Translational Animal Models Research Articles

The Pig as a Translational Animal Model for Biobehavioral and Neurotrauma Research.

In recent decades, the pig has attracted considerable attention as an important intermediary model animal in translational biobehavioral research due to major similarities between pig and human neuroanatomy, physiology, and behavior. As a result, there is growing interest in using pigs to model many human neurological conditions and injuries. Pigs are highly intelligent and are capable of performing a wide range of behaviors, which can provide valuable insight into the effects of various neurological disease states. One area in which the pig has emerged as a particularly relevant model species is in the realm of neurotrauma research. Indeed, the number of investigators developing injury models and assessing treatment options in pigs is ever-expanding. In this review, we examine the use of pigs for cognitive and behavioral research as well as some commonly used physiological assessment methods. We also discuss the current usage of pigs as a model for the study of traumatic brain injury. We conclude that the pig is a valuable animal species for studying cognition and the physiological effect of disease, and it has the potential to contribute to the development of new treatments and therapies for human neurological and psychiatric disorders.

Preclinical study of diabetic foot ulcers: From pathogenesis to vivo/vitro models and clinical therapeutic transformation.

Diabetic foot ulcer (DFU), a common intractable chronic complication of diabetes mellitus (DM), has a prevalence of up to 25%, with more than 17% of the affected patients at risk of amputation or even death. Vascular risk factors, including vascular stenosis or occlusion, dyslipidemia, impaired neurosensory and motor function, and skin infection caused by trauma, all increase the risk of DFU in patients with diabetes. Therefore, diabetic foot is not a single pathogenesis. Preclinical studies have contributed greatly to the pathogenesis determination and efficacy evaluation of DFU. Many therapeutic tools are currently being investigated using DFU animal models for effective clinical translation. However, preclinical animal models that completely mimic the pathogenesis of DFU remain unexplored. Therefore, in this review, the preparation methods and evaluation criteria of DFU animal models with three major pathological mechanisms: neuropathy, angiopathy and DFU infection were discussed in detail. And the advantages and disadvantages of various DFU animal models for clinical sign simulation. Furthermore, the current status of vitro models of DFU and some preclinical studies have been transformed into clinical treatment programs, such as medical dressings, growth factor therapy, 3D bioprinting and pre-vascularization, Traditional Chinese Medicine treatment. However, because of the complexity of the pathological mechanism of DFU, the clinical transformation of DFU model still faces many challenges. We need to further optimize the existing preclinical studies of DFU to provide an effective animal platform for the future study of pathophysiology and clinical treatment of DFU.

New Pieces for an Old Puzzle: Approaching Parkinson's Disease from Translatable Animal Models, Gut Microbiota Modulation, and Lipidomics.

Parkinson's disease (PD) is a severe neurodegenerative disease characterized by disabling motor alterations that are diagnosed at a relatively late stage in its development, and non-motor symptoms, including those affecting the gastrointestinal tract (mainly constipation), which start much earlier than the motor symptoms. Remarkably, current treatments only reduce motor symptoms, not without important drawbacks (relatively low efficiency and impactful side effects). Thus, new approaches are needed to halt PD progression and, possibly, to prevent its development, including new therapeutic strategies that target PD etiopathogeny and new biomarkers. Our aim was to review some of these new approaches. Although PD is complex and heterogeneous, compelling evidence suggests it might have a gastrointestinal origin, at least in a significant number of patients, and findings in recently developed animal models strongly support this hypothesis. Furthermore, the modulation of the gut microbiome, mainly through probiotics, is being tested to improve motor and non-motor symptoms and even to prevent PD. Finally, lipidomics has emerged as a useful tool to identify lipid biomarkers that may help analyze PD progression and treatment efficacy in a personalized manner, although, as of today, it has only scarcely been applied to monitor gut motility, dysbiosis, and probiotic effects in PD. Altogether, these new pieces should be helpful in solving the old puzzle of PD.

Translational large animal model of coronary microvascular embolism: characterization by serial cardiac magnetic resonance and histopathology.

