Pig Model Research Articles

Acute enhanced liquid aspirin administration improves performance and intestinal function in nursery pigs.

Aspirin (acetylsalicylic acid) is a nonsteroidal anti-inflammatory drug which has been a widely used analgesic for pain relief as well as an anti-inflammatory medication. However, it also causes negative effects to the gastrointestinal (GI) tract including GI bleeding, peptic ulcers, and can also impact the small intestine. Enhanced liquid aspirin (ELA) contains a combination of a salicylate compound, glycerin, triacetate, and saccharin which is more stable than aspirin alone and may reduce negative effects on the GI tract, while still exerting positive effects on inflammatory processes. The objective of this pilot study was to evaluate oral ELA on healthy weaning pigs. 8 pigs per treatment were gavaged daily for 5 d with either saline controls (CON) or 2mg/kg body weight ELA. After the 5-d dosing period, pigs were weighed and then euthanized for intestinal sample collection. ELA-administered pigs gained significantly more body weight relative to initial body weights compared to CON pigs (8% vs. 13.7%; P<0.05). Additionally, there was tendency for an increase of 24% in villus height in ELA pigs compared to CON (P = 0.06) and significant increases in relative protein expression of Claudins (CLDN) 3 and 7 (P<0.05). Finally, several genes were altered in ELA-fed pigs compared to CON including stem cell markers and immune markers. All in all, this data showed that ELA was well tolerated in a pig model, showed a preliminary improvement in body weight, and had no observable negative impacts.

Interventional real-time molecular MRI for targeting early myocardial injury in a pig model

Myocardial ischemia induces tissue injury with subsequent inflammation and recruitment of immune cells. Besides myocardial tissue characterization, magnetic resonance imaging (MRI) allows for functional assessment using molecular imaging contrast agents. Here, we assessed ischemic cardiac lesions non-invasively directly after ischemia/reperfusion (I/R) in a porcine model by advanced MRI techniques and molecular imaging, targeting the cell adhesion molecule P-selectin functionalized with microparticles of iron oxide (MPIO). We used a closed-chest model of I/R by temporary coronary balloon-occlusion, real time 3T MRI-guided coronary injection of MPIO-based contrast agents, as well as injury, edema and iron-sensitive MRI. Within the first hours after I/R, we found T1 mapping to be most sensitive for tissue injury, with no changes in edema-sensitive MRI. Intriguingly, P-selectin MPIO contrast agent selectively enhanced the ischemic area in iron-sensitive MRI. In conclusion, this approach allows for sensitive detection of early myocardial inflammation beyond traditional edema-sensitive imaging.

Anti-Ebola virus mAb 3A6 protects highly viremic animals from fatal outcome via binding GP(1,2) in a position elevated from the virion membrane

Monoclonal antibodies (mAbs) against Ebola virus (EBOV) glycoprotein (GP1,2) are the standard of care for Ebola virus disease (EVD). Anti-GP1,2 mAbs targeting the stalk and membrane proximal external region (MPER) potently neutralize EBOV in vitro and are protective in a mouse model of EVD. However, their neutralization mechanism is poorly understood because they target a GP1,2 epitope that has evaded structural characterization. Using X-ray crystallography and cryo-electron tomography of mAb 3A6 complexed with its stalk–MPER epitope, we reveal a previously undescribed mechanism in which 3A6 binds to a conformation of GP1,2 that is lifted from the virion membrane. We further show that in both domestic guinea pig and rhesus monkey EVD models, 3A6 provides therapeutic benefit at high-viremia advanced disease stages and at the lowest dose yet demonstrated for any anti-EBOV mAb-based monotherapy. The findings reported here can guide design of next-generation highly potent anti-EBOV therapeutics and vaccines.

Impact of microbial diversity on inflammatory cytokines and respiratory pattern measured in whole-body plethysmography in guinea pig models.

