Reading and Generalist Genes

Twin-study research suggests that many (but not all) of the same genes contribute to genetic influence on diverse learning abilities and disabilities, a hypothesis called generalist genes. This generalist genes hypothesis was tested using a set of 10 DNA markers (single nucleotide polymorphisms [SNPs]) found to be associated with early reading ability in a study of 4,258 7-year-old children that screened 100,000 SNPs. Using the same sample, we show that this early reading SNP set also correlates with other aspects of literacy, components of mathematics, and more general cognitive abilities. These results provide support for the generalist genes hypothesis. Although the effect size of the current SNP set is small, such SNP sets could eventually be used to predict genetic risk for learning disabilities as well as to prescribe genetically tailored intervention and prevention programs

Applying Stretch to Evoke Hyperreflexia in Spasticity Testing: Velocity vs. Acceleration

\ua9 Copyright \ua9 2021 Sloot, Weide, van der Krogt, Desloovere, Harlaar, Buizer and Bar-On. In neurological diseases, muscles often become hyper-resistant to stretch due to hyperreflexia, an exaggerated stretch reflex response that is considered to primarily depend on the muscle\u27s stretch velocity. However, there is still limited understanding of how different biomechanical triggers applied during clinical tests evoke these reflex responses. We examined the effect of imposing a rotation with increasing velocity vs. increasing acceleration on triceps surae muscle repsonse in children with spastic paresis (SP) and compared the responses to those measured in typically developing (TD) children. A motor-operated ankle manipulator was used to apply different bell-shaped movement profiles, with three levels of maximum velocity (70, 110, and 150\ub0/s) and three levels of maximum acceleration (500, 750, and 1,000\ub0/s2). For each profile and both groups, we evaluated the amount of evoked triceps surae muscle activation. In SP, we evaluated two additional characteristics: the intensity of the response (peak EMG burst) and the time from movement initiation to onset of the EMG burst. As expected, the amount of evoked muscle activation was larger in SP compared to TD (all muscles: p < 0.001) and only sensitive to biomechanical triggers in SP. Further investigation of the responses in SP showed that peak EMG bursts increased in profiles with higher peak velocity (lateral gastrocnemius: p = 0.04), which was emphasized by fair correlations with increased velocity at EMG burst onset (all muscles: r > 0.33–0.36, p ≤ 0.008), but showed no significant effect for acceleration. However, the EMG burst was evoked faster with higher peak acceleration (all muscles p < 0.001) whereas it was delayed in profiles with higher peak velocity (medial gastrocnemius and soleus: p < 0.006). We conclude that while exaggerated response intensity (peak EMG burst) seems linked to stretch velocity, higher accelerations seem to evoke faster responses (time to EMG burst onset) in triceps surae muscles in SP. Understanding and controlling for the distinct effects of different biological triggers, including velocity, acceleration but also length and force of the applied movement, will contribute to the development of more precise clinical measurement tools. This is especially important when aiming to understand the role of hyperreflexia during functional movements where the biomechanical inputs are multiple and changing

Long-term follow-up of 17 patients with childhood Pompe disease treated with enzyme replacement therapy

Objectives: Pompe disease is a progressive metabolic myopathy for which enzyme replacement therapy (ERT) was approved in 2006. While various publications have examined the effects of ERT in classic-infantile patients and in adults, little has been published on ERT in children with non-classic presentations. Study design: This prospective study was conducted from June 1999 to May 2015. Seventeen patients from various countries participated. Outcome measures comprised muscle function (6-minute walk test, quick motor-function test (QMFT)), muscle strength (hand-held dynamometry; manual muscle testing), and lung function (FVC sitting and supine). For each outcome measure, we used linear mixed-effects models to calculate the difference at group level between the start of therapy and 7 years of ERT. Patients’ individual responses over time were also evaluated. Results: Eleven males and six females started ERT at ages between 1.1 and 16.4 years (median 11.9 years); 82% of them carried the common c.-32-13T > G GAA gene variant on one allele. At group level, distance walked increased by 7.4 percentage points (p < 0.001) and QMFT scores increased by 9.2 percentage points (p = 0.006). Muscle strength scores seemed to remain stable. Results on lung function were more variable. Patients’ individual data show that the proportion of patients who stabilized or improved during treatment ranged between 56 and 69% for lung function outcomes and between 71 and 93% for muscle strength and muscle function outcomes. Conclusions: We report a positive effect of ERT in patients with childhood Pompe disease at group level. For some patients

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

Discontinuation of enzyme replacement therapy in adults with Pompe disease: Evaluating the European POmpe Consortium stop criteria

Enzyme replacement therapy for Pompe disease received market authorization in 2006. To implement this costly treatment in the Netherlands in the most sensible way, a multidisciplinary expert committee was installed. We evaluated decision making in adult patients in relation to the European POmpe Consortium stop criteria. Of 125 adult Pompe patients, 111 started treatment; subsequently treatment stopped in 24 patients (21%). In 10 patients, treatment was discontinued for medical or personal reasons, as defined in the six stop criteria (median treatment duration: 2.1 years, range: 0.3–14.6 years). Three of these patients continued follow-up (follow-up: 1.3–8.0 years), these patients did not display a more rapid decline after discontinuation. In 14 of 24 patients, therapy ended at time of death. In 10 patients death was related to Pompe disease (median treatment duration: 7.2 years, range: 0.4–10.3 years). All 10 patients were severely affected at start of treatment, treatment had elicited positive effects in eight. The European POmpe Consortium guidelines worked well in decision making on stopping treatment. However, (re)evaluation of the rationale for continuation of treatment in advanced disease stage is not addressed. We suggest to add this to the treatment evaluation and to handle treatment decisions in a multidisciplinary expert team

