Ultrasounds induce blood-brain barrier opening across a sonolucent polyolefin plate in an in vitro isolated brain preparation

The blood-brain barrier (BBB) represents a major obstacle to the delivery of drugs to the central nervous system. The combined use of low-intensity pulsed ultrasound waves and intravascular microbubbles (MB) represents a promising solution to this issue, allowing reversible disruption of the barrier. In this study, we evaluate the feasibility of BBB opening through a biocompatible, polyolefin-based plate in an in vitro whole brain model. Twelve in vitro guinea pig brains were employed; brains were insonated using a planar transducer with or without interposing the polyolefin plate during arterial infusion of MB. Circulating MBs were visualized with an ultrasonographic device with a linear probe. BBB permeabilization was assessed by quantifying at confocal microscopy the extravasation of FITC-albumin perfused after each treatment. US-treated brains displayed BBB permeabilization exclusively in the volume under the US beam; no significant differences were observed between brains insonated with or without the polyolefin plate. Control brains not perfused with MB did not show signs of FITC-albumin extravasation. Our preclinical study suggests that polyolefin cranial plate could be implanted as a skull replacement to maintain craniotomic windows and perform post-surgical repeated BBB opening with ultrasound guidance to deliver therapeutic agents to the central nervous system

Arterially Perfused Neurosphere-Derived Cells Distribute Outside the Ischemic Core in a Model of Transient Focal Ischemia and Reperfusion In Vitro

BACKGROUND: Treatment with neural stem cells represents a potential strategy to improve functional recovery of post-ischemic cerebral injury. The potential benefit of such treatment in acute phases of human ischemic stroke depends on the therapeutic viability of a systemic vascular delivery route. In spite of the large number of reports on the beneficial effects of intracerebral stem cells injection in experimental stroke, very few studies demonstrated the effectiveness of the systemic intravenous delivery approach. METODOLOGY/PRINCIPAL FINDINGS: We utilized a novel in vitro model of transient focal ischemia to analyze the brain distribution of neurosphere-derived cells (NCs) in the early 3 hours that follow transient occlusion of the medial cerebral artery (MCA). NCs obtained from newborn C57/BL6 mice are immature cells with self-renewal properties that could differentiate into neurons, astrocytes and oligodendrocytes. MCA occlusion for 30 minutes in the in vitro isolated guinea pig brain preparation was followed by arterial perfusion with 1x10(6) NCs charged with a green fluorescent dye, either immediately or 60 minutes after reperfusion onset. Changes in extracellular pH and K(+) concentration during and after MCAO were measured through ion-sensitive electrodes. CONCLUSION/SIGNIFICANCE: It is demonstrated that NCs injected through the vascular system do not accumulate in the ischemic core and preferentially distribute in non-ischemic areas, identified by combined electrophysiological and morphological techniques. Direct measurements of extracellular brain ions during and after MCA occlusion suggest that anoxia-induced tissue changes, such as extracellular acidosis, may prevent NCs from entering the ischemic area in our in vitro model of transitory focal ischemia and reperfusion suggesting a role played by the surrounding microenviroment in driving NCs outside the ischemic core. These findings strongly suggest that the potential beneficial effect of NCs in experimental focal brain ischemia is not strictly dependent on their homing into the ischemic region, but rather through a bystander mechanism possibly mediated by the release of neuroprotective factors in the peri-infarct region

Revisiting the usefulness of the short acute octreotide test to predict treatment outcomes in acromegaly

Introduction: We previously described that a short version of the acute octreotide test (sAOT) can predict the response to first-generation somatostatin receptor ligands (SRLs) in patients with acromegaly. We have prospectively reassessed the sAOT in patients from the ACROFAST study using current ultra-sensitive GH assays. We also studied the correlation of sAOT with tumor expression of E-cadherin and somatostatin receptor 2 (SSTR2) .Methods: A total of 47 patients treated with SRLs for 6 months were evaluated with the sAOT at diagnosis and correlated with SRLs' response. Those patients whose IGF1 decreased to = 3SDS, were considered non-responders. The 2 hours GH value (GH2h) after s.c. administration of 100 mcg of octreotide was used to define predictive cutoffs. E-cadherin and SSTR2 immunostaining in somatotropinoma tissue were investigated in 24/47 and 18/47 patients, respectively.Results: In all, 30 patients were responders and 17 were non-responders. GH(2h) was 0.68 (0.25-1.98) ng/mL in responders vs 2.35 (1.59-9.37) ng/mL in non-responders (p<0.001). GH(2h) = 1.4ng/mL showed the highest ability to identify responders (accuracy of 81%, sensitivity of 73.3%, and specificity of 94.1%). GH(2h) = 4.3ng/mL was the best cutoff for non-response prediction (accuracy of 74%, sensitivity of 35.3%, and specificity of 96.7%). Patients with E-cadherin-positive tumors showed a lower GH(2h) than those with E-cadherin-negative tumors [0.9 (0.3-2.1) vs 3.3 (1.5-12.1) ng/mL; p<0.01], and patients with positive E-cadherin presented a higher score of SSTR2 (7.5 +/- 4.2 vs 3.3 +/- 2.1; p=0.01).Conclusion: The sAOT is a good predictor tool for assessing response to SRLs and correlates with tumor E-cadherin and SSTR2 expression. Thus, it can be useful in clinical practice for therapeutic decision-making in patients with acromegaly

