Uterine pseudoaneurysm on the basis of deep infiltrating endometriosis during pregnancy-a case report.

BACKGROUND: Pseudoaneurysm of the uterine artery (UPA) is a rare cause of potentially life-threatening hemorrhage during pregnancy and puerperium. It is an uncommon condition that mainly occurs after traumatic injury to a vessel following pelvic surgical intervention, but also has been reported based on underlying endometriosis. There is an increased risk of developing UPA during pregnancy. Diagnosis includes clinical symptoms, with severe abdominal pain and is confirmed by sonographic or magnetic resonance imaging (MRI). Due to its potential risk of rupture, with a subsequent hypovolemic maternal shock and high fetal mortality, an interdisciplinary treatment should be considered expeditiously. CASE PRESENTATION: We present the case of a 34-year old pregnant symptomatic patient, where a large UPA was detected at 26 weeks, based on deep infiltrating endometriosis (DIE). The UPA was successfully treated by selective arterial embolization. After embolization, the pain decreased but the woman still required intravenous analgesics during follow-up. At 37 weeks she developed a sepsis from the intravenous catheter which led to a cesarean section and delivery of a healthy boy. She was discharged 10 days postpartum. CONCLUSIONS: UPA should be considered in pregnant women with severe abdominal and pelvic pain, once other obstetrical factors have been excluded. DIE might be the underlying diagnosis. It is a rare but potentially life-threatening condition for mother and fetus.

A laparoscopic study investigating 3D vs 2D imaging systems using a pelvitrainer model with experts, non-experts, and students.

BACKGROUND: Vision is an essential element of laparoscopic surgery that defines the outcome of an operation in regards to time, mistakes and precision. A 3-dimensional (3D) perspective may improve vision during an operation. Therefore, this study was designed to compare 3D versus 2-dimensional (2D) perspectives using a pelvitrainer model. METHODS: Fifty candidates were divided into 3 categories based on different experience levels. The candidates were randomised into two groups, with each group performing the same 4 standardised tasks. Group A approached the tasks first with 3D high definition and in a second turn with 2D high definition. Group B carried out the tasks with the systems in reverse order. Task completion time and the number of mistakes made for each task were recorded. After completing the tasks, participants answered questions concerning the two systems. RESULTS: Group A was, on average, 20% faster at all four tasks and made approximately 18% fewer mistakes in two of the tasks in comparison to group B. The experts significantly benefited from the 3D system in terms of accuracy compared to non-experts and students. The students demonstrated a significantly greater benefit from the 3D system when performing non-linear, continuous movements. Loss of concentration occurred at the same rate for subjects using the 2D and 3D systems. Nausea and dizziness were reported only when working with the 3D system. 91% found the 3D system advantageous for accomplishing the tasks. CONCLUSIONS: Irrespective of experience level, 3D laparoscopy shows advantages in saving time, increasing accuracy and reducing mistakes. These benefits were also accompanied by subjective advantages that were noted by the participants. However, the more complex the task, the less significant the benefit of the 3D system and some people feel handicapped by the eyewear.

The Lectin-like Domain of TNF Increases ENaC Open Probability through a Novel Site at the Interface between the Second Transmembrane and C-terminal Domains of the α-Subunit.

Regulation of the epithelial sodium channel (ENaC), which regulates fluid homeostasis and blood pressure, is complex and remains incompletely understood. The TIP peptide, a mimic of the lectin-like domain of TNF, activates ENaC by binding to glycosylated residues in the extracellular loop of ENaC-α, as well as to a hitherto uncharacterized internal site. Molecular docking studies suggested three residues, Val567, Glu568, and Glu571, located at the interface between the second transmembrane and C-terminal domains of ENaC-α, as a critical site for binding of the TIP peptide. We generated Ala replacement mutants in this region of ENaC-α and examined its interaction with TIP peptide (3M, V567A/E568A/E571A; 2M, V567A/E568A; and 1M, E571A). 3M and 2M ENaC-α, but not 1M ENaC-α, displayed significantly reduced binding capacity to TIP peptide and to TNF. When overexpressed in H441 cells, 3M mutant ENaC-α formed functional channels with similar gating and density characteristics as the WT subunit and efficiently associated with the ß and γ subunits in the plasma membrane. We subsequently assayed for increased open probability time and membrane expression, both of which define ENaC activity, following addition of TIP peptide. TIP peptide increased open probability time in H441 cells overexpressing wild type and 1M ENaC-α channels, but not 3M or 2M ENaC-α channels. On the other hand, TIP peptide-mediated reduction in ENaC ubiquitination was similar in cells overexpressing either WT or 3M ENaC-α subunits. In summary, this study has identified a novel site in ENaC-α that is crucial for activation of the open probability of the channel, but not membrane expression, by the lectin-like domain of TNF.

