Isolation of Diverse Simian Arteriviruses Causing Hemorrhagic Disease.

Genetically diverse simian arteriviruses (simarteriviruses) naturally infect geographically and phylogenetically diverse monkeys, and cross-species transmission and emergence are of considerable concern. Characterization of most simarteriviruses beyond sequence analysis has not been possible because the viruses fail to propagate in the laboratory. We attempted to isolate 4 simarteriviruses, Kibale red colobus virus 1, Pebjah virus, simian hemorrhagic fever virus, and Southwest baboon virus 1, by inoculating an immortalized grivet cell line (known to replicate simian hemorrhagic fever virus), primary macaque cells, macrophages derived from macaque induced pluripotent stem cells, and mice engrafted with macaque CD34+-enriched hematopoietic stem cells. The combined effort resulted in successful virus isolation; however, no single approach was successful for all 4 simarteriviruses. We describe several approaches that might be used to isolate additional simarteriviruses for phenotypic characterization. Our results will expedite laboratory studies of simarteriviruses to elucidate virus-host interactions, assess zoonotic risk, and develop medical countermeasures.

Thyroid hormone concentrations in female baboons: Metabolic consequences of living in a highly seasonal environment.

How female mammals adapt metabolically in response to environmental variation remains understudied in the wild, because direct measures of metabolic activity are difficult to obtain in wild populations. However, recent advances in the non-invasive measurement of fecal thyroid hormones, triiodothyronine (T3), an important regulator of metabolism, provide an opportunity to understand how female baboons living in the harsh Amboseli ecosystem in southern Kenya adapt to environmental variability and escape strict reproductive seasonality. Specifically, we assessed how a female's activity budget, diet, and concentrations of fecal T3 metabolites (mT3) changed over the course of the year and between years. We then tested which of several environmental variables (season, rainfall, and temperature) and behavioral variables (female activity budget and diet) best predicted mT3 concentrations. Finally, we determined if two important reproductive events - onset of ovarian cycling and conception of an offspring - were preceded by changes in female mT3 concentrations. We found female baboons' mT3 concentrations varied markedly across the year and between years as a function of environmental conditions. Further, changes in a female's behavior and diet only partially mediated the metabolic response to the environment. Finally, mT3 concentrations increased in the weeks prior to menarche and cycling resumption, regardless of the month or season in which cycling started. This pattern indicates that metabolic activation may be an indicator of reproductive readiness in female baboons as their energy balance is restored.

Novel factors potentially initiating acute antibody-mediated rejection in pig kidney xenografts despite an efficient immunosuppressive regimen.

Antibody-mediated rejection (AMR) is a common cause of graft failure after pig-to-nonhuman primate organ transplantation, even when the graft is from a pig with multiple genetic modifications. The specific factors that initiate AMR are often uncertain. We report two cases of pig kidney transplantation into immunosuppressed baboons in which we identify novel factors associated with the initiation of AMR. In the first, membranous nephropathy was the initiating factor that was then associated with the apparent loss of the therapeutic anti-CD154 monoclonal antibody in the urine when severe proteinuria was present. This observation suggests that proteinuria may be associated with the loss of any therapeutic monoclonal antibody, for example, anti-CD154 or eculizumab, in the urine, resulting in xenograft rejection. In the second case, the sequence of events and histopathology tentatively suggested that pyelonephritis may have initiated acute-onset AMR. The association of a urinary infection with graft rejection has been well-documented in ABO-incompatible kidney allotransplantation based on the expression of an antigen on the invading microorganism shared with the kidney graft, generating an immune response to the graft. To our knowledge, these potential initiating factors of AMR in pig xenografts have not been highlighted previously.

Successful surgical management of a pyothorax in a Guinea baboon (Papio papio).

A 16-year-old male Guinea baboon (Papio papio) was evaluated for weakness and focal wet fur of 1-week duration. A pyothorax caused by Streptococcus anginosus was diagnosed. A surgical approach was chosen, combined with a systemic antibiotic therapy. Medical imaging and C-reactive protein follow-up revealed the resolution of the pyothorax.

