Theories of developmental dyslexia: Insights from a multiple case study of dyslexic adults

A multiple case study was conducted in order to assess three leading theories of developmental dyslexia: the phonological, the magnocellular (auditory and visual) and the cerebellar theories. Sixteen dyslexic and 16 control university students were administered a full battery of psychometric, phonological, auditory, visual and cerebellar tests. Individual data reveal that all 16 dyslexics suffer from a phonological deficit, 10 from an auditory deficit, 4 from a motor deficit, and 2 from a visual magnocellular deficit. Results suggest that a phonological deficit can appear in the absence of any other sensory or motor disorder, and is sufficient to cause a literacy impairment, as demonstrated by 5 of the dyslexics. Auditory disorders, when present, aggravate the phonological deficit, hence the literacy impairment. However, auditory deficits cannot be characterised simply as rapid auditory processing problems, as would be predicted by the magnocellular theory. Nor are they restricted to speech. Contrary to the cerebellar theory, we find little support for the notion that motor impairments, when found, have a cerebellar origin, or reflect an automaticity deficit. Overall, the present data support the phonological theory of dyslexia, while acknowledging the presence of additional sensory and motor disorders in certain individuals

History of contaminant inputs into Lake Mead derived from sediment cores

Assessing the changes in contaminant inputs (both organic and inorganic) over time is important in determining sources and sinks of these inputs. Variations in contaminant input were assessed in four sediment cores taken in 1998 from three different parts of Lake Mead (two from Las Vegas Bay and one from Overton Arm and Virgin Basin). Sediments were analyzed for major and trace elements, radionuclides, and organic compounds. Anthropogenic contaminant concentrations are greatest in Las Vegas Bay reflecting inputs from the Las Vegas urban area, although concentrations are low compared to sediment quality guidelines and to other USA lakes. One exception to this pattern was higher mercury concentrations in the Virgin Basin core. The Virgin Basin core is in the main body of the reservoir and is influenced by the hydrology of the Colorado River, which changed after completion of Glen Canyon Dam. Major- and trace-elements in the core show pronounced shifts in the early 1960s and, in many cases, gradually return to concentrations more typical of pre-1960s by the 1980s and 1990s, after the filling of Lake Powell upstream. The Overton Arm is the sub-basin least effected by anthropogenic contaminant inputs. Cores from Las Vegas Bay taken in 2007 were analyzed for emerging contaminants and although data are still preliminary, detections of musk fragrances have been found only in the upper 10 – 15 cm of the core, indicating that these compounds either degrade with time or have only been accumulating for the past 10 – 20 years

Sonographic evaluation of the association between calcific tendinopathy and rotator cuff tear: a case-controlled comparison

Objectives: To compare the incidence of rotator cuff (RC) tears on shoulder ultrasounds of patients with RC calcific tendinopathy (CaT) to that of a control group without CaT. Method: In this retrospective case-control study, 50 shoulder ultrasounds of patients with CaT were compared independently by 2 musculoskeletal radiologists to 50 patients from a control group without CaT to catalog the number and type of RC tears. RC tears in the CaT group were further characterized based on location, into tears in the specific tendon(s) containing calcium versus all tendon tears. Results: RC tears were diagnosed in 38% (19/50) of the control group (16 full-thickness) as compared to 22% (11/50) with CaT (6 full-thickness). The fewer full-thickness tears in the CaT group (12%, 6 of 50) compared to that in the control group (32%, 16 of 50) was statistically significant (P = 0.016, odds ratio 0.29). Only 7 of the 11 tears in the CaT group were in a calcium-containing tendon (3 full-thickness). The fewer calcium-containing tendon tears compared to tears in the control group was also statistically significant (P = 0.006, odds ratio 0.27). Furthermore, the fewer full-thickness calcium-containing tendon tears (6%, 3/50) compared to full-thickness tears in the control group (32%, 16/50) were yet more statistically significant (P = 0.001, odds ratio 0.14). Conclusions: In patients with shoulder pain and CaT, we observed a decreased number of RC tears and especially calcium-containing tendon tears, as compared to similar demographic patients with shoulder pain but without CaT. Key Points • Patients with rotator cuff calcific tendinopathy have few rotator cuff tears, especially full-thickness tears, compared to a control group without calcific tendinopathy. • The tendons containing the calcium hydroxyapatite deposition were the least likely to have a rotator cuff tear. • Future studies could evaluate if calcium hydroxyapatite deposition provides a protective mechanism against rotator cuff tears. • Musculoskeletal ultrasound is more sensitive than MRI in the evaluation of rotator cuff calcific tendinopathy

Motor recovery and cortical reorganization after constraint-induced movement therapy in stroke patients: a preliminary study.

