Rhesus Monkeys Macaca Research Articles

Autologous transplantation of mesenchymal stromal cells tends to prevent progress of interstitial fibrosis in a rhesus Macaca mulatta monkey model of chronic kidney disease

Background aimsChronic kidney disease (CKD) attributed to cisplatin is well documented. Mesenchymal stromal cells (MSCs) are proven to be renotropic. Although they have been shown to improve function in CKD and reduce fibrosis in different experimental rodent models, their efficiency in primates is unknown. The present study aimed to evaluate the prevention of CKD and reduction of fibrosis in monkeys treated with MSCs after cisplatin nephrotoxicity. MethodsWe induced CKD in adult rhesus Macaca mulatta monkeys by means of intravenous administration of cisplatin. Autologous MSCs were transplanted by means of intrarenal arterial injections to assess the adverse effects of cisplatin in two CKD models: preventative and stable. Preventative CKD monkeys (n = 3) underwent cell transplantation 4 days after the cisplatin injection. The stable CKD monkeys (n = 2) underwent cell transplantation 6 months after the cisplatin injection. Non-treated (n = 4) and normal saline–injected animals (n = 3) comprised the control and vehicle groups, respectively. We followed the animals for survival rate, serum biochemistry, urine analysis and histopathological indices. ResultsIn the preventive CKD model, MSC transplantation tended to improve some renal functions but significantly reduced the histopathologic score compared with the vehicle and control groups. In the stable CKD model, MSCs did not ameliorate renal function or pathological score. ConclusionsThese results suggest that MSCs tend to delay progression of CKD and fibrosis but do not reduce established interstitial fibrosis in this unique primate model of cisplatin-induced nephrotoxicity.

A Reevaluation of the Question: Is the Pubertal Resurgence in Pulsatile GnRH Release in the Male Rhesus Monkey (Macaca mulatta) Associated With a Gonad-Independent Augmentation of GH Secretion?

A somatic signal has been posited to trigger the pubertal resurgence in pulsatile GnRH secretion that initiates puberty in highly evolved primates. That GH might provide such a signal emerged in 2000 as a result of a study reporting that circulating nocturnal GH concentrations in castrated juvenile male monkeys increased in a 3-week period immediately preceding the pubertal resurgence of LH secretion. The present study was conducted to reexamine this intriguing relationship, again in an agonadal model. Four castrated juvenile male monkeys were implanted with indwelling jugular catheters, housed in remote sampling cages, and subjected to 24 hours of sequential blood sampling (every 30 min) every 2 weeks from 19.5 to 22 months of age. Twenty-four-hour profiles of circulating GH concentrations were analyzed using the pulse detection algorithm, PULSAR, and developmental changes in pulsatile GH release with respect to the initiation of the pubertal rise of LH secretion (week 0; observed between 22.5 and 32 mo of age) were examined for significance by a repeated-measures ANOVA. Changes in the parameters of pulsatile GH secretion, including mean 24-hour GH concentration and GH pulse frequency and pulse amplitude for 3 (n = 4) and 6 (n = 3) months before week 0 were unremarkable and nonsignificant. These findings fail to confirm those of the earlier study and lead us to conclude that the timing of the pubertal resurgence of GnRH release in the male monkey is not dictated by GH. Reasons for the discrepancy between the two studies are unclear.

High-fat diet combined with low-dose streptozotocin injections induces metabolic syndrome in Macaca mulatta.

