Aotus nancymaae model predicts human immune response to the placental malaria vaccine candidate VAR2CSA.

Placental malaria vaccines (PMVs) are being developed to prevent severe sequelae of placental malaria (PM) in pregnant women and their offspring. The leading candidate vaccine antigen VAR2CSA mediates parasite binding to placental receptor chondroitin sulfate A (CSA). Despite promising results in small animal studies, recent human trials of the first two PMV candidates (PAMVAC and PRIMVAC) generated limited cross-reactivity and cross-inhibitory activity to heterologous parasites.

Barcode clonal tracking of tissue-resident immune cells in rhesus macaque highlights distinct clonal distribution pattern of tissue NK cells.

Tissue resident (TR) immune cells play important roles in facilitating tissue homeostasis, coordinating immune responses against infections and tumors, and maintaining immunological memory. While studies have shown these cells are distinct phenotypically and functionally from cells found in the peripheral blood (PB), the clonal relationship between these populations across tissues has not been comprehensively studied in primates or humans. We utilized autologous transplantation of rhesus macaque hematopoietic stem and progenitor cells containing high diversity barcodes to track the clonal distribution of T, B, myeloid and natural killer (NK) cell populations across tissues, including liver, spleen, lung, and gastrointestinal (GI) tract, in comparison with PB longitudinally post-transplantation, in particular we focused on NK cells which do not contain endogenous clonal markers and have not been previously studied in this context.

Plasmodium falciparum in Aotus nancymaae: A New Model for Placental Malaria.

Plasmodium falciparum-infected erythrocytes that display the variant surface antigen VAR2CSA bind chondroitin sulfate A (CSA) to sequester in placental intervillous spaces, causing severe sequelae for mother and offspring. Here, we establish a placental malaria (PM) monkey model. Pregnant Aotus infected with CSA-binding P.

A bi-institutional multi-disciplinary failure mode and effects analysis (FMEA) for a Co-60 based total body irradiation technique.

Background: We aim to assess the risks associated with total body irradiation (TBI) delivered using a commercial dedicated Co-60 irradiator, and to evaluate inter-institutional and inter-professional variations in the estimation of these risks.

Methods: A failure mode and effects analysis (FMEA) was generated using guidance from the AAPM TG-100 report for quantitative estimation of prospective risk metrics. Thirteen radiation oncology professionals from two institutions rated possible failure modes (FMs) for occurrence (O), severity (S), and detectability (D) indices to generate a risk priority number (RPN).

Flow Rate and Apparent Volume of Cerebrospinal Fluid in Rhesus Macaques () Based on the Pharmacokinetics of Intrathecally Administered Inulin.

Cerebrospinal fluid (CSF) flow rate and volume are fundamental to the design and interpretation of preclinical pharmacokinetics and pharmacodynamics studies in NHP. To determine the values of CSF flow rate and volume, we evaluated the plasma and CSF pharmacokinetics of inulin, an inert polysaccharide tracer, in 5 rhesus macaques with CSF ventricular res- ervoirs and lumbar ports; these reservoirs and ports facilitate humane intrathecal administration and serial CSF sampling in unanesthetized macaques. Inulin was administered intrathecally via the CSF ventricular reservoir ( = 3), followed by the collection of lumbar CSF via the lumbar port and plasma.

Plasma and cerebrospinal fluid pharmacokinetics of the DNA methyltransferase inhibitor, 5-azacytidine, alone and with inulin, in nonhuman primate models.

Background: Epigenetic modifiers are being investigated for a number of CNS malignancies as tumor-associated mutations such as isocitrate dehydrogenase mutations (IDH1/IDH2) and H3K27M mutations, which result in aberrant signaling, are identified. We evaluated the CNS exposure of the DNA methyltransferase inhibitor, 5-azacytidine (5-AZA), in preclinical nonhuman primate (NHP) models to inform its clinical development for CNS tumors.

Methods: 5-AZA and 5-AZA+Inulin pharmacokinetics (PK) were evaluated in NHPs ( = 10) following systemic (intravenous [IV]) and intrathecal (intraventricular [IT-V], intralumbar [IT-L], and cisternal [IT-C]) administration.

A primate model of severe malarial anaemia: a comparative pathogenesis study.

Severe malarial anaemia (SMA) is the most common life-threatening complication of Plasmodium falciparum infection in African children. SMA is characterised by haemolysis and inadequate erythropoiesis, and is associated with dysregulated inflammatory responses and reduced complement regulatory protein levels (including CD35). However, a deeper mechanistic understanding of the pathogenesis requires improved animal models.

Plasmodium vivax chloroquine resistance links to pvcrt transcription in a genetic cross.

