired glucose regulation, an injury by diabetogenic maintenance agents (tacrolimus and sirolimus).

Albuminuria after renal transplantation: maintenance with sirolimus/low-dose tacrolimus vs. mycophenolate mofetil/high-dose tacrolimus.

Maintenance immunosuppression with sirolimus (SRL) in renal transplantation has been associated with proteinuria. We report long-term outcomes of kidney transplant recipients maintained on steroid-free regimens, either SRL with low-dose tacrolimus (SRL/L-Tac) or mycophenolate mofetil (MMF) with high-dose tacrolimus (MMF/H-Tac). We conducted a case-matched study of 50 patients receiving MMF/H-Tac, matched 1:2 with 100 patients maintained on SRL/L-Tac. All patients were induced with rabbit antithymocyte globulin followed by early steroid withdrawal. Comparisons were made of patient and graft survival, graft function, acute rejection, and albuminuria. There were no significant differences between the SRL/L-Tac and MMF/H-Tac groups for patient survival, graft survival, occurrence of acute rejection, or graft function. There was no difference in the proportion of patients with albumin/creatinine ratio (ACR) ≥300 µg/mg (19% vs. 20%), but more patients in the SRL group were receiving renin-angiotensin system blocking agents (72% vs. 53%, p = 0.04). Only flushing the donor kidney with histidine-tryptophan-ketoglutarate solution (vs. UW solution) was predictive of albuminuria. Long-term outcomes are similar at our center for kidney transplant patients receiving either SRL/L-Tac or MMF/H-Tac. Although the occurrence of albuminuria was not different, significantly more SRL-treated patients were receiving antiproteinuric medications.

Gender differences in severity of writing and reading disabilities.

Gender differences in mean level of reading and writing skills were examined in 122 children (80 boys and 42 girls) and 200 adults (115 fathers and 85 mothers) who showed behavioral markers of dyslexia in a family genetics study. Gender differences were found in writing and replicated prior results for typically developing children: Boys and men were more impaired in handwriting and composing than were girls and women, but men, who were more impaired in those writing skills, were also more impaired in spelling than women. Men were more impaired than women in accuracy and rate of reading passages orally, but boys were not more impaired than girls on any of the reading measures. Males were consistently more impaired than females in orthographic skills, which may be the source of gender differences in writing, but not motor skills. Population-based studies that report gender differences in reading in children with dyslexia may be confounding reading and writing disorders--the latter being the true source of gender differences in both children and adults with dyslexia.

Genome scan of a nonword repetition phenotype in families with dyslexia: evidence for multiple loci.

To understand the genetic architecture of dyslexia and identify the locations of genes involved, we performed linkage analyses in multigenerational families using a phonological memory phenotype--Nonword Repetition (NWR). A genome scan was first performed on 438 people from 51 families (DS-1) and linkage was assessed using variance components (VC), Bayesian oligogenic (BO), and parametric analyses. For replication, the genome scan and analyses were repeated on 693 people from 93 families (DS-2). For the combined set (DS-C), analyses were performed with all three methods in the regions that were identified in both samples. In DS-1, regions on chromosomes 4p, 6q, 12p, 17q, and 22q exceeded our initial threshold for linkage, with 17q providing a parametric LOD score of 3.2. Analysis with DS-2 confirmed the locations on chromosomes 4p and 12p. The strongest VC and BO signals in both samples were on chromosome 4p in DS-C, with a parametric multipoint LOD(max) of 2.36 for the 4p locus. Our linkage analyses of NWR in dyslexia provide suggestive and reproducible evidence for linkage to 4p12 and 12p in both samples, and significant evidence for linkage to 17q in one of the samples. These results warrant further studies of phonological memory and chromosomal regions identified here in other datasets.

Randomized trial of single-dose versus divided-dose rabbit anti-thymocyte globulin induction in renal transplantation: an interim report.

BACKGROUND: The optimal dosing protocol for rabbit anti-thymocyte globulin (rATG) induction in renal transplantation has not been determined, but evidence exists that rATG infusion before renal allograft reperfusion improves early graft function. Infusing a large rATG dose over a short interval has not previously been evaluated for its effect on renal function and allograft nephropathy in a prospective, randomized comparison against conventional rATG induction. METHODS: Between April 20, 2004 and December 26, 2007 we enrolled renal transplant patients into a prospective, randomized, nonblinded trial of two rATG dosing protocols (single dose, 6 mg/kg vs. divided doses, 1.5 mg/kg every other day x 4; target enrollment=160) followed after 6 months by calcineurin-inhibitor withdrawal. Primary endpoints are renal function by calculated glomerular filtration rate (GFR) and chronic allograft nephropathy at protocol biopsy. We now present the early GFR data of all 160 patients and safety and efficacy data of the first 142 patients with 6 months follow up and before calcineurin inhibitor withdrawal (average follow up=23.3+/-11.6 months). RESULTS: There were no differences between groups in rATG-related adverse events, patient and graft survival, acute rejection, or chronic allograft nephropathy rate at 6 months. Calculated DeltaGFR (POD 1-4) was significantly better in the single-dose group (P=0.02), with a trend toward improved renal function from months 2 to 6 in recipients of deceased donor kidneys (P=0.08). CONCLUSIONS: This study demonstrates that administering 6 mg/kg of rATG over 24 hr is safe and is associated with improved early renal function compared with administering rATG in alternate-day doses.