Metabolic syndrome (MetS) is associated with abdominal obesity, hyperlipidemia, insulin resistance, and type 2 diabetes mellitus, and increases the risk of cardiovascular disease. Given the complex multifactorial pathogenesis of MetS, qualified animal models are currently seriously limited for researchers. The aim of our study was to develop a MetS model in juvenile rhesus monkeys (Macaca mulatta). Rhesus monkeys (1-year-old) fed a high-fat diet (15 % fat, 2 % cholesterol) were used as the HF group (n = 6), and those on a normal diet (5 % fat) were used as the control group (n = 4). After being fed a high-fat diet for approximately 12 months, 2 monkeys (HF + STZ group) were injected with low-dose streptozotocin (STZ, 25 mg/kg) twice, with a 7 days interval, and were then fed the same diet continuously for another 24 months. After 36 months of treatment, the high-fat diet monkeys, including the HF and HF + STZ groups, had acquired increased body weights, abnormal serum lipids, and impaired glucose tolerance compared to the control group. In addition, much more marked metabolic changes were observed in the two monkeys of the HF + STZ group, particularly in terms of high-blood glucose level and insulin resistance. Morphological observation of biopsies of liver and pancreatic tissues showed decreased islet number and mass and decreased insulin staining in the monkeys of the HF + STZ group. In addition, Oil red O staining suggested remarkable accumulation of lipid droplets in the hepatocytes. Our study suggested that a long-term high-fat diet followed with a low-dose STZ was able to induce MetS in juvenile rhesus monkeys with faster pathophysiological progress compared with high-fat diet induction alone. Our primary data showed that this method may have potentials to develop MetS animal model in non-human primates.

Cellular immunity standard values in Macaca fascicularis.

Cellular immunity of clinically healthy Macaca fascicularis was studied by fl ow cytometry with monoclonal antibodies. Parameters of cellular immunity in Macaca fascicularis and Macaca rhesus virtually coincided and were maximally close to those in humans.

Persistence and activation of malaria hypnozoites in long-term primary hepatocyte cultures

Malaria relapses, resulting from the activation of quiescent hepatic hypnozoites of Plasmodium vivax and Plasmodium ovale, hinder global efforts to control and eliminate malaria. As primaquine, the only drug capable of eliminating hypnozoites, is unsuitable for mass administration, an alternative drug is needed urgently. Currently, analyses of hypnozoites, including screening of compounds that would eliminate them, can only be made using common macaque models, principally Macaca rhesus and Macaca fascicularis, experimentally infected with the relapsing Plasmodium cynomolgi. Here, we present a protocol for long-term in vitro cultivation of P. cynomolgi-infected M. fascicularis primary hepatocytes during which hypnozoites persist and activate to resume normal development. In a proof-of-concept experiment, we obtained evidence that exposure to an inhibitor of histone modification enzymes implicated in epigenetic control of gene expression induces an accelerated rate of hypnozoite activation. The protocol presented may further enable investigations of hypnozoite biology and the search for compounds that kill hypnozoites or disrupt their quiescence.

Influence of methamphetamine self-administration on sleep in rhesus monkeys using actigraphy

Introduction Sleep disorders and substance abuse are highly comorbid. Although methamphetamine is a very commonly abused drug, to the best of our knowledge, no study has evaluated its effects on sleep during drug use and abstinence under well- controlled conditions in laboratory animals. The objective of this study was to examine the effects of methamphetamine self-administration on sleep-like measures in nonhuman primates. Materials and methods Adult male rhesus monkeys (Macaca mulatta; n = 4) self-administered methamphetamine (0.01 and 0.03 mg/kg/injection, i.v.) under a fixed- ratio 20 schedule of reinforcement (60-min sessions once a day, 5 days per week) for 5 weeks. Sleep-like measures were evaluated with Actiwatch monitors before, during, and after each period of drug self- administration. Results Both doses of methamphetamine reliably maintained self- administration. Methamphetamine (0.03 mg/kg) increased derived measures of latency to sleep onset and sleep fragmentation, and decreased sleep efficiency compared to abstinence, and higher methamphetamine intake predicted worse sleep quality. However, sleep normalized immediately after the discontinuation of methamphetamine self-administration. Conclusion Methamphetamine markedly disrupted sleep-like measures; however, methamphetamine self-administration did not disrupt sleep quality during subsequent periods of drug abstinence. Acknowledgements This research was supported by USPHS Grants DA10344 (LLH), DA31246 (LLH), P51OD11132 (Yerkes National Primate Research Center), and by AFIP and CNPq (MLA).

