Tailoring the pressure-drop in multi-layered open-cell porous inconel structures

This study investigates the pressure-drop behaviour associated with airflow through bulk and structurally tailored multi-layered, open-cell porous Inconel structures over a wide airflow velocity range (0–50 m s-1). The effect of airflow velocity on the pressure-drop behaviour as a function of the sample thickness is presented and related to the flow behaviour corresponding to the relevant flow regimes (Darcy, Forchheimer, Turbulent and Postturbulent). Entrance effects are highlighted as a source of the pressure-drop increase for porous structures with air gaps, regardless of their sizes, as long as they are larger than those generated by loosely-stacked structures. The pressure-drops for gapped porous structures and the mathematical-summation of the pressure drop for the corresponding individual components, were in very good agreement, at lower airflow velocities. The potential for mass-efficient porous structures, providing a high pressure drop, was demonstrated using multiple thin porous laminates separated by air gaps

Intraoperative local infiltration anesthesia effect on post-operative pain after total knee replacement

Background: Pain following TKA renders rehabilitation difficult. Local infiltration anesthesia (LIA) could significantly decrease post-operative pain. Aim was to assess the effect of peri-articular intraoperative LIA during primary TKA on post-operative pain. Methods: This prospective, randomized and double-blind study included 150 patients, aged 65-74 years, of both sexes with stage 4 knee osteoarthritis who were assigned for primary TKA at Queen Alia Military hospital, Amman-Jordan, during the period May 2022–December 2022. Patients were divided into two groups. LIA group (GI, n=75) received a single peri-articular LIA during surgery. The cocktail comprised 75 mg diclofenac sodium, 100 mg bupivacaine, and 0.5 mg adrenaline. The cocktail was diluted in 100 ml of normal saline and split into two syringes, 50 ml each. Patients in control group (GII, n=75) received only 100 ml of normal saline. When patients had pain postoperatively, 1 mg morphine was given intravenously at 15-minute intervals. Primary outcomes were verbal analog scale (VAS) pain score from day 1 to 6 after surgery and overall morphine administration. Results: On day 1 after surgery, the average VAS was 4.19 in the LIA group vs. 6.08 in group II (p<0.002), while it was 4.01 versus 4.78 (p>0.05) on day 6. Overall morphine requirement and pain scores from day 1 to day 6 after surgery were less in the LIA group than in the other group, 13.06 mg versus 20.75 mg (p<0.004). Conclusions: Peri-articular LIA during TKA significantly improve post-operative pain and decreases morphine use.

Experimental investigation of pressure-drop characteristics across multi-layer porous metal structures

This study investigates the effect of airflow (in the range of 0–70 m s-1) on the pressure-drop characteristics for a novel multi-layered, nickel-based porous metal, as a function of thickness (affected by sectioning) and density (affected by compression). In addition to generating unique data for these materials, the study highlights the need for precise pinpointing of the different flow regimes (Darcy, Forchheimer and Turbulent) in order to enable accurate determination of the permeability (K) and form drag coefficient (C) defined by the Forchheimer equation and to understand the complex dependence of length-normalised pressure drop on sample thickness

Pharmacological Inhibition of Epac1 Averts Ferroptosis Cell Death by Preserving Mitochondrial Integrity

Exchange proteins directly activated by cAMP (Epac) proteins are implicated in a wide range of cellular functions including oxidative stress and cell survival. Mitochondrial-dependent oxidative stress has been associated with progressive neuronal death underlying the pathology of many neurodegenerative diseases. The role of Epac modulation in neuronal cells in relation to cell survival and death, as well as its potential effect on mitochondrial function, is not well established. In immortalized hippocampal (HT-22) neuronal cells, we examined mitochondria function in the presence of various Epac pharmacological modulators in response to oxidative stress due to ferroptosis. Our study revealed that selective pharmacological modulation of Epac1 or Epac2 isoforms, exerted differential effects in erastin-induced ferroptosis conditions in HT-22 cells. Epac1 inhibition prevented cell death and loss of mitochondrial integrity induced by ferroptosis, while Epac2 inhibition had limited effects. Our data suggest Epac1 as a plausible therapeutic target for preventing ferroptosis cell death associated with neurodegenerative diseases

Pore-scale numerical investigation of pressure drop behaviour across open-cell metal foams

The development and validation of a grid-based pore-scale numerical modelling methodology applied to five different commercial metal foam samples is described. The 3-D digital representation of the foam geometry was obtained by the use of X-ray microcomputer tomography scans, and macroscopic properties such as porosity, specific surface and pore size distribution are directly calculated from tomographic data. Pressure drop measurements were performed on all the samples under a wide range of flow velocities, with focus on the turbulent flow regime. Airflow pore-scale simulations were carried out solving the continuity and Navier–Stokes equations using a commercial finite volume code. The feasibility of using Reynolds-averaged Navier–Stokes models to account for the turbulence within the pore space was evaluated. Macroscopic transport quantities are calculated from the pore-scale simulations by averaging. Permeability and Forchheimer coefficient values are obtained from the pressure gradient data for both experiments and simulations and used for validation. Results have shown that viscous losses are practically negligible under the conditions investigated and pressure losses are dominated by inertial effects. Simulations performed on samples with varying thickness in the flow direction showed the pressure gradient to be affected by the sample thickness. However, as the thickness increased, the pressure gradient tended towards an asymptotic value