Outcomes of transsphenoidal surgery for pituitary adenomas in Spain: a retrospective multicenter study

Background The outcomes of transsphenoidal surgery (TSS) for pituitary adenoma (PA) depend on many factors, including the availability of an expert team and the volume of surgeries performed. Data on the outcomes of TSS for PA are scarce in our country. TESSPAIN evaluates TSS outcomes in Spanish centers to assess the influence of surgical volume and specialized neurosurgical teams on success and complication rates. Methods A retrospective, nationwide, study of Spanish centers performing TSS between January 2018 and December 2022. Centers were classified as high volume (HV) [n=11, defined as centers with recognized expertise in Spain or those performing more than 25 TSS/year] or non-HV. Data collection included surgical success rates, complications, and pituitary adenoma resectability (R-PA). Additional analyses evaluated the impact of dedicated neurosurgical teams (DNT) within HV centers. Results A total of 2815 TSS from 29 Spanish centers were included (1421 NSPA, 436 GH-secreting, 323 Cushing's disease, 127 PRL-secreting and 25 TSH-secreting PA). The overall success rate was 50.5%, 76.8% for R-PA. HV centers had a higher overall success rate (53.1 vs. 47.7%; p=0.03). Better TSS outcomes for NSPA accounted for this difference. The overall TSS complication rate was 22.1%, which was higher for NSPA than for SPA (25.0 vs. 17.7%). The overall complication rate of TSS for PA was significantly higher in non-HV centers than in HV centers (24 vs 20.4.0; p <0.01). Centers with a DNT showed a trend to higher success rate in R-PA, while having a lower overall incidence of complications in TSS for PA than HV centers without a DNT (18.5 vs. 23.0; p=0.058), mainly reducing the rate of permanent ADH deficiency in all TSS for PA (2.7 vs. 8.4%; p<0.001). Conclusion Higher surgical volume and DNT are associated with improved TSS outcomes for PA in Spain. Our results support the recommendation of concentration of pituitary surgery in a reduced number of centers of expertise in our country in order to improve the success rate and reduce complications, mainly postoperative ADH deficiency

Characterisation of analogue Monolithic Active Pixel Sensor test structures implemented in a 65 nm CMOS imaging process

Analogue test structures were fabricated using the Tower Partners Semiconductor Co. CMOS 65 nm ISC process. The purpose was to characterise and qualify this process and to optimise the sensor for the next generation of Monolithic Active Pixels Sensors for high-energy physics. The technology was explored in several variants which differed by: doping levels, pixel geometries and pixel pitches (10-25 $\mu$m). These variants have been tested following exposure to varying levels of irradiation up to 3 MGy and $10^{16}$ 1 MeV n$_\text{eq}$ cm$^{-2}$. Here the results from prototypes that feature direct analogue output of a 4$\times$4 pixel matrix are reported, allowing the systematic and detailed study of charge collection properties. Measurements were taken both using $^{55}$Fe X-ray sources and in beam tests using minimum ionizing particles. The results not only demonstrate the feasibility of using this technology for particle detection but also serve as a reference for future applications and optimisations

Revisiting the usefulness of the short acute octreotide test to predict treatment outcomes in acromegaly