Evaluating the specificity of primers employed for PCR-based diagnostics of Leishmaniases using multiple alignment analysis

The purpose of this study was to assess the specificity of distinct primers used in the molecular diagnosis for Leishmania detection by using biological sequence search and alignment tools. Four primer pairs routinely employed in the PCR-based diagnostics for Leishmaniasis detection were evaluated through the software Primer-BLAST, which compares nucleotide sequences against user-selected database to avoid primer pairs cause non-specific amplifications. The LU5A-LB3C primer pair showed good specificity among all primers analyzed, generating alignments exclusively against distinct sequences of Leishmania species and no matches were found with other parasite species. Whereas the primer pairs designated MP3H - MP1L, B1-B2 and 13A-13B demonstrated matches against distinct sequences of Leishmania strains and other species, such as Rhesus monkey (Macaca mulatta) and starlet sea anemone (Nematostella vectensis). These findings emphasize the importance of selecting suitable primers for diagnosis of molecular diseases by conducting previous screenings in order to infer their specificity and identity against target templates within biological sequence annotation database.

Methemoglobinemia In Rhesus Monkeys Due To M-Hemoglobinopathy

M-hemoglobinopathies in humans are usually due to amino acid changes, which tend to stabilize the heme iron in ferric state and inaccessible to methemoglobin reductase. Consequently, blood methemoglobin concentrations are elevated despite normal methemoglobin reductase activity. No naturally-occurring animal models for M-hemoglobinopathies have been described. In contrast to humans where thousands of hereditary disorders and genetic predispositions to disease have been described, inborn errors of metabolism in non-human primates have been very rarely documented (e.g. globoid cell leukodystrophy). As part of an NIH-supported National Referral Center for Animal Models of Human Genetic Disease, which focuses on homologous hereditary diseases in dogs and cats, we present here the discovery and characterization of an M-hemogobinopathy in rhesus monkeys (Macaca mulatta). Adult rhesus monkeys of Chinese origin with persistent cyanotic mucous membranes and healthy controls were studied from two institutions. Despite the apparent cyanosis, these primates did clinically not show any other overt signs. Routine complete blood cell counts, chemistry screens and urinalyses as well as cardiopulmonary examinations did not reveal any abnormalities. Fresh EDTA blood samples were analyzed to determine the degree and cause of methemoglobinemia and results were compared to healthy rhesus monkeys from the same institutions. Blood methemoglobin concentrations were persistently increased to 15-30% in affected monkeys, while control animals had <1% methemoglobin levels. Methemoglobin (cytochrome b5) reductase activities in erythrocytes were repeatedly measured in vitro and found to be normal compared to controls. Based upon the hemoglobin-oxygen dissociation curves and p50 values (14.8 mmHg; compared to 14.5 and 14.6 mmHg for controls) the oxygen transport function was normal. Both cation-exchange as well as reversed-phase and high performance liquid chromatography analyses revealed normal elution patterns of hemoglobin isotype and globin chains. DNA studies identified a disease-associated polymorphism in the alpha globin gene (CAC → CAA) in the affected animals. This change in the alpha globin protein was confirmed by mass spectrometry (α78 His → Gln). Our findings indicate an electrophoretically silent α-globin polymorphism is associated with methemoglobinemia in these rhesus monkeys. This is the first description of methemoglobinemia in a non-human primate and represents the first animal model of an M-hemoglobinopathy. While clinical signs were relatively mild in these rhesus monkeys, our findings represent one of the first inborn errors of metabolism described in non-human primates, thus emphasizing how unusual disorders caused by “experiments of nature” provide rare opportunities to gain a better understanding of both medicine and biology. Rhesus monkeys represent unique, valuable animal models for developing and testing new treatment options for hemoglobinopathies. Disclosures: No relevant conflicts of interest to declare.