Performance of Kymerax© precision-drive articulating surgical system compared to conventional laparoscopic instruments in a pelvitrainer model.

BACKGROUND: The Kymerax© Precision-Drive Articulating Surgical System by Terumo© is a handheld laparoscopic robot which permits motion in two additional degrees of freedom (deflection and rotation in the instrument tip). In a pelvitrainer model, we compared the performance of participants with different laparoscopic experiences and compared Kymerax© to conventional laparoscopic instruments. METHODS: 20 expert surgeons, performing more than 50 laparoscopic procedures per year, and 25 medical students without any experience in surgery at all were selected. Each participant was randomized into two groups: Group TK performed the tasks using the traditional laparoscopic Instruments (TLI) first and Kymerax© thereafter, group KT vice versa. Six standardized tasks were used: Two instructional exercises and four tasks where time, number of mistakes, and overall precision were measured. Finally, a questionnaire had to be answered. RESULTS: All four tasks were performed significantly more slowly with the Kymerax© device. Improved needle control in stitches towards the surgeon, significantly less deviation while cutting along different lines as well as a significantly reduced fraying of the cutting edge were found when participants were using Kymerax©. By questionnaire more than 90% of the participants indicated clear advantages using Kymerax©. However, participants needed more training time and had an earlier loss of concentration with Kymerax©. Further complaints about Kymerax© were its limitations in rotation and deflection, the impaired view as well as the non-ergonomic instrument handle. Rotation force, instrument weight, digital instrument-tip control, and needle fixation were rated as accurate. CONCLUSIONS: This study shows that more time is needed to solve tasks with Kymerax© compared to conventional laparoscopic instruments. Kymerax© is superior to conventional laparoscopy for suturing at difficult angles and cutting along complex structures. Kymerax© can potentially bring benefits for certain laparoscopic tasks, but as seen in this study, further developments are necessary. Terumo© meanwhile closed down its Kymerax

A novel tumor necrosis factor-mediated mechanism of direct epithelial sodium channel activation.

RATIONALE: Alveolar liquid clearance is regulated by Na(+) uptake through the apically expressed epithelial sodium channel (ENaC) and basolaterally localized Na(+)-K(+)-ATPase in type II alveolar epithelial cells. Dysfunction of these Na(+) transporters during pulmonary inflammation can contribute to pulmonary edema. OBJECTIVES: In this study, we sought to determine the precise mechanism by which the TIP peptide, mimicking the lectin-like domain of tumor necrosis factor (TNF), stimulates Na(+) uptake in a homologous cell system in the presence or absence of the bacterial toxin pneumolysin (PLY). METHODS: We used a combined biochemical, electrophysiological, and molecular biological in vitro approach and assessed the physiological relevance of the lectin-like domain of TNF in alveolar liquid clearance in vivo by generating triple-mutant TNF knock-in mice that express a mutant TNF with deficient Na(+) uptake stimulatory activity. MEASUREMENTS AND MAIN RESULTS: TIP peptide directly activates ENaC, but not the Na(+)-K(+)-ATPase, upon binding to the carboxy-terminal domain of the α subunit of the channel. In the presence of PLY, a mediator of pneumococcal-induced pulmonary edema, this binding stabilizes the ENaC-PIP2-MARCKS complex, which is necessary for the open probability conformation of the channel and preserves ENaC-α protein expression, by means of blunting the protein kinase C-α pathway. Triple-mutant TNF knock-in mice are more prone than wild-type mice to develop edema with low-dose intratracheal PLY, correlating with reduced pulmonary ENaC-α subunit expression. CONCLUSIONS: These results demonstrate a novel TNF-mediated mechanism of direct ENaC activation and indicate a physiological role for the lectin-like domain of TNF in the resolution of alveolar edema during inflammation.

Comparison of 2D 4K vs. 3D HD laparoscopic imaging systems in bariatric surgery: study protocol for a randomized controlled prospective trial.