Mainstay treatment for Plasmodium vivax malaria has long relied on chloroquine (CQ) against blood-stage parasites plus primaquine against dormant liver-stage forms (hypnozoites), however drug resistance confronts this regimen and threatens malaria control programs. Understanding the basis of P. vivax chloroquine resistance (CQR) will inform drug discovery and malaria control.

Reducing Dental Plaque Scores in Long-term Care Facilities Using a Checklist and Random Inspections: A Pilot Study.

The development and use of tailored interventions in overcoming barriers to optimum health in long-term care facility residents is of the highest importance. One successful approach to improving health outcomes is the use of a checklist by health care providers. Despite the evidence of the success of such checklists in nursing and medicine, there is little evidence on their use in improving dental outcomes.

Regional Anesthesia for Dentistry and Orofacial Surgery in Rhesus Macaques ().

Regional anesthesia is a commonly used adjunct to orofacial dental and surgical procedures in companion animals and humans. However, appropriate techniques for anesthetizing branches of the mandibular and maxillary nerves have not been described for rhesus monkeys. Skulls of 3 adult rhesus monkeys were examined to identify relevant foramina, establish appropriate landmarks for injection, and estimate injection angles and depth.

Artemisinin resistance phenotypes and K13 inheritance in a cross and model.

Concerns about malaria parasite resistance to treatment with artemisinin drugs (ARTs) have grown with findings of prolonged parasite clearance s (>5 h) and their association with mutations in Kelch-propeller protein K13. Here, we describe a laboratory cross of K13 C580Y mutant with C580 wild-type parasites to investigate ART response phenotypes in vitro and in vivo. After genotyping >400 isolated progeny, we evaluated 20 recombinants in vitro: IC measurements of dihydroartemisinin were at similar low nanomolar levels for C580Y- and C580-type progeny (mean ratio, 1.

Cardiac xenografts show reduced survival in the absence of transgenic human thrombomodulin expression in donor pigs.

A combination of genetic manipulations of donor organs and target-specific immunosuppression is instrumental in achieving long-term cardiac xenograft survival. Recently, results from our preclinical pig-to-baboon heterotopic cardiac xenotransplantation model suggest that a three-pronged approach is successful in extending xenograft survival: (a) α-1,3-galactosyl transferase (Gal) gene knockout in donor pigs (GTKO) to prevent Gal-specific antibody-mediated rejection; (b) transgenic expression of human complement regulatory proteins (hCRP; hCD46) and human thromboregulatory protein thrombomodulin (hTBM) to avoid complement activation and coagulation dysregulation; and (c) effective induction and maintenance of immunomodulation, particularly through co-stimulation blockade of CD40-CD40L pathways with anti-CD40 (2C10R4) monoclonal antibody (mAb). Using this combination of manipulations, we reported significant improvement in cardiac xenograft survival.

Circulating cell-free DNA as a biomarker of tissue injury: Assessment in a cardiac xenotransplantation model.

Background: Observational studies suggest that cell-free DNA (cfDNA) is a biomarker of tissue injury in a range of conditions including organ transplantation. However, the lack of model systems to study cfDNA and its relevance to tissue injury has limited the advancements in this field. We hypothesized that the predictable course of acute humoral xenograft rejection (AHXR) in organ transplants from genetically engineered donors provides an ideal system for assessing circulating cfDNA as a marker of tissue injury.

SiSSR: Simultaneous subdivision surface registration for the quantification of cardiac function from computed tomography in canines.

Recent improvements in cardiac computed tomography (CCT) allow for whole-heart functional studies to be acquired at low radiation dose (<2mSv) and high-temporal resolution (<100ms) in a single heart beat. Although the extraction of regional functional information from these images is of great clinical interest, there is a paucity of research into the quantification of regional function from CCT, contrasting with the large body of work in echocardiography and cardiac MR. Here we present the Simultaneous Subdivision Surface Registration (SiSSR) method: a fast, semi-automated image analysis pipeline for quantifying regional function from contrast-enhanced CCT.

CD4+CD25 FoxP3+ regulatory T cells in long-term cardiac xenotransplantation.

Background: CD4+CD25 FoxP3+ T (Treg) cells are a small subset of CD4+ T cells that have been shown to exhibit immunoregulatory function. Although the absolute number of Treg cells in peripheral blood lymphocytes (PBL) is very small, they play an important role in suppressing immune reactivity. Several studies have demonstrated that the number of Treg cells, rather than their intrinsic suppressive capacity, may contribute to determining the long-term fate of transplanted grafts.

