Retinoic acid action is altered within endometrium of baboons affected with endometriosis

Objective: Using a baboon model, we determined the changing expression of Retinoic Acid (RA) target genes during the menstrual cycle and during disease progression. This change could explain the cellular response and changes characteristic of endometriosis. In previous studies, we established that endometriosis affects the CRABP2:FABP5 ratio in an in vitro environment, shifting toward apoptosis and differentiation with higher CRABP2, and anti-apoptosis with higher levels of FABP5. Intervention(s): Endometriosis was induced in female baboons with intraperitoneal inoculation of menstrual endometrium ( n = 2–4). Tissue was harvested via endometrectomy during different stages of the menstrual cycle as well at 3, 6, and 12 month timepoints after inoculation with endometriosis. Main outcome measure(s): Real time PCR was used to quantify STRA6 (a gene responsible for retinol uptake), CRABP2 (a gene necessary for apoptotic and anti-apoptotic estrogenic RA effects), and FABP5 (a gene that mediates the anti-apoptotic actions of RA). Results: STRA6 and CRABP2 expression were highest in the proliferative phase and lowest in the late secretory phase. FABP5 expression remained stable throughout the 12 months following the induction of the disease, whereas STRA6 and CRABP2 continued to decrease during the same period. Conclusions: Our study confirms that a shift in the CRABP2:FABP5 ratio has similar in vivo effects as it does in vitro: changing RA expression with disease induction and progression. As CRABP2 may be important in determining cell fate in the endometrium, gene expression changes could contribute to the anti-apoptotic behavior of affected cells. As expression changes more during progression, earlier rather than later treatment becomes more critical in reducing the rate of disease progression.

Endometriosis related sex steroid hormones, hypothalamic pituitary gonadal axis hormones and related animal modeling: A comprehensive review of published articles and endometriosis induction methods from 2010 to 2021 with scoring based approach

Endometriosis is an enigmatic gynecological disease initiated by the ectopic growth of endometrial tissue and causes critical symptoms such as chronic pelvic pain, cyclic menstrual pain, subfertility or infertility. Considering extensive investigations for explaining the underlying pathophysiology of endometriosis, origin and distinctive processes which lead to endometritic state are not completely understood. In this comprehensive review, studies published from 2010 to 2021 are reviewed in order to provide a bright insight through the applications of translational animal models and endometriosis induction methods for evaluation of endometriosis pathogenesis and treatment. We provided method based inclusion criteria and reviewed all hormone-based studies with concentration on animal models. Additionally, studies with novel induction methods and approaches are categorized separately and analyzed by a novel scoring table for suitability of further investigations. Eventually, our scoring system suggested that the best-evaluated animal model for hormone related endometriosis studies is an “unopposed estrogenicity baboon model of endometriosis”.

Functional morphometry to estimate the alveolar surface area by using a premature baboon model

The main respiratory pathophysiological process following premature birth is the delayed or arrested alveolar development which translates to a smaller alveolar surface area (S­A). Histological morphometry is the gold standard method to measure the SA but requires invasive tissue sampling or the removal of the whole organ for analysis. Alternatively, the SA could be measured in living subjects by "functional morphometry" using Fick's first law of diffusion and non-invasive measurements of the ventilation perfusion ratio (VA/Q). We herein aim to describe a novel functional morphometric method to measure SA using a premature baboon model. We used both functional morphometry and post-mortem histological morphometry to measure SA in 11 premature baboons born at 135 days who received intensive care treatment for 14 days. For the calculation of the SA by functional morphology we measured the septal wall thickness using microscopy, the alveolar arterial oxygen gradient using concurrent measurements of arterial pressure of O2 and CO2 and pulmonary perfusion using echocardiography and integrated Doppler signals. The median (IQR) SA using functional morphometry was 3,100 (2,080-3,640) cm2 and using histological morphometry was 1,034 (634-1,210) cm2 (left lung only). The SA measured by functional morphometry was not related to the SA measured by histological morphometry. Following linear regression analysis, the VA/Q significantly predicted the histologically measured SA (R2=0.659,p=0.002). In conclusion, functional measurements of ventilation to perfusion ratio could be used to estimate the alveolar surface area in prematurely born baboons and the ventilation perfusion ratio was the main determinant of the alveolar surface area.

De Novo Valve Tissue Morphology Following Bioscaffold Mitral Valve Replacement in a Juvenile Non-Human Primate Model

The utility of implanting a bioscaffold mitral valve consisting of porcine small intestinal submucosa (PSIS) in a juvenile baboon model (12 to 14 months old at the time of implant; n = 3) to assess their in vivo tissue remodeling responses was investigated. Our findings demonstrated that the PSIS mitral valve exhibited the robust presence of de novo extracellular matrix (ECM) at all explantation time points (at 3-, 11-, and 20-months). Apart from a significantly lower level of proteoglycans in the implanted valve’s annulus region (p < 0.05) at 3 months compared to the 11- and 20-month explants, there were no other significant differences (p > 0.05) found between any of the other principal valve ECM components (collagen and elastin) at the leaflet, annulus, or chordae tendinea locations, across these time points. In particular, neochordae tissue had formed, which seamlessly integrated with the native papillary muscles. However, additional processing will be required to trigger accelerated, uniform and complete valve ECM formation in the recipient. Regardless of the specific processing done to the bioscaffold valve, in this proof-of-concept study, we estimate that a 3-month window following bioscaffold valve replacement is the timeline in which complete regeneration of the valve and integration with the host needs to occur.

