The nonsense mutation stop+4 model correlates with motor changes in Duchenne muscular dystrophy

The aim was to assess 3-year longitudinal data using 6MWT in 26 ambulant boys affected by DMD carrying nonsense mutations and to compare their results to other small mutations. We also wished to establish, within the nonsense mutations group, patterns of change according to several variables. Patients with nonsense mutations were categorized according to the stop codon type newly created by the mutation and also including the adjacent 5′ (upstream) and 3′ (downstream) nucleotides. No significant difference was found between nonsense mutations and other small mutations (p > 0.05) on the 6MWT. Within the nonsense mutations group, there was no difference in 6MWT when the patients were subdivided according to: Type of stop codon, frame status of exons involved, protein domain affected. In contrast, there was a difference when the stop codon together with the 3′ adjacent nucleotide (“stop+4 model”) was considered (p < 0.05) with patients with stop codon TGA and 3′ adjacent nucleotide G (TGAG) having a more rapid decline. Our finding suggest that the stop+4 model may help in predicting functional changes. This data will be useful at the time of interpreting the long term follow up of patients treated with Ataluren that are becoming increasingly available.     

Early outcomes of migraine after erenumab discontinuation: data from a real-life setting

Neurological Sciences - Monoclonal antibodies targeting the calcitonin gene-related peptide, including erenumab, are migraine-specific preventive treatments, whose long-term effectiveness has still...     

Prospective Comparison of Infective Endocarditis in Khon Kaen,Thailand and Rennes,France

Prospectively collected, contemporary data are lacking on how the features of infective endocarditis (IE) vary according to region. We, therefore, compared IE in Rennes, France and Khon Kaen, Thailand. Fifty-eight patients with confirmed IE were enrolled at each site during 2011 and 2012 using a common protocol. Compared with French patients, Thais had a lower median age (47 versus 70 years old; P < 0.001) and reported more animal contact (86% versus 21%; P < 0.001). There were more zoonotic infections among Thai than France patients (6 and 1 cases; P = 0.017) and fewer staphylococcal infections (4 versus 15 cases; P = 0.011). Underlying rheumatic heart disease was more prevalent in Thai than in French patients (31% and 4%; P = 0.001), whereas prosthetic heart valves were less prevalent (9% and 35%; P = 0.001). Our data strengthen previous observations that IE in the tropics has distinctive demographic characteristics, risk factors, and etiologies and underscore the need for improved prevention and control strategies.     

“Not Just Right Experiences” in Adolescents: Phenomenology and Associated Characteristics

Efforts to understand the nature of “Not Just Right Experiences” (NJREs) have expanded the scientific understanding of obsessive–compulsive (OC) behavior. Approximately 80 % of unselected adults report experiencing NJREs and these experiences have been found to highly correlate with OC behavior. The purpose of this study was to assess NJREs in an unselected sample of adolescents (ages 14–17; N = 152), to compare their experience with adults (N = 237), and to assess the relation between NJREs and OC symptoms. Findings from questionnaires completed on the Internet were consistent with previous findings in adults, 81 % of adolescents endorsed recently having an NJRE. Some reactions differed according to age: adults reported NJREs as more frequent and adolescents endorsed feeling more compelled to respond. Surprisingly, OC symptoms were not significantly related to NJREs in the adolescents. Implications, limitations, and future directions for the study of NJREs in youth are discussed.     

