Heart failure has a poor prognosis and no curative treatment exists. Clinical trials are investigating gene- and cell-based therapies to improve cardiac function. The safe and efficient delivery of ...these therapies to solid organs is challenging. Herein, we demonstrate the feasibility of using an endovascular intramyocardial delivery approach to safely administer mRNA drug products and perform cell transplantation procedures in swine. Using a trans-vessel wall (TW) device, we delivered chemically modified mRNAs (modRNA) and mRNA-enhanced mesenchymal stromal cells expressing vascular endothelial growth factor A (VEGF-A) directly to the heart. We monitored and mapped the cellular distribution, protein expression, and safety tolerability of such an approach. The delivery of modRNA-enhanced cells via the TW device with different flow rates and cell concentrations marginally affect cell viability and protein expression in situ. Implanted cells were found within the myocardium for at least 3 days following administration, without the use of immunomodulation and minimal impact on tissue integrity. Finally, we could increase the protein expression of VEGF-A over 500-fold in the heart using a cell-mediated modRNA delivery system compared with modRNA delivered in saline solution. Ultimately, this method paves the way for future research to pioneer new treatments for cardiac disease.
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Holmin and colleagues used a minimally invasive endovascular approach to successfully deliver mRNA therapies using mesenchymal stem cells as vectors to swine hearts. This method, showing minimal tissue impact and enhanced protein expression, offers a promising avenue for advancing cardiac disease treatments.
This cross-sectional study examined nationwide real-world associations between anti-inflammatory agent fills and suicide-related death rates in 20–24-year-olds across the 21 Swedish regions during ...2006–2021.
Nationwide Swedish registers were used to compare regional year-wise suicide-related mortality (SRM) and dispensations for anti-inflammatory agents (ATC-code: M01) in 20–24-year-olds. Dispensations for paracetamol (ATC-code: N02BE01) was applied as a control variable. Associations between regional year-wise SRM and dispensation rates were analyzed by sex-stratified zero-inflated generalized linear mixed effect models (GLMM). Dispensation rates of paracetamol and inflammatory agents were designated as independent fixed effects variables, and year and region constituted random-intercept effects.
Acetic acid derivatives and related substances (M01AB) and propionic acid derivates (M01A3) accounted for ∼71% of measured dispensation fills for anti-inflammatory agents. Diclofenac fills constituted ∼98% of the former category, whereas dispensations for Ibuprofen (∼21%), Naproxen (∼62%) and Ketoprofen (∼13%) constituted the most prescribed agents in the latter category. Regional yearly dispensation rates of anti-inflammatory agents in 20–24-year-old females were inversely associated with female SRM (β = −0.095, p = 0.0393, 95% CI -0.186, −0.005) – independent of paracetamol rates, which were unassociated to SRM (p = 0.2094). Results were confirmed in validation analyses for anti-inflammatory agents (OR = 0.7232, p = 0.0354, 95% CI OR 0.5347, 0.9781). No association was demonstrated in males (p = 0.833).
Anti-inflammatory agent dispensation rates were independently associated to lower suicide-related death rates in female 20-24-year-olds. This adds to growing evidence implicating inflammatory processes in mental disorders, warranting trials focusing on the suicide preventative potential of anti-inflammatories in young adults.
•2006–2021 study across the 21 Swedish regions encompassing 3453 suicide-related deaths.•Female SRM inversely correlated with anti-inflammatory agent use (p = 0.0393).•Validation confirms anti-inflammatory agents' suicide risk reduction (p = 0.0354).•Study supports link between inflammation & mental disorders.•Trials of anti-inflammatories for suicide prevention in young adults warranted.
Aims
In experimental studies, morphine pharmacokinetics is different in the brain compared with other tissues due to the properties of the blood–brain barrier, including action of efflux pumps. It ...was hypothesized in this clinical study that active efflux of morphine occurs also in human brain, and that brain injury would alter cerebral morphine pharmacokinetics.
Methods
Patients with traumatic brain injury, equipped with one to three microdialysis catheters in the brain and one in abdominal subcutaneous fat for metabolic monitoring, were studied. The cerebral catheter locations were classified as ‘better’ and ‘worse’ brain tissue, referring to the degree of injury. Morphine (10 mg) was infused intravenously over a 10‐min period in seven patients in the intensive care setting. Tissue and plasma morphine concentrations were obtained during the subsequent 3‐h period with microdialysis and regular blood sampling.
Results
The area under the concentration–time curve (AUC) ratio of unbound morphine in brain tissue to plasma was 0.64 (95% confidence interval 0.40, 0.87) in ‘better’ brain tissue (P < 0.05 vs. the subcutaneous fat/plasma ratio), 0.78 (0.49, 1.07) in ‘worse’ brain tissue and 1.00 (0.86, 1.13) in subcutaneous fat. The terminal half‐life and Tmax were longer in the brain vs. plasma and fat, respectively. The relative recovery for morphine was higher in ‘better’ than in ‘worse’ brain tissue. The Tmax value tended to be shorter in ‘worse’ brain tissue.
