A randomized controlled trial of subcutaneous nerve stimulation for back pain due to failed back surgery syndrome: the SubQStim study

Objectives: To compare the effectiveness of peripheral nerve stimulation utilizing a subcutaneous lead implant technique—subcutaneous nerve stimulation (SQS) plus optimized medical management (SQS + OMM arm) vs. optimized medical management alone (OMM arm) in patients with back pain due to failed back surgery syndrome. Patients and Methods: Patients were recruited from 21 centers, in Europe, Israel, and Australia. Eligible patients were randomized (1:1) to SQS + OMM or OMM arms. Those in the SQS arm were implanted with a neurostimulator and up to two subcutaneous percutaneous cylindrical leads in the area of pain. Patients were evaluated pre‐randomization and at one, three, six, and nine months post‐randomization. The primary endpoint was the proportion of subjects with a ≥50% reduction in back pain intensity (“responder”) from baseline to nine months. Secondary outcomes included proportion of responders with a ≥50% reduction in back pain intensity at six months and ≥30% reduction at nine months, and the mean change from baseline in back pain intensity at six and nine months between the two arms. Results: Due to the slow rate of recruitment, the study was terminated early with 116 subjects randomized. A total of 33.9% (19/56, missing: n = 20 [36%]) of subjects in the SQS + OMM arm and 1.7% (1/60, missing: n = 24 [40%]) in the OMM arm were responders at Month 9 (p < 0.0001). Secondary objectives showed a significant difference in favor of SQS + OMM arm. Conclusion: The results indicate that the addition of SQS to OMM is more effective than OMM alone in relieving low back pain at up to nine months

Hrs and SNX3 Functions in Sorting and Membrane Invagination within Multivesicular Bodies

After internalization, ubiquitinated signaling receptors are delivered to early endosomes. There, they are sorted and incorporated into the intralumenal invaginations of nascent multivesicular bodies, which function as transport intermediates to late endosomes. Receptor sorting is achieved by Hrs—an adaptor-like protein that binds membrane PtdIns3P via a FYVE motif—and then by ESCRT complexes, which presumably also mediate the invagination process. Eventually, intralumenal vesicles are delivered to lysosomes, leading to the notion that EGF receptor sorting into multivesicular bodies mediates lysosomal targeting. Here, we report that Hrs is essential for lysosomal targeting but dispensable for multivesicular body biogenesis and transport to late endosomes. By contrast, we find that the PtdIns3P-binding protein SNX3 is required for multivesicular body formation, but not for EGF receptor degradation. PtdIns3P thus controls the complementary functions of Hrs and SNX3 in sorting and multivesicular body biogenesis

Late Endosomal Cholesterol Accumulation Leads to Impaired Intra-Endosomal Trafficking

Background Pathological accumulation of cholesterol in late endosomes is observed in lysosomal storage diseases such as Niemann-Pick type C. We here analyzed the effects of cholesterol accumulation in NPC cells, or as phenocopied by the drug U18666A, on late endosomes membrane organization and dynamics. Methodology/Principal Findings Cholesterol accumulation did not lead to an increase in the raft to non-raft membrane ratio as anticipated. Strikingly, we observed a 2–3 fold increase in the size of the compartment. Most importantly, properties and dynamics of late endosomal intralumenal vesicles were altered as revealed by reduced late endosomal vacuolation induced by the mutant pore-forming toxin ASSP, reduced intoxication by the anthrax lethal toxin and inhibition of infection by the Vesicular Stomatitis Virus. Conclusions/Significance These results suggest that back fusion of intralumenal vesicles with the limiting membrane of late endosomes is dramatically perturbed upon cholesterol accumulation

Dynamic properties of endosomal membranes: implications for endocytic sorting and viral infection

Like other enveloped viruses, vesicular stomatitis virus infects cells through endosomes. There, the viral envelope undergoes fusion with endosomal membranes, thereby releasing the nucleocapsid into the cytoplasm and allowing infection to proceed. Here, we report that the viral envelope fuses preferentially with the membrane of vesicles present within multivesicular endosomes. Then, these intra-endosomal vesicles (containing nucleocapsids) are transported to late endosomes, where back-fusion with the endosome limiting membrane delivers the nucleocapsid into the cytoplasm. Presumably, export of cargo proteins from within endosomes also occurs "via" back-fusion with the limiting membrane, so that they become available for subsequent transport to their final destination. We further find out that this back-fusion process is altered by cholesterol accumulation and is regulated by the ESCRT component Tsg101, the endosomal lipid lysobisphosphatidic acid under the control of Ali/Vps31p and by phosphatidylinositol-3-phosphate "via" SNX16

