Odontogenic abscesses in rhesus macaques (Macaca mulatta) of Cayo Santiago.

OBJECTIVES: Odontogenic abscesses are one of the most common dental diseases causing maxillofacial skeletal lesions. They affect the individual's ability to maintain the dental structures necessary to obtain adequate nutrition for survival and reproduction. In this study, the prevalence and pattern of odontogenic abscesses in relation to age, sex, matriline, and living periods were investigated in adult rhesus macaque skeletons of the free-ranging colony on Cayo Santiago, Puerto Rico. MATERIALS AND METHODS: The skulls used for this study were from the skeletons of 752 adult rhesus macaques, aged 8-31 years, and born between 1951 and 2000. They came from 66 matrilines ranging from 1 to 88 individuals. Fistulae or skeletal lesions caused by odontogenic abscesses drainage, carious lesions, tooth fractures, tooth loss, and alveolar resorption were evaluated visually. RESULTS: Seventy-two specimens (9.57%) had odontogenic abscesses of varying severity. Males had a significantly higher prevalence than females. The prevalence of odontogenic abscesses in several matrilines was significantly higher than in the population as a whole. Animals born between 1950 and 1965 tended to have a higher prevalence of odontogenic abscesses than those born in later periods. DISCUSSION: These results suggest that oral pathologies, such as dental and periodontal abscesses in rhesus macaques are fairly common, which may indicate familial effects interwoven with ecological and social factors. The closeness of the rhesus and human genomes allows insights to understand of the epidemiology of these diseases in the human population. Further assessment of the role played by environmental and familial factors on rhesus oral health and disease are warranted.

Locomotor effects of a low-frequency fire alarm on C57BL/6 male mice: a preliminary study.

Maintaining appropriate acoustic conditions for animal welfare and data collection are crucial in biomedical research facilities. Negative impacts of disruptive sound are known and can include auditory damage, immune function changes, and behavioral alterations. One type of disruptive sound occurring in research facilities is that of fire alarms. To ameliorate this problem, many facilities have incorporated the use of low-frequency fire alarms that emit tones outside the rodent audible range. The impact of these devices has been assumed to be negligible. However, this has yet to be evaluated with controlled behavioral experiments. Thus, our objective was to investigate the impact of low-frequency fire alarm exposure on locomotor behavior in the open field, a test sensitive to acoustic stimuli disruption. Male mice were randomized to three alarm exposure groups (No-Alarm; Alarm-During; and Alarm-After) and placed in individual photobeam-activated locomotor chambers. The Alarm-During group displayed significantly reduced horizontal locomotion, with a trend towards reduced vertical locomotion. These data suggest that a low-frequency brief alarm tone can temporarily disrupt movement, a valuable insight should an alarm be deployed. Further, findings support close collaboration between researchers and institutional facility staff to ensure appropriate acoustic conditions are maintained, whenever possible, for research animals.

Mitochondrial Impairment in Cerebrovascular Endothelial Cells is Involved in the Correlation between Body Temperature and Stroke Severity.

Stroke is the second leading cause of death worldwide. The prognostic influence of body temperature on acute stroke in patients has been recently reported; however, hypothermia has confounded experimental results in animal stroke models. This work aimed to investigate how body temperature could prognose stroke severity as well as reveal a possible mitochondrial mechanism in the association of body temperature and stroke severity. Lipopolysaccharide (LPS) compromises mitochondrial oxidative phosphorylation in cerebrovascular endothelial cells (CVECs) and worsens murine experimental stroke. In this study, we report that LPS (0.1 mg/kg) exacerbates stroke infarction and neurological deficits, in the mean time LPS causes temporary hypothermia in the hyperacute stage during 6 hours post-stroke. Lower body temperature is associated with worse infarction and higher neurological deficit score in the LPS-stroke study. However, warming of the LPS-stroke mice compromises animal survival. Furthermore, a high dose of LPS (2 mg/kg) worsens neurological deficits, but causes persistent severe hypothermia that conceals the LPS exacerbation of stroke infarction. Mitochondrial respiratory chain complex I inhibitor, rotenone, replicates the data profile of the LPS-stroke study. Moreover, we have confirmed that rotenone compromises mitochondrial oxidative phosphorylation in CVECs. Lastly, the pooled data analyses of a large sample size (n=353) demonstrate that stroke mice have lower body temperature compared to sham mice within 6 hours post-surgery; the body temperature is significantly correlated with stroke outcomes; linear regression shows that lower body temperature is significantly associated with higher neurological scores and larger infarct volume. We conclude that post-stroke body temperature predicts stroke severity and mitochondrial impairment in CVECs plays a pivotal role in this hypothermic response. These novel findings suggest that body temperature is prognostic for stroke severity in experimental stroke animal models and may have translational significance for clinical stroke patients - targeting endothelial mitochondria may be a clinically useful approach for stroke therapy.