Nanobodies as allosteric modulators of Parkinson's disease-associated LRRK2

Mutations in the gene coding for leucine-rich repeat kinase 2 (LRRK2) are a leading cause of the inherited form of Parkinson’s disease (PD), while LRRK2 overactivation is also associated with the more common idiopathic form of PD. LRRK2 is a large multidomain protein, including a GTPase as well as a Ser/Thr protein kinase domain. Common, disease-causing mutations increase LRRK2 kinase activity, presenting LRRK2 as an attractive target for drug discovery. Currently, drug development has mainly focused on ATP-competitive kinase inhibitors. Here, we report the identification and characterization of a variety of nanobodies that bind to different LRRK2 domains and inhibit or activate LRRK2 in cells and in in vitro. Importantly, nanobodies were identified that inhibit LRRK2 kinase activity while binding to a site that is topographically distinct from the active site and thus act through an allosteric inhibitory mechanism that does not involve binding to the ATP pocket or even to the kinase domain. Moreover, while certain nanobodies completely inhibit the LRRK2 kinase activity, we also identified nanobodies that specifically inhibit the phosphorylation of Rab protein substrates. Finally, in contrast to current type I kinase inhibitors, the studied kinase-inhibitory nanobodies did not induce LRRK2 microtubule association. These comprehensively characterized nanobodies represent versatile tools to study the LRRK2 function and mechanism and can pave the way toward novel diagnostic and therapeutic strategies for PD

Baroreflex function, haemodynamic responses to an orthostatic challenge, and falls in haemodialysis patients

From PLOS via Jisc Publications Router.History: collection 2018, received 2018-05-24, accepted 2018-11-12, epub 2018-12-06Publication status: PublishedBackground Stage 5 chronic kidney disease patients on haemodialysis (HD) often present with dizziness and pre-syncopal events as a result of the combined effect of HD therapy and cardiovascular disease. The dysregulation of blood pressure (BP) during orthostasis may be implicated in the aetiology of falls in these patients. Therefore, we explored the relationship between baroreflex function, the haemodynamic responses to a passive orthostatic challenge, and falls in HD patients. Methods Seventy-six HD patients were enrolled in this cross-sectional study. Participants were classified as “fallers” and “non-fallers” and completed a passive head up tilting to 60o (HUT-60°) test on an automated tilt table. ECG signals, continuous and oscillometric BP measurements and impedance cardiography were recorded. The following variables were derived from these measurements: heart rate (HR) stroke volume (SV), cardiac output (CO), total peripheral resistance (TPR), number of baroreceptor events, and baroreceptor effectiveness index (BEI). Results The forty-four participants who were classified as fallers (57.9%) had a lower number of baroreceptor events (6.5±8.5 vs 14±16.7, p = .027) and BEI (20.8±24.2% vs 33.4±23.3%, p = .025). In addition, fallers experienced a significantly larger drop in systolic (-6.4±10.9 vs -0.4±7.7 mmHg, p = .011) and diastolic (-2.7±7.3 vs 1.8±6 mmHg, p = .027) oscillometric BP from supine to HUT-60° compared with non-fallers. None of the variables taken for the analysis were significantly associated with falls in multivariate logistic regression analysis. Conclusions This cross-sectional comparison indicates that, at rest, HD patients with a positive history of falls present with a lower count of baroreceptor sequences and BEI. Short-term BP regulation warrants further investigation as BP drops during a passive orthostatic challenge may be implicated in the aetiology of falls in HD

Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin with gemtuzumab ozogamicin improves event-free survival in younger patients with newly diagnosed aml and overall survival in patients with npm1 and flt3 mutations

Purpose To determine the optimal induction chemotherapy regimen for younger adults with newly diagnosed AML without known adverse risk cytogenetics. Patients and Methods One thousand thirty-three patients were randomly assigned to intensified (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin [FLAG-Ida]) or standard (daunorubicin and Ara-C [DA]) induction chemotherapy, with one or two doses of gemtuzumab ozogamicin (GO). The primary end point was overall survival (OS). Results There was no difference in remission rate after two courses between FLAG-Ida + GO and DA + GO (complete remission [CR] + CR with incomplete hematologic recovery 93% v 91%) or in day 60 mortality (4.3% v 4.6%). There was no difference in OS (66% v 63%; P = .41); however, the risk of relapse was lower with FLAG-Ida + GO (24% v 41%; P < .001) and 3-year event-free survival was higher (57% v 45%; P < .001). In patients with an NPM1 mutation (30%), 3-year OS was significantly higher with FLAG-Ida + GO (82% v 64%; P = .005). NPM1 measurable residual disease (MRD) clearance was also greater, with 88% versus 77% becoming MRD-negative in peripheral blood after cycle 2 (P = .02). Three-year OS was also higher in patients with a FLT3 mutation (64% v 54%; P = .047). Fewer transplants were performed in patients receiving FLAG-Ida + GO (238 v 278; P = .02). There was no difference in outcome according to the number of GO doses, although NPM1 MRD clearance was higher with two doses in the DA arm. Patients with core binding factor AML treated with DA and one dose of GO had a 3-year OS of 96% with no survival benefit from FLAG-Ida + GO. Conclusion Overall, FLAG-Ida + GO significantly reduced relapse without improving OS. However, exploratory analyses show that patients with NPM1 and FLT3 mutations had substantial improvements in OS. By contrast, in patients with core binding factor AML, outcomes were excellent with DA + GO with no FLAG-Ida benefit