Too Good to Be True: Rhesus Monkeys React Negatively to Better-than-Expected Offers

To succeed in a dynamically changing world, animals need to predict their environments. Humans, in fact, exhibit such a strong desire for consistency that one of the most well-established findings in social psychology is the effort people make to maintain consistency among their beliefs, attitudes, and behavior. However, displeasure with unpredictability leads to a potential paradox, because a positive outcome that exceeds one’s expectations often leads to increased subjective value and positive affect, not the opposite. We tested the hypothesis that two evolutionarily-conserved evaluation processes underlie goal-directed behavior: (1) consistency, concerned with prediction errors, and (2) valuation, concerned with outcome utility. Rhesus monkeys (Macaca mulatta) viewed a food item and then were offered an identical, better, or worse food, which they could accept or reject. The monkeys ultimately accepted all offers, attesting to the influence of the valuation process. However, they were slower to accept the unexpected offers, and they exhibited aversive reactions, especially to the better-than-expected offers, repeatedly turning their heads and looking away before accepting the food item. Our findings (a) provide evidence for two separable evaluation processes in primates, consistency and value assessment, (b) reveal a direct relationship between consistency assessment and emotional processes, and (c) show that our wariness with events that are much better than expected is shared with other social primates.

Correction: Behavioral Inhibition in Rhesus Monkeys (Macaca mulatta) Is Related to the Airways Response, but Not Immune Measures, Commonly Associated with Asthma

Correction: Behavioral Inhibition in Rhesus Monkeys (Macaca mulatta) Is Related to the Airways Response, but Not Immune Measures, Commonly Associated with Asthma

Abstract 3356: Comparative plasma and cerebrospinal (CSF) pharmacokinetics (PK) of vincristine sulfate standard preparation (VCR) and vincristine sulfate liposomes injection (VSLI) in a non-human primate (NHP) model.

Abstract Background: Vincristine has been used as standard therapy for adult and pediatric malignancies for 50 years. Cumulative neurotoxicity often requires capping the maximum single and cumulative VCR dose. VSLI is a novel preparation of VCR encapsulated in sphingomyelin/cholesterol liposomes. Following clinical trials that demonstrated safety, tolerability and efficacy in adults with relapsed/refractory acute lymphoblastic leukemia, VSLI has been granted FDA accelerated approval at a dose of 2.25 mg/m2given once weekly for that population. A pediatric Phase I trial is ongoing. We evaluated plasma and CSF PK of intravenously (IV) administered VCR and total VSLI (liposomal encapsulated and non-encapsulated) in our NHP model. Methods: 0.1 mg/kg (1.2 mg/m2 human-equivalent dose) VCR over 1 minute or VSLI over 15 minutes was administered on separate occasions to each of 3 adult rhesus monkeys (Macaca mulatta). Serial paired plasma and CSF samples were collected for up to 48 hrs. Drug concentrations were quantified using HPLC/tandem mass spectrometry assays. For plasma samples, VCR standard curves were linear over a range of .0025-10.0 μg/ml (lower limit of quantification, .0025 μg/ml). Lower limit of detection for VCR in NHP CSF was .001 μg/ml. PK parameters were estimated using non-compartmental methods. Results: Plasma PK parameters (median and range) for VCR and VSLI Cmax (μg/ml) AUC0-infinity (μg*hr/ml) Cl (ml/min) Terminal T1/2 (hours) VCR 1.07 (0.99–2.1) 0.614 (0.336–0.676) 33.8 (29.6–54) 24.3 (14.2–54.4) VSLI 4.8 (3.7–7.3) 195 (163–312) 0.089 (0.073–0.113) 17.9 (13.9–21.5) Cmax = maximal concentration, AUC = area under the concentration x time curve, Cl = clearance, T1/2 = half life VCR demonstrated a multi-exponential and VSLI a near-monoexponential plasma concentration versus time curve. The ratios ClVCR: ClVSLI for the individual NHP were 300, 463 and 477. Vincristine was not detected in any CSF sample. Conclusions: The NHP model allowed for a direct comparison of VCR and VSLI PK. VCR Cl exceeds that of VSLI by approximately 400-fold. No penetration into the CSF was observed for either preparation. Citation Format: Diane E. Cole, Cynthia M. Lester-McCully, Nirali N. Shah, Katherine E. Warren, Alan S. Wayne, Brigitte C. Widemann. Comparative plasma and cerebrospinal (CSF) pharmacokinetics (PK) of vincristine sulfate standard preparation (VCR) and vincristine sulfate liposomes injection (VSLI) in a non-human primate (NHP) model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3356. doi:10.1158/1538-7445.AM2013-3356