Successful experimental infant baboon model for childhood cryptosporidiosis studies

Background Cryptosporidiosis causes high morbidity and mortality in children under 2 years of age globally. The lack of an appropriate animal model that mimics the pathogenesis of disease in humans has hampered the development and testing of potential therapeutic options. This study aimed to develop and validate an infant baboon infection model of cryptosporidiosis. Methods Eighteen immunocompetent weaned infant baboons aged 12 to 16 months were used. The animals were n = 3 controls and three experimental groups of n = 5 animals each inoculated with Cryptosporidium parvum oocysts as follows: group 1: 2 × 104, group 2: 2 × 105, group 3: 2 × 106 followed by daily fecal sampling for oocyst evaluation. Blood sampling for immunological assay was done on the day of infection and weekly thereafter until the end of the experiment, followed by necropsy and histopathology. Statistical analysis was performed using R, SPSS, and GraphPad Prism software. Analysis of variance (ANOVA) and Bonferroni post hoc tests were used for comparison of the means, with p < 0.05 considered as a significant difference. Correlation coefficient and probit analysis were also performed. Results In all experimental animals but not controls, the onset of oocyst shedding occurred between days 2 and 4, with the highest oocyst shedding occurring between days 6 and 28. Histological analysis revealed parasite establishment only in infected animals. Levels of cytokines (TNF-α, IFN-γ, and IL-10) increased significantly in experimental groups compared to controls. Conclusion For developing a reproducible infant baboon model, 2 × 104 oocysts were an effective minimum quantifiable experimental infection dose. Graphic abstract

Successful Experimental Infant Baboon Model for Childhood Cryptosporidiosis Studies

Background: Cryptosporidiosis causes high morbidity and fatality to children under two years globally. The lack of an appropriate animal model that mimics the pathogenesis of disease in humans has hampered the development and testing of potential therapeutic options. This study aimed to develop and validate an infant baboon infection model of cryptosporidiosis.Methods: Eighteen immunocompetent weaned infant baboons aged 12 to 16 months were used. The animals were: n=3 controls and three experimental groups of n=5 animals each inoculated with Cryptosporidium parvum oocysts as follows: Group 1: 2x104, Group 2: 2x105, Group 3: 2x106 followed by daily fecal sampling for oocysts evaluation. Blood sampling for immunological assay was done on infection day and thereafter weekly until the end of the experiment followed by necropsy and histopathology. Statistical analysis was done using R, statistical package for the social sciences (SPSS) and Graph Pad Prism software. Analysis of variance (ANOVA) and Bonferroni post-hoc tests were used for comparison of the means, with p<0.05 considered as a significant difference. Correlation coefficient and Probit analysis were also performed.Results: In all experimental animals but not controls, the onset of oocysts shedding occurred between days 2 and 4, with the highest oocyst shedding occurring between days 6 and 28. Histological analysis revealed parasites establishment only in infected animals. Levels of cytokines (TNF-α, IFN-γ, and IL-10) significantly increased in experimental groups compared to controls. Conclusion: 2x104 oocysts were an effective minimum quantifiable experimental infection dose for developing a reproducible infant baboon model.

Factor XII plays a pathogenic role in organ failure and death in baboons challenged with Staphylococcus aureus

Activation of coagulation factor (F) XI promotes multi-organ failure in rodent models of sepsis and in a baboon model of lethal systemic inflammation induced by infusion of heat-inactivated Staphylococcus (S.) aureus. Here we employed the anticoagulant FXII-neutralizing antibody 5C12 to verify the mechanistic role of FXII in this baboon model. Compared to untreated controls, repeated 5C12 administration before and at 8h and 24h after bacterial challenge prevented the dramatic increase in circulating complexes of contact system enzymes FXIIa, FXIa and kallikrein with antithrombin or C1 inhibitor, and prevented cleavage and consumption of high-molecular-weight kininogen. Activation of several coagulation factors and fibrinolytic enzymes were also prevented. D-dimer levels showed profound increase in untreated but not in the treated animals. The antibody also blocked the increase in plasma biomarkers of inflammation and cell damage, including tumor necrosis factor, interleukin (IL)-1β, IL-6, IL-8, IL-10, granulocyte-macrophage colony-stimulating factor, nucleosomes, and myeloperoxidase. Based on clinical presentation and circulating biomarkers, inhibition of FXII prevented fever, terminal hypotension, respiratory distress and multi-organ failure. All animals receiving 5C12 had milder and transient clinical symptoms and were asymptomatic at day 7, while untreated controls suffered irreversible multi-organ failure and had to be euthanized within 2 days after the bacterial challenge. This study confirms and extends our previous finding that at least two enzymes of the contact activation complex, FXIa and FXIIa, play critical roles in the development of an acute and terminal inflammatory response in baboons challenged with heat-inactivated S. aureus.

Cardiac magnetic resonance imaging: insights into developmental programming and its consequences for aging

Cardiovascular diseases (CVD) are important consequences of adverse perinatal conditions such as fetal hypoxia and maternal malnutrition. Cardiac magnetic resonance imaging (CMR) can produce a wealth of physiological information related to the development of the heart. This review outlines the current state of CMR technologies and describes the physiological biomarkers that can be measured. These phenotypes include impaired ventricular and atrial function, maladaptive ventricular remodeling, and the proliferation of myocardial steatosis and fibrosis. The discussion outlines the applications of CMR to understanding the developmental pathways leading to impaired cardiac function. The use of CMR, both in animal models of developmental programming and in human studies, is described. Specific examples are given in a baboon model of intrauterine growth restriction (IUGR). CMR offers great potential as a tool for understanding the sequence of dysfunctional adaptations of developmental origin that can affect the human cardiovascular system.