Discovery of Cathepsin S Inhibitor LY3000328 for the Treatment of Abdominal Aortic Aneurysm

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The relationship between the diameter of chemically-functionalized multi-walled carbon nanotubes and their organ biodistribution profiles in vivo

Carbon nanotubes (CNTs) exhibit unique properties which have led to their applications in the biomedical field as novel delivery systems for diagnosis and therapy purposes. We have previously reported that the degree of functionalization of CNTs is a key factor determining their biological behaviour. The present study broadens the spectrum by investigating the impact of the diameter of CNTs using two series of multi-walled CNTs (MWNTs) with distinct differences in their diameters. Both MWNTs were doubly functionalized by 1,3-dipolar cycloaddition and amidation reactions, allowing the appended functional groups to be further conjugated with radionuclide chelating moieties and antibodies or antibody fragments. All constructs possessed comparable degree of functionalization and were characterized by thermogravimetric analysis, transmission electron microscopy, gel electrophoresis and surface plasmon resonance. The MWNT conjugates were radio-labelled with indium-111, which thereby enabled in vivo single photon emission computed tomography/computed tomography (SPECT/CT) imaging and organ biodistribution study using γ-scintigraphy. The narrow MWNTs (average diameter: 9.2 nm) demonstrated enhanced tissue affinity including non-reticular endothelial tissues compared to the wider MWNTs (average diameter: 39.5 nm). The results indicate that the higher aspect ratio of narrow MWNTs may be beneficial for their future biological applications due to higher tissue accumulation.     

Neural coding of action in three dimensions: Task- and time-invariant reference frames for visuospatial and motor-related activity in parietal area V6A

Goal-directed movements involve a series of neural computations that compare the sensory representations of goal location and effector position, and transform these into motor commands. Neurons in posterior parietal cortex (PPC) control several effectors (e.g., eye, hand, foot) and encode goal location in a variety of spatial coordinate systems, including those anchored to gaze direction, and to the positions of the head, shoulder, or hand. However, there is little evidence on whether reference frames depend also on the effector and/or type of motor response. We addressed this issue in macaque PPC area V6A, where previous reports using a fixate-to-reach in depth task, from different starting arm positions, indicated that most units use mixed body/hand-centered coordinates. Here, we applied singular value decomposition and gradient analyses to characterize the reference frames in V6A while the animals, instead of arm reaching, performed a nonspatial motor response (hand lift). We found that most neurons used mixed body/hand coordinates, instead of “pure” body-, or hand-centered coordinates. During the task progress the effect of hand position on activity became stronger compared to target location. Activity consistent with body-centered coding was present only in a subset of neurons active early in the task. Applying the same analyses to a population of V6A neurons recorded during the fixate-to-reach task yielded similar results. These findings suggest that V6A neurons use consistent reference frames between spatial and nonspatial motor responses, a functional property that may allow the integration of spatial awareness and movement control.     

Does Adherence to the Mediterranean Diet Have a Protective Effect against Asthma and Allergies in Children? A Systematic Review

Dietary pattern may potentially impact on the pathogenesis of asthma and allergies. The Mediterranean Diet (MD) has significant health benefits due to its antioxidant and anti-inflammatory properties. The aim of this systematic review was to investigate the effectiveness of adherence to the MD against asthma and allergies in childhood. Hence, a systematic literature search was conducted on PubMed, ESBCO (Cinahl), Scopus, and the Cochrane Library databases up to 26 January 2022. The total number of articles obtained, after the initial search on the databases was conducted, was 301. Twelve studies were included, after the removal of duplicates and screening for eligibility. Our findings indicated a protective role of the MD against childhood asthma, but they also imply that the MD probably does not affect the development of allergies. Nevertheless, the heterogeneity and limitations of the studies highlight the need for randomized controlled trials that will focus on the pediatric population and hopefully provide more robust evidence.     

