Size and surface charge of gold nanoparticles determine absorption across intestinal barriers and accumulation in secondary target organs after oral administration

It is of urgent need to identify the exact physico-chemical characteristics which allow maximum uptake and accumulation in secondary target organs of nanoparticulate drug delivery systems after oral ingestion. We administered radiolabelled gold nanoparticles in different sizes (1.4-200 nm) with negative surface charge and 2.8 nm nanoparticles with opposite surface charges by intra-oesophageal instillation into healthy adult female rats. The quantitative amount of the particles in organs, tissues and excrements was measured after 24 h by gamma-spectroscopy. The highest accumulation in secondary organs was mostly found for 1.4 nm particles; the negatively charged particles were accumulated mostly more than positively charged particles. Importantly, 18 nm particles show a higher accumulation in brain and heart compared to other sized particles. No general rule accumulation can be made so far. Therefore, specialized drug delivery systems via the oral route have to be individually designed, depending on the respective target organ

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

‘Deep Deltoid Paradox Sign’ - Anterior Talofibular Ligament Laxity Prevents Development of Deep Deltoid Ligament Laxity in the Presence of Unstable Planus - A Cadaveric Study

Category: Hindfoot; Sports Introduction/Purpose: Adult Acquired Flatfoot Deformity (AAFD)/Progressive collapsing foot deformity (PCFD) starts with failure of the medial longitudinal arch. Determining which feet progress to anteromedial instability of the tibiotalar joint, prior to complete deltoid ligament rupture, is not fully understood. We have observed clinically that, in the presence of anterior talofibular ligament (ATFL) laxity, deep deltoid ligament (DD) laxity and anteromedial ankle instability does not develop (indicated by a negative neutral heel external rotation test/anteromedial drawer test). To date, the protective effect that ATFL rupture/laxity (the most common foot ligament injury) has on preventing DD laxity and anteromedial ankle instability developing in AAFD/PCFD has not been investigated. This understanding is crucial for accurate staging, treatment, and prognosis of both AAFD/PCFD and ATFL repairs. Methods: Unstable planus was induced in 12 cadaveric feet from 6 donors by complete sectioning of the plantar fascia, spring ligament and the plantar 1st tarsometatarsal joint. Paired feet were randomly assigned to having ATFL sectioned or ATFL intact. Feet underwent cyclic loading (2000 cycles) on a custom mounted jig and photos were taken with positional markers on the medial malleolus, fibula, and the talus before and after antero-posterior force application. ImageJ quantified anteromedial and anterolateral ankle joint displacement to reflect DD and ATFL laxity respectively. Results: In ATFL-intact feet, anteromedial displacement increased by 3.46 ± 0.41 µm/cycle (mean ± SD; P = 0.000005; two-tailed, one-sample t-test). In ATFL-sectioned feet, displacement increased 0.61 ± 0.66 µm/cycle (p = 0.072), an 82% reduction in DDL laxity development (P = 0.00006; two-tailed, paired t-test). There was minimal cycle-induced change in anterolateral displacement (ATFL-intact: 0.50 ± 0.50 µm/cycle (p = 0.06); ATFL-sectioned: -0.04 ± 0.90 µm/cycle (p = 0.17). However, absolute anterolateral displacement increased in ATFL-sectioned feet by 7.40 ± 0.12 mm (p = 0.00002). Conclusion: These findings corroborate our clinical findings; in AAFD/PCFD, feet with ATFL laxity paradoxically do not develop DD instability (negative heel external test and anteromedial draw test), which we ascribe the ‘deep deltoid paradox sign’. This phenomenon has significant implications in determining which feet progress to DD laxity in AAFD/PCFD and ultimately DD rupture. Furthermore, surgical management of ATFL ruptures may require patient counselling regarding the development of DD laxity after ATFL repair if AAFD/PCFD is also present. Finally, we propose putative mechanisms based on differential axes of talar rotation and navicular abduction during stance, straining DD when ATFL is intact

Homeostatic Control of the Crypt-Villus Axis by the Bacterial Enterotoxin Receptor Guanylyl Cyclase C Restricts the Proliferating Compartment in Intestine

Guanylyl cyclase C (GC-C), the receptor for diarrheagenic enterotoxins and the paracrine ligands guanylin and uroguanylin, regulates intestinal secretion. Beyond volume homeostasis, its importance in modulating cancer cell proliferation and its uniform dysregulation early in colon carcinogenesis, reflecting loss of ligand expression, suggests a role for GC-C in organizing the crypt-villus axis. Here, eliminating GC-C expression in mice increased crypt length along a decreasing rostral-caudal gradient by disrupting component homeostatic processes. Crypt expansion reflected hyperplasia of the proliferating compartment with reciprocal increases in rapidly cycling progenitor cells and reductions in differentiated cells of the secretory lineage, including Paneth and goblet cells, but not enteroendocrine cells. GC-C signaling regulated proliferation by restricting the cell cycle at the G1/S transition. Moreover, crypt expansion in GC-C−/− mice was associated with adaptive increases in cell migration and apoptosis. Reciprocal alterations in proliferation and differentiation resulting in expansion associated with adaptive responses in migration and apoptosis suggest that GC-C coordinates component processes maintaining homeostasis of the crypt progenitor compartment. In the context of uniform loss of GC-C signaling during tumorigenesis, dysregulation of those homeostatic processes may contribute to mechanisms underlying colon cancer