This study aimed to construct a large animal model of coronary microvascular embolism, and investigate whether it could mimic the clinical imaging phenotypes of myocardial hypoperfusion in patients with ST-segment elevation myocardial infarction (STEMI). Nine minipigs underwent percutaneous coronary embolization with microspheres, followed by cardiac magnetic resonance (CMR) on week 1, 2 and 4 post operation. Microvascular obstruction (MVO) was defined as the isolated hypointense core within the enhanced area on late gadolinium enhancement images, which evolved during a 4-week follow-up. Fibrotic fraction of the segments was measured by Masson trichrome staining using a panoramic analysis software. Iron deposit and macrophage infiltration were quantified based on Perl's blue and anti-CD163 staining, respectively. Seven out of 9 (77.8%) minipigs survived and completed all of the imaging follow-ups. Four out of 7 (57.1%) minipigs were identified as transmural infarct with MVO. The systolic wall thickening (SWT) of MVO zone was similar to that of infarct zone (P = 0.762). Histopathology revealed transmural deposition of collagen, with microvessels obstructed by microspheres. The fibrotic fraction of infarct with MVO segments was similar to that of infarct without MVO segments (P = 0.954). The fraction of iron deposit in infarct with MVO segments was higher than that of infarct without MVO segments (P < 0.05), but the fraction of macrophage infiltration between these two segments did not show statistical difference (P = 0.723). Large animal model of coronary microvascular embolism could mimic most clinical imaging phenotypes of myocardial hypoperfusion in patients with STEMI, demonstrated by serial CMR and histopathology.

Luvadaxistat: A Novel Potent and Selective d-Amino Acid Oxidase Inhibitor Improves Cognitive and Social Deficits in Rodent Models for Schizophrenia

N-methyl-d-aspartate (NMDA) receptor hypofunctionality is a well-studied hypothesis for schizophrenia pathophysiology, and daily dosing of the NMDA receptor co-agonist, d-serine, in clinical trials has shown positive effects in patients. Therefore, inhibition of d-amino acid oxidase (DAAO) has the potential to be a new therapeutic approach for the treatment of schizophrenia. TAK-831 (luvadaxistat), a novel, highly potent inhibitor of DAAO, significantly increases d-serine levels in the rodent brain, plasma, and cerebrospinal fluid. This study shows luvadaxistat to be efficacious in animal tests of cognition and in a translational animal model for cognitive impairment in schizophrenia. This is demonstrated when luvadaxistat is dosed alone and in conjunction with a typical antipsychotic. When dosed chronically, there is a suggestion of change in synaptic plasticity as seen by a leftward shift in the maximum efficacious dose in several studies. This is suggestive of enhanced activation of NMDA receptors in the brain and confirmed by modulation of long-term potentiation after chronic dosing. DAAO is highly expressed in the cerebellum, an area of increasing interest for schizophrenia, and luvadaxistat was shown to be efficacious in a cerebellar-dependent associative learning task. While luvadaxistat ameliorated the deficit seen in sociability in two different negative symptom tests of social interaction, it failed to show an effect in endpoints of negative symptoms in clinical trials. These results suggest that luvadaxistat potentially could be used to improve cognitive impairment in patients with schizophrenia, which is not well addressed with current antipsychotic medications.

The effect of cardioplegic supplementation with sildenafil on cardiac energetics in a piglet model of cardiopulmonary bypass and cardioplegic arrest with warm or cold cardioplegia.

Cardioplegic cardioprotection strategies used during paediatric open-heart surgery remain suboptimal. Sildenafil, a phosphodiesterase 5 (PDE-5) inhibitor, has been shown to be cardioprotective against ischemia/reperfusion injury in a variety of experimental models and this study therefore tested the efficacy of supplementation of cardioplegia with sildenafil in a piglet model of cardiopulmonary bypass and arrest, using both cold and warm cardioplegia protocols. Piglets were anaesthetized and placed on coronary pulmonary bypass (CPB), the aorta cross-clamped and the hearts arrested for 60 min with cardioplegia with or without sildenafil (10 nM). Twenty minutes after removal of cross clamp (reperfusion), attempts were made to wean the pigs from CPB. Termination was carried out after 60 min reperfusion. Throughout the protocol blood and left ventricular tissue samples were taken for analysis of selected metabolites (using HPLC) and troponin I. In both the cold and warm cardioplegia protocols there was evidence that sildenafil supplementation resulted in faster recovery of ATP levels, improved energy charge (a measure of metabolic flux) and altered release of hypoxanthine and inosine, two purine catabolites. There was no effect on troponin release within the studied short timeframe. In conclusion, sildenafil supplementation of cardioplegia resulted in improved cardiac energetics in a translational animal model of paediatric CPB surgery.