BACKGROUND: Vision is an important and defining element of laparoscopy and significantly affects the outcome of surgery in terms of time, error, and precision. Several new imaging systems have become available for laparoscopic surgery, including three-dimensional (3D) high-definition (HD) and two-dimensional (2D) ultra-high-resolution (4K) monitors. 3D HD systems offer a number of potential benefits to surgeons and patients over traditional 2D systems, including reduced operating time, blood loss, and hospital stay. However, the performance of 3D systems against the new, ultra-high definition 4K systems is barely known and highly controversial. There is a paucity of studies comparing them in clinical settings. The aim of this study is to compare 2D 4K and 3D HD perspectives in gastric bypass surgery. METHODS: Forty-eight patients with an indication for gastric bypass will be randomized to receive laparoscopic gastric bypass surgery using either 2D 4K or 3D HD systems. The operations will be performed by a well-coordinated team of three senior surgeons. The primary outcome is operative time. Secondary outcomes include intraoperative complications, blood loss, operator workload as assessed by the validated Surg-TLX questionnaire, and postoperative complications according to the Clavien-Dindo classification. An interim analysis is planned after enrollment of 12 participants for each group. DISCUSSION: This prospective, randomized trial is designed to test the hypothesis that the use of a 3D HD system will result in a significant improvement in operative time compared to a 2D 4K system in bariatric surgery. The objective is to provide clinical evidence for new laparoscopic imaging systems and to evaluate potential benefits. TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov under the identifier NCT05895058. Registered 30 May 2023. BASEC2023-D0014 [Registry ID Swissethics, approved 3 May 2023]. SNCTP000005489 [SNCTP study register, last updated 13 July 2023].

Intracorporeal vs. extracorporeal open and closed knot tying techniques in laparoscopy: A randomized, controlled study.

Objective: Tying knots during suturing is one of the most challenging tasks in laparoscopic surgery. Therefore, measures aimed at ensuring both the ease and speed of knot tying not only benefit the surgeon but can also reduce operating time significantly. This study compared extracorporeal and intracorporeal knot tying techniques using a Szabo pelvic trainer model from the Gynaecological Endoscopic Surgical Education and Assessment program. Design: The students tied intra- and extracorporeal knots using closed- and open-jaw knot pushers. Using an artificial tissue suturing pad in a certified Szabo pelvic trainer, students tied three knots using each technique according to block randomization. Task completion time, knot strength, knot-spread ability, and number of errors were recorded. The Wilcoxon test and mixed-effects models were used to analyze the results. After completing the exercises, participants answered a questionnaire concerning knot-tying techniques and their performance. Setting: University Hospital Basel, which provides tertiary-level clinical care. Participants: Fifty-seven medical students with no experience in laparoscopy voluntarily signed up for this study. Results: Open and closed extracorporeal knot tying was significantly faster (p < 0.001, p < 0.001, respectively), more precise (p = 0.007, p = 0.003), and associated with reduced knot-spread ability (p < 0.001, p < 0.001) compared to intracorporeal knot tying. Open- and closed-jaw knot pushers were shown to be equal in terms of speed (p = 0.563), knot-spread ability (p = 0.49), and precision (p = 0.831). The study participants rated open (30 %) and closed (49 %) extracorporeal knot tying as more intuitive than intracorporeal (21 %) knot tying. Improved concentration was significantly correlated with tighter knots (p = 0.011). Conclusions: Students achieved significantly better results using extracorporeal knot-tying techniques than intracorporeal ones, including greater speed, tighter knots, and optimized precision. These results suggest that beginners in the field of laparoscopy should be encouraged to practice extracorporeal knot-tying techniques.

Comparison of different suture techniques for laparoscopic vaginal cuff closure.