This study investigates the breathing patterns and immune status of guinea pigs raised under specific pathogen-free (SPF) conditions compared to conventionally bred (CON). Breathing pattern parameters were assessed using whole-body plethysmography (WBP) during quiet breathing and saline nebulisation. Blood and bronchoalveolar lavage fluid (BALF) were analysed for white blood cell, neutrophil and eosinophil counts, and cytokine levels (TNF-α, IL-1β, IL-4). SPF guinea pigs exhibited higher tidal volume, expired volume, minute volume, and airflow parameters than CON guinea pigs. The immune analysis revealed lower white blood cell counts and IL-4 levels in SPF guinea pigs. These findings indicate that SPF guinea pigs have different respiratory and immune responses than CON guinea pigs. The study highlights that the maturation processes affecting breathing pattern parameters in SPF guinea pigs differ significantly from those in CON guinea pigs. This suggests potential limitations of SPF animals in respiratory physiology research due to their different immune and respiratory responses.

Temporary bilateral clamping of renal arteries induces ischemia-reperfusion: A new pig model of acute kidney injury using total intravenous anesthesia.

Ischemia-reperfusion (IR) is a leading cause of acute kidney injury (AKI), and pigs are commonly used in preclinical AKI models. However, existing models often vary in the methods used to induce ischemia, and the resulting AKI tends to be mild-to-moderate. Moreover, follow-up is often performed under volatile anesthesia, which, in contrast to total intravenous anesthesia (TIVA), can induce malignant hyperthermia and cause hemodynamic instability. Here we present a novel surgical model of IR-induced AKI using bilateral renal artery clamping under TIVA. Anesthesia was induced via TIVA with diazepam, ketamine, and morphine. After retroperitoneal exposure, the renal arteries were isolated and clamped with a plastic tube for 90 min, followed by 8 h of reperfusion. The IR group (n = 6) was compared with a Sham group (n = 5) that underwent the same procedure without IR. The IR group developed moderate-to-severe AKI as evidenced by reduced glomerular filtration, a 158% increase in plasma creatinine versus 21% in the Sham group, and elevated neutrophil gelatinase-associated lipocalin levels (+280% in IR vs. 0% in Sham), indicating tubular injury. Histopathology confirmed these findings. Thus, this preclinical model successfully induced moderate-to-severe AKI in pigs. The TIVA anesthetic protocol offered several advantages compared to halogenated gas anesthesia.

Comprehensive Echocardiographic Protocol for Pigs with Emphasis on Diastolic Function: Advantages over MRI Assessment.

Swine are increasingly utilized in cardiovascular research due to their anatomical and physiological similarities to humans, particularly for studying diastolic dysfunction. While MRI offers excellent structural imaging, echocardiography provides superior real-time assessment of diastolic parameters. To address the lack of standardized methods and reduce variability across studies, we present a comprehensive guide for performing echocardiography in Yorkshire pigs, detailing anatomical considerations, equipment requirements, and technical approaches. We describe systematic approaches for obtaining and optimizing right parasternal long and short-axis views, apical four-chamber, and subcostal imaging windows, with specific attention to anatomical variations from human cardiac orientation and standard clinical transducer positioning. These tomographic views enable comprehensive assessment of systolic and diastolic function, including ventricular volumes, wall thicknesses, chamber dimensions, ejection fraction, and Doppler measurements of blood flow and tissue velocities. This standardized methodology for echocardiographic images acquisition enhances data reliability in cardiovascular pig models, improving the interpretation of preclinical study results and strengthening translational research outcomes. The protocol also provides consistency for veterinary applications, making echocardiography a preferred modality for longitudinal studies in this valuable translational model.

Single-cell transcriptomics predict novel potential regulators of acute epithelial restitution in the ischemia-injured intestine.

Intestinal ischemic injury damages the epithelial barrier predisposes patients to life-threatening sepsis unless that barrier is rapidly restored. There is an age-dependency of intestinal recovery in that neonates are the most susceptible to succumb to disease of the intestinal barrier versus older patients. We have developed a pig model that demonstrates age-dependent failure of intestinal barrier restitution in neonatal pigs which can be rescued by the direct application of juvenile pig mucosal tissue, but the mechanisms of rescue remain undefined. We hypothesized that by identifying a subpopulation of restituting enterocytes by their expression of cell migration transcriptional pathways, we can then predict novel upstream regulators of age-dependent restitution response programs. Superficial mucosal epithelial cells from recovering ischemic jejunum of juvenile pigs underwent single cell transcriptomics and predicted upstream regulator CSF-1 was interrogated in our model. A subcluster of absorptive enterocytes expressed several cell migration pathways key to restitution. Differentially expressed genes in this subcluster predicted their upstream regulation by colony stimulating factor-1 (CSF-1). We validated age-dependent induction of CSF-1 by ischemia and documented that CSF-1 and CSF1R co-localized in ischemic juvenile, but not neonatal, wound-adjacent epithelial cells and in the restituted epithelium of juveniles and rescued neonates. Further, the CSF-1 blockade reduced restitution in vitro, and CSF-1 improved barrier function in injured neonatal pig in preliminary ex vivo experiments. These studies validate an approach to inform potential novel therapeutic targets, such as CSF-1, to improve outcomes in neonates with intestinal injury in a unique pig model.