The Known, the Unknown and the Future of the Pathophysiology of Endometriosis.

Endometriosis is one of the most common causes of chronic pelvic pain and infertility, affecting 10% of women of reproductive age. A delay of up to 9 years is estimated between the onset of symptoms and the diagnosis of endometriosis. Endometriosis is currently defined as the presence of endometrial epithelial and stromal cells at ectopic sites; however, advances in research on endometriosis have some authors believing that endometriosis should be re-defined as "a fibrotic condition in which endometrial stroma and epithelium can be identified". There are several theories on the etiology of the disease, but the origin of endometriosis remains unclear. This review addresses the role of microRNAs (miRNAs), which are naturally occurring post-transcriptional regulatory molecules, in endometriotic lesion development, the inflammatory environment within the peritoneal cavity, including the role that cytokines play during the development of the disease, and how animal models have helped in our understanding of the pathology of this enigmatic disease.

Antigen Discovery for Next-Generation Pertussis Vaccines Using Immunoproteomics and Transposon-Directed Insertion Sequencing.

BACKGROUND: Despite high vaccination rates, the United States has experienced a resurgence in reported cases of pertussis after switching to the acellular pertussis vaccine, indicating a need for improved vaccines that enhance infection control. METHODS: Bordetella pertussis antigens recognized by convalescent-baboon serum and nasopharyngeal wash were identified by immunoproteomics and their subcellular localization predicted. Genes essential or important for persistence in the baboon airway were identified by transposon-directed insertion-site sequencing (TraDIS) analysis. RESULTS: In total, 314 B. pertussis antigens were identified by convalescent baboon serum and 748 by nasopharyngeal wash. Thirteen antigens were identified as immunogenic in baboons, essential for persistence in the airway by TraDIS, and membrane-localized: BP0840 (OmpP), Pal, OmpA2, BP1485, BamA, Pcp, MlaA, YfgL, BP2197, BP1569, MlaD, ComL, and BP0183. CONCLUSIONS: The B. pertussis antigens identified as immunogenic, essential for persistence in the airway, and membrane-localized warrant further investigation for inclusion in vaccines designed to reduce or prevent carriage of bacteria in the airway of vaccinated individuals.

Enamel chipping and its ecological correlates in African papionins: Implications for hominin feeding behavior.

African papionins are classic paleoecological referents for fossil hominins. Enamel chips on the teeth of baboons and hominins are argued to represent responses to similar dietary habits; however, a comprehensive analysis of modern papionin chipping is lacking, leaving open the question of analog suitability. Here, we investigate patterns of antemortem enamel chipping across a diverse set of African papionin species occupying a range of ecological niches. We compare papionin chipping frequencies to estimates for Plio-Pleistocene hominins to address hypotheses of habitat and/or dietary similarities. Antemortem chips in seven African papionin species were scored on intact postcanine teeth (P3-M3) using established protocols. Chip size was scored on a tripartite scale. Papio hamadryas and Papio ursinus-two common paleoecological referents-display higher levels of chipping than Plio-Pleistocene hominin taxa (Australopithecus and Paranthropus) posited to have similar dietary habits. Papio populations occupying dry or highly seasonal habitats accumulate more large chips than Papio taxa occupying more mesic habitats, and terrestrial papionins chip their teeth more often than closely related taxa occupying arboreal niches. Chipping is present on the teeth of all Plio-Pleistocene hominins; however, chipping in baboons (P. ursinus and P. hamadryas) consistently exceeds most hominin taxa. Chipping frequencies on their own do not reliably sort taxa into major dietary groupings. We conclude that the large differences in chipping frequency may instead reflect habitat use and food processing idiosyncrasies. Less chipping in Plio-Pleistocene hominin teeth compared to modern Papio is more likely attributable to differences in dental morphology rather than diet.

Assessment of glomerular filtration and tubular secretion in baboons with life-supporting pig kidney grafts.