Constraint-induced movement therapy (CIMT) is a physical rehabilitation regime that has been previously shown to improve motor function in chronic hemiparetic stroke patients. However, the neural mechanisms supporting rehabilitation-induced motor recovery are poorly understood. The goal of this study was to assess motor cortical reorganization after CIMT using functional magnetic resonance imaging (fMRI). In a repeated-measures design, 4 incompletely recovered chronic stroke patients treated with CIMT underwent motor function testing and fMRI. Five age-matched normal subjects were also imaged. A laterality index (LI) was determined from the fMRI data, reflecting the distribution of activation in motor cortices contralateral compared with ipsilateral to the moving hand. Pre-intervention fMRI showed a lower LI during affected hand movement of stroke patients (LI = 0.23+/-0.07) compared to controls (LI unaffected patient hand = 0.65+/-0.10; LI dominant normal hand = 0.65+/-0.11; LI nondominant normal hand = 0.69+/-0.11; P < 0.05) due to trends toward increased ipsilateral motor cortical activation. Motor function testing showed that patients made significant gains in functional use of the stroke-affected upper extremity (detected by the Motor Activity Log) and significant reductions in motor impairment (detected by the Fugl-Meyer Stroke Scale and the Wolf Motor Function Test) immediately after CIMT, and these effects persisted at 6-month follow-up. The behavioral effects of CIMT were associated with a trend toward a reduced LI from pre-intervention to immediately post-intervention (LI = -0.01+/-0.06, P = 0.077) and 6 months post-intervention (LI = -0.03+/-0.15). Stroke-affected hand movement was not accompanied by mirror movements during fMRI, and electromyographic measures of mirror recruitment under simulated fMRI conditions were not correlated with LI values. These data provide preliminary evidence that gains in motor function produced by CIMT in chronic stroke patients may be associated with a shift in laterality of motor cortical activation toward the undamaged hemisphere

Factors That Influence Medical Student Selection of an Emergency Medicine Residency Program: Implications for Training Programs

Objectives:  An understanding of student decision‐making when selecting an emergency medicine (EM) training program is essential for program directors as they enter interview season. To build upon preexisting knowledge, a survey was created to identify and prioritize the factors influencing candidate decision‐making of U.S. medical graduates. Methods:  This was a cross‐sectional, multi‐institutional study that anonymously surveyed U.S. allopathic applicants to EM training programs. It took place in the 3‐week period between the 2011 National Residency Matching Program (NRMP) rank list submission deadline and the announcement of match results. Results:  Of 1,525 invitations to participate, 870 candidates (57%) completed the survey. Overall, 96% of respondents stated that both geographic location and individual program characteristics were important to decision‐making, with approximately equal numbers favoring location when compared to those who favored program characteristics. The most important factors in this regard were preference for a particular geographic location (74.9%, 95% confidence interval [CI] = 72% to 78%) and to be close to spouse, significant other, or family (59.7%, 95% CI = 56% to 63%). Factors pertaining to geographic location tend to be out of the control of the program leadership. The most important program factors include the interview experience (48.9%, 95% CI = 46% to 52%), personal experience with the residents (48.5%, 95% CI = 45% to 52%), and academic reputation (44.9%, 95% CI = 42% to 48%). Unlike location, individual program factors are often either directly or somewhat under the control of the program leadership. Several other factors were ranked as the most important factor a disproportionate number of times, including a rotation in that emergency department (ED), orientation (academic vs. community), and duration of training (3‐year vs. 4‐year programs). For a subset of applicants, these factors had particular importance in overall decision‐making. Conclusions:  The vast majority of applicants to EM residency programs employed a balance of geographic location factors with individual program factors in selecting a residency program. Specific program characteristics represent the greatest opportunity to maximize the success of the immediate interview experience/season, while others provide potential for strategic planning over time. A working knowledge of these results empowers program directors to make informed decisions while providing an appreciation for the limitations in attracting applicants.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91198/1/ACEM_1323_sm_DataSupplementS1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/91198/2/j.1553-2712.2012.01323.x.pd