Laparoscopic hysterectomy is a commonly performed procedure. However, one high-risk complication is vaginal cuff dehiscence. Currently, there is no standardization regarding thread material or suturing technique for vaginal cuff closure. Therefore, this study aimed to compare extracorporeal and intracorporeal suturing techniques for vaginal cuff closure using a pelvic trainer model. Eighteen experts in laparoscopic surgery performed vaginal cuff closures with interrupted sutures using intracorporeal knotting, extracorporeal knotting and continuous, unidirectional barbed sutures. While using an artificial tissue suturing pad in a pelvic trainer, experts performed vaginal cuff closure using each technique according to block randomization. Task completion time, tension resistance, and the number of errors were recorded. After completing the exercises, participants answered a questionnaire concerning the suturing techniques and their performance. Experts completed suturing more quickly (p < 0.001, p < 0.001, respectively) and with improved tension resistance (p < 0.001, p < 0.001) when using barbed suturing compared to intracorporeal and extracorporeal knotting. Furthermore, the intracorporeal knotting technique was performed faster (p = 0.04) and achieved greater tension resistance (p = 0.023) compared to extracorporeal knotting. The number of laparoscopic surgeries performed per year was positively correlated with vaginal cuff closure duration (p = 0.007). Barbed suturing was a time-saving technique with improved tension resistance for vaginal cuff closure.

Mechanism of action of novel lung edema therapeutic AP301 by activation of the epithelial sodium channel.

AP301 [Cyclo(CGQRETPEGAEAKPWYC)], a cyclic peptide comprising the human tumor necrosis factor lectin-like domain (TIP domain) sequence, is currently being developed as a treatment for lung edema and has been shown to reduce extravascular lung water and improve lung function in mouse, rat, and pig models. The current paradigm for liquid homeostasis in the adult mammalian lung is that passive apical uptake of sodium via the amiloride-sensitive epithelial Na⁺ channel (ENaC) and nonselective cyclic-nucleotide-gated cation channels creates the major driving force for reabsorption of water through the alveolar epithelium in addition to other ion channels such as potassium and chloride channels. AP301 can increase amiloride-sensitive current in A549 cells as well as in freshly isolated type II alveolar epithelial cells from different species. ENaC is expressed endogenously in all of these cell types. Consequently, this study was undertaken to determine whether ENaC is the specific target of AP301. The effect of AP301 in A549 cells as well as in human embryonic kidney cells and Chinese hamster ovary cells heterologously expressing human ENaC subunits (α, ß, γ, and δ) was measured in patch clamp experiments. The congener TIP peptide AP318 [Cyclo(4-aminobutanoic acid-GQRETPEGAEAKPWYD)] activated ENaC by increasing single-channel open probability. AP301 increased current in proteolytically activated (cleaved) but not near-silent (uncleaved) ENaC in a reversible manner. αßγ- or δßγ-ENaC coexpression was required for maximal activity. No increase in current was observed after deglycosylation of extracellular domains of ENaC. Thus, our data suggest that the specific interaction of AP301 with both endogenously and heterologously expressed ENaC requires precedent binding to glycosylated extracellular loop(s).

Investigation of gas exchange processes in peat bog ecosystems by means of innovative Raman gas spectroscopy.

Highly sensitive Raman gas spectroscopy is introduced for simultaneous real time analysis of O(2), CO(2), CH(4), and N(2) in order to elucidate the dynamics of greenhouse gases evolving from climate-sensitive ecosystems. The concentrations and fluxes of this suite of biogenic gases were quantified in the head space of a water-saturated, raised peat bog ecotron. The intact peat bog, exhibiting various degradation stages of peat and sphagnum moss, was exposed to various light regimes in order to determine important ecosystem parameters such as the maximum photosynthesis rate of the sphagnum as well as the extent of soil and plant respiration. Miniaturized Raman gas spectroscopy was proven to be an extremely versatile analytical technique that allows for onsite multigas analysis in high temporal resolution. Therefore it is an urgently needed tool for elucidation of complex biochemical processes especially in climate-sensitive ecosystems and consequently for the estimation of climate-relevant gas budgets.

AP301, a synthetic peptide mimicking the lectin-like domain of TNF, enhances amiloride-sensitive Na(+) current in primary dog, pig and rat alveolar type II cells.