O12 | The pig as a translational animal model to explore a new concept in the treatment of sepsis, today's largest unmet medical need

Journal of Veterinary Pharmacology and TherapeuticsVolume 46, Issue S1 p. 33-34 ORAL PRESENTATIONS O12 | The pig as a translational animal model to explore a new concept in the treatment of sepsis, today's largest unmet medical need First published: 11 June 2023 https://doi.org/10.1111/jvp.13178Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. Volume46, IssueS1Special Issue: 15th International Congress of the European Association for Veterinary Pharmacology and Toxicology held Bruges, Belgium, July 2–5, 2023June 2023Pages 33-34 RelatedInformation

Whole exome and transcriptome analysis revealed the activation of ERK and Akt signaling pathway in canine histiocytic sarcoma

Histiocytic sarcoma (HS) is an incurable aggressive tumor, and no consensus has been made on the treatment due to its rare occurrence. Since dogs spontaneously develop the disease and several cell lines are available, they have been advocated as translational animal models. In the present study, therefore, we explored gene mutations and aberrant molecular pathways in canine HS by next generation sequencing to identify molecular targets for treatment. Whole exome sequencing and RNA-sequencing revealed gene mutations related to receptor tyrosine kinase pathways and activation of ERK1/2, PI3K-AKT, and STAT3 pathways. Analysis by quantitative PCR and immunohistochemistry revealed that fibroblast growth factor receptor 1 (FGFR1) is over-expressed. Moreover, activation of ERK and Akt signaling were confirmed in all HS cell lines, and FGFR1 inhibitors showed dose-dependent growth inhibitory effects in two of the twelve canine HS cell lines. The findings obtained in the present study indicated that ERK and Akt signaling were activated in canine HS and drugs targeting FGFR1 might be effective in part of the cases. The present study provides translational evidence that leads to establishment of novel therapeutic strategies targeting ERK and Akt signaling in HS patients.

Evaluation of a photodynamic therapy agent using a canine prostate cancer model.

Male dogs can develop spontaneous prostate cancer, which is similar physiologically to human disease. Recently, Tweedle and coworkers have developed an orthotopic canine prostate model allowing implanted tumors and therapeutic agents to be tested in a more translational large animal model. We used the canine model to evaluate prostate-specific membrane antigen (PSMA)-targeted gold nanoparticles as a theranostic approach for fluorescence (FL) imaging and photodynamic therapy (PDT) of early stage prostate cancer. Dogs (four in total) were immunosuppressed with a cyclosporine-based immunosuppressant regimen and their prostate glands were injected with Ace-1-hPSMA cells using transabdominal ultrasound (US) guidance. Intraprostatic tumors grew in 4-5 weeks and were monitored by ultrasound (US). When tumors reached an appropriate size, dogs were injected intravenously (iv) with PSMA-targeted nano agents (AuNPs-Pc158) and underwent surgery 24 h later to expose the prostate tumors for FL imaging and PDT. Ex vivo FL imaging and histopathological studies were performed to confirm PDT efficacy. All dogs had tumor growth in the prostate gland as revealed by US. Twenty-four hours after injection of PSMA-targeted nano agents (AuNPs-Pc158), the tumors were imaged using a Curadel FL imaging device. While normal prostate tissue had minimal fluorescent signal, the prostate tumors had significantly increased FL. PDT wasactivated by irradiating specific fluorescent tumor areas with laser light (672 nm). PDT bleached the FL signal, while fluorescent signals from the other unexposed tumor tissues were unaffected. Histological analysis of tumors and adjacent prostate revealed that PDT damaged the irradiated areas to a depth of 1-2 mms with the presence of necrosis, hemorrhage, secondary inflammation, and occasional focal thrombosis. The nonirradiated areas showed no visible damages by PDT. We have successfully established a PSMA-expressing canine orthotopic prostate tumor model and used the model to evaluate the PSMA-targeted nano agents (AuNPs-Pc158) in the application of FL imaging and PDT. It was demonstrated that the nano agents allowed visualization of the cancer cells and enabled their destruction when they were irradiated with a specific wavelength of light.

