Regenerative phenotype in mice with a point mutation in transforming growth factor beta type I receptor (TGFBR1)

Regeneration of peripheral differentiated tissue in mammals is rare, and regulators of this process are largely unknown. We carried out a forward genetic screen in mice using N-ethyl-N-nitrosourea mutagenesis to identify genetic mutations that affect regenerative healing in vivo. More than 400 pedigrees were screened for closure of a through-and-through punch wound in the mouse ear. This led to the identification of a single pedigree with a heritable, fast, and regenerative wound-healing phenotype. Within 5 wk after ear-punch, a threefold decrease in the diameter of the wound was observed in the mutant mice compared with the wild-type mice. At 22 wk, new cartilage, hair follicles, and sebaceous glands were observed in the newly generated tissue. This trait was mapped to a point mutation in a receptor for TGF-β, TGFBR1. Mouse embryonic fibroblasts from the affected mice had increased expression of a subset of TGF-β target genes, suggesting that the mutation caused partial activation of the receptor. Further, bone marrow stromal cells from the mutant mice more readily differentiated to chondrogenic precursors, providing a plausible explanation for the enhanced development of cartilage islands in the regenerated ears. This mutant mouse strain provides a unique model to further explore regeneration in mammals and, in particular, the role of TGFBR1 in chondrogenesis and regenerative wound healing.     

Aging effects on the control of grip force magnitude: an fMRI study

Functional neuroimaging techniques have allowed for investigations into the mechanisms of age-related deterioration in motor control. This study used functional Magnetic Resonance Imaging (fMRI) to investigate age related differences in the control of grip force magnitude. Using an event-related design, fMRI scans were completed on 13 older adults, and 13 gender matched younger adults, while using their dominant hand to squeeze a rubber bulb for 4 s at 10%, 40% or 70% of their maximum voluntary contraction. Both groups were able to match the relative force targets, however the older adults produced significantly lower levels of absolute force. fMRI analysis consisted of a 1) region of interest (ROI) approach to detect differences in selected motor areas within brain and 2) a voxel-wise whole brain comparison to find areas of differential activation that were not defined a priori between the older and younger group. The ROI analysis revealed that despite producing lower levels of absolute force, the older adults showed higher levels of activity predominantly in subcortical structures (putamen, thalamus and cerebellum) when compared to the younger group. The older adults also showed higher levels of activity in the ipsilateral ventral premotor cortex. A total of 19 of the 22 ROIs analyzed showed a significant main effect of the required force-level. In the majority of the ROIs that showed a significant force effect there were no significant differences in the magnitude of the blood-oxygen-level-dependent (BOLD) signal between the 10% and 40% conditions but a significantly higher BOLD signal in the 70% condition, suggesting that the modulation of brain activation with grip force may not be controlled in a linear fashion. It was also found that the older adult group demonstrate higher levels of activation in 7 areas during a force production task at higher force levels using a voxel-wise analysis. The 7 clusters that showed significant differences tended to be areas that are involved in visual-spatial and executive processing. The results of this study revealed that older adults require significantly higher activation of several areas to perform the same motor task as younger adults. Higher magnitudes of the BOLD signal in older adults may represent a compensatory pattern to counter age related deterioration in motor control systems.     

Investigating synapse formation and function using human pluripotent stem cell-derived neurons

A major goal of stem-cell research is to identify conditions that reliably regulate their differentiation into specific cell types. This goal is particularly important for human stem cells if they are to be used for in vivo transplantation or as a platform for drug development. Here we describe the establishment of procedures to direct the differentiation of human embryonic stem cells and human induced pluripotent stem cells into forebrain neurons that are capable of forming synaptic connections. In addition, HEK293T cells expressing Neuroligin (NLGN) 3 and NLGN4, but not those containing autism-associated mutations, are able to induce presynaptic differentiation in human induced pluripotent stem cell-derived neurons. We show that a mutant NLGN4 containing an in-frame deletion is unable to localize correctly to the cell surface when overexpressed and fails to enhance synapse formation in human induced pluripotent stem cell-derived neurons. These findings establish human pluripotent stem cell-derived neurons as a viable model for the study of synaptic differentiation and function under normal and disorder-associated conditions.     

Selective Visual Attention at Twelve Months: Signs of Autism in Early Social Interactions

We examined social attention and attention shifting during (a) a play interaction between 12-month olds and an examiner and (b) after the examiner pretended to hurt herself. We coded the target and duration of infants’ visual fixations and frequency of attention shifts. Siblings of children with autism and controls with no family history of autism were tested at 12 months and screened for ASD at 36 months. Groups did not differ on proportion of attention to social stimuli or attention shifting during the play condition. All groups demonstrated more social attention and attention shifting during the distress condition. Infants later diagnosed with ASD tended to continue looking at a toy during the distress condition despite the salience of social information.     

Use of spectral analysis with iterative filter for voxelwise determination of regional rates of cerebral protein synthesis with L-[1-11C]leucine PET

A spectral analysis approach was used to estimate kinetic parameters of the L-[1-(11)C]leucine positron emission tomography (PET) method and regional rates of cerebral protein synthesis (rCPS) on a voxel-by-voxel basis. Spectral analysis applies to both heterogeneous and homogeneous tissues; it does not require prior assumptions concerning number of tissue compartments. Parameters estimated with spectral analysis can be strongly affected by noise, but numerical filters improve estimation performance. Spectral analysis with iterative filter (SAIF) was originally developed to improve estimation of leucine kinetic parameters and rCPS in region-of-interest (ROI) data analyses. In the present study, we optimized SAIF for application at the voxel level. In measured L-[1-(11)C]leucine PET data, voxel-level SAIF parameter estimates averaged over all voxels within a ROI (mean voxel-SAIF) generally agreed well with corresponding estimates derived by applying the originally developed SAIF to ROI time-activity curves (ROI-SAIF). Region-of-interest-SAIF and mean voxel-SAIF estimates of rCPS were highly correlated. Simulations showed that mean voxel-SAIF rCPS estimates were less biased and less variable than ROI-SAIF estimates in the whole brain and cortex; biases were similar in white matter. We conclude that estimation of rCPS with SAIF is improved when the method is applied at voxel level than in ROI analysis.     