Dynamic pathophysiological features of early primary blast lung injury: a novel functional incapacity pig model

IntroductionWhile there is evidence supporting the use of ultrasound for real-time monitoring of primary blast lung injury (PBLI), uncertainties remain regarding the timely detection of early PBLI and the limited data correlating it with commonly used clinical parameters. Our objective is to develop a functional incapacity model for PBLI that better addresses practical needs and to verify the early diagnostic effectiveness of lung ultrasound in identifying PBLI.MethodsWe selected six healthy male pigs to develop an animal model using a bio-shock tube (BST-I). The injuries were induced at a pressure of 4.8 MPa. We monitored the animals before and after the injury using various methods to detect changes in vital signs, lung function, and hemodynamics.ResultsThe experimental peak overpressure was measured at 405.89 ± 4.14KPa, with the duration of the first positive peak pressure being 50.01ms. The mortality rate six hours after injury was 50%. The average Military Combat Injury Scale was higher than 3. Significant increases were observed in heart rate (HR), shock index (SI), alveolar-arterial oxygen gradient (AaDO2), lung ultrasound scores(LUS), and pulmonary vascular permeability index (PVPI) at 0.5 h, 3 h, and 6 h after-injury (p < 0.05). Conversely, there were notable decreases in average arterial pressure(MAP), oxygenation index (OI), stroke volume per heartbeat(SV), cardiac output power index(CPI), global end-diastolic index (GEDI), and intrathoracic blood volume index (ITBI) during the same time periods (p < 0.05). Meanwhile, the extrapulmonary water index (ELWI) showed a significant increase at 0.5 h and 6 h after injury (p < 0.05). At 6 h after injury, pulmonary ultrasound scores were positively correlated with HR (R = 0.731, p < 0.001), AaDO2 (R = 0.612, p = 0.012), SI (R = 0.661, p = 0.004), ELWI (R = 0.811, p < 0.001), PVPI (R = 0.705, p = 0.002). In contrast, these scores were negatively correlated with SpO2 (R = -0.583, p = 0.007),OI (R = -0.772, p < 0.001), ITBI (R = -0.637, p = 0.006).ConclusionWe have successfully developed a novel, and highly reproducible animal model for assessing serious PBLI functional incapacity. This model displays immediate symptoms of hypoxia, decreased cardiac output, decreased blood volume, and abnormal lung ultrasound findings within 0.5 h of injury, with syptoms lasting for up to 6 h. Lung ultrasound evaluation is crucial for the early assessment of injuries, and is comparable to commonly used clinical parameters.

Effects of a New Enzymatic Debrider (SN514-066b) on Eschar Protein Digestion, Burn Wound Debridement, and Healthy Skin Irritation.