With pig kidney xenotransplantation nearing clinical reality, it is imperative to measure pig kidney function in the graft recipients. Our aims were (i) to compare inulin clearance after a short intravenous (IV) bolus with steady-state inulin IV infusion, (ii) to use this method to measure the glomerular filtration rate (GFR), and (iii) to determine the tubular secretory function using cefoxitin in a pig-to-baboon renal transplant model. A short IV infusion of inulin and cefoxitin were followed by a maintenance IV infusion of inulin over 5 h in seven healthy baboons, three healthy pigs, and five baboons after bilateral native nephrectomy and intra-abdominal pig renal transplantation. Blood and urine samples were collected. Serum and urinary inulin and serum cefoxitin concentrations measured by validated assays were used to calculate GFR and renal secretion. GFR calculated were similar by both methods. The body weight normalized total body clearance of inulin was similar in pigs and baboons despite differences in absolute clearances. Pig kidney transplanted into baboons provided similar clearance in baboons when normalized to baboon body weight and sustained filtration and secretory functions. The study documented that pig kidneys support the physiologic needs of baboons and are likely to support human recipients as well.

Observations on hydronephrosis after pig kidney transplantation in baboons.

We have seen hydronephrosis (obstructive nephropathy) at necropsy in 3 of 11 (21%) genetically-engineered pig kidneys that functioned in baboons for >36 days, even when the clinical and histopathological features of rejection were minimal. We briefly report one such case and illustrate the macroscopic and microscopic appearances of such a kidney and ureter. The causes of the observed changes remain uncertain. In our small experience, there seems to be no correlation between the development of hydronephrosis and (i) the surgical technique, (ii) the genotype of the pig, (iii) the length of the pig ureter, or (iv) the immunosuppressive and anti-inflammatory therapy administered. We suggest that the distal ureteric thickening may be the result of an inflammatory response. In two cases, we resolved the problem by carrying out a secondary side-to-side anastomosis between the proximal pig ureter and the baboon bladder.

Systemic allergic dermatitis (systemic contact dermatitis) from pharmaceutical drugs: A review.

The literature on systemic allergic dermatitis (SAD; also known as systemic contact dermatitis) is reviewed. Both topical drugs (from absorption through mucosae or skin) and systemic drugs (oral, parenteral, rectal) may be responsible for the disorder. The topical route appears to be rare with 41 culprit topical drugs found to cause SAD in 95 patients. Most reactions are caused by budesonide (especially from inhalation), bufexamac, and dibucaine. SAD from systemic drugs is infrequent with 95 culprit drugs found to cause SAD in 240 patients. The drugs most frequently implicated are mitomycin C, methylprednisolone (salt, ester), and hydrocortisone (salt). The largest group of culprit drugs consisted of corticosteroids (19%), being responsible for >30% of the reactions, of which nearly 40% were not caused by therapeutic drugs, but by drug provocation tests. The most frequent manifestations of SAD from drugs are eczematous eruptions (scattered, widespread, generalized, worsening, reactivation), maculopapular eruptions, symmetrical drug-related intertriginous and flexural exanthema (SDRIFE [baboon syndrome]) and widespread erythema or erythroderma. Therapeutic systemic drugs hardly ever cause reactivation of previously positive patch tests and infrequently of previous allergic contact dermatitis. The pathophysiology of SAD has received very little attention. Explanations for the rarity of SAD are suggested.

The Long and Winding Road to Clinical Xenotransplantation: A Personal Journey.