Translocation mechanisms of chemically functionalised carbon nanotubes across plasma membranes

Understanding the mechanisms responsible for carbon nanotube (CNT) internalisation into live cells is considered critical both from a fundamental point of view and for further engineering of CNT-based delivery systems to intracellular targets. While several studies are focused on the development of such CNT-based delivery systems, attempts to systematically elucidate the cellular uptake mechanisms of CNTs are still rather limited. The aim of the present study is to evaluate the cellular internalisation of chemically functionalised multi-walled carbon nanotubes (f-MWCNTs) in the presence of different well-known cellular uptake inhibitors. Our data reveal how f-MWCNTs are able to translocate across cell membranes of both phagocytic and non-phagocytic cell lines. We have evidenced that at least 30-50% of f-MWCNTs are taken up by cells through an energy-independent mechanism. This characteristic makes nanotubes loaded with therapeutic or diagnostic cargos extremely interesting as the release of active molecules directly into the cytoplasm increase their biological activity and therapeutic efficacy.     

Use of the Trellis™ Peripheral Infusion System for Enhancement of rt-PA Thrombolysis in Acute Lower Limb Ischemia

The Trellis Peripheral Infusion System is an over-the-wire 0.035 guidewire compatible device, designed to isolate a region of the peripheral vasculature to allow for lytic drug infusion and dispersion. We used it successfully through a percutaneous approach in two cases of acute thrombosis of a native lower limb artery. The total amount of rt-PA used was 12 and 9 mg, respectively and was delivered through bolus injections obviating the need for a supplementary continuous infusion of the agent. The time for dissolution of thrombus was 45 and 35 minutes, respectively. No complications were observed.     

LigaSure versus clamp-and-tie thyroidectomy for benign nodular disease

BACKGROUND: LigaSure is an alternative bipolar diathermy system (BDS) combining vessel sealing with reduced thermal spread, which has been successfully used in many abdominal operations; however, there is a little experience in open thyroidectomy. This study compares the efficacy and the advantages of the LigaSure BDS when used for total thyroidectomy for benign thyroid disease with the conventional clamp-and-tie technique. METHODS: Between May 1998 and October 2002, 517 patients underwent total thyroidectomy for benign thyroid multinodular goiter. Among them, from May 1998 until May 2000, 247 patients (group I) were operated on with the conventional clamp-and-tie technique, whereas from May 2000 until October 2003, 270 patients (group II) underwent total thyroidectomy for benign multinodular goiter with LigaSure BDS through a 4-cm transverse suprasternal incision. Demographics, pathologic characteristics, gland mass, operative time, blood loss, and complications were assessed. RESULTS: There were no intraoperative complications. Thyroid mass was similar in both groups, but the operative time was shorter in group II than in group I (mean +/- standard deviation, 71 +/- 14 minutes vs 86 +/- 22 minutes; p < .01). Intraoperative total blood loss was similar between the two groups, but postoperative drain volume was less in group II than in group I (21 +/- 15 mL; p < .01). Major post-thyroidectomy complications (ie, laryngeal nerve palsy, hematoma, and hypocalcemia) occurred less frequently in the LigaSure group than in the clamp-and-tie group (0.7%, 0.4%, 1.1% vs 4%, 2%, 4.8%, respectively; p < .05). The mean +/- standard deviation postoperative hospital stay was significantly less for the patients in group II than for those in group I (2.3 +/- 1.7 days vs 2.8 +/- 1.3 days; p < .05). CONCLUSIONS: The use of the LigaSure vessel sealer for thyroid surgery is an effective and safe alternative that reduces the overall operative time and could be successfully applied through a narrow surgical incision.     

Toxicity after prolonged (more than four weeks) administration of intravenous colistin

Background  

The intravenous use of polymyxins has been considered to be associated with considerable nephrotoxicity and neurotoxicity. For this reason, the systemic administration of polymyxins had been abandoned for about 20 years in most areas of the world. However, the problem of infections due to multidrug-resistant (MDR) Gram-negative bacteria such us Pseudomonas aeruginosa and Acinetobacter baumanniii has led to the re-use of polymyxins. Our objective was to study the toxicity of prolonged intravenous administration of colistin (polymyxin E).