Quality of Life Assessment: The Value of Longitudinal Data in Making the End-of-Life Care Decision for a Macaque (Macaca Silenus/Macaca Nemestrina).

Assessing quality of life in animals is an art as much as a science. Despite the use of questionnaires and keeper reports which consider several aspects of well-being, the process often remains subjective. Keepers have unique insights, and anecdotal observations can be enhanced with objective data. We combined the art and science of assessments in this study on a geriatric macaque (1.0 lion-tailed/pig-tailed (Macaca silenus/macaca nemestrina) hybrid), using historic data to inform management decisions. Following the unexpected death of his cage mate, his activity and engagement with keepers decreased, and new concerning behaviors presented. While the zoo worked to identify new social opportunities, we used these data to develop a plan to improve his quality of life (e.g., increase training sessions, enrichment, social interactions). After intense implementation, we saw a significant increase in activity level and engagement with keepers; the frequency of unexpected behaviors suggesting a lower quality of life, however, increased over time. Our data allowed us to objectively compare changes in behavior, enabling the zoo to make the most informed animal management decision possible. [Figure: see text].

Molecular confirmation and anthelmintic efficacy assessment against natural trichurid infections in zoo-housed non-human primates.

INTRODUCTION: This study aimed to assess Trichuris species infection and evaluate the anthelmintic efficacy of fenbendazole and ivermectin against natural trichurid infections in non-human primates (NHPs), kept at Mahendra Chaudhury (MC) Zoological Park, Chhatbir, India. MATERIALS AND METHODS: Molecular confirmation of Trichuris infection was carried out using polymerase chain reaction targeting internal transcribed spacer sequences, and anthelmintic efficacy was assessed by fecal egg count reduction test, respectively. RESULTS: A 710 base pair product confirmed Trichuris species infection in NHPs. Fenbendazole, 10 mg/kg body weight orally for 5 consecutive days and ivermectin, 100 µg/kg body weight orally for 3 alternate days proved effective and showed a maximum fecal egg reduction of 99.20% and 100% (P < .05) at day 7 post-treatment. CONCLUSIONS: This study highlighted the molecular confirmation of Trichuris species in non-human primates and its management using fenbendazole and ivermectin.

Sparse code of conflict in a primate society.

Animals living in groups collectively produce social structure. In this context individuals make strategic decisions about when to cooperate and compete. This requires that individuals can perceive patterns in collective dynamics, but how this pattern extraction occurs is unclear. Our goal is to identify a model that extracts meaningful social patterns from a behavioral time series while remaining cognitively parsimonious by making the fewest demands on memory. Using fine-grained conflict data from macaques, we show that sparse coding, an important principle of neural compression, is an effective method for compressing collective behavior. The sparse code is shown to be efficient, predictive, and socially meaningful. In our monkey society, the sparse code of conflict is composed of related individuals, the policers, and the alpha female. Our results suggest that sparse coding is a natural technique for pattern extraction when cognitive constraints and small sample sizes limit the complexity of inferential models. Our approach highlights the need for cognitive experiments addressing how individuals perceive collective features of social organization.

Multiple time-scales and the developmental dynamics of social systems.

To build a theory of social complexity, we need to understand how aggregate social properties arise from individual interaction rules. Here, I review a body of work on the developmental dynamics of pigtailed macaque social organization and conflict management that provides insight into the mechanistic causes of multi-scale social systems. In this model system coarse-grained, statistical representations of collective dynamics are more predictive of the future state of the system than the constantly in-flux behavioural patterns at the individual level. The data suggest that individuals can perceive and use these representations for strategical decision-making. As an interaction history accumulates the coarse-grained representations consolidate. This constrains individual behaviour and provides the foundations for new levels of organization. The time-scales on which these representations change impact whether the consolidating higher-levels can be modified by individuals and collectively. The time-scales appear to be a function of the 'coarseness' of the representations and the character of the collective dynamics over which they are averages. The data suggest that an advantage of multiple timescales is that they allow social systems to balance tradeoffs between predictability and adaptability. I briefly discuss the implications of these findings for cognition, social niche construction and the evolution of new levels of organization in biological systems.