Mediators and moderators of functional impairment in adults with obsessive–compulsive disorder

The current study examined correlates, moderators, and mediators of functional impairment in 98 treatment-seeking adults with obsessive–compulsive disorder (OCD). Participants completed or were administered measures assessing obsessive–compulsive symptom severity, functional impairment, resistance against symptoms, interference due to obsessive–compulsive symptoms, depressive symptoms, insight, and anxiety sensitivity. Results indicated that all factors, except insight into symptoms, were significantly correlated with functional impairment. The relationship between obsessive–compulsive symptom severity and functional impairment was not moderated by patient insight, resistance against obsessive–compulsive symptoms, or anxiety sensitivity. Mediational analyses indicated that obsessive–compulsive symptom severity mediated the relationship between anxiety sensitivity and obsessive–compulsive related impairment. Indeed, anxiety sensitivity may play an important contributory role in exacerbating impairment through increases in obsessive–compulsive symptom severity. Depressive symptoms mediated the relationship between obsessive–compulsive symptom severity and obsessive–compulsive related impairment. Implications for assessment and treatment are discussed.     

Insight in adults with obsessive–compulsive disorder

The present study examined the clinical correlates of insight among adults with obsessive–compulsive disorder (OCD). One hundred and thirty treatment-seeking adults with a primary diagnosis of OCD, aged 18 to 68 years (mean 31.4 years) participated. Measures of clinical severity, obsessive–compulsive symptom dimensions, anxiety symptoms, depressive symptoms, and ability to resist and control OCD symptoms were obtained. Results indicated that poor insight was positively related to greater OCD symptom severity and poorer ability to resist and control OCD symptoms; this pattern of associations held when insight was examined continuously and categorically (i.e., high versus low insight). Insight was generally not associated with other clinical characteristics, except for a relationship with mental neutralizing behaviors. Insight did not mediate the relationship between the ability to resist and control OCD symptoms and obsessive–compulsive symptom severity. Overall, this study provides further information into the nature and role of insight in adults with OCD.     

Transgene-mediated cosuppression and RNA interference enhance germ-line apoptosis in Caenorhabditis elegans

Introduction of multiple copies of a germ-line-expressed gene elicits silencing of the corresponding endogenous gene during Caenorhabditis elegans oogenesis; this process is referred to as germ-line cosuppression. Transformed plasmids assemble into extrachromosomal arrays resembling extra minichromosomes with repetitive structures. Loss of the transgene extrachromosomal array leads to reversion of the silencing phenomenon. Cosuppression and RNAi depend upon some of the same genes. In the C. elegans germ line, about half the cells undergo a physiological programmed cell death that shares most genetic requirements with somatic apoptosis. In addition, apoptosis is stimulated by DNA damage and synaptic failure mediated through different apoptotic checkpoints. We found that both germ-line cosuppression and RNAi of germ-line-expressed genes enhance apoptosis during C. elegans oogenesis. In contrast, apoptosis is not enhanced by extrachromosomal arrays carrying genes not driven by germ-line-specific promoters that thus do not elicit transgene-mediated cosuppression/silencing. Similarly, introduction of doubled-stranded RNA that shares no homology with endogenous genes has no effect on apoptosis. "Silencing-induced apoptosis" is dependent upon sir-2.1 and cep-1 (the worm p53 ortholog), and is accompanied by a rise in RAD-51 foci, a marker for ongoing DNA repair, indicating induction of DNA double-strand breaks. This finding suggests that the DNA damage-response pathway is involved. RNAi and cosuppression have been postulated as defense mechanisms against genomic intruders. We speculate that the mechanism here described may trigger the elimination of germ cells that have undergone viral infection or transposon activation.     

Cortical evolution in mammals: the bane and beauty of phenotypic variability

Evolution by natural selection, the unifying theory of all biological sciences, provides a basis for understanding how phenotypic variability is generated at all levels of organization from genes to behavior. However, it is important to distinguish what is the target of selection vs. what is transmitted across generations. Physical traits, behaviors, and the extended phenotype are all selected features of an individual, but genes that covary with different aspects of the targets of selection are inherited. Here we review the variability in cortical organization, morphology, and behavior that have been observed across species and describe similar types of variability within species. We examine sources of variability and the constraints that limit the types of changes that evolution has and can produce. Finally, we underscore the importance of how genes and genetic regulatory networks are deployed and interact within an individual, and their relationship to external, physical forces within the environment that shape the ultimate phenotype.