Encouraging experience using multi-transgenic xenografts in a pig-to-baboon cardiac xenotransplantation model.

Background: Innovations in transgenic technology have facilitated improved xenograft survival. Additional gene expression appears to be necessary to overcome the remaining immune and biologic incompatibilities. We report for the first time the novel use of six-gene modifications within a pig-to-baboon cardiac xenotransplantation model.

Dual-contrast agent photon-counting computed tomography of the heart: initial experience.

To determine the feasibility of dual-contrast agent imaging of the heart using photon-counting detector (PCD) computed tomography (CT) to simultaneously assess both first-pass and late enhancement of the myocardium. An occlusion-reperfusion canine model of myocardial infarction was used. Gadolinium-based contrast was injected 10 min prior to PCD CT.

Minimally Invasive Lumbar Port System for the Collection of Cerebrospinal Fluid from Rhesus Macaques (Macaca mulatta).

Biomedical translational research frequently incorporates collection of CSF from NHP, because CSF drug levels are used as a surrogate for CNS tissue penetration in pharmacokinetic and dynamic studies. Surgical placement of a CNS ventricular catheter reservoir for CSF collection is an intensive model to create and maintain and thus may not be feasible or practical for short-term studies. Furthermore, previous NHP lumbar port models require laminectomy for catheter placement.

Genetic diversity of Klebsiella pneumoniae isolates during an outbreak in a non-human primate research colony.

Background: Klebsiella pneumoniae can be a serious pathogen in non-human primates, particularly Neotropical monkeys.

Methods: During a K. pneumoniae outbreak in an owl monkey research colony, 13 K.

Development of a cerebrospinal fluid lateral reservoir model in rhesus monkeys (Macaca mulatta).

Rapid, serial, and humane collection of cerebrospinal fluid (CSF) in nonhuman primates (NHP) is an essential element of numerous research studies and is currently accomplished via two different models. The CSF reservoir model (FR) combines a catheter in the 4th ventricle with a flexible silastic reservoir to permit circulating CSF flow. The CSF lateral port model (LP) consists of a lateral ventricular catheter and an IV port that provides static access to CSF and volume restrictions on sample collection.

Genetically engineered pigs and target-specific immunomodulation provide significant graft survival and hope for clinical cardiac xenotransplantation.

Objectives: Cardiac transplantation and available mechanical alternatives are the only possible solutions for end-stage cardiac disease. Unfortunately, because of the limited supply of human organs, xenotransplantation may be the ideal method to overcome this shortage. We have recently seen significant prolongation of heterotopic cardiac xenograft survival from 3 to 12 months and beyond.

Model for concomitant microdialysis sampling of the pons and cerebral cortex in rhesus macaques (Macaca mulatta).

Pediatric diffuse intrinsic pontine gliomas are aggressive brainstem tumors that fail to respond to treatment. We hypothesize that the protective features of the pons may hinder chemotherapeutic agents from entering pontine tissue compared with cortical brain tissue. To test this hypothesis, we developed a unique nonhuman primate model using microdialysis, a continuous in vivo extracellular sampling technique, to compare drug exposure concurrently in pontine tissue, cortical tissue, CSF, and plasma after intravenous administration of chemotherapeutic agents.

Role of anti-CD40 antibody-mediated costimulation blockade on non-Gal antibody production and heterotopic cardiac xenograft survival in a GTKO.hCD46Tg pig-to-baboon model.

Background: Recently, we have shown that an immunosuppression regimen including costimulation blockade via anti-CD154 antibody significantly prolongs the cardiac xenograft survival in a GTKO.hCD46Tg pig-to-baboon heterotopic xenotransplantation model. Unfortunately, many coagulation disorders were observed with the use of anti-CD154 antibody, and recipient survival was markedly reduced by these complications.

Gender influences infectivity in C57BL/6 mice exposed to mouse minute virus.

Two natural outbreaks of mouse minute virus (MMV) are described. Observations during management of the naturally infected colonies led to a study in which 4-wk-old C57BL/6NCr and C57BL/6Tac mice were inoculated oronasally with an immunosuppressive variant of MMV (MMVi), as were adult C57BL/6NCr lactating dams or their pups (age, 10 d). By day 28 postinoculation, 100% of the 4-wk-old male C57BL/6NCr and C57BL/6Tac mice, 56.

The husbandry and care of dendrobatid frogs.

Dendrobatid frogs are studied primarily for the bioactive alkaloids found in their skin. Also known as poison-dart frogs, these animals accumulate toxic alkaloids from dietary sources. The function and uses of the many alkaloids, the alkaloid accumulation system, and the basic biology and physiology of the frogs themselves are of research interest.