Objective: SN514 is a thermolysin-like enzyme under development as a debrider. Preclinical and non-clinical studies supported a first in human healthy volunteer study to predict the need for protection of periwound skin. Approach: Pharmacologic activity testing compared in vitro digestion of collagen, fibrin, and elastin with relevant enzymes. A Yorkshire pig model of burn injury was used to evaluate debridement over 10 days and effects on intact skin. A human 21-day cumulative irritation study using Webril patches taped to the backs of 38 healthy adult volunteers compared four enzyme concentrations (0.10%, 0.20%, 0.40%, and 0.80% w/w) with the hydrogel vehicle, saline (low irritant control), and 0.2% sodium lauryl sulfate (positive irritant control) using randomized placements and blinded evaluation. Results: SN514 showed excellent digestion of fibrin, elastin, and collagen in vitro. Burn wound studies in Yorkshire pigs showed efficient eschar debridement with minimal periwound erythema. Direct treatment on intact porcine skin for 5 days produced no to limited erythema. The preclinical findings of minimal irritation with SN514 were verified by a Phase 1 first-in-human 21-day cumulative skin irritation test. Irritation was observed to increase stepwise by concentration, confirming formulation accuracy. Each enzyme concentration was found to be "possibly mild in use" (Berger and Bowman method). No treatment emergent adverse events were observed during the study. Innovation: A fast-acting enzyme with a favorable irritation profile, prepared as a stable, ready to use hydrogel formulation, overcomes many recognized shortcomings of enzyme debriders. Conclusion: The overall findings support clinical dose range testing for tolerance and preliminary efficacy.

Development and characterization of a reverse genetics system for the lineage II Chicava strain of Machupo virus in a guinea pig model.

Machupo virus (MACV) is a New World mammarenavirus (hereafter referred to as "arenavirus") and the etiologic agent of Bolivian hemorrhagic fever (BHF). No vaccine or antiviral therapy exists for BHF, which causes up to 35% mortality in humans. New World arenaviruses evolve separately in different locations. To date, up to eight lineages of MACV have been identified in Bolivia. While the prototype MACV Carvallo strain belongs to lineage I discovered in the Memore Province in the 1960, the MACV lineage II strains have become the dominantly-circulating lineage in the same province since 1993. We report the development of a reverse genetics system for the MACV lineage II Chicava strain, using a pRF42 plasmid encoding the L and S segment genomic RNA under the transcriptional control of a murine DNA-dependent RNA polymerase I promoter sequence. Rescue of the recombinant MACV Chicava strain (rMACV-Chicava) was accomplished by expression of the L protein and nucleoprotein genes of the MACV Carvallo strain in trans in transfected baby hamster kidney (BHK-21) cells. We characterized the multiplication kinetics of rMACV-Chicava in African green monkey kidney epithelial Vero cells, followed by determining the virulence phenotype in outbred Hartley guinea pigs. We demonstrated that the multiplication kinetics in Vero cells, virulence phenotype in guinea pigs, and neutralizing antibody titers are indistinguishable between rMACV-Chicava and the wild-type parental virus. We conclude that rMACV-Chicava provides a useful model system to investigate the emergence of MACV lineage II strains and the guinea pig model has utility for the development of candidate vaccines and therapeutic antibodies for BHF.

Endovascular procedures for stroke in large animals: advantages and limitations

Abstract Introduction The translation of stroke research to clinical settings has been limited in recent decades. Large animal models offer advantages in translational stroke research, especially for the development of novel endovascular treatments. The species-specific cerebrovascular architecture can significantly influence the suitability of a stroke model. The purpose of this study was to assess the feasibility of the endovascular approach to the cerebral vasculature in large animal models. Methods Four different species were selected, including dogs, rabbits, pigs, and sheep. Angiographies of the common carotid artery were performed to visualize the internal carotid artery (ICA) and, subsequently, to access the cerebral vasculature. Additionally, angiographies of the vertebral arteries were conducted as an alternative approach. Catheterization of the cerebral vasculature was attempted in each species. Results The endovascular approach to the cerebral vasculature was successfully achieved in rabbits and dogs through catheterization of the ICA. In contrast, in pigs and sheep, this endovascular access was hindered by the rete mirabile, a vascular network that connects the ICA to the cerebral vasculature. Alternatively, the vertebral artery approach was attempted but failed to reach the basilar artery due to the tortuosity of the vessels. Conclusion The dog and rabbit models were suitable for cerebral endovascular approaches. However, the use of dogs is limited due to ethical considerations, while rabbits provide a viable alternative for neurointerventional procedures. In contrast, stroke models in pigs or sheep are only feasible with external surgical approaches, as the endovascular route was not achievable.

The Circulatory Arrest Recovery Ammonia Problem (CARAP) Hypothesis: a 1H-MRS study of brain metabolism during neonatal cardiopulmonary bypass surgery.