Inhibition of prejunctional parasympathetic pathways by β3-adrenoceptor agonists in the isolated pig detrusor: comparison with human detrusor studies.

Adrenergic receptors of the β3-subtype (β3-ADRs) seem to represent a new target for a more effective pharmacological treatment of overactive bladder (OAB), a wide spread urinary disorder. A promising opportunity for OAB therapy might rely on the development of selective β3-ADR agonists, but an appropriate preclinical screening, as well as investigation of their pharmacological mechanism(s), is limited by poor availability of human bladder samples and of translational animal models. In this study, we used the porcine urinary bladder as experimental tool to ascertain the functions of β3-ADRs in the control the parasympathetic motor drive. Tritiated acetylcholine ([3H]-ACh), mainly originated from neural stores, was released by electrical field stimulation (EFS) in epithelium-deprived detrusor strips from pigs bred without estrogens. EFS produced simultaneously [3H]-ACh release and smooth muscle contraction allowing to asses neural (pre-junctional) and myogenic (postjunctional) effects in the same experiment. Isoprenaline and mirabegron produced on the EFS-evoked effects a concentration-dependent inhibition antagonized by L-748,337, a high selective β3-ADR antagonist. The analysis of the resultant pharmacodynamic parameters supports the notion that in pig detrusors, as well as in previously described human detrusors, the activation of inhibitory β3-ADRs can modulate neural parasympathetic pathways. In such inhibitory control, the involvement of membrane K+ channels, mainly of the SK type, seems to play a pivotal role similarly to what previously described in humans. Therefore, the isolated porcine detrusor can provide a suitable experimental tool to study the mechanisms underlying the clinical efficacy of selective β3-ADR compounds for human use.

The first endovascular rat glioma model for pre-clinical evaluation of intra-arterial therapeutics.

Several translational animal models have been described assessing intra-arterial (IA) treatments for malignant gliomas. We describe the first endovascular animal model that allows testing of IA drug delivery as a first-line treatment, which is difficult to do in actual patients. We report a unique protocol for vascular access and IA delivery in the rat model that, unlike prior reports, does not require direct puncture and opening of proximal cerebrovasculature which carries risk of ischemia in the animal brain post-delivery. Wistar rats underwent left femoral artery catherization with a Balt Magic 1.2F catheter or Marathon Flow directed 1.5F Microcatheter with an Asahi Chikai 0.008 micro-guidewire which was navigated to the left internal carotid artery under x-ray. 25% mannitol was administered to test blood brain barrier breakdown (BBBB). Additional rats were implanted with C6 glioma cells in the left frontal lobe. C6 Glioma-Implanted Rats (C6GRs) were monitored for overall survival and tumor growth. Tumor volumes from MRI images were calculated utilizing 3D slicer. Additional rats underwent femoral artery catheterization with Bevacizumab, carboplatin, or irinotecan injected into the left internal carotid artery to test feasibility and safety. A successful endovascular access and BBBB protocol was established. BBBB was confirmed with positive Evans blue staining. 10 rats were successfully implanted with C6 gliomas with confirmed growths on MRI. Overall survival was 19.75 ± 2.21 days. 5 rats were utilized for the development of our femoral catheterization protocol and BBBB testing. With regards to IA chemotherapy dosage testing, control rats tolerated targeted 10 mg/kg of bevascizumab, 2.4 mg/kg of carboplatin, and 15 mg/kg of irinotecan IA ICA injections without any complications. We present the first endovascular IA rat glioma model that allows selective catheterization of the intracranial vasculature and assessment of IA therapies for gliomas without need for access and sacrifice of proximal cerebrovasculature.