Longitudinal assessment of pigtailed macaque lower genital tract microbiota by pyrosequencing reveals dissimilarity to the genital microbiota of healthy humans.

Vaginal bacterial communities play an important role in human health and have been shown to influence HIV infection. Pigtailed macaques (Macaca nemestrina) are used as an animal model of HIV vaginal infection of women. Since the bacterial microbiota could influence retrovirus infection of pigtailed macaques, the genital microbiota in 10 cycling macaques was determined by pyrosequencing. The microbiota of all macaques was polymicrobial with a median of 13 distinct genera. Strikingly, the genera Sneathia and Fusobacterium, both in the phylum Fusobacteria, accounted for 18.9% and 13.3% of sequences while the next most frequent were Prevotella (5.6%), Porphyromonas (4.1%), Atopobium (3.6%), and Parvimonas (2.6%). Sequences corresponding to Lactobacillus comprised only 2.2% of sequences on average and were essentially all L. amylovorus. Longitudinal sampling of the 10 macaques over an 8-week period, which spanned at least one full ovulatory cycle, showed a generally stable presence of the major types of bacteria with some exceptions. These studies show that the microbiota of the pigtailed macaques is substantially dissimilar to that found in most healthy humans, where the genital microbiota is usually dominated by Lactobacillus sp. The polymicrobial makeup of the macaque bacterial populations, the paucity of lactobacilli, and the specific types of bacteria present suggest that the pigtailed macaque microbiota could influence vaginal retrovirus infection.

Inductive game theory and the dynamics of animal conflict.

Conflict destabilizes social interactions and impedes cooperation at multiple scales of biological organization. Of fundamental interest are the causes of turbulent periods of conflict. We analyze conflict dynamics in an monkey society model system. We develop a technique, Inductive Game Theory, to extract directly from time-series data the decision-making strategies used by individuals and groups. This technique uses Monte Carlo simulation to test alternative causal models of conflict dynamics. We find individuals base their decision to fight on memory of social factors, not on short timescale ecological resource competition. Furthermore, the social assessments on which these decisions are based are triadic (self in relation to another pair of individuals), not pairwise. We show that this triadic decision making causes long conflict cascades and that there is a high population cost of the large fights associated with these cascades. These results suggest that individual agency has been over-emphasized in the social evolution of complex aggregates, and that pair-wise formalisms are inadequate. An appreciation of the empirical foundations of the collective dynamics of conflict is a crucial step towards its effective management.

In vivo fitness costs of different Gag CD8 T-cell escape mutant simian-human immunodeficiency viruses for macaques.

The kinetics of immune escape and reversion depend upon the efficiency of CD8 cytotoxic T lymphocytes (CTL) and the fitness cost of escape mutations. Escape kinetics of three simian immunodeficiency virus Gag CTL epitopes in pigtail macaques were variable; those of KP9 and AF9 were faster than those of KW9. Kinetics of reversion of escape mutant virus to wild type upon passage to naïve major histocompatibility complex-mismatched macaques also varied. Rapid reversion occurred at KP9, gradual biphasic reversion occurred at AF9, and escape mutant KW9 virus failed to revert. The fitness impact of these mutations is KP9 > AF9 > KW9. These data provide insights into the differential utility of CTL in controlling viremia.

Use of human nasal cannulas during bronchoscopy procedures as a simple method for maintaining adequate oxygen saturation in pigtailed macaques (Macaca nemestrina).