Congenital heart disease affects 1% of US births, with many babies requiring major cardiothoracic surgery under cardiopulmonary bypass (CPB), exposing the more critical patients to neurodevelopmental impairment. Optimal surgical parameters to minimize neuronal injury are unknown. We used 1H MRS and blood ammonia assays in a neonatal pig model of CPB to compare two approaches, complete circulatory arrest (CA) versus antegrade cerebral perfusion (ACP). Two-week old piglets (N=17) were put on a CPB pump and placed in a 3T MRI to study brain metabolism during CPB. Dynamic single-voxel 1H MRS brain data were acquired while animals underwent one of four CPB protocols: ∼50 min CA at 18ºC and 28ºC or ACP at 18ºC and 28ºC, followed by a ∼1-hr recovery period. Based on 1H MRS findings suggesting the presence of brain ammonia upon reperfusion, a second cohort of piglets (N=22) underwent the same CPB conditions without MRS to allow regular venous blood sampling with ammonia assays. All animals showed a transitory temperature-dependent rise in blood ammonia (p < .001) immediately following restart of whole-body perfusion . In contrast, metabolic processing of brain ammonia, as detected by an increased 1H MRS glutamine/glutamate ratio, was also temperature dependent (p =.002) but only significantly observed in the CA studies (p =.009). Serial 1H-MRS and blood ammonia assays in this preclinical CPB model identified a previously unreported build-up of ammonia, hypothesized to arise from gut bacterial production, following reperfusion, that may contribute to brain injury in these pediatric surgeries.

Perinatal dysfunction of innate immunity in cystic fibrosis.

In patients with cystic fibrosis (CF), repeated cycles of infection and inflammation eventually lead to fatal lung damage. Although diminished mucus clearance can be restored by highly effective CFTR modulator therapy, inflammation and infection often persist. To elucidate the role of the innate immune system in CF etiology, we investigated a CF pig model and compared these results with those for preschool children with CF. In newborn CF pigs, we observed changes in lung immune cell composition before the onset of infection that were dominated by increased monocyte infiltration, whereas neutrophil numbers remained constant. Flow cytometric and transcriptomic profiling revealed that the infiltrating myeloid cells displayed a more immature status. Cells with comparably immature transcriptomic profiles were enriched in the blood of CF pigs at birth as well as in preschool children with CF. This pattern coincided with decreased CD16 expression in the myeloid cells of both pigs and humans, which translated into lower phagocytic activity and reduced production of reactive oxygen species in both species. These results were indicative of a congenital, translationally conserved, and functionally relevant aberration of the immune system in CF. In newborn wild-type pigs, CFTR transcription in immune cells, including lung-derived and circulating monocytes, isolated from the bone marrow, thymus, spleen, and blood was below the detection limits of highly sensitive assays, suggesting an indirect etiology of the observed effects. Our findings highlight the need for additional immunological treatments to target innate immune deficits in patients with CF.

Artificial biomarker-based feedback-regulated personalized and precise thrombolysis with lower hemorrhagic risk.

The body weight-based thrombolytic medication strategy in clinical trials shows critical defects in recanalization rate and post-thrombolysis hemorrhage. Methods for perceiving thrombi heterogeneity of thrombolysis resistance is urgently needed for precise thrombolysis. Here, we revealed the relationship between the thrombin heterogeneity and the thrombolysis resistance in thrombi and created an artificial biomarker-based nano-patrol system with robotic functional logic to perceive and report the thrombolysis resistance of thrombi. The nano-patrols are contrallable and are able to accomplish thrombolysis resistance-matched personalized and precise therapy according to the feedback signal from artificial biomarkers. This nano-patrol system depicted more enhanced thrombolytic efficiency (elevated by 25%) than alteplase for mini pig model and clinical thrombi and achieved recanalization in thrombotic model where alteplase encountered failure. Moreover, the nano-patrol remarkably reduced the infarct volume and the hemorrhagic transformation risk (0.12-fold of alteplase) of cerebral thrombosis. Therefore, we developed a unique tool for diagnosing thrombolysis resistance and achieving personalized and precise thrombolysis.