Modelling Niche Differentiation of Co-Existing, Elusive and Morphologically Similar Species: A Case Study of Four Macaque Species in Nakai-Nam Theun National Protected Area, Laos.

Simple SummaryWe investigated the niche separation of four macaque species (Macaca arctoides, M. assamensis, M. leonina, M. mulatta) occurring within Nakai-Nam Theun National Protected Area, central-eastern Laos using the environmental niche modelling software MaxEnt. The respective suitable habitat predicted for each species reveals niche segregation between the four species with a gradual geographical distribution following an environmental gradient of, notably, temperature, precipitation, elevation and slope within the study area. This means that the four species seem adapted to different ecological conditions within the area. This information has implications for future research on these species and for their management and conservation.Species misidentification often occurs when dealing with co-existing and morphologically similar species such as macaques, making the study of their ecology challenging. To overcome this issue, we use reliable occurrence data from camera-trap images and transect survey data to model their respective ecological niche and potential distribution locally in Nakai-Nam Theun National Protected Area (NNT NPA), central-Eastern Laos. We investigate niche differentiation of morphologically similar species using four sympatric macaque species in NNT NPA, as our model species: rhesus Macaca mulatta (Taxonomic Serial Number, TSN 180099), Northern pig-tailed M. leonina (TSN not listed); Assamese M. assamensis (TSN 573018) and stump-tailed M. arctoides (TSN 573017). We examine the implications for their conservation. We obtained occurrence data of macaque species from systematic 2006–2011 camera-trapping surveys and 2011–2012 transect surveys and model their niche and potential distribution with MaxEnt software using 25 environmental and topographic variables. The respective suitable habitat predicted for each species reveals niche segregation between the four species with a gradual geographical distribution following an environmental gradient within the study area. Camera-trapping positioned at many locations can increase elusive-species records with a relatively reduced and more systematic sampling effort and provide reliable species occurrence data. These can be used for environmental niche modelling to study niche segregation of morphologically similar species in areas where their distribution remains uncertain. Examining unresolved species’ niches and potential distributions can have crucial implications for future research and species’ management and conservation even in the most remote regions and for the least-known species.

Monkeys would rather see and do: preference for agentic control in rhesus macaques

Rhesus monkeys (Macaca mulatta) engaged in a series of computerized tasks modeled on billiards and arcade games in order to determine their degree of preference for scenarios in which food rewards were contingent on their actions, as opposed to those in which outcomes appeared externally caused. Throughout these tasks, subjects showed a consistent preference for "agentic control," a state in which goal-directed behavior is directly responsible for motivating outcomes. Other factors like the frequency and timing of reward deliveries were precisely controlled and did not explain observed preferences.

The prolonged gastrointestinal syndrome in rhesus macaques: the relationship between gastrointestinal, hematopoietic, and delayed multi-organ sequelae following acute, potentially lethal, partial-body irradiation.