Pulmonary permeability oedema is a frequent complication in a number of life-threatening lung conditions, such as ALI and ARDS. Apart from ventilation strategies, no specific therapy yet exists for treatment of these potentially fatal illnesses. The oedema-reducing capacity of the lectin-like domain of TNF (TIP) and of synthetic peptides, mTIP and hTIP, which mimic the TIP domain of mouse and human TNF, have been demonstrated in various studies in rodents. Cell-based electrophysiological studies have revealed that the alveolar fluid clearing capacity of TNF and the TIP peptides is due to activation of the amiloride-sensitive Na(+) current in alveolar epithelial cells and that the primary site of action is on the apical side of these cells. AP301, a synthetic cyclic peptide mimicking the TIP domain of human TNF is currently undergoing clinical trials as a therapy for pulmonary permeability oedema. AP301 has been shown to improve alveolar liquid clearance and lung function in a porcine model of ALI. For non-clinical regulatory assessment, dog, pig and rat are standard animal models; accordingly, pre-clinical toxicological and pharmacological safety studies have been conducted with AP301 in dogs and rats. Hitherto, no studies have assessed the pharmacodynamic effect of AP301 on primary canine or porcine type II AEC. The current study describes the effect of AP301 on the amiloride-sensitive Na(+) current in type II AEC isolated from dog, pig and rat lungs. In whole cell patch clamp experiments with dog type II AEC, an increase in the amiloride-sensitive Na(+) current from 3.7 pA to 49.4 pA was observed in the presence of AP301; in pig type II AEC, an increase from 10.0 pA to 159.6 pA was observed, and in rat AEC, from 6.9 pA to 62.4 pA. In whole cell patch clamp experiments in A549 cells, AP301-induced enhancement of the amiloride-sensitive current was eliminated when Na(+) in the bath solution was replaced with N-methyl-d-glucamine (NMDG), and when the cells were pre-incubated with 5-aminoimidazole-4-carboxamide-1-ß-d-ribofuranoside (AICAR), an inhibitor of ENaC, but enhancement was unaffected by addition of cyclic nucleotide-gated (CNG) channel inhibitors Zn(2+) or l-cis-diltiazem prior to AP301. These results provide strong evidence that AP301 activates the amiloride-sensitive Na(+) current through ENaC in type II AEC from dog, pig and rat. To our knowledge, this is the first cell-based analysis of the oedema-clearing effect of AP301 observed in the porcine model of pulmonary oedema. Furthermore, the results validate the dog and pig models in non-clinical assessment of AP301.

Direct endothelial ENaC activation mitigates vasculopathy induced by SARS-CoV2 spike protein.

Introduction: Although both COVID-19 and non-COVID-19 ARDS can be accompanied by significantly increased levels of circulating cytokines, the former significantly differs from the latter by its higher vasculopathy, characterized by increased oxidative stress and coagulopathy in lung capillaries. This points towards the existence of SARS-CoV2-specific factors and mechanisms that can sensitize the endothelium towards becoming dysfunctional. Although the virus is rarely detected within endothelial cells or in the circulation, the S1 subunit of its spike protein, which contains the receptor binding domain (RBD) for human ACE2 (hACE2), can be detected in plasma from COVID-19 patients and its levels correlate with disease severity. It remains obscure how the SARS-CoV2 RBD exerts its deleterious actions in lung endothelium and whether there are mechanisms to mitigate this. Methods: In this study, we use a combination of in vitro studies in RBD-treated human lung microvascular endothelial cells (HL-MVEC), including electrophysiology, barrier function, oxidative stress and human ACE2 (hACE2) surface protein expression measurements with in vivo studies in transgenic mice globally expressing human ACE2 and injected with RBD. Results: We show that SARS-CoV2 RBD impairs endothelial ENaC activity, reduces surface hACE2 expression and increases reactive oxygen species (ROS) and tissue factor (TF) generation in monolayers of HL-MVEC, as such promoting barrier dysfunction and coagulopathy. The TNF-derived TIP peptide (a.k.a. solnatide, AP301) -which directly activates ENaC upon binding to its a subunit- can override RBD-induced impairment of ENaC function and hACE2 expression, mitigates ROS and TF generation and restores barrier function in HL-MVEC monolayers. In correlation with the increased mortality observed in COVID-19 patients co-infected with S. pneumoniae, compared to subjects solely infected with SARS-CoV2, we observe that prior intraperitoneal RBD treatment in transgenic mice globally expressing hACE2 significantly increases fibrin deposition and capillary leak upon intratracheal instillation of S. pneumoniae and that this is mitigated by TIP peptide treatment.

Protein kinase C-α and arginase I mediate pneumolysin-induced pulmonary endothelial hyperpermeability.