Positive association between physical outcomes and patient-reported outcomes in late-onset Pompe disease: a cross sectional study

BACKGROUND: Pompe disease is a rare, progressive metabolic myopathy. The aim of this study is to investigate the associations of physical outcomes with patient-reported outcome measures (PROMs) in late-onset Pompe disease. METHODS: We included 121 Dutch adult patients with Pompe disease. Physical outcomes comprised muscle strength (manual muscle testing using Medical Research Council [MRC] grading, hand-held dynamometry [HHD]), walking ability (6-min walk test [6MWT]), and pulmonary function (forced vital capacity [FVC] in upright and supine positions). PROMs comprised quality of life (Short Form 36 health survey [SF-36]), participation (Rotterdam Handicap Scale [RHS]) and daily-life activities (Rasch-Built Pompe-Specific Activity [R-PAct] Scale). Analyses were cross-sectional: the time-point before, and closest to, start of Enzyme Replacement Therapy was chosen. Associations between PROMs and physical outcomes were investigated using linear regression models. RESULTS: RHS and R-PAct scores were better in patients with higher FVC supine and upright, HHD, MRC and 6MWT scores, accounting for the effect of sex, disease duration, use of wheelchair and ventilator support. While the SF-36 Physical Component Summary (PCS) was correlated positively with FVC upright, HHD, MRC and 6MWT scores, there was no significant relationship between the SF-36 Mental Component Summary (MCS) and any of the physical outcomes. CONCLUSIONS: Participation, daily-life activities, and the physical component of quality of life of adult Pompe patients are positively correlated to physical outcomes. This work serves as a first step towards assessing how changes over time in physical outcomes are related to changes in PROMs, and to define the minimal change in physical outcomes required to make an important difference for the patient

The anatomical limits of the posterior vaginal vault toward its use as route for intra-abdominal procedures

Background: The use of natural openings for abdominal surgery started at the beginning of the 21th century. A trans-Douglas endoscopic device has been designed to perform most of the intra-abdominal operations in women through the pouch of Douglas. The posterior vaginal vault is limited in size and could be damaged by an oversized instrument. This study investigates the optimal dimensions of the instrument by measuring the limiting factor in the passage. Methods: In ten female embalmed bodies the transversal and sagittal diameter of the fornix posterior vaginalis was measured by two observers. The pouch of Douglas was filled to its maximal capacity with mouldable latex through an open abdomen. By internal vaginal examination the connective tissue borders of the fornix posterior were palpated and the impression in the cast was measured. The mean value of these two diameters was evaluated in this study. The level of agreement between the observers was calculated. Results: The mean fornix posterior diameter was 2.6 cm (standard deviation, SD 0.5 cm) with a range of 2.0-3.4 cm. The mean difference between the two observers of all measurements was 0.08 cm (not significant). Both observers had an acceptable intraobserver variation. The interobserver agreement was excellent. Conclusion: Instruments with dimensions within the measured limits can be used safely for intra-abdominal operations via the natural orifice of the vagina

Self-restoration of cardiac excitation rhythm by anti-arrhythmic ion channel gating

Homeostatic regulation protects organisms against hazardous physiological changes. However, such regulation is limited in certain organs and associated biological processes. For example, the heart fails to self-restore its normal electrical activity once disturbed, as with sustained arrhythmias. Here we present proof-of-concept of a biological self-restoring system that allows automatic detection and correction of such abnormal excitation rhythms. For the heart, its realization involves the integration of ion channels with newly designed gating properties into cardiomyocytes. This allows cardiac tissue to i) discriminate between normal rhythm and arrhythmia based on frequency-dependent gating and ii) generate an ionic current for termination of the detected arrhythmia. We show in silico, that for both human atrial and ventricular arrhythmias, activation of these channels leads to rapid and repeated restoration of normal excitation rhythm. Experimental validation is provided by injecting the designed channel current for arrhythmia termination in human atrial myocytes using dynamic clamp

Lateral Trunk Motion and Knee Pain in Osteoarthritis of the Knee: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Patients with osteoarthritis of the knee may change their gait in an attempt to reduce loading of the affected knee, thereby reducing pain. Especially changes in lateral trunk motion may be potentially effective, since these will affect the position of the centre of mass relative to the knee, enabling minimization of the load on the knee and thereby knee pain. The aim of the study was to test the hypothesis that a higher level of knee pain is associated with higher lateral trunk motion in patients with knee OA.</p> <p>Methods</p> <p>Fifty-two patients with OA of the knee were tested. Lateral trunk motion was measured during the stance phase of walking with an optoelectronic motion analysis system and a force plate. Knee pain was measured with the VAS and the WOMAC pain questionnaire. Regression analyses were performed to assess the relationship between lateral trunk motion and knee pain.</p> <p>Results</p> <p>It was shown that in bivariate analyses knee pain was not associated with lateral trunk motion. In regression analyses, pain was associated with more lateral trunk motion. In addition, more lateral trunk motion was associated with younger age, being female, higher self-reported knee stiffness and higher maximum walking speed.</p> <p>Conclusion</p> <p>Pain is associated with lateral trunk motion. This association is weak and is influenced by age, gender, self-reported stiffness and maximum walking speed.</p