Rising concerns over respiratory illnesses caused by agents such as avian influenza viruses and SARS coronavirus have prompted intensive research efforts and the resurgence of nonhuman primates as models for these human diseases. In the context of studying influenza infection and vaccine development, serial bronchoscopic procedures, including bronchial brush biopsies and bronchoalveolar lavage, were performed in pigtailed macaques (Macaca nemestrina). The possible need for oxygen supplementation during these procedures was anticipated because of the size of the animals relative to the 5-mm bronchoscope. We therefore monitored oxyhemoglobin saturation, a measure of arterial blood oxygen content, before and after insertion of the bronchoscope, during bronchoalveolar lavage, and after initiation of oxygen supplementation. Although more data are required to draw definitive conclusions, our findings suggested the need for oxygen supplementation during such procedures in nonhuman primates, despite the fact that human patients undergoing bronchoscopy and lavage do not routinely get oxygen unless they are already compromised. Our data also suggested that the need for supplementation could not be predicted from simple parameters such as size of the animal, presence of respiratory clinical signs, or experimental treatment. Finally, we show a simple and cost-effective method of using human nasal cannulas for delivering oxygen to pigtailed macaques during bronchoscopic procedures, and we believe that, after further testing, this method could be used safely and effectively in other nonhuman primate species.

Robustness mechanisms in primate societies: a perturbation study.

Conflict management mechanisms have a direct, critical effect on system robustness because they mitigate conflict intensity and help repair damaged relationships. However, robustness mechanisms can also have indirect effects on system integrity by facilitating interactions among components. We explore the indirect role that conflict management mechanisms play in the maintenance of social system robustness, using a perturbation technique to 'knockout' components responsible for effective conflict management. We explore the effects of knockout on pigtailed macaque (Macaca nemestrina) social organization, using a captive group of 84 individuals. This system is ideal in addressing this question because there is heterogeneity in performance of conflict management. Consequently, conflict managers can be easily removed without disrupting other control structures. We find that powerful conflict managers are essential in maintaining social order for the benefit of all members of society. We show that knockout of components responsible for conflict management results in system destabilization by significantly increasing mean levels of conflict and aggression, decreasing socio-positive interaction and decreasing the operation of repair mechanisms.

Rapid viral escape at an immunodominant simian-human immunodeficiency virus cytotoxic T-lymphocyte epitope exacts a dramatic fitness cost.

Escape from specific T-cell responses contributes to the progression of human immunodeficiency virus type 1 (HIV-1) infection. T-cell escape viral variants are retained following HIV-1 transmission between major histocompatibility complex (MHC)-matched individuals. However, reversion to wild type can occur following transmission to MHC-mismatched hosts in the absence of cytotoxic T-lymphocyte (CTL) pressure, due to the reduced fitness of the escape mutant virus. We estimated both the strength of immune selection and the fitness cost of escape variants by studying the rates of T-cell escape and reversion in pigtail macaques. Near-complete replacement of wild-type with T-cell escape viral variants at an immunodominant simian immunodeficiency virus Gag epitope KP9 occurred rapidly (over 7 days) following infection of pigtail macaques with SHIVSF162P3. Another challenge virus, SHIVmn229, previously serially passaged through pigtail macaques, contained a KP9 escape mutation in 40/44 clones sequenced from the challenge stock. When six KP9-responding animals were infected with this virus, the escape mutation was maintained. By contrast, in animals not responding to KP9, rapid reversion of the K165R mutation occurred over 2 weeks after infection. The rapidity of reversion to the wild-type sequence suggests a significant fitness cost of the T-cell escape mutant. Quantifying both the selection pressure exerted by CTL and the fitness costs of escape mutation has important implications for the development of CTL-based vaccine strategies.

Social structure, robustness, and policing cost in a cognitively sophisticated species.

Conflict management is one of the primary requirements for social complexity. Of the many forms of conflict management, one of the rarest and most interesting is third-party policing, or intervening impartially to control conflict. Third-party policing should be hard to evolve because policers personally pay a cost for intervening, while the benefits are diffused over the whole group. In this study we investigate the incidence and costs of policing in a primate society. We report quantitative evidence of non-kin policing in the nonhuman primate, the pigtailed macaque. We find that policing is effective at reducing the intensity of or terminating conflict when performed by the most powerful individuals. We define a measure, social power consensus, that predicts effective low-cost interventions by powerful individuals and ineffective, relatively costly interventions by low-power individuals. Finally, we develop a simple probabilistic model to explore whether the degree to which policing can effectively reduce the societal cost of conflict is dependent on variance in the distribution of power. Our data and simple model suggest that third-party policing effectiveness and cost are dependent on power structure and might emerge only in societies with high variance in power.