The dose response relationship for the acute gastrointestinal syndrome following total-body irradiation prevents analysis of the full recovery and damage to the gastrointestinal system, since all animals succumb to the subsequent 100% lethal hematopoietic syndrome. A partial-body irradiation model with 5% bone marrow sparing was established to investigate the prolonged effects of high-dose radiation on the gastrointestinal system, as well as the concomitant hematopoietic syndrome and other multi-organ injury including the lung. Herein, cellular and clinical parameters link acute and delayed coincident sequelae to radiation dose and time course post-exposure. Male rhesus Macaca mulatta were exposed to partial-body irradiation with 5% bone marrow (tibiae, ankles, feet) sparing using 6 MV linear accelerator photons at a dose rate of 0.80 Gy min(-1) to midline tissue (thorax) doses in the exposure range of 9.0 to 12.5 Gy. Following irradiation, all animals were monitored for multiple organ-specific parameters for 180 d. Animals were administered medical management including administration of intravenous fluids, antiemetics, prophylactic antibiotics, blood transfusions, antidiarrheals, supplemental nutrition, and analgesics. The primary endpoint was survival at 15, 60, or 180 d post-exposure. Secondary endpoints included evaluation of dehydration, diarrhea, hematologic parameters, respiratory distress, histology of small and large intestine, lung radiographs, and mean survival time of decedents. Dose- and time-dependent mortality defined several organ-specific sequelae, with LD50/15 of 11.95 Gy, LD50/60 of 11.01 Gy, and LD50/180 of 9.73 Gy for respective acute gastrointestinal, combined hematopoietic and gastrointestinal, and multi-organ delayed injury to include the lung. This model allows analysis of concomitant multi-organ sequelae, thus providing a link between acute and delayed radiation effects. Specific and multi-organ medical countermeasures can be assessed for efficacy and interaction during the concomitant evolution of acute and delayed key organ-specific subsyndromes.

Intuitive statistics in non-human primates

Fig 1. Schematic of basic set up Fig 3. shows animals‘ choice behavior as percent of animals who chose correct/incorrect out of 12 across all four experiments. In each experiment, animals chose the sample with the greater likelihood of containing their preferred item (Correct) significantly more often than the sample containing their non-preferred item (Incorrect). [1] Xu, F. & Garcia, V. (2008). Intuitive Statistics by 8-month-old infants. PNAS, 105, 5012-15. [2] Xu, F. & Denison, S. (2009). Statistical inference and sensitivity to sampling in 11-month-old infants.Cognition 112, 97-104. [3] Teglas, E., Girotto, V., Gonzalez, M.,& Bonatti, L.L. (2007). Intuitions of probabilities shape expectations about the future at 12 months and beyond. PNAS 104, 19156 -59. [4] Hauser, M., MacNeilage, P & Ware, M. (1996). Numerical representations in primates. PNAS 9, 1514-17. [5] Flombaum, J.I., Junge, J.A. & Hauser, M.D.(2005). Rhesus monkeys (Macaca mulatta) spontaneously compute addition operations over large numbers. Cognition 97, 315 -25. Fig 2. Schematic of item distributions (banana pellets:carrot pieces) used in each experiment.

The delivery of tyrosine hydroxylase accelerates the neurorestoration of Macaca Rhesus model of Parkinson's disease provided by Neurturin

Neurturin (NTN) is a desired candidate therapeutic gene for PD treatment, however, only neuroprotective effect may not work for PD clinical remission due to nearly 50% of the dopaminergic neurons have died way when symptoms appear. In this study, we constructed a bicistronic adenovirus expressing both Neurturin and tyrosine hydroxylase (TH). We hypothesized that the expression of NTN could provide neuroprotection to dopaminergic neurons and stop progressive neurodegeneration, while TH enhanced the synthesis of dopamine and accelerated the recovery of Parkinsonism. The chimeric adenovirus have been prepared and assayed in vitro and delivered into the target nucleuses of PD Macaca Rhesus models by MRI based stereotaxic injection. The observation assessments and physiological results indicated that compared to the group treated with NTN only, instant behavior recovery was seen after bicistronic adenovirus infusion. Although both groups displayed neuroprotection of dopaminergic neurons finally, the addition of TH genuinely accelerated animal behavior recovery, which showed great potential for clinical application.