BACKGROUND: The recent clinical pig-heart transplant carried out at the University of Maryland in Baltimore is hopefully the first of many xenotransplants that will resolve the problem of the lack of availability of organs from deceased human donors. I offer my personal recollections of how xenotransplantation research has progressed since the mid-1980s, when the pig-to-nonhuman primate (NHP) organ transplant model was established. SUMMARY: Initially, hyperacute rejection or early antibody-mediated rejection was almost uniform. Among the milestones that were subsequently achieved are (i) the introduction of the first genetically engineered pigs that expressed a human complement regulatory protein, CD55, which was associated with prolonged graft function, extending to several weeks; (ii) the observation that conventional immunosuppressive therapy did not prevent an adaptive immune response, whereas the administration of an agent that blocked the CD40/CD154 T-cell costimulation pathway was successful in this respect; (iii) the identification of the major pig carbohydrate xenoantigen as galactose-α1,3-galactose (Gal), followed by gene editing to delete its expression, and the demonstration of prolonged survival of organs from these pigs in NHPs; (iv) the resolution of coagulation dysfunction between a pig and primate by the introduction of genes for human coagulation regulatory proteins; (v) the recognition of a prolonged systemic inflammatory response to a xenograft and its suppression either by drug therapy or by further gene editing, and (vi) identification of two pig "non-Gal" xenoantigens and the production of triple-knockout (TKO) pigs. However, although many humans do not have antibodies against TKO pig cells, all Old World NHPs do have antibodies against these cells. This has provided an unexpected new barrier to testing TKO pig organ transplants in NHPs. KEY MESSAGES: The optimal gene-edited pig for clinical xenotransplantation may be one with 10 genetic manipulations. A pig with this genetic background provided the heart for the recent first clinical xenotransplant. In view of the current barrier to progress in the TKO pig-to-NHP model, the time has surely come when we need to consider moving from the laboratory to the clinic. Selection of patients for the first clinical trials is briefly discussed.

Early Left-Planum Temporale Asymmetry in newborn monkeys (Papio anubis): A longitudinal structural MRI study at two stages of development.

The "language-ready" brain theory suggests that the infant brain is pre-wired for language acquisition prior to language exposure. As a potential brain marker of such a language readiness, a leftward structural brain asymmetry was found in human infants for the Planum Temporale (PT), which overlaps with Wernicke's area. In the present longitudinal in vivo MRI study conducted in 35 newborn monkeys (Papio anubis), we found a similar leftward PT surface asymmetry. Follow-up rescanning sessions on 29 juvenile baboons at 7-10 months showed that such an asymmetry increases across the two ages classes. These original findings in non-linguistic primate infants strongly question the idea that the early PT asymmetry constitutes a human infant-specific marker for language development. Such a shared early perisylvian organization provides additional support that PT asymmetry might be related to a lateralized system inherited from our last common ancestor with Old-World monkeys at least 25-35 million years ago.

Dynamic cytoplasmic projections connect mammalian spermatogonia in vivo.

Throughout the male reproductive lifespan, spermatogonial stem cells (SSCs) produce committed progenitors that proliferate and then remain physically connected in growing clones via short cylindrical intercellular bridges (ICBs). These ICBs, which enlarge in meiotic spermatocytes, have been demonstrated to provide a conduit for postmeiotic haploid spermatids to share sex chromosome-derived gene products. In addition to ICBs, spermatogonia exhibit multiple thin cytoplasmic projections. Here, we have explored the nature of these projections in mice and find that they are dynamic, span considerable distances from their cell body (≥25 µm), either terminate or physically connect multiple adjacent spermatogonia, and allow for sharing of macromolecules. Our results extend the current model that subsets of spermatogonia exist as isolated cells or clones, and support a model in which spermatogonia of similar developmental fates are functionally connected through a shared dynamic cytoplasm mediated by thin cytoplasmic projections.

Benserazide racemate and enantiomers induce fetal globin gene expression in vivo: Studies to guide clinical development for beta thalassemia and sickle cell disease.

Increased expression of developmentally silenced fetal globin (HBG) reduces the clinical severity of ß-hemoglobinopathies. Benserazide has a relatively benign safety profile having been approved for 50 years in Europe and Canada for Parkinson's disease treatment. Benserazide was shown to activate HBG gene transcription in a high throughput screen, and subsequent studies confirmed fetal hemoglobin (HbF) induction in erythroid progenitors from hemoglobinopathy patients, transgenic mice containing the entire human ß-globin gene (ß-YAC) and anemic baboons. The goal of this study is to evaluate efficacies and plasma exposure profiles of benserazide racemate and its enantiomers to select the chemical form for clinical development. Intermittent treatment with all forms of benserazide in ß-YAC mice significantly increased proportions of red blood cells expressing HbF and HbF protein per cell with similar pharmacokinetic profiles and with no cytopenia. These data contribute to the regulatory justification for development of the benserazide racemate. Additionally, dose ranges and frequencies required for HbF induction using racemic benserazide were explored. Orally administered escalating doses of benserazide in an anemic baboon induced γ-globin mRNA up to 13-fold and establish an intermittent dose regimen for clinical studies as a therapeutic candidate for potential treatment of ß-hemoglobinopathies.