Markovian models for the developmental study of social behavior.

Behavioral development involves changes in the probabilities of both social and nonsocial activities and the sequential pattern of activities over time. A number of methods have been offered for the analysis of these patterns of behavioral sequences. However, there continue to be problematic issues, including the analysis of nonstationary data; accommodation of changes in patterns within an observation period, or over repeated observations or age; and identification of differences in pattern changes between individuals or groups, and the factors responsible for these differences. In this work, we analyze data from 15 young monkeys (Macaca nemestrina) using classification and Markovian methods, including a new approach to nonstationary data called the double-chain Markov model (DCCM). These methods allowed us to identify differences in behavior patterns that differentiate between normal subjects and those presenting developmental anomalies.

Use of herpesvirus saimiri-immortalized macaque CD4(+) T cell clones as stimulators and targets for assessment of CTL responses in macaque/AIDS models.

Herpesvirus saimiri (HVS), a nonhuman primate gamma herpes virus, was used to immortalize pig-tailed macaque CD4(+) T lymphocytes. The HVS-immortalized T cell lines were used to develop CD4(+) T cell clones from two animals. Three CD4(+) T cell clones were further characterized for the expression of cell surface markers. All expressed CD2, CD4, CD58, CD69 and CD80 and therefore resembled activated T cells. These clones required exogenous IL-2 for efficient growth and were found to be highly susceptible to infection by the challenge virus, Chimeric simian/human immunodeficiency virus (SHIV(KU-1)). They could also be productively infected not only by the quasispecies of the challenge virus (SHIV(KU-1/PDJ) and SHIV(KU-1/PNA), isolated from macaque PDj and PNa, respectively) but also by a different chimeric simian/human immunodeficiency virus (SHIV(89.6P)) and simian immunodeficiency virus (SIV(MAC239)). The virus-infected CD4(+) T cell clones were also used as stimulators for generation of CTL effectors. These effectors exhibited excellent virus-specific lysis in chromium-release assays when syngenic SHIV(KU-1) infected autologous CD4(+) T cell clones were used as targets. The target cell lysis was virus specific, as uninfected control cells showed no or minimal lysis.

Assessment of fetal and placental blood flow in primates using contrast enhanced ultrasonography.

Ultrasonographic contrast agents that stay within the vascular space and do not cross the placenta may permit differentiation between the maternal and fetal portions of the placenta and may be clinically useful for diagnosis of placental abnormalities. This study was performed to assess the effects of Levovist (Schering AG, Berlin) on the placental circulation and to determine whether hemodynamic effects on the fetus occur. Ten studies were performed in five pregnant macaques (median weight, 9.15 kg; range, 6.15 to 11 kg; median gestational age, 121 days; range, 34 days to term) under anesthesia. Gray scale, color, and duplex Doppler sonographic scans of the fetus and placenta were acquired using a 5 MHz curved array transducer. Fetal heart rate, resistive index, and systolic-diastolic ratios were measured in the fetal middle cerebral artery, aorta, umbilical artery, and uterine artery before and after administration of contrast agent. The following dose regimen was tested: 5 ml of physiologic saline solution followed by 0.1 ml/kg of 300 mg/ml Levovist (diagnostic dose), 0.5 ml/kg of 400 mg/ml Levovist (maximum dose), and 5 ml physiologic saline solution. The order of diagnostic dose and maximal dose was randomized among animals. Color enhancement of the basal portions of the placenta was documented after administration of contrast agent. Heart rate and middle cerebral artery systolic-diastolic ratio did not change between baseline and injections. A 7% decrease of the resistive index from baseline to maximum dose was measured in the uterine artery (not significant). A 7.7% decrease in the systolic-diastolic ratio from baseline to maximum dose was recorded in the umbilical artery. However, an identical change was measured after saline solution was injected. The resistive index in the aorta increased by 2.6% from baseline to maximum dose, a change that was not significant (P > 0.5). Ultrasonographic contrast enhancement of the maternal circulation in placenta is demonstrated to be without significant effects on the fetal circulation as measured in this limited population.