Safety and efficacy of botulinum toxin type B for treatment of sialorrhea in Parkinson's disease: a prospective double-blind trial

Sialorrhea (drooling) is a common symptom of Parkinson's disease (PD) that can significantly impair a patient's health and quality of life. Fifty-four PD subjects with troublesome sialorrhea were enrolled using a multicenter, randomized, double-blind, sequential-dose escalation design in which subjects received a single intraglandular treatment with botulinum toxin type B (doses of 1,500 Units [0.3 mL]; 2,500 Units [0.5 ml]; or 3,500 Units [0.7 ml]) or placebo. Postinjection, subjects were followed acutely for 4 weeks and long-term for up to 20 weeks. Safety/tolerability, as assessed by adverse events, was the primary outcome measure. Efficacy, as assessed by the Drooling Frequency and Severity Scale and unstimulated salivary flow rate, was secondary. Gastrointestinal-related adverse events occurred more frequently in the active groups versus placebo group (31% vs 7%), with dry mouth being most common (15%). There were no serious adverse events attributed to botulinum toxin type B or discontinuations due to adverse events from treatment. At 4 weeks postinjection, Drooling Frequency and Severity Scale scores significantly improved versus placebo (-1.3 ± 1.3) in a dose-related manner (-2.1 ± 1.2, P = 0.0191; -3.3 ± 1.4, P < 0.0001; -3.5 ± 1.1, P < 0.0001, respectively) and unstimulated salivary flow rates significantly decreased in all active groups versus placebo (P ≤ 0.0009). Furthermore, treated subjects appeared to have more sustained improvement in sialorrhea than placebo subjects. We conclude that intraglandular injection of botulinum toxin type B was safe, tolerable, and efficacious in treating sialorrhea in PD patients. Additional studies are warranted to further confirm the drug's robust efficacy, as well as evaluate its effect with repeated dosing.     

The effects of developmental quotient and diagnostic criteria on challenging behaviors in toddlers with developmental disabilities

Previous research has found that individuals with intellectual disability and/or autism spectrum disorder (ASD), and those with greater symptom severity within these diagnoses, show higher rates of aggressive/destructive behavior, stereotypic behavior, and self-injurious behavior. In this exploratory cross-sectional study, toddlers at-risk for a developmental disorder (n=1509) ranging from 17 to 36 months fell into one of three diagnostic categories: Autistic Disorder, Pervasive Developmental Disorder-Not Otherwise Specified [PDD-NOS], and atypically developing - no ASD diagnosis. Mental health professionals from EarlySteps, Louisiana's Early Intervention System, interviewed parents and guardians using the Baby and Infant Screen for Children with aUtIsm Traits (BISCUIT) -Part 3 (Matson, Boisjoli, & Wilkins, 2007) to obtain measures of challenging behaviors and the Battelle Developmental Inventory, 2nd Edition (BDI-2) (Newborg, 2005) to obtain developmental quotients (DQ). Toddlers diagnosed with Autistic Disorder or PDD-NOS showed a positive relationship between total DQ and challenging behavior; whereas, atypically developing toddlers with no ASD diagnosis showed a more adaptive, negative relationship. The DQ domains that were most influential on challenging behaviors varied by diagnosis, with communication and motor domains playing greater roles for toddlers with Autistic Disorder or PDD-NOS, and personal-social and cognitive domains playing greater roles for atypically developing toddlers with no ASD diagnosis.     

Clinical characteristics of heavy and non-heavy smokers with schizophrenia

Up to 50-90% of persons with schizophrenia smoke cigarettes. Limited data and theories suggest persons with schizophrenia may smoke for different reasons than persons without schizophrenia, making smoking cessation interventions particularly challenging in this population. Although health consequences of smoking are widely known, less information is available regarding characteristics of different amounts of smoking exposure in this population. This study was performed to investigate differences between heavy (≥ 1 pack per day) and non-heavy (<1 pack per day) smoking in patients with schizophrenia. Data from 745 patients, mean age 41.3+/-12.6 years, were drawn from a population of smokers admitted to State of Maryland inpatient mental health facilities (1994-2000). Records were reviewed to obtain demographic information, diagnosis, medication, smoking and substance use. 43% of patients were characterized as heavy smokers. Heavy and non-heavy groups did not differ in age, GAF, weight, or BMI. No differences were found in race, gender or antipsychotic treatments. However, patients smoking ≥ 1 packs per day were more likely to use other substances such as alcohol (χ(2)=6.67, df=1, p=0.01), cocaine (χ(2)=6.66, df=1, p=0.01), and other substances (χ(2)=9.95, df=1, p=0.003) compared to non-heavy smokers. No differences in cannabis or heroin use were found by smoking category. Controlling for age, race, sex and BMI, heavy smokers had higher total cholesterol (190.7(51.6)mg/dL) compared to non-heavy smokers (178.2 (43.0)mg/dL, p=0.03), but no differences were found in glucose or blood pressure. Heavy smoking may be a particular health risk in schizophrenia and significant efforts for smoking cessation or reduction are needed.