Maternal Zika Virus (ZIKV) Infection following Vaginal Inoculation with ZIKV-Infected Semen in Timed-Pregnant Olive Baboons.

Zika virus (ZIKV) infection is now firmly linked to congenital Zika syndrome (CZS), including fetal microcephaly. While Aedes species of mosquito are the primary vector for ZIKV, sexual transmission of ZIKV is a significant route of infection. ZIKV has been documented in human, mouse, and nonhuman primate (NHP) semen. It is critical to establish NHP models of the vertical transfer of ZIKV that recapitulate human pathogenesis. We hypothesized that vaginal deposition of ZIKV-infected baboon semen would lead to maternal infection and vertical transfer in the olive baboon (Papio anubis). Epidemiological studies suggest an increased rate of CZS in the Americas compared to the original link to CZS in French Polynesia; therefore, we also compared the French Polynesian (FP) ZIKV isolate to the Puerto Rican (PR) isolate. Timed-pregnant baboons (n = 6) were inoculated via vaginal deposition of baboon semen containing 106 focus-forming units (FFU) of ZIKV (n = 3 for FP isolate H/PF/2013; n = 3 for PR isolate PRVABC59) at midgestation (86 to 95 days of gestation [dG]; term, 183 dG) on day 0 (all dams) and then at 7-day intervals through 3 weeks. Maternal blood, saliva, and cervicovaginal wash (CVW) samples were obtained. Animals were euthanized at 28 days (n = 5) or 39 days (n = 1) after the initial inoculation, and maternal/fetal tissues were collected. Viremia was achieved in 3/3 FP ZIKV-infected dams and 2/3 PR ZIKV-infected dams. ZIKV RNA was detected in CVW samples of 5/6 dams. ZIKV RNA was detected in lymph nodes but not the ovaries, uterus, cervix, or vagina in FP isolate-infected dams. ZIKV RNA was detected in lymph nodes (3/3), uterus (2/3), and vagina (2/3) in PR isolate-infected dams. Placenta, amniotic fluid, and fetal tissues were ZIKV RNA negative in the FP isolate-infected dams, whereas 2/3 PR isolate-infected dam placentas were ZIKV RNA positive. We conclude that ZIKV-infected semen is a means of ZIKV transmission during pregnancy in primates. The PR isolate appeared more capable of widespread dissemination to tissues, including reproductive tissues and placenta, than the FP isolate.IMPORTANCE Zika virus remains a worldwide health threat, with outbreaks still occurring in the Americas. While mosquitos are the primary vector for the spread of the virus, sexual transmission of Zika virus is also a significant means of infection, especially in terms of passage from an infected to an uninfected partner. While sexual transmission has been documented in humans, and male-to-female transmission has been reported in mice, ours is the first study in nonhuman primates to demonstrate infection via vaginal deposition of Zika virus-infected semen. The latter is important since a recent publication indicated that human semen inhibited, in a laboratory setting, Zika virus infection of reproductive tissues. We also found that compared to the French Polynesian isolate, the Puerto Rican Zika virus isolate led to greater spread throughout the body, particularly in reproductive tissues. The American isolates of Zika virus appear to have acquired mutations that increase their efficacy.

Evidence suggesting that deletion of expression of N-glycolylneuraminic acid (Neu5Gc) in the organ-source pig is associated with increased antibody-mediated rejection of kidney transplants in baboons.