Antibiotics-induced release of the pore-forming virulence factor pneumolysin (PLY) in patients with pneumococcal pneumonia results in its presence days after lungs are sterile and is a major factor responsible for the induction of permeability edema. Here we sought to identify major mechanisms mediating PLY-induced endothelial dysfunction. We evaluated PLY-induced endothelial hyperpermeability in human lung microvascular endothelial cells (HL-MVECs) and human lung pulmonary artery endothelial cells in vitro and in mice instilled intratracheally with PLY. PLY increases permeability in endothelial monolayers by reducing stable and dynamic microtubule content and modulating VE-cadherin expression. These events, dependent upon an increased calcium influx, are preceded by protein kinase C (PKC)-α activation, perturbation of the RhoA/Rac1 balance, and an increase in myosin light chain phosphorylation. At later time points, PLY treatment increases the expression and activity of arginase in HL-MVECs. Arginase inhibition abrogates and suppresses PLY-induced endothelial barrier dysfunction by restoring NO generation. Consequently, a specific PKC-α inhibitor and the TNF-derived tonoplast intrinsic protein peptide, which blunts PLY-induced PKC-α activation, are able to prevent activation of arginase in HL-MVECs and to reduce PLY-induced endothelial hyperpermeability in mice. Arginase I (AI)(+/-)/arginase II (AII)(-/-) C57BL/6 mice, displaying a significantly reduced arginase I expression in the lungs, are significantly less sensitive to PLY-induced capillary leak than their wild-type or AI(+/+)/AII(-/-) counterparts, indicating an important role for arginase I in PLY-induced endothelial hyperpermeability. These results identify PKC-α and arginase I as potential upstream and downstream therapeutic targets in PLY-induced pulmonary endothelial dysfunction.

Histopathological analysis of intracerebral hemorrhage: implications for clinical management.

BACKGROUND: The clinical impact of routine neuropathologic examination of samples from patients with intracerebral hemorrhage (ICH) is unclear. METHODS: Therefore, we evaluated a consecutive series of 378 surgical specimens from patients with ICH concerning demographic data, localization of hemorrhage, preoperative clinical diagnosis and neuropathological diagnosis. RESULTS: Histological examination revealed the putative origin of ICH in 143 cases (37.8%). Vascular pathologies were detected in 127 patients (33.6%), while tumors were identified in 9 patients (2.4%), infarction in 6 patients (1.6%) and abscess in 1 patient (0.3%). Preoperatively, tumor was considered in 65 patients (17.2%), while vascular malformations were supposed in 94 patients (24.9%), infarction in 18 cases (4.8%) and abscess in 3 cases (0.8%). In 198 patients (52.4%) no specific assumption was made. CONCLUSIONS: Comparing preoperative assumptions and histological diagnoses, tumor, vascular malformations and infarctions were clinically overestimated, while arteriolosclerosis and amyloid angiopathy were underestimated. In conclusion, we found that histological findings potentially affecting clinical management and prognosis were obtained in 37.8% of cases. Our data suggest that histopathological examination of intracerebral hemorrhage provides important information for patient management and should be routinely performed.

Conformational ensemble of the TNF-derived peptide solnatide in solution.

Tumor necrosis factor (TNF) is a homotrimer that has two spatially distinct binding regions, three lectin-like domains (LLD) at the TIP of the protein and three basolaterally located receptor-binding sites, the latter of which are responsible for the inflammatory and cell death-inducing properties of the cytokine. Solnatide (a.k.a. TIP peptide, AP301) is a 17-mer cyclic peptide that mimics the LLD of human TNF which activates the amiloride-sensitive epithelial sodium channel (ENaC) and, as such, recapitulates the capacity of TNF to enhance alveolar fluid clearance, as demonstrated in numerous preclinical studies. TNF and solnatide interact with glycoproteins and these interactions are necessary for their trypanolytic and ENaC-activating activities. In view of the crucial role of ENaC in lung liquid clearance, solnatide is currently being evaluated as a novel therapeutic agent to treat pulmonary edema in patients with moderate-to-severe acute respiratory distress syndrome (ARDS), as well as severe COVID-19 patients with ARDS. To facilitate the description of the functional properties of solnatide in detail, as well as to further target-docking studies, we have analyzed its folding properties by NMR. In solution, solnatide populates a set of conformations characterized by a small hydrophobic core and two electrostatically charged poles. Using the structural information determined here and also that available for the ENaC protein, we propose a model to describe solnatide interaction with the C-terminal domain of the ENaCα subunit. This model may serve to guide future experiments to validate specific interactions with ENaCα and the design of new solnatide analogs with unexplored functionalities.

Comparison of 2D 4K vs. 3D HD laparoscopic imaging systems using a pelvitrainer model: a randomized controlled study.