Conclusions
The unbound AUC ratio below unity in the ‘better’ human brain tissue demonstrates an active efflux of morphine across the blood–brain barrier. The ‘worse’ brain tissue shows a decrease in relative recovery for morphine and in some cases also an increase in permeability for morphine over the blood–brain barrier.
This paper studies the effect of Green Public Procurement (GPP) on competition, bids, and winning bids under two different regulation periods where the latter include more explicitly expressed GPP ...ambitions. Based on detailed data from Swedish internal cleaning service procurements, our results imply that environmental considerations might not influence the bids as required for GPP to be considered an effective environmental policy instrument. Over time, lower degree of competition and increased bids are found. This phenomenon can be attributed, at least in part, to regulatory influences, signifying an escalating complexity in the process of submitting bids.
•Contract characteristics other than green demands impact bids and winning bids.•Environmental criteria alone do not influence bids and winning bids.•The number of criteria has a influence on bids and winnings bids.•Findings indicate increased complexity in public procurement bid submission.•In this market, criteria maintain standards rather than driving greener practices.
Background: Levosimendan improves resuscitation rates and cardiac performance in animal cardiac arrest models. The aim of this study was to describe the use of levosimendan in out-of-hospital cardiac ...arrest (OHCA) patients and its association with outcome. Methods: A retrospective observational study of OHCA patients admitted to six intensive care units in Stockholm, Sweden, between 2010 and 2016. Patients treated with levosimendan within 24 h from admission were compared with those not treated with levosimendan. Propensity score matching and multivariable logistic regression analysis were used to assess the association between levosimendan treatment and 30-day mortality Results: Levosimendan treatment was initiated in 94/940 (10%) patients within 24 h. The proportion of men (81%, vs. 67%, p = 0.007), initial shockable rhythm (66% vs. 37%, p < 0.001), acute myocardial infarction, AMI (47% vs. 24%, p < 0.001) and need for vasoactive support (98% vs. 61%, p < 0.001) were higher among patients treated with levosimendan. After adjustment for age, sex, bystander cardiopulmonary resuscitation, witnessed status, initial rhythm and AMI, the odds ratio (OR) for 30-day mortality in the levosimendan group compared to the no-levosimendan group was 0.94 (95% Confidence interval CI, 0.56−1.57, p = 0.82). Similar results were seen when using a propensity score analysis comparing patients with circulatory shock. Conclusions: In this observational study of OHCA patients, levosimendan was used in a limited patient group, most often in those with initial shockable rhythms, acute myocardial infarction and with a high need for vasopressors. In this limited patient cohort, levosimendan treatment was not associated with 30-day mortality. However, a better matching of patient factors and indications for use is required to derive conclusions on associations with outcome.
Stem cell transplantation procedures using intraparenchymal injections cause tissue injury in addition to associated surgical risks. Intravenous cell administration give engraftment in parenchymal ...lesions although the method has low efficacy and specificity. In pathological conditions with inflammation, such as traumatic brain injury, there is a transient up-regulation of ICAM-1 and VCAM-1 which might provide environmental cues for migration of stem cells from blood to parenchyma. The aim of this study was to i) analyze the effect of intra-arterial administration on cellular engraftment, ii) compare engraftment and side effects between three different stem cell systems, and iii) analyze gene expression in these three systems. We performed specific intra-arterial transplantations with human mesenchymal stem cells (hMSCs), human neural progenitor cells (hNPCs), and rat neural progenitor cells (rNPCs) in a rat model of traumatic brain injury. These results were compared to the intravenous route for each cell type, respectively. Analysis of engraftment and recipient characterization was performed by immunohistochemistry. We further characterized the different types of cells by microarray and RT-qPCR analysis. Specific intra-arterial transplantations produced significantly higher engraftment compared to intravenous transplantation with hMSCs and rNPCs. No engraftment was detected after intra-arterial or intravenous administration of hNPCs. Characterization of integrin expression indicated that CD49dVCAM-1 and possibly ICAM-1 interactions through CD18 and CD11a, respectively, are important for engraftment after intravascular cell administration. No side effects, such as thromboembolic complications, were detected. When translating stem cell therapies to clinical practice, the route of transplantation and the properties of the cell lines (homing, diapedesis, and migration) become important. This study supports the use of selective intra-arterial transplantation for improving engraftment after traumatic brain injury. In addition, we conclude that careful analysis of cells intended for local, intra-arterial transplantation with respect to integrin expression is important.