Pigs deficient in three glycosyltransferase enzymes (triple-knockout [TKO] pigs) and expressing "protective" human transgenes are likely sources of organs for transplantation into human recipients. Testing of human sera against red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) from TKO pigs has revealed minimal evidence of natural antibody binding. However, unlike humans, baboons exhibit natural antibody binding to TKO pig cells. The xenoantigen specificities of these natural antibodies are postulated to be one or more carbohydrate moieties exposed when N-glycolylneuraminic acid (Neu5Gc) is deleted. The aim of this study was to compare the survival of renal grafts in baboons from pigs that either expressed Neu5Gc (GTKO pigs; Group1, n = 5) or did not express Neu5Gc (GTKO/CMAHKO [DKO] or TKO pigs; Group2, n = 5). An anti-CD40mAb-based immunosuppressive regimen was administered in both groups. Group1 kidneys functioned for 90-260 days (median 237, mean 196 days), with histopathological features of antibody-mediated rejection in two kidneys. Group2 kidneys functioned for 0-183 days (median 35, mean 57), with all of the grafts exhibiting histologic features of antibody-mediated rejection. These findings suggest that the absence of expression of Neu5Gc on pig kidneys impacts graft survival in baboon recipients.

Antibody reactivity with new antigens revealed in multi-transgenic triple knockout pigs may cause early loss of pig kidneys in baboons.

BACKGROUND: Recent advances in gene editing technology have enabled the production of multi-knockout (KO) and transgenic pigs in order to overcome immunologic barriers in xenotransplantation (XTx). However, the genetic manipulations required to produce these changes may have the unintended consequence of producing or revealing neoantigens reactive with natural antibodies present in baboons. In this study, we examined whether the neoantigens that develop in multi-transgenic (mTg) GalT, Cytidine monophospho-N-acetylneuraminic acid hydroxylase (CMAH), ß-1,4-N-acetyl-galactosaminyl transferase 2 (B4) KO pigs can cause rejection of xenografts in baboons. METHODS: Five baboons that had <35% cytotoxicity against GalT-KO peripheral blood mononuclear cells (PBMCs) in a pre-screening assay received pig kidneys and vascularized thymic grafts (VT + K) from multi-transgenic hCD47, human thrombomodulin (hTBM), human endothelial protein C receptor (EPCR) with/without hCD46 and hCD55 with GalT-KO/NeuGC-KO/B4-KO (mTg Tri-KO) swine. In order to further examine the effects of anti-donor non-Gal natural antibody (nAb), anti-pig preformed IgM and IgG nAb binding against the GalT-KO PBMCs was compared with the donor-type PBMCs using donor pretransplant sera as well as 5 additional naïve baboon sera by flow cytometric analysis. RESULTS: Five baboons that received VT + K grafts had stable renal function in the first 11 days (serum creatinine < 1.5 mg/dL). Two of the five baboons had higher binding of preformed IgG to mTg Tri-KO PBMCs than to GalT-KO PBMCs (mTg Tri-KO > GalT-KO), and they rejected their grafts at POD 20. In contrast, the other three baboons demonstrated either mTg Tri-KO = GalT-KO or mTg Tri-KO < GalT-KO, and they maintained renal function 43, 52, and 154 days without rejection. Among 10 baboon sera, two had less antibody binding against PBMCs that were syngeneic to the mTg Tri-KO than against GalT-KO PBMCs (mTg Tri-KO < GalT-KO); three had similar binding to mTg Tri-KO and GalT-KO PBMCs (mTg Tri-KO = GalT-KO); and five had higher binding to m Tg Tri-KO than to GalT-KO PBMCs (mTg Tri-KO > GalT-KO). CONCLUSIONS: These data suggest that neoantigens associated with mTg Tri-KO promote acute xenograft rejection in a pig-to-baboon VT + K XTx model. The screening assays may be useful to select "safe" recipients to receive mTg Tri-KO kidneys.

Histopathology of pig kidney grafts with/without expression of the carbohydrate Neu5Gc in immunosuppressed baboons.