Abstract 2430: PET imaging of c-Met expression in non-human primates using [18F]AH113804

Abstract [18F]AH113804 is a peptide based molecular imaging agent with high affinity for the human c-Met receptor. The objective of this study was to investigate the biodistribution, specific uptake and elimination of [18F]AH113804 in the non-human primate. Cynomolgus monkey (Macaca fascicularis) was selected since [18F]AH113804 retains high affinity to c-Met in this species. The route of administration was intravenous as this is the route of administration in humans. The target compound was prepared in a two-step synthesis route starting with synthesis of 4-[18F]fluorobenzaldehyde which was reacted with the peptide precursor to produce the corresponding oxime. Following semipreparative HPLC purification the pure product was obtained. Frozen section autoradiography using Rhesus monkey (Macaca mulatta) liver (relatively high c-Met expression) and muscle (relatively low c-Met) was performed in PBS buffer with [18F]AH113804 (2.5 kBq/ml) and with and without 0.5 μg/ml of AH113804 to establish specific binding in vitro. In vivo dynamic and repeated whole body PET/CT [18F]AH113804 imaging was performed (GE Discovery16 ST scanner, General Electric, USA), in female Cynomolgus monkeys (n=3) before and after administration of 0.15 mg/ml AH113804 or AH112361 (a scrambled peptide i.e. a negative control). The binding of [18F]AH113804 in Rhesus monkey liver sections was blocked by 40% following co-incubation of unlabelled AH113804 (>1000-fold excess) whereas binding in muscle was unaffected. This result demonstrated specific binding in vitro in Rhesus monkey liver with a certain amount of unspecific binding. In vivo PET imaging studies in the Cynomolgus monkey showed rapid uptake in liver which was reduced by 42% after co-injection of 0.15 mg/kg of AH113804. Consistent with in vitro results, there was no noteworthy muscle retention in vivo. In liver the individual SUV varied but the magnitude of effect by blockade was similar. The ratio of baseline to blockade scans in liver was 1.7, suggesting the presence of specific binding. [18F]AH113804 uptake in liver or muscle was however not significantly reduced after co-injection of 0.15 mg/kg of AH112361 (negative control), the ratio of baseline and blockade scans in liver was <1.25. These results further confirmed that the reduction in [18F]AH113804 liver uptake and retention observed after competition with non-radioactive AH113804 reflects specific binding of [18F]AH113804. Dynamic distribution studies showed a rapid uptake in liver and kidney and mainly urinary excretion. There were no obvious effects on body temperature, blood pressure or heart rate following co-injection of 0.15 mg/kg of AH113804. Overall, these results confirmed that [18F]AH113804 has desirable properties for a c-Met targeted molecular imaging agent. Since there are a number of anti-c-Met therapies in clinical development, [18F]AH113804 has potential to be used as an aid in therapy selection and/or monitoring. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2430. doi:1538-7445.AM2012-2430

Differential Response of the Primate HPG Axis to N-Methyl-d, l-aspartate, but not to Kisspeptin Challenge under Euglycemic and Hypoglycemic Conditions

