Mutant C9orf72 human iPSC-derived astrocytes cause non-cell autonomous motor neuron pathophysiology

Mutations in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS). Accumulating evidence implicates astrocytes as important non-cell autonomous contributors to ALS pathogenesis, although the potential deleterious effects of astrocytes on the function of motor neurons remains to be determined in a completely humanized model of C9orf72-mediated ALS. Here, we use a human iPSC-based model to study the cell autonomous and non-autonomous consequences of mutant C9orf72 expression by astrocytes. We show that mutant astrocytes both recapitulate key aspects of C9orf72-related ALS pathology and, upon co-culture, cause motor neurons to undergo a progressive loss of action potential output due to decreases in the magnitude of voltage-activated Na⁺ and K⁺ currents. Importantly, CRISPR/Cas-9 mediated excision of the C9orf72 repeat expansion reverses these phenotypes, confirming that the C9orf72 mutation is responsible for both cell-autonomous astrocyte pathology and non-cell autonomous motor neuron pathophysiology.     

Biallelic Pathogenic GFRA1 Variants Cause Autosomal Recessive Bilateral Renal Agenesis

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A multivariable analysis of patient dental satisfaction and oral health-related quality-of-life. A cross-sectional study based on DVSS and OHIP-14

Objective. The aim of this paper was to study the association between dental satisfaction and oral health-related quality-of-life (OHRQoL) when controlling for individual, clinical and psychological factors. Materials. Secondary analysis was conducted using data from a large study carried out in the Swedish region of Värmland in 2004. The questionnaire included demographic variables, clinical assessment and the following instruments: the Dental Visit Satisfaction Scale (DVSS), the short version of Oral Health Impact Profile (OHIP-14) and a modified version of the revised helping alliance questionnaire. Internal consistency analysis was undertaken on the instruments to assess reliability; bivariate comparisons were assessed to compare DVSS scores with individual factors (age, gender and education). In addition, a three step hierarchical multiple regression analysis was performed with DVSS as a dependent variable. Results. Data were completed for 485 randomly selected patients. The mean age of participants was 43.5 years, 54.6% were women,and 41.2% had high education. The median DVSS score was 48 (range 10–50) and the median OHIP was 3.0 (range 0–56). All the instruments showed good reliability. Bivariate analysis showed that females were more satisfied than males (p ≤ 0.01) and patients of 50 years or older were more satisfied than the younger ones (p ≤ 0.05). Finally, the following variables explained 31% of the variance of being very satisfied with dental visit: a good OHRQoL and patients' positive perceptions of the relationship with their care provider. Conclusion. This study showed positive associations between dental satisfaction and OHRQoL when controlling for related factors. The result suggests that care providers should take into account the various dimensions of OHRQoL rather than use only clinical measurements when they evaluate patient satisfaction.