RNA-Targeting CRISPR/CasRx system relieves disease symptoms in Huntington’s disease models

BackgroundHD is a devastating neurodegenerative disorder caused by the expansion of CAG repeats in the HTT. Silencing the expression of mutated proteins is a therapeutic direction to rescue HD patients, and recent advances in gene editing technology such as CRISPR/CasRx have opened up new avenues for therapeutic intervention.MethodsThe CRISPR/CasRx system was employed to target human HTT exon 1, resulting in an efficient knockdown of HTT mRNA. This therapeutic effect was substantiated in various models: HEK 293 T cell, the HD 140Q-KI mouse, and the HD-KI pig model. The efficiency of the knockdown was analyzed through Western blot and RT-qPCR. Additionally, neuropathological changes were examined using Western blot, immunostaining, and RNA sequencing. The impact on motor abilities was assessed via behavioral experiments, providing a comprehensive evaluation of the treatment's effectiveness.ResultsCRISPR/CasRx system can significantly reduce HTT mRNA levels across various models, including HEK 293 T cells, HD 140Q-KI mice at various disease stages, and HD-KI pigs, and resulted in decreased expression of mHTT. Utilizing the CRISPR/CasRx system to knock down HTT RNA has shown to ameliorate gliosis in HD 140Q-KI mice and delay neurodegeneration in HD pigs.ConclusionsThese findings highlight the effectiveness of the RNA-targeting CRISPR/CasRx as a potential therapeutic strategy for HD. Furthermore, the success of this approach provides valuable insights and novel avenues for the treatment of other genetic disorders caused by gene mutations.

Pharmacokinetics, toxicities, and tissue concentrations of belotecan sprayed by rotational intraperitoneal pressurized aerosol chemotherapy in a pig model.

We evaluated the pharmacokinetics, tissue concentrations, and toxicities of belotecan during rotational intraperitoneal pressurized aerosol chemotherapy (RIPAC) in pigs. We sprayed belotecan in 10% and 30% of doses for intravenous chemotherapy in six pigs (cohort 1, n=3, 0.50 mg/m²; cohort 2, n=3, 1.5 mg/m²). We evaluated the time-dependent plasma concentrations of belotecan before RIPAC to 120 hours for the pharmacokinetics, tissue concentrations in twelve peritoneal regions, and hepatic and renal functions before RIPAC to 120 hours in the 2 cohorts. Mean values of the peak plasma concentration (Cmax), the time to Cmax, the time taken for Cmax to drop in half, and the area under the curve from time zero to the time of last quantifiable concentration were 905 and 3,700 ng/mL, 1.42 and 1.50 hours, 3.64 and 5.60 hours, and 2,260 and 17,900 pg·hr/mL in cohorts 1 and 2, respectively. Mean values of tissue concentrations were 1.5 to 15.3 times higher in cohort 1 than in cohort 2 despite the similar ratio of tissue to plasma concentration, and tissue concentrations in the two cohorts were higher in the parietal peritoneum than in the visceral peritoneum. However, hepatic and renal functions were not different before RIPAC to 120 hours in the two cohorts. RIPAC using belotecan of 0.5 mg/m² and 1.5 mg/m² may be feasible with fewer hepatic and renal toxicities in pigs. Thus, belotecan of 1.5 mg/m² may be considered as the starting dose for RIPAC in a phase 1 trial.

Millisecond-level transient heating and temperature monitoring technique for ultrasound-induced thermal strain imaging.

Background: Ultrasound-induced thermal strain imaging (US-TSI) is a promising ultrasound imaging modality that has been demonstrated in preclinical studies to identify a lipid-rich necrotic core of an atherosclerotic plaque. However, human physiological motion, e.g., cardiac pulsation, poses challenges in implementing US-TSI applications, where achieving a millisecond-level temperature rise by delivering acoustic energy from a compact US-TSI probe is a key requirement. This study aims to develop a transient ultrasound heating and thermocouple monitoring technique at the millisecond level for US-TSI applications. Methods: We designed, prototyped, and characterized a novel US-TSI probe that includes a high-power, 3.5 MHz heating transducer with symmetrical dual 1D concave array. Additionally, millisecond-level temperature monitoring was demonstrated with fast-response thermocouples in laser- and ultrasound- induced thermal tests. Subsequently, we demonstrated the prototyped US-TSI probe can produce a desired temperature rise in a millisecond-short time window in vitro phantom and in vivo animal tests. Results: The prototyped US-TSI probe delivered zero-to-peak acoustic pressure up to 6.2 MPa with a 90 VPP input voltage. Both laser- and ultrasound- induced thermal tests verified that the selected thermocouples can monitor temperature change within 50 ms. The fast-response thermocouple confirmed the transient heating ability of the US-TSI probe, achieving a 3.9 °C temperature rise after a 25 ms heating duration (50% duty cycle) in the gel phantom and a 2.0 °C temperature rise after a 50 ms heating duration (50% duty cycle) in a pig model. Conclusions: We successfully demonstrated a millisecond-level transient heating and temperature monitoring technique utilizing the novel US-TSI probe and fast-response thermocouples. The reported transient ultrasound heating and thermocouple monitoring technique is promising for future in vivo human subject studies in US-TSI or other ultrasound-related thermal investigations.