Lessons on Conditional Gene Targeting in Mouse Adipose Tissue

Conditional gene targeting has been extensively used for in vivo analysis of gene function in adipocyte cell biology but often with debate over the tissue specificity and the efficacy of inactivation. To directly compare the specificity and efficacy of different Cre lines in mediating adipocyte specific recombination, transgenic Cre lines driven by the adipocyte protein 2 (aP2) and adiponectin (Adipoq) gene promoters, as well as a tamoxifen-inducible Cre driven by the aP2 gene promoter (iaP2), were bred to the Rosa26R (R26R) reporter. All three Cre lines demonstrated recombination in the brown and white fat pads. Using different floxed loci, the individual Cre lines displayed a range of efficacy to Cre-mediated recombination that ranged from no observable recombination to complete recombination within the fat. The Adipoq-Cre exhibited no observable recombination in any other tissues examined, whereas both aP2-Cre lines resulted in recombination in endothelial cells of the heart and nonendothelial, nonmyocyte cells in the skeletal muscle. In addition, the aP2-Cre line can lead to germline recombination of floxed alleles in ∼2% of spermatozoa. Thus, different “adipocyte-specific” Cre lines display different degrees of efficiency and specificity, illustrating important differences that must be taken into account in their use for studying adipose biology

Regulation of SOX11 expression through CCND1 and STAT3 in mantle cell lymphoma

The neural transcription factor SOX11 is usually highly expressed in typical mantle cell lymphoma (MCL), but it is absent in the more indolent form of MCL. Despite being an important diagnostic marker for this hard-to-treat malignancy, the mechanisms of aberrant SOX11 expression are largely unknown. Herein, we describe 2 modes of SOX11 regulation by the cell-cycle regulator cyclin D1 (CCND1) and the signal transducer and activator of transcription 3 (STAT3). We found that ectopic expression of CCND1 in multiple human MCL cell lines resulted in increased SOX11 transcription, which correlated with increased acetylated histones H3K9 and H3K14 (H3K9/14Ac). Increased H3K9/14Ac and SOX11 expression was also observed after histone deacetylase 1 (HDAC1) or HDAC2 was depleted by RNA interference or inhibited by the HDAC inhibitor vorinostat. Mechanistically, we showed that CCND1 interacted with and sequestered HDAC1 and HDAC2 from the SOX11 locus, leading to SOX11 upregulation. Interestingly, our data revealed a potential inverse relationship between phosphorylated Y705 STAT3 and SOX11 expression in MCL cell lines, primary tumors, and patient-derived xenografts. Functionally, inactivation of STAT3 by inhibiting the upstream Janus kinase (JAK) 1 or JAK2 or by STAT3 knockdown was found to increase SOX11 expression, whereas interleukin-21 (IL-21)–induced STAT3 activation or overexpression of the constitutively active form of STAT3 decreased SOX11 expression. In addition, targeting SOX11 directly by RNA interference or indirectly by IL-21 treatment induced toxicity in SOX11^+ MCL cells. Collectively, we demonstrate the involvement of CCND1 and STAT3 in the regulation of SOX11 expression, providing new insights and therapeutic implications in MCL

The HLA class II allele DRB1*1501 is over-represented in patients with idiopathic pulmonary fibrosis