Neutrophilia and neutrophil-derived extracellular traps as innate immune markers of SARS-CoV-2 infection in a feline animal model

Abstract Excessive neutrophil recruitment and dysregulation contribute to worsened clinical outcomes in hospitalized COVID-19 patients. Targeting this dysregulated response offers therapeutic potential in the treatment of SARS-CoV-2 infections which can be enhanced by the availability of reliable, translational animal models for disease. Domestic cats are naturally infected and exhibit clinical disease similar to that seen in COVID-19. Utilizing our previously developed feline model for COVID-19, we hypothesize that neutrophil dysregulation and the release of neutrophil extracellular traps (NETs) significantly worsen pulmonary damage in domestic cats. Specific-pathogen-free cats (n=12) were inoculated with SARS CoV-2 (B.1.617.2) or vehicle (n=6). Plasma, bronchoalveolar lavage, and tissues were collected over 12 days. Detection of NETs using MPO-DNA ELISA and Quant-iT PicoGreen® dsDNA assay indicate significant elevations at 4dpi and 8dpi in the plasma as compared to vehicle, with the peak NETs detection at 4dpi(p&amp;lt;0.05). These findings were similarly evident in the BAL fluid of infected versus vehicle-inoculated cats(p&amp;lt;0.05). Immunohistochemistry of respiratory tissues utilizing three major markers of activated neutrophils and NETS; citrullinated histone 3, MPO, and neutrophil elastase, show marked amplifications compared to vehicle. These findings co-localize to areas of significant pulmonary damage. Elucidating these innate markers and their functional changes provides insight into understanding the immunopathogenesis and potential therapeutic interventions in SARS-CoV-2 infection. These data enforce the role of domestic cats as a flexible translational model to develop these interventions. NIH-NIGMS (P20GM103648)

Identification of Gene Expression Signatures for Phenotype-Specific Drug Targeting of Cardiac Fibrosis.

We have designed translational animal models to investigate cardiac profibrotic gene signatures. Domestic pigs were treated with cardiotoxic drugs (doxorubicin, DOX, n = 5 or Myocet®, MYO, n = 5) to induce replacement fibrosis via cardiotoxicity. Reactive interstitial fibrosis was triggered by LV pressure overload by artificial isthmus stenosis with stepwise developing myocardial hypertrophy and final fibrosis (Hyper, n = 3) or by LV volume overload in the adverse remodeled LV after myocardial infarction (RemoLV, n = 3). Sham interventions served as controls and healthy animals (Control, n = 3) served as a reference in sequencing study. Myocardial samples from the LV of each group were subjected to RNA sequencing. RNA-seq analysis revealed a clear distinction between the transcriptomes of myocardial fibrosis (MF) models. Cardiotoxic drugs activated the TNF-alpha and adrenergic signaling pathways. Pressure or volume overload led to the activation of FoxO pathway. Significant upregulation of pathway components enabled the identification of potential drug candidates used for the treatment of heart failure, such as ACE inhibitors, ARB, ß-blockers, statins and diuretics specific to the distinct MF models. We identified candidate drugs in the groups of channel blockers, thiostrepton that targets the FOXM1-regulated ACE conversion to ACE2, tyrosine kinases or peroxisome proliferator-activated receptor inhibitors. Our study identified different gene targets involved in the development of distinct preclinical MF protocols enabling tailoring expression signature-based approach for the treatment of MF.

Abstract 4680: Intracranial breast cancer brain metastases (BCBM) models - stereotactic vs. intracarotid inoculation