6-[18F]fluoro-L-dopa metabolism in MPTP-treated monkeys: assessment of tracer methodologies for positron emission tomography.

6-[18F]Fluoro-L-DOPA (FDOPA) is an L-DOPA analog that is used to assess the functional integrity of central dopaminergic systems in vivo with positron emission tomography (PET). FDOPA metabolites from putamen of normal and MPTP-treated monkeys were characterized to correlate FDOPA metabolism changes with those of the endogenous dopamine system. In MPTP-lesioned putamen, 6-[18F]fluorodopamine and dopamine levels were less than 2% those of controls. Increases in endogenous dopamine metabolism were reflected by similar increases in 6-[18F]fluorodopamine metabolites. These results suggest that changes in the central dopamine system biochemistry can be monitored in vivo with FDOPA and PET.

Functional arterial changes in chronic cerebrovasospasm in monkeys: an in vitro assessment of the contribution to arterial narrowing.

Cerebral arteries from monkeys with chronic cerebral vasospasm arising from experimental subarachnoid hemorrhage produced 5-6 days previously were examined for changes in their functional properties in an attempt to understand the basis of the narrowing. Hemorrhage was caused by puncture of the internal carotid artery just proximal to the circle of Willis. Segments taken close to the origins of the anterior and middle cerebral arteries consistently showed decreased distensibility. In addition, they exhibited large, prolonged, spontaneous increases in muscle tone. Other alterations observed include a marked reduction in the capacity of the vessel wall to contract, reduction in constrictor and dilator nerve influences on vascular tone, and some increased sensitivity to serotonin. Small pial arteries (150-200 micron o.d.) from the side of the injury showed large spontaneous irregular increases in tone. It is proposed that 5-6 days after experimental subarachnoid hemorrhage in monkeys the change most responsible for persistent narrowing in the larger arteries is an increased rigidity of the vessel wall. This is probably caused by an inflammatory response. In the smaller arteries, abnormal spontaneous contractile activity is a major factor in narrowing. This activity is not stretch-dependent. We suggest that the initial cause of the arterial narrowing after hemorrhage is the action of vasoactive substances released in the close vicinity of the arterial wall, which lead to tissue damage, abnormal tone, and an inflammatory response with fibrosis.

Experimental chronic cerebrovascular spasm in the monkey: an assessment of the functional changes in the cerebral arteries and their protection by diltiazem.

The structure and function of cerebral arteries obtained from a monkey model of chronic cerebral vascular spasm 5 days after hemorrhage have been examined. Narrowing of the larger cerebral arteries demonstrated by angiography at all sites of measurement seems to be due primarily to an increased wall rigidity associated with cellular damage, the resultant inflammatory response and large, long-lasting spontaneous increases in muscle tone. Changes in agonist sensitivity were extremely variable. The reduction of contractility of the vessel wall to a mean of 30% of control diminished the consequence of any changes in active tone characteristics. Neurogenic control on the side of the lesion was remarkably depressed. When treated with diltiazem, beginning 1 day before induction of hemorrhage and continuing to the time of sacrifice, arterial diameter was reduced at only 1 of the 6 standard sites of measurement and then by only a small amount. Neurologic effects invariably seen in the untreated monkeys were prevented by diltiazem. Many of the changes in the artery wall, including structural alterations, were diminished by the drug. Abnormal spontaneous myogenic tone was present but was less in the diltiazem-treated group; however, nerve damage and its functional consequences were not prevented. It is concluded that diltiazem, presumably by preventing the accumulation of intracellular calcium within the cell, prevents the initial events in the evolution of chronic cerebrovasospasm or narrowing. This is probably achieved by a diminishing of the direct vasoconstrictor effects and the toxicity of putative spasmogens released from blood clots, nerves and the brain on the vascular smooth muscle, thus interrupting the sequence leading to pathologic change.