La musique populaire et les traditions folkloriques en Suisse: Le canton du Jura

Qu'est-ce qui fait le Jura à travers sa musique et ses traditions populaires? Le Jura se distingue par l'accordéon, instrument très complet, permet de jouer un grand répertoire. De nombreux choeurs et fanfares exercent également leurs activités dans le Jura. "Les roches d'or" interprété par Fabienne et Corinne Chapuis. La défense du patois est assurée grâce à un disque qui vient d'être enregistré par des personnes âgées. Les nuances des différents accents jurassiens. Le parlé jurassien. Le caractère des Jurassiens, frondeur, La Rauracienne, les Pétignats. Gilbert Lovis s'est lancé dans la recherche des archives se rapportant à la littérature orale tansmise par les vieilles gens. La Société jurassienne d'émulation et ses productions. Fond sonore : Fabienne et Corinne Chapuis à l'accordéon ("Les Roches d'or", "Cabri d'Ajoie")

Understanding daytime functioning in insomnia: responder and correlation analyses in patients treated with daridorexant

Abstract Background Improving daytime functioning is a key treatment goal for patients with insomnia disorder. In a phase 3 study, using the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ), daridorexant 50 mg significantly improved daytime functioning in adults with insomnia, as well as sleep parameters. These data are further analyzed to evaluate the clinically meaningful changes in IDSIQ scores at weekly intervals and investigate the correlation between the effects of daridorexant on daytime functioning and on sleep quality and quantity. Methods Nine hundred thirty patients with insomnia randomized to daridorexant 25 mg (n = 310), 50 mg (n = 310) or placebo (n = 310) for 12 weeks were analyzed, with focus on daridorexant 50 mg and placebo. Patients recorded daily their daytime functioning using the IDSIQ and their self-reported total sleep time (sTST) and sleep quality using a sleep diary questionnaire; weekly mean changes from baseline were calculated. A clinically meaningful improvement (‘response’) at a given week was defined as a ≥ 20-point decrease in IDSIQ total score from baseline. Results Weekly responder rates increased over time in both groups but were consistently higher each week with daridorexant. Overall, 53% (n = 165/310) of patients in the daridorexant 50 mg group perceived a response for ≥ 1 week versus 41% in the placebo group (n = 126/310). This response, which could be achieved at any time during the 12 weeks of the study, was more often continuous on daridorexant and more often intermittent on placebo. Time-to-first response was significantly different between daridorexant and placebo (hazard ratio 1.55; 95% confidence intervals [CI] 1.22, 1.97; p = 0.0003) with shorter time observed in daridorexant. Patient perception of the response also lasted longer on daridorexant than placebo (mean number of continuous responder weeks; 9.2 vs. 7.9 respectively). A decrease in IDSIQ total score was correlated with an increase in sTST and sleep quality and a decrease in morning sleepiness, from Week 1 onwards. Conclusion Patients with insomnia are more likely to perceive a clinically meaningful improvement in their daytime functioning each week with daridorexant 50 mg than placebo. The response, which can fluctuate over time, is also perceived earlier and sustained for longer than placebo. The correlations between improved daytime functioning and improved sleep quantity and quality support the benefits of daridorexant on both the night and daytime symptoms in patients with insomnia disorder. Trial registration ClinicalTrials.gov: NCT03545191

Inefficient targeting to the endoplasmic reticulum by the signal recognition particle elicits selective defects in post-ER membrane trafficking

The signal recognition particle (SRP) is required for protein translocation into the endoplasmic reticulum (ER). With RNA interference we reduced its level about ten-fold in mammalian cells to study its cellular functions. Such low levels proved insufficient for efficient ER-targeting, since the accumulation of several proteins in the secretory pathway was specifically diminished. Although the cells looked unaffected, they displayed noticeable and selective defects in post-ER membrane trafficking. Specifically, the anterograde transport of VSV-G and the retrograde transport of the Shiga toxin B-subunit were stalled at the level of the Golgi whereas the endocytosed transferrin receptor failed to recycle to the plasma membrane. Endocytic membrane trafficking from the plasma membrane to lysosomes or Golgi was undisturbed and major morphological changes in the ER and the Golgi were undetectable at low resolution. Selective membrane trafficking defects were specifically suppressed under conditions when low levels of SRP became sufficient for efficient ER-targeting and are therefore a direct consequence of the lower targeting capacity of cells with reduced SRP levels. Selective post-ER membrane trafficking defects occur at SRP levels sufficient for survival suggesting that changes in SRP levels and their effects on post-ER membrane trafficking might serve as a mechanism to alter temporarily the localization of selected proteins

Peripheral Nerve Field Stimulation for Chronic Back Pain: Therapy Outcome Predictive Factors

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