Abstract Breast cancer is the most prevalent cancer in women worldwide. 30% of breast cancer patients develops metastases at distant organs, with 10-20% of these patients developing brain metastases. The median survival time for patients with brain metastases is only 7.2 months and there is an urgent need for effective therapies. Development of novel therapies relies on good translational animal models. Subcutaneous tumors are technically easy and highly reproducible but lacks the natural tumor environment and the impact of the blood brain barrier. Breast cancer brain metastasis (BCBM) models are most often established by stereotactic intracranial inoculation. However, this leads to formation of single tumors and does not take the extravasation and seeding part of the metastatic cascade into account and resembles primary tumors to a larger extend. Intracarotid inoculation incorporates extravasation and seeding of micro metastases making it a better suited translational animal model for BCBM. A panel of intracranial BCBM was established through stereotactic and intracarotid inoculation of breast cancer cell lines with high survival and take rates (&amp;gt;85%). The panel included the ST941 PDX model, an estrogen receptor positive model harbouring the ESR1-Y537S mutation and exhibiting resistance to fulvestrant. The panel also included the triple negative breast cancer cell line MDA-MB-231 as well as HER2+ models. Tumor establishment and progression were evaluated using bioluminescence and magnetic resonance imaging (MRI). Whole brain and tumors were isolated, and paraffin embedded for histological evaluation of tumor establishment, invasiveness, and infiltration. Intracranial tumor establishment was evident early after inoculation using bioluminescence imaging and tumor growth was later confirmed by MRI. Tumor growth rate were dependent on inoculation method with rapid tumor growth observed with stereotactic inoculation. While stereotactic inoculation led to single tumor establishment with defined tumor borders, intracarotid inoculation led to micro seeding with multiple foci established throughout the brain. At early timepoints, the metastases consisted of &amp;lt;150 cells per metastases, but at later timepoints larger metastases were formed. Tumor infiltration was more diffused in brains with multiple metastases and the blood brain barrier integrity was different when comparing the models and inoculation methods. A panel of BCBM was successfully established using both stereotactic and intracarotid inoculation. While bioluminescence allowed the earliest tumor imaging, MRI provided additional information on tumor establishment such as location, numbers, and blood brain barrier permeability. The models showed varying tumor establishment, infiltration, and marker expression. The established panel can be used as a platform for testing novel anti-cancer therapies targeting BCBM. Citation Format: Sigrid Cold, Moritz Braig, Trine Bjoernbo Engel, Maria Zeiler Alfsen, Maria Nikoline Kristiansen, Lotte Kellemann Kristensen, Andreas Kjaer, Carsten Haagen Nielsen. Intracranial breast cancer brain metastases (BCBM) models - stereotactic vs. intracarotid inoculation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4680.

An Insula-Enriched Regulator of Retinoic Acid Marks a New Intersection in the Neural Circuitry of Mouse Social Behavior

An Insula-Enriched Regulator of Retinoic Acid Marks a New Intersection in the Neural Circuitry of Mouse Social Behavior

HISTOPATHOLOGICAL CHARACTERIZATION OF A CHRONIC DSS-INDUCED MOUSE MODEL OF IBD WITH INTESTINAL FIBROSIS

Inflammatory bowel disease (IBD) comprises a group of intestinal disorders, including ulcerative colitis and Crohn’s disease. Intestinal fibrosis, as result of chronic inflammation, is a common complication in IBD. High treatment failure rates associated with existing interventions indicate a high unmet need for more effective drugs to improve the management and outcomes of IBD. Consequently, translational animal models of IBD demonstrating chronic, progressive colonic fibrosis are important tools in preclinical drug discovery for IBD. The aim of the present study was to characterize intestinal histopathology in a chronic DSS-induced mouse model of IBD.

Utilizing Contrast-Enhanced Ultrasonography with Phosphatidylserine Microbubbles to Detect Placental Inflammation in Rhesus Macaques.

The ability to comprehensively monitor physiological and detect pathophysiologic processes early during pregnancy can reduce maternal and fetal morbidity and mortality. Contrast-enhanced ultrasound (CEUS) is a non-invasive imaging technology that utilizes the acoustic detection of microbubbles to examine vascular spaces. Furthermore, microbubbles conjugated to specific compounds can focus studies on precise physiological pathways. We hypothesized that CEUS with phosphatidylserine microbubbles (MB-PS) could be employed to monitor placental inflammation. We tested this hypothesis in rhesus macaques (Macaca mulatta), a translational and relevant animal model of human placental health. As placental inflammation impacts many at-risk pregnancies, we performed CEUS with MB-PS in pregnant macaques fed a high-fat diet (e.g., a western-style diet, WSD) in the presence or absence of testosterone (T) to mimic the increased risk of polycystic ovary syndrome and subfertility. We have previously demonstrated a placental inflammation phenotype in this model, and, thus, we related the MB-PS CEUS signal intensity to placental inflammation markers: selectin p and angiopoietins. Testosterone exposure increased the MB-PS signal in the placental microcirculation on the maternal side compared to control animals. We found that T increased placental weight and decreased angiopoietin 2 (ANGPT2) immunoreactivity. Furthermore, a significant inverse correlation was found between MB-PS signal and ANGPT2. This indicated that CEUS with MB-PS can be used to monitor placental parameters. We propose that CEUS with MB-PS could aid in the identification of pregnancies at risk of placental vascular compromise.

Feline myocardial transcriptome in health and in hypertrophic cardiomyopathy-A translational animal model for human disease.