Writing problems in developmental dyslexia: under-recognized and under-treated.

The International Dyslexia Association defines dyslexia as unexpected problems of neurobiological origin in accuracy and rate of oral reading of single real words, single pseudowords, or text or of written spelling. However, prior research has focused more on the reading than the spelling problems of students with dyslexia. A test battery was administered to 122 children who met inclusion criteria for dyslexia and qualified their families for participation in a family genetics study that has been ongoing for over a decade. Their parents completed the same test battery. Although a past structural equation modeling study of typically developing children identified a significant path from handwriting to composition quality, the current structural equation modeling study identified a significant path from spelling to composition for children and their parents with dyslexia. Grapho-motor planning did not contribute uniquely to their composition, showing that writing is not just a motor skill. Students with dyslexia do have a problem in automatic letter writing and naming, which was related to impaired inhibition and verbal fluency, and may explain their spelling problems. Results are discussed in reference to the importance of providing explicit instruction in the phonological, orthographic, and morphological processes of spelling and in composition to students with dyslexia and not only offering accommodation for their writing problems.

Evaluation of candidate genes for DYX1 and DYX2 in families with dyslexia.

Dyslexia is a common heterogeneous disorder with a significant genetic component. Multiple studies have replicated the evidence for linkage between variously defined phenotypes of dyslexia and chromosomal regions on 15q21 (DYX1) and 6p22.2 (DYX2). Based on association studies and the possibility for functional significance of several polymorphisms, candidate genes responsible for the observed linkage signal have been proposed-DYX1C1 for 15q21, and KIAA0319 and DCDC2 for 6p22.2. We investigated the evidence for contribution of these candidate genes to dyslexia in our sample of multigenerational families. Our previous quantitative linkage analyses in this dataset provided supportive evidence for linkage of dyslexia to the locus on chromosome 15, but not to the locus on chromosome 6. In the current study, we used probands from 191 families for a case control analysis, and proband-parent trios for family-based TDT analyses. The observation of weak evidence for transmission disequilibrium for one of the two studied polymorphisms in DYX1C1 suggests involvement of this gene in dyslexia in our dataset. We did not find evidence for the association of KIAA0319 or DCDC2 alleles to dyslexia in our sample. We observed a slight tendency for an intronic deletion in DCDC2 to be associated with worse performance on some quantitative measures of dyslexia in the probands in our sample, but not in their parents.

Directed evolution and characterization of Escherichia coli glucosamine synthase.

Glucosamine synthase (GlmS) converts fructose-6-phosphate to glucosamine-6-phosphate. Overexpression of GlmS in Escherichia coli increased synthesis of glucosamine-6-P, which was dephosphorylated and secreted as glucosamine into the growth medium. The E. coli glmS gene was improved through error-prone polymerase chain reaction (PCR) in order to develop microbial strains for fermentation production of glucosamine. Mutants producing higher levels of glucosamine were identified by a plate cross-feeding assay and confirmed in shake flask cultures. Over 10 mutants were characterized and all showed significantly reduced sensitivity to inhibition by glucosamine-6-phosphate. Ki of mutants ranged from 1.4 to 4.0 mM as compared to 0.56 mM for the wild type enzyme. Product resistance resulted from single mutations (L468P, G471S) and/or combinations of mutations in the sugar isomerase domain. Most overexpressed GlmS protein was found in the form of inclusion bodies. Cell lysate from mutant 2123-72 contained twice as much soluble GlmS protein and enzyme activity as the strain overexpressing the wild type gene. Using the product-resistant mutant, glucosamine production was increased 60-fold.

Genomewide scan for real-word reading subphenotypes of dyslexia: novel chromosome 13 locus and genetic complexity.

Dyslexia is a common learning disability exhibited as a delay in acquiring reading skills despite adequate intelligence and instruction. Reading single real words (real-word reading, RWR) is especially impaired in many dyslexics. We performed a genome scan, using variance components (VC) linkage analysis and Bayesian Markov chain Monte Carlo (MCMC) joint segregation and linkage analysis, for three quantitative measures of RWR in 108 multigenerational families, with follow up of the strongest signals with parametric LOD score analyses. We used single-word reading efficiency (SWE) to assess speed and accuracy of RWR, and word identification (WID) to assess accuracy alone. Adjusting SWE for WID provided a third measure of RWR efficiency. All three methods of analysis identified a strong linkage signal for SWE on chromosome 13q. Based on multipoint analysis with 13 markers we obtained a MCMC intensity ratio (IR) of 53.2 (chromosome-wide P < 0.004), a VC LOD score of 2.29, and a parametric LOD score of 2.94, based on a quantitative-trait model from MCMC segregation analysis (SA). A weaker signal for SWE on chromosome 2q occurred in the same location as a significant linkage peak seen previously in a scan for phonological decoding. MCMC oligogenic SA identified three models of transmission for WID, which could be assigned to two distinct linkage peaks on chromosomes 12 and 15. Taken together, these results indicate a locus for efficiency and accuracy of RWR on chromosome 13, and a complex model for inheritance of RWR accuracy with loci on chromosomes 12 and 15.