Hypoglycemia inhibits the hypothalamic-pituitary-gonadal (HPG) axis by still incompletely deciphered mechanisms. Many evidences suggest that the hypoglycemia-induced inhibition of the HPG axis involves alteration of the hypothalamic gonadotropin-releasing hormone (GnRH) release, but neuroendocrine factors responsible for this alteration are yet to be completely elucidated. The current study was carried out to ascertain whether insulin-induced hypoglycemic suppression of the HPG axis involves modulation of responsiveness of the GnRH neuron to kisspeptin and excitatory amino acids (EAA) drives. Five intact chair-restraint habituated adult male rhesus monkeys (Macaca mulatta) were given intravenous boli of GnRH, hCG, human kisspeptin-10 (KP10), NMDA (N-methyl-D, L-aspartate, an EAA analogue), and vehicle in both insulin (1 IU/kg)-induced hypoglycemic (IIH) and normal euglycemic conditions. Specific RIAs were used for measuring plasma cortisol and T concentrations. KP10 and NMDA administration stimulated significantly (p<0.005) T secretion in both euglycemic and hypoglycemic monkeys. Mean post-KP10 T concentrations and AUC were comparable between euglycemic and hypoglycemic monkeys. However, mean post-NMDA T levels and AUC in hypoglycemic animals were significantly lower (p<0.01-0.005) as compared to the corresponding values in euglycemic animals. T response to GnRH and hCG was similar between hypoglycemic and euglycemic monkeys. Vehicle did not affect plasma T concentrations in all conditions. Our results demonstrate that while the primate HPG axis response to kisspeptin stimulation remains intact that to EAA excitation is attenuated in hypoglycemic conditions, suggesting that hypogonadism in IIH is contributed, in part, by reduced sensitivity of the GnRH neurons to EAA signaling in the primate hypothalamus.

Islet microarchitecture and glucose transporter expression of the pancreas of the marmoset monkey display similarities to the human

The common marmoset New World monkey (Callithrix jacchus), is a primate model with great potential for scientific research, including research on diabetes. However, in opposite to Rhesus and Java monkeys (Macaca mulatta and Macaca fascicularis) little is known about the marmosets islet microarchitecture, glucose transporter and pancreatic marker gene expression. In this work we analyze differences and similarities in size, shape, cellular composition and intra-islet topography between the common marmoset and the human endocrine pancreas. Different sized, circular and a-circular shaped islets of the common marmoset and human display α-cells in the whole islet organ leading to a ribbon-like islet type. The number of islets was significantly higher in the common marmoset compared with humans. However, the area of insulin-producing cells was significantly higher in the human pancreas. Intra-islet distribution pattern of δ- and β-cells was similar in both species. The morphology of the exocrine pancreas regarding acinar and ductal cells was quite similar as confirmed by ultrastructural analysis. Additionally the ultrastructure of secretory granules from α-, δ- and β-cells of human and non-human primate pancreas showed the same characteristics. Molecular analysis showed the presence of endocrine pancreatic marker genes like PMCA2, NCX1, SUR1, KIR6.2, MAFA, NGN3 and PDX1 also expressed in the human. For the first time we could show presence of Glut 5 and 9 transporters in addition to the low abundance transporter Glut2 and the highly expressed Glut1 glucose transporter. We propose that Callithrix jacchus displays a new animal model for diabetes research and regenerative medicine.

Neural basis of feature-based contextual effects on visual search behavior

Searching for a visual object is known to be adaptable to context, and it is thought to result from the selection of neural representations distributed on a visual salience map, wherein stimulus-driven and goal-directed signals are combined. Here we investigated the neural basis of this adaptability by recording superior colliculus (SC) neurons while three female rhesus monkeys (Macaca mulatta) searched with saccadic eye movements for a target presented in an array of visual stimuli whose feature composition varied from trial to trial. We found that sensory-motor activity associated with distracters was enhanced or suppressed depending on the search array composition and that it corresponded to the monkey's search strategy, as assessed by the distribution of the occasional errant saccades. This feature-related modulation occurred independently from the saccade goal and facilitated the process of saccade target selection. We also observed feature-related enhancement in the activity associated with distracters that had been the search target during the previous session. Consistent with recurrent processing, both feature-related neuronal modulations occurred more than 60 ms after the onset of the visually evoked responses, and their near coincidence with the time of saccade target selection suggests that they are integral to this process. These results suggest that SC neuronal activity is shaped by the visual context as dictated by both stimulus-driven and goal-directed signals. Given the close proximity of the SC to the motor circuit, our findings suggest a direct link between perception and action and no need for distinct salience and motor maps.