Beyond the Surface Desai Boström, Adrian E.; Lundberg, Johan
Journal of the American College of Cardiology,
11/2023, Letnik:
82, Številka:
19
Journal Article
Endovascular techniques are providing options to surgical/percutaneous cell transplantation methods. Some cells, e.g. insulin producing cells, are not suitable for intra-luminal transplantation and ...for such cells, other options must be found. We have constructed a "nanocatheter" with a penetrating tip for vessel perforation, thereby creating a working channel for parenchymal access by endovascular technique. To finish the procedure safely, the distal tip is detached to provide a securing plug in the vessel wall defect.
We have performed interventions with full clinical integration in the superior mesenteric artery (SMA), the subclavian artery and the external carotid artery in rabbits. No hemorrhagic- or thromboembolic events occurred during the procedure. Stenosis formation and distal embolisation were analyzed by angiography and macroscopic inspection during autopsy at five, 30 and 80 days. All animals and implanted devices were also evaluated by micro-dissections and histochemical analysis.
In this study we show safety data on the trans-vessel wall technique by behavioral, angiographical and histological analysis. No stenosis formation was observed at any of the follow-up time points. No animals or organs have shown any signs of distress due to the intervention. Histological examination showed no signs of hemorrhage, excellent biocompatibility with no inflammation and a very limited fibrous capsule formation around the device, comparable to titanium implants. Further, no histological changes were detected in the endothelia of the vessels subject to intervention.
The trans-vessel wall technique can be applied for e.g. cell transplantations, local substance administration and tissue sampling with low risk for complications during the procedure and low risk for hemorrhage, stenosis development or adverse tissue reactions with an 80 days follow-up time. The benefit should be greatest in organs that are difficult or risky to reach with surgical techniques, such as the pancreas, the CNS and the heart.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Postoperative pain after total knee arthroplasty (TKA) is severe, and achieving adequate analgesia remains a clinical challenge. We tested the hypothesis that, in patients having unilateral TKA under ...intrathecal (IT) anesthesia, the addition of a femoral nerve block would provide superior analgesia when compared with IT morphine and demonstrate fewer adverse side effects. In a single-blinded and controlled trial, 41 ASA I-III patients undergoing unilateral TKA were randomized into 2 groups. Both groups received 15 mg of IT hyperbaric bupivacaine for the surgical anesthetic. Group ITM received 250 microg of IT morphine and group FNB received an ultrasound-assisted femoral nerve block with 40 mL of 0.5% ropivacaine, 5 microg/mL of epinephrine, and 75 microg of clonidine. At 1, 2, 4, 6, 12, and 24 h postoperatively, we measured visual analog scales for pain, cumulative IV morphine consumption, hemodynamics, and side effects. There were no statistically significant differences in morphine consumption, pain at rest, or pain with movement. However, group FNB had fewer perioperative side effects including nausea, vomiting, and pruritus (P < 0.05 for each event). This corresponded to a decrease in patient satisfaction in group ITM, in which 20% of the patients rated their experience as "unsatisfactory" (P < 0.05). We conclude that, in comparison with IT morphine, a single injection femoral nerve block provides equivalent analgesia but with a significant reduction in side effects for patients having TKA under bupivacaine intrathecal anesthesia.
Morphine metabolism after major liver surgery RUDIN, Asa; LUNDBERG, Johan F; HAMMARLUND-UDENAES, Margareta ...
Anesthesia and analgesia,
06/2007, Letnik:
104, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Impaired metabolism of morphine may lead to an increase in sedation and respiratory depression.
In the present study we investigated morphine pharmacokinetics in patients who had undergone liver ...resection (n = 15) compared to a control group undergoing colon resection (n = 15). Morphine was administered IV by patient-controlled analgesia. Plasma concentrations of morphine, morphine-6-glucuronide, and morphine-3-glucuronide were measured 2-3 times daily for the first two postoperative days. Pain intensity scores were assessed three times daily and respiratory rate and sedation scores every third hour.
There were no differences in morphine requirements 1.1 (0.8-2.5 median, interquartile range) mg/h (liver resection) and 1.5 (1.1-1.7) mg/h (colon resection) P = 0.84) or in pain intensity scores (P > 0.3) between the groups. Plasma morphine concentrations were higher in patients undergoing liver resection than in the control group (P < 0.01) reflecting a lower rate of morphine metabolism. Plasma morphine concentrations were correlated with the volume of liver resection (P < 0.02). However, plasma concentrations of morphine-6-glucuronide and morphine-3-glucuronide did not differ between the groups (P = 0.62 and P = 0.48, respectively). There was a higher incidence of sedation (P = 0.02), but not respiratory depression (P = 0.48), after liver resection.
The study demonstrates that plasma concentrations of morphine are higher in patients undergoing liver resection compared with patients undergoing colon resection. Sedation scores were higher in patients undergoing liver resection. Caution is therefore recommended when administering morphine to this patient group.
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