Novel iNAV-based 3D whole heart late gadolinium enhancement low-field (0.55T) CMR – an investigation in a pig model

Novel iNAV-based 3D whole heart late gadolinium enhancement low-field (0.55T) CMR – an investigation in a pig model

Circulating factors, in both donor and ex-vivo heart perfusion, correlate with heart recovery in a pig model of DCD

BackgroundHeart transplantation with donation after circulatory death and ex-situ heart perfusion offers excellent outcomes and increased transplantation rates. However, improved graft evaluation techniques are required to ensure effective utilization of grafts. Therefore, we investigated circulating factors, both in-situ and ex-situ, as potential biomarkers for cardiac graft quality. MethodsCirculatory death was simulated in anesthetized male pigs with warm ischemic durations of 0, 10, 20, or 30 min. Hearts were explanted and underwent ex-situ perfusion for 3h in an unloaded mode, followed by left ventricular loading for 1h, to evaluate cardiac recovery (outcomes). Multiple donor blood and ex-situ perfusate samples were used for biomarker evaluation with either standard biochemical techniques or nuclear magnetic resonance spectroscopy. ResultsCirculating adrenaline, both in the donor and at 10 min ex-situ heart perfusion, negatively correlated with cardiac recovery (p <0.05 for all). We identified several new potential biomarkers for cardiac graft quality that can be measured rapidly and simultaneously with nuclear magnetic resonance spectroscopy. At multiple timepoints during unloaded ex-situ heart perfusion, perfusate levels of acetone, betaine, creatine, creatinine, fumarate, hypoxanthine, lactate, pyruvate and succinate (p <0.05 for all) significantly correlated with outcomes; the optimal timepoint being 60 min. ConclusionsIn heart donation after circulatory death, circulating adrenaline levels are valuable for cardiac graft evaluation. Nuclear magnetic resonance spectroscopy is of particular interest, as it measures multiple metabolites in a short timeframe. Improved biomarkers may allow more precision and therefore better support clinical decisions about transplantation suitability.

Ferulic acid mediates microbial fermentation of arabinoxylan to enhance host immunity by suppressing TLR4/NF-κB signaling.

The study was conducted to explore the relationship between arabinoxylan (AX) structure and microbial fermentation characteristics, and reveal molecular mechanism of AX on regulating immune function of the host. Results indicated that the group of wheat bran AX showed greater activity of feruloyl esterase, production of short chain fatty acids and ferulic acid compared with the blank group (P < 0.05). The AX increased sIgA concentration and protein expression of protein expression of TLR4 and NF-κB (p65), but decreased mRNA expression of pro-inflammatory cytokines in the ileum of weaned pig model, leading to the reduced diarrhea (P < 0.05). The AX increased an abundance of Bifidobacterium pseudocatenulatum, production of butyric acid and ferulic acid in the ileal digesta of pigs (P < 0.05). In a LPS-treated mouse model, butyric acid and ferulic acid combination increased IL-10 concentration and abundance of Bifidobacterium pseudocatenulatum, but reduced mRNA expression of IL-6 and gene expression of TLR4 and NF-κB (p65) in the jejunum. In summary, AX is fermented by gut microbiota to produce ferulic acid, as well as butyric acid, which improved host immunity by promoting relative abundance of Bifidobacterium pseudocatenulatum and suppressing activation of TLR4/NF-κB signaling.