Hypertrophic cardiomyopathy (HCM) is the most common heart disease in cats, characterized by primary left ventricular hypertrophy. Feline HCM closely resembles human HCM and is suggested as translational animal model for the human disease. A genetic cause is established in humans and suspected for cats, but little is known about the gene expression and pathways involved in the pathogenesis of HCM. To investigate the myocardial transcriptome changes in HCM, RNA sequencing was conducted on left ventricle (LV) and left atrium (LA) samples of healthy cats and cats with HCM (each n = 5; 20 samples). Ingenuity Pathway Analysis was used to determine functional pathways, regulators, and networks. Distinct gene expression profiles were identified in the LV and LA of the feline healthy and HCM myocardium. Analysis of differentially expressed mRNAs (>2 fold; FDR < 0.01) found chamber-specific (LV vs. LA) expression in both healthy and HCM groups, with higher transcriptional activity in the LA. Genes that contribute to the distinct structure and function of each chamber in health and HCM were identified in the regional comparison. The gene expression profiles of HCM compared to healthy hearts revealed disease related genes, including THBS4 and KLHL33 (LV), FAM177B and THRSP (LA), the latter 3 have not been reported for the myocardium so far, as the top differently expressed genes in the HCM heart. Differently expressed genes and functional pathways found in the HCM heart are associated with cardiac remodeling and fibrosis, inflammation, microvascular changes, calcium signaling and cardiac metabolism, with some regional differences. RhoGDI-RhoGTPase signaling, integrin and ILK signaling pathways, the LXR/RXR pathway in the LA, and the PPARα/RXRα, HIF1α and CXCR4 pathways in the LV might be of particular importance in the HCM disease process. This study identified region-specific myocardial gene transcription patterns as well as novel genes and pathways associated with HCM.

The impact of maternal obesity on in vivo uterine contractile activity during parturition in the rat.

Maternal obesity is associated with increased risk of prolonged and dysfunctional labor and emergency caesarean section. To elucidate the mechanisms behind the associated uterine dystocia, a translational animal model is required. Our previous work identified that exposure to a high-fat, high-cholesterol (HFHC) diet to induce obesity down-regulates uterine contractile associated protein expression and causes asynchronous contractions ex vivo. This study aims to investigate the impact of maternal obesity on uterine contractile function in vivo using intrauterine telemetry surgery. Virgin female Wistar rats were fed either a control (CON, n=6) or HFHC (n=6) diet for 6 weeks prior to conception, and throughout pregnancy. On Day 9 of gestation, a pressure-sensitive catheter was surgically implanted aseptically within the gravid uterus. Following 5 days recovery, intrauterine pressure (IUP) was recorded continuously until delivery of the 5th pup (Day 22). HFHC induced obesity led to a significant 1.5-fold increase in IUP (p=0.026) and fivefold increase in frequency of contractions (p=0.013) relative to CON. Determination of the time of labor onset identified that HFHC rats IUP (p=0.046) increased significantly 8h prior to 5th pup delivery, which contrasts to CON with no significant increase. Myometrial contractile frequency in HFHC rats significantly increased 12 h prior to delivery of the 5th pup (p=0.023) compared to only 3h in CON, providing evidence that labor in HFHC rats was prolonged by 9h. In conclusion, we have established a translational rat model that will allow us to unravel the mechanism behind uterine dystocia associated with maternal obesity.

Preclinical and translational models for delirium: Recommendations for future research from the NIDUS delirium network.

Delirium is a common, morbid, and costly syndrome that is closely linked to Alzheimer's disease (AD) and AD-related dementias (ADRD) as a risk factor and outcome. Human studies of delirium have advanced our knowledge of delirium incidence and prevalence, risk factors, biomarkers, outcomes, prevention, and management. However, understanding of delirium neurobiology remains limited. Preclinical and translational models for delirium, while challenging to develop, could advance our knowledge of delirium neurobiology and inform the development of new prevention and treatment approaches. We discuss the use of preclinical and translational animal models in delirium, focusing on (1) a review of current animal models, (2) challenges and strategies for replicating elements of human delirium in animals, and (3) the utility of biofluid, neurophysiology, and neuroimaging translational markers in animals. We conclude with recommendations for the development and validation of preclinical and translational models for delirium, with the goal of advancing awareness in this important field.