INTRODUCTION: Pigs deficient in three glycosyltransferase enzymes (triple-knockout [TKO] pigs, that is, not expressing the three known carbohydrate xenoantigens) and expressing 'protective' human transgenes are considered a likely source of organs for transplantation into human recipients. Some human sera have no or minimal natural antibody binding to red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) from TKO pigs. However, all Old World monkeys exhibit natural antibody binding to TKO pig cells. The xenoantigen targets of Old World monkey natural antibodies are postulated to be carbohydrate moieties exposed when the expression of the carbohydrate N-glycolylneuraminic acid (Neu5Gc) is deleted. The aim of this study was to compare the survival in baboons and histopathology of renal grafts from pigs that either (a) expressed Neu5Gc (GTKO pigs; Group 1) or (b) did not express Neu5Gc (GTKO/CMAHKO [DKO] or TKO pigs; Group 2). METHODS: Life-supporting renal transplants were carried out using GTKO (n = 5) or DKO/TKO (n = 5) pig kidneys under an anti-CD40mAb-based immunosuppressive regimen. RESULTS: Group 1 baboons survived longer than Group 2 baboons (median 237 vs. 35 days; mean 196 vs. 57 days; p < 0.07) and exhibited histopathological features of antibody-mediated rejection in only two kidneys. Group 2 exhibited histopathological features of antibody-mediated rejection in all five grafts, with IgM and IgG binding to renal interstitial arteries and peritubular capillaries. Rejection-free survival was significantly longer in Group 1 (p < 0.05). CONCLUSIONS: The absence of expression of Neu5Gc on pig kidney grafts is associated with increased binding of baboon antibodies to pig endothelium and reduced graft survival.

The baboon in epilepsy research: Revelations and challenges.

The baboon offers a natural model for genetic generalized epilepsy with photosensitivity. In this review, we will summarize some of the more important clinical, neuroimaging, and elctrophysiological findings form recent work performed at the Southwest National Primate Research Center (SNPRC, Texas Biomedical Research Institute, San Antonio, Texas), which houses the world's largest captive baboon pedigree. Due to the phylogenetic proximity of the baboon to humans, many of the findings are readily translatable, but there may be some important differences, such as the mutlifocality of the ictal and interictal epileptic discharges (IEDs) on intracranial electroencephalography (EEG) and greater parieto-occipital connectivity of baboon brain networks compared to juvenile myoclonic epilepsy in humans. Furthermore, there is still limited knowledge of the natural history of the epilepsy, which could be transformative for research into epileptogenesis in genetic generalized epilepsy (GGE) and sudden unexpected death in epilepsy (SUDEP).

Cortical responsive neurostimulation in a baboon with genetic generalized epilepsy.

OBJECTIVE: To evaluate the efficacy of cortical responsive neurostimulation (CRN) in a male baboon with epilepsy and with genetic generalized epilepsy (GGE), as well as the alteration of seizure patterns and their circadian rhythms due to treatment. METHODS: The baboon was implanted with two subdural frontoparietal strips, bridging the medial central sulci bilaterally. Electrocorticography (ECoG) data were downloaded daily during a three-month baseline, then every 2-3 days over a five-month treatment period. Long episodes, reflecting ictal or interictal epileptic discharges, were also quantified. RESULTS: Twenty-three generalized tonic-clonic seizures (GTCS) and 2 episodes of nonconvulsive status epilepticus (NCSE) were recorded at baseline (median 8 events/month), whereas 26 GTCS were recorded under treatment (median 5/month). Similarly, daily indices of long episodes decreased from 0.46 at baseline to 0.29 with treatment. Ictal ECoG patterns and the circadian distribution of GTCS were also altered by RNS therapy. SIGNIFICANCE: This case study provides the proof-of-concept for RNS therapy in the baboon model of GGE. Cortical responsive neurostimulation (CRN) demonstrated a 38% median reduction in GTCS. Distinct ictal patterns were identified, which changed over the treatment period; the circadian pattern of his GTCS also shifted gradually from night to daytime with treatment. Future studies targeting the thalamic nuclei, or combining cortical and subcortical sites, may further improve detection and control of GTCS as well as other generalized seizure types. More broadly, this study demonstrates opportunities for evaluating seizure detection as well as chronic therapeutic interventions over long term in the baboon.