Transcriptional silencing of nonsense codon-containing immunoglobulin micro genes requires translation of its mRNA

Eukaryotes have evolved quality control mechanisms that prevent the expression of genes in which the protein coding potential is crippled by the presence of a premature translation-termination codon (PTC). In addition to nonsense-mediated mRNA decay (NMD), a well documented posttranscriptional consequence of the presence of a PTC in an mRNA, we recently reported the transcriptional silencing of PTC-containing immunoglobulin (Ig) mu and gamma minigenes when they are stably integrated into the genome of HeLa cells. Here we demonstrate that this transcriptional silencing of PTC-containing Ig-mu constructs requires active translation of the cognate mRNA, as it is not observed under conditions where translation of the PTC-containing mRNA is inhibited through an iron-responsive element in the 5'-untranslated region. Furthermore, RNA interference-mediated depletion of the essential NMD factor Upf1 not only abolishes NMD but also reduces the extent of nonsense-mediated transcriptional gene silencing (NMTGS). Collectively, our data indicate that NMTGS and NMD are linked, relying on the same mechanism for PTC recognition, and that the NMTGS pathway branches from the NMD pathway at a step after Upf1 function.

Quality of life after pulmonary embolism: validation of the French version of the PEmb-QoL questionnaire.

BackgroundThe PEmb-QoL is a validated 40-item questionnaire to quantify health-related quality of life in patients having experienced pulmonary embolism (PE). It covers six health dimensions: frequency of complaints, activities of daily living limitations, work-related problems, social limitations, intensity of complaints, and emotional complaints. Originally developed in Dutch and English, we sought to prospectively validate the psychometric properties of a French version of the PEmb-QoL.MethodsWe performed a forward and backward translation of the English version of the PEmb-QoL into French. French-speaking consecutive adult patients with an acute, objectively confirmed PE admitted to the emergency department of a Swiss university hospital between 08/2009 and 09/2011 were recruited telephonically. We used standard psychometric tests and criteria to evaluate the acceptability, reliability, and validity of the French version of the PEmb-QoL. We also performed an exploratory factor analysis.ResultsOverall, 102 patients were enrolled in the study. The French version of the PEmb-QoL showed good reliability (internal consistency, item¿total and inter-item correlations), reproducibility (test-retest reliability), and validity (convergent, discriminant) in French-speaking patients with PE. The exploratory factor analysis suggested three underlying dimensions: limitations in daily activity (items 4b-m, 5a-d), symptoms (items 1a-h and 7), and emotional complaints (items 9a-f and j).ConclusionWe successfully validated the French version of the PEmb-QoL questionnaire in patients with PE. Our results show that the PEmb-QoL is a valuable tool for assessing health-related quality of life after PE in French-speaking patients.

Quality of life after pulmonary embolism: Prospective validation of the German version of the PEmb-QoL questionnaire.

BACKGROUND The Pulmonary Embolism Quality of Life questionnaire (PEmb-QoL) is a 40-item questionnaire to measure health-related quality of life in patients with pulmonary embolism. It covers six 6 dimensions: frequency of complaints, limitations in activities of daily living, work-related problems, social limitations, intensity of complaints, and emotional complaints. Originally developed in Dutch and English, we prospectively validated a German version of the PEmb-QoL. METHODS A forward-backward translation of the English version of the PEmb-QoL into German was performed. German-speaking consecutive adult patients aged ≥18 years with an acute, objectively confirmed pulmonary embolism discharged from a Swiss university hospital (01/2011-06/2013) were recruited telephonically. Established psychometric tests and criteria were used to evaluate the acceptability, reliability, and validity of the German PEmb-QoL questionnaire. To assess the underlying dimensions, an exploratory factor analysis was performed. RESULTS Overall, 102 patients were enrolled in the study. The German version of the PEmb-QoL showed a good internal consistency (Cronbach's alpha ranging from 0.72 to 0.96), item-total (0.53-0.95) and inter-item correlations (>0.4), and test-retest reliability (intra-class correlation coefficients 0.59-0.89) for the dimension scores. A moderate correlation of the PEmb-QoL with SF-36 dimension and summary scores (0.21-0.83) indicated convergent validity, while low correlations of PEmb-QoL dimensions with clinical characteristics (-0.16-0.37) supported discriminant validity. The exploratory factor analysis suggested four underlying dimensions: limitations in daily activities, symptoms, work-related problems, and emotional complaints. CONCLUSION The German version of the PEmb-QoL questionnaire is a valid and reliable disease-specific measure for quality of life in patients with pulmonary embolism.