IntroductionWe previously described that a short version of the acute octreotide test (sAOT) can predict the response to first-generation somatostatin receptor ligands (SRLs) in patients with acromegaly. We have prospectively reassessed the sAOT in patients from the ACROFAST study using current ultra-sensitive GH assays. We also studied the correlation of sAOT with tumor expression of E-cadherin and somatostatin receptor 2 (SSTR2) .MethodsA total of 47 patients treated with SRLs for 6 months were evaluated with the sAOT at diagnosis and correlated with SRLs’ response. Those patients whose IGF1 decreased to &lt;3SDS from normal value were considered responders and those whose IGF1 was ≥3SDS, were considered non-responders. The 2 hours GH value (GH2h) after s.c. administration of 100 mcg of octreotide was used to define predictive cutoffs. E-cadherin and SSTR2 immunostaining in somatotropinoma tissue were investigated in 24/47 and 18/47 patients, respectively.ResultsIn all, 30 patients were responders and 17 were non-responders. GH2h was 0.68 (0.25-1.98) ng/mL in responders vs 2.35 (1.59-9.37) ng/mL in non-responders (p&lt;0.001). GH2h = 1.4ng/mL showed the highest ability to identify responders (accuracy of 81%, sensitivity of 73.3%, and specificity of 94.1%). GH2h = 4.3ng/mL was the best cutoff for non-response prediction (accuracy of 74%, sensitivity of 35.3%, and specificity of 96.7%). Patients with E-cadherin-positive tumors showed a lower GH2h than those with E-cadherin-negative tumors [0.9 (0.3-2.1) vs 3.3 (1.5-12.1) ng/mL; p&lt;0.01], and patients with positive E-cadherin presented a higher score of SSTR2 (7.5 ± 4.2 vs 3.3 ± 2.1; p=0.01).ConclusionThe sAOT is a good predictor tool for assessing response to SRLs and correlates with tumor E-cadherin and SSTR2 expression. Thus, it can be useful in clinical practice for therapeutic decision-making in patients with acromegaly

The centrality of the public in theatrical creation : study of the experiments of the artist Laura Hurt from 2014 to 2018

En prenant appui sur quatre années d'expérimentations artistiques et théâtrales (2014-2018) dans la ville de Nice et le département des Alpes-Maritimes, cette thèse tente de rendre compte de la démarche intellectuelle et des processus mis en œuvre dans une création post-contemporaine. Elle donne à voir la particularité des expériences de l’artiste Laura Hurt qui est à la fois auteur, metteur en scène et chercheur-praticien-reflexif dans le cadre de cette thèse de création. Dans un va-et-vient de la théorie à la pratique et inversement, nous avons essayé de mettre en avant comment un parcours personnel chaotique et une solide formation artistique amènent à de nouvelles pistes de travail, en mettant notamment le public au cœur de toutes démarches artistiques, la question de la centralité du public dans une œuvre théâtrale constituant une donnée principale, capitale même, dans l'élaboration d'un spectacle afin d’aller dans la continuité du « théâtre pour tous », du « théâtre pauvre » ou encore du « théâtre élitaire pour tous » afin de découvrir comment aujourd’hui, l'acte de création peut mettre en avant des notions comme la fraternité et la concorde universelle par une attention particulière vis-à-vis du public et notamment celui qui a peu accès à l'art, le public dit « empêché ». Cette thèse analyse par une méthode heuristique l'en-dedans et l'en-dehors de la représentation scénique, et montre que l’interdisciplinaire, le performatif et l'acte poétique permettent une nouvelle liberté pour se rapprocher du public et effacent tout ce qui nous sépare, pour mieux retrouver ce qui nous rassemble. Cette thèse découle d'une volonté de théoriser, d'analyser, de décrypter, d'expliquer, de découvrir a posteriori les actes engagés dans une démarche artistique et de faire émerger le savoir muet, discret, intime, de la genèse épistémologique de l'artiste dans son acte créateur.Drawing upon four years of artistic and theatrical experimentation (2014-2018) in the city of Nice and the department of Alpes-Maritimes, this thesis attempts to take account of the intellectual approach and processes involved in a post-contemporary creation. It reveals the particular nature of the experience of the artist Laura Hurt, who is both producer and researcher-practitioner-thinker in the framework of this thesis on creativity. Moving freely between theory and practice, we have tried to put forward how a chaotic personal journey and a solid artistic training lead to new ways of working, notably placing the public at the heart of all artistic approaches and whenever the question of the public’s central role in theatre might be of primary, even essential pertinence in the putting on of a spectacle aiming to continue the art of ‘theatre for all’, ‘poor or minimal theatre’ or even ‘elite theatre for everyone’, thereby discovering how, today, the creative act may promote notions such as fraternity and universal concord by paying special attention to the public and particularly that public having little access to art, the so-called handicapped public. This thesis analyses via its heuristic model the inner world and outer world of stage performance, and reveals how the interdisciplinary, the performative and the poetic act allow for a new freedom to draw closer to the public, erasing all that separates, so as to better reclaim what we share. The thesis derives from a desire to theorise, analyse, decode, explain and discover a posteriori those acts involved in an artistic approach, and to bring to light the intimate, discreet, unsaid knowledge of the artist’s epistemological genesis in her creative gesture