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and medically refractory lung disease with a grim prognosis. Although the etiology of IPF remains perplexing, abnormal adaptive immune responses are evident in many afflicted patients. We hypothesized that perturbations of human leukocyte antigen (HLA) allele frequencies, which are often seen among patients with immunologic diseases, may also be present in IPF patients. Methods/Principal Findings: HLA alleles were determined in subpopulations of IPF and normal subjects using molecular typing methods. HLA-DRB1*15 was over-represented in a discovery cohort of 79 Caucasian IPF subjects who had lung transplantations at the University of Pittsburgh (36.7%) compared to normal reference populations. These findings were prospectively replicated in a validation cohort of 196 additional IPF subjects from four other U.S. medical centers that included both ambulatory patients and lung transplantation recipients. High-resolution typing was used to further define specific HLA-DRB1*15 alleles. DRB1*1501 prevalence in IPF subjects was similar among the 143 ambulatory patients and 132 transplant recipients (31.5% and 34.8%, respectively, p = 0.55). The aggregate prevalence of DRB1*1501 in IPF patients was significantly greater than among 285 healthy controls (33.1% vs. 20.0%, respectively, OR 2.0; 95%CI 1.3-2.9, p = 0.0004). IPF patients with DRB1*1501 (n = 91) tended to have decreased diffusing capacities for carbon monoxide (DLCO) compared to the 184 disease subjects who lacked this allele (37.8±1.7% vs. 42.8±1.4%, p = 0.036). Conclusions/Significance: DRB1*1501 is more prevalent among IPF patients than normal subjects, and may be associated with greater impairment of gas exchange. These data are novel evidence that immunogenetic processes can play a role in the susceptibility to and/or manifestations of IPF. Findings here of a disease association at the HLA-DR locus have broad pathogenic implications, illustrate a specific chromosomal area for incremental, targeted genomic study, and may identify a distinct clinical phenotype among patients with this enigmatic, morbid lung disease

The HLA Class II Allele Allele DRB1*15 is over-represented in patients with Idiopathic Pulmonary Fibrosis

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and medically refractory lung disease with a grim prognosis. Although the etiology of IPF remains perplexing, abnormal adaptive immune responses are evident in many afflicted patients. We hypothesized that perturbations of human leukocyte antigen (HLA) allele frequencies, which are often seen among patients with immunologic diseases, may also be present in IPF patients. METHODS/PRINCIPAL FINDINGS: HLA alleles were determined in subpopulations of IPF and normal subjects using molecular typing methods. HLA-DRB1*15 was over-represented in a discovery cohort of 79 Caucasian IPF subjects who had lung transplantations at the University of Pittsburgh (36.7%) compared to normal reference populations. These findings were prospectively replicated in a validation cohort of 196 additional IPF subjects from four other U.S. medical centers that included both ambulatory patients and lung transplantation recipients. High-resolution typing was used to further define specific HLA-DRB1*15 alleles. DRB1*1501 prevalence in IPF subjects was similar among the 143 ambulatory patients and 132 transplant recipients (31.5% and 34.8%, respectively, p = 0.55). The aggregate prevalence of DRB1*1501 in IPF patients was significantly greater than among 285 healthy controls (33.1% vs. 20.0%, respectively, OR 2.0; 95%CI 1.3-2.9, p = 0.0004). IPF patients with DRB1*1501 (n = 91) tended to have decreased diffusing capacities for carbon monoxide (DL(CO)) compared to the 184 disease subjects who lacked this allele (37.8±1.7% vs. 42.8±1.4%, p = 0.036). CONCLUSIONS/SIGNIFICANCE: DRB1*1501 is more prevalent among IPF patients than normal subjects, and may be associated with greater impairment of gas exchange. These data are novel evidence that immunogenetic processes can play a role in the susceptibility to and/or manifestations of IPF. Findings here of a disease association at the HLA-DR locus have broad pathogenic implications, illustrate a specific chromosomal area for incremental, targeted genomic study, and may identify a distinct clinical phenotype among patients with this enigmatic, morbid lung disease

De novo assembly of the cattle reference genome with single-molecule sequencing.

BackgroundMajor advances in selection progress for cattle have been made following the introduction of genomic tools over the past 10-12 years. These tools depend upon the Bos taurus reference genome (UMD3.1.1), which was created using now-outdated technologies and is hindered by a variety of deficiencies and inaccuracies.ResultsWe present the new reference genome for cattle, ARS-UCD1.2, based on the same animal as the original to facilitate transfer and interpretation of results obtained from the earlier version, but applying a combination of modern technologies in a de novo assembly to increase continuity, accuracy, and completeness. The assembly includes 2.7 Gb and is >250× more continuous than the original assembly, with contig N50 >25 Mb and L50 of 32. We also greatly expanded supporting RNA-based data for annotation that identifies 30,396 total genes (21,039 protein coding). The new reference assembly is accessible in annotated form for public use.ConclusionsWe demonstrate that improved continuity of assembled sequence warrants the adoption of ARS-UCD1.2 as the new cattle reference genome and that increased assembly accuracy will benefit future research on this species