Laparoscopic surgery provides well-known benefits, but it has technological limitations. Depth perception is particularly crucial, with three-dimensional (3D) imaging being superior to two-dimensional (2D) HD imaging. However, with the introduction of 4K resolution monitors, 2D rendering is capable of providing higher-quality visuals. Therefore, this study aimed to compare 3D HD and 2D 4K imaging using a pelvitrainer model. Eight experts and 32 medical students were performing the same four standardized tasks using 2D 4K and 3D HD imaging systems. Task completion time and the number of errors made were recorded. The Wilcoxon test and mixed-effects models were used to analyze the results. Students were significantly faster in all four tasks when using the 3D HD perspective. The median difference ranged from 18 s in task 3 (P < 0.003) up to 177.5 s in task 4 (P < 0.001). With the exception of task 4, students demonstrated significantly fewer errors in all tasks involving 3D HD imaging. The experts' results confirmed these findings, as they were also faster in all four tasks using 3D HD, which was significant for task 1 (P < 0.001) and task 4 (P < 0.006). The expert group also achieved better movement accuracy using the 3D HD system, with fewer mistakes made in all four tasks, which was significant in task 4 (P < 0.001). Participants in both groups achieved better results with the 3D HD imaging system than with the 2D 4K system. The 3D HD image system should be used when available. Trial registration: this trial is registered at research registry under the identifier researchregistry6852.

Potent anti-inflammatory activity of the lectin-like domain of TNF in joints.

In view of the crucial role of tumor necrosis factor (TNF) in joint destruction, TNF inhibitors, including neutralizing anti-TNF antibodies and soluble TNF receptor constructs, are commonly used therapeutics for the treatment of arthropathies like rheumatoid arthritis (RA). However, not all patients achieve remission; moreover, there is a risk of increased susceptibility to infection with these agents. Spatially distinct from its receptor binding sites, TNF harbors a lectin-like domain, which exerts unique functions that can be mimicked by the 17 residue solnatide peptide. This domain binds to specific oligosaccharides such as N'N'-diacetylchitobiose and directly target the α subunit of the epithelial sodium channel. Solnatide was shown to have anti-inflammatory actions in acute lung injury and glomerulonephritis models. In this study, we evaluated whether the lectin-like domain of TNF can mitigate the development of immune-mediated arthritis in mice. In an antigen-induced arthritis model, solnatide reduced cell influx and release of pro-inflammatory mediators into the joints, associated with reduction in edema and tissue damage, as compared to controls indicating that TNF has anti-inflammatory effects in an acute model of joint inflammation via its lectin-like domain.

Safety and preliminary efficacy of sequential multiple ascending doses of solnatide to treat pulmonary permeability edema in patients with moderate-to-severe ARDS-a randomized, placebo-controlled, double-blind trial.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a complex clinical diagnosis with various possible etiologies. One common feature, however, is pulmonary permeability edema, which leads to an increased alveolar diffusion pathway and, subsequently, impaired oxygenation and decarboxylation. A novel inhaled peptide agent (AP301, solnatide) was shown to markedly reduce pulmonary edema in animal models of ARDS and to be safe to administer to healthy humans in a Phase I clinical trial. Here, we present the protocol for a Phase IIB clinical trial investigating the safety and possible future efficacy endpoints in ARDS patients. METHODS: This is a randomized, placebo-controlled, double-blind intervention study. Patients with moderate to severe ARDS in need of mechanical ventilation will be randomized to parallel groups receiving escalating doses of solnatide or placebo, respectively. Before advancing to a higher dose, a data safety monitoring board will investigate the data from previous patients for any indication of patient safety violations. The intervention (application of the investigational drug) takes places twice daily over the course of 7 days, ensued by a follow-up period of another 21 days. DISCUSSION: The patients to be included in this trial will be severely sick and in need of mechanical ventilation. The amount of data to be collected upon screening and during the course of the intervention phase is substantial and the potential timeframe for inclusion of any given patient is short. However, when prepared properly, adherence to this protocol will make for the acquisition of reliable data. Particular diligence needs to be exercised with respect to informed consent, because eligible patients will most likely be comatose and/or deeply sedated at the time of inclusion. TRIAL REGISTRATION: This trial was prospectively registered with the EU Clinical trials register (clinicaltrialsregister.eu). EudraCT Number: 2017-003855-47 .