Managing the Cayo Santiago rhesus macaque population: The role of density.

Cayo Santiago is the oldest continuously operating free-ranging rhesus monkey colony in the world. Population control of this colony has historically been carried out by periodic live capture and removal of animals. However, the effect of such a strategy on the size, growth rate, age structure, and sex ratio of the population has not been analyzed. This study reviews past removal data and uses a population projection model to simulate the effects of different removal schemes based on Cayo Santiago demographic data from 2000-2012. The model incorporates negative density-dependence in female fertility, as well as male and female survival rates, to determine the population-level effects of selective removal by age and sex. Modeling revealed that removal of sexually immature individuals has negligible effects on the population dynamics explaining why with an initial population of 1309 in 2000 and annual removals of immature monkeys a mean annual population growth rate of 12% and a final population size of ∼1,435 individuals by 2012 (∼0.009 animal/m(2) ) was observed. With no removals, the population is expected to exhibit dampened oscillations until reaching equilibrium at ∼1,690 individuals (∼0.0111 animal/m(2) ) in 2,100. In contrast, removal of adult females (≥4 yrs) would significantly reduce the population size, but would also promote an increase in population growth rate due to density feedback. A maximum annual production of 275 births is expected when 550 adult females are present in the population. Sensitivity analyses showed that removing females, in contrast to controlling their fertility through invasive treatments would contribute the most to changes in population growth rate. Given the density compensation on fertility, stabilizing the population would require removing ∼80% of the current population of adult females. This study highlights the importance of addressing the population-level density effects, as well as sensitivity analyses, to optimize management strategies.

Free-ranging Cayo Santiago rhesus monkeys (Macaca mulatta): III. Dental eruption patterns and dental pathology.

This article describes the dental eruption patterns, dentition, and dental wear, including tooth loss and breakage, of the free-ranging population of rhesus monkeys (Macaca mulatta) on Cayo Santiago (CS), Puerto Rico, ranging from 24 hr to 25 years old. Of the 694 monkeys on the island in the year 1985, 688 (99.1%; 366 males, 322 females) were captured and the dentition of 685 subjects (98.7% of the total population; 366 males, 319 females) was examined. Animals ranged in age from less than 24 hr to 331 months (27.58 years), encompassing the entire life span of the CS macaques. Results demonstrated that the first deciduous teeth appeared as early as the third day of life and that the sequence of dental eruption was comparable to the pattern observed in laboratory rhesus. However, there were slight differences in the age of eruption of individual teeth. For example, the canines and third molars erupted about a year later in the CS macaques compared to some laboratory rhesus. Overall, CS rhesus had good oral health and dental condition although tooth wear, loss, and breakage were common in aged animals, especially in males. This report, combined with earlier studies on morphological characteristics and skeletal remains of the CS macaques, provides the basis for further studies on the biology, genetics, life history, and effects of the environment on rhesus monkeys.

The mandibles of castrated male rhesus macaques (Macaca mulatta): The effects of orchidectomy on bone and teeth.

OBJECTIVES: The objectives of this study were to evaluate the long-term effects of orchidectomy and low testosterone on the craniofaciodental development and maintenance of skeletal and oral health in rhesus macaques. MATERIALS AND METHODS: Mandibles of four castrated and intact age-matched male rhesus monkeys (Macaca mulatta) from Cayo Santiago were compared for mandibular morphology and teeth, abnormalities, pathology, and cortical bone thickness and density using a digital sliding caliper and analysis of three-dimensional X-ray images. RESULTS: Although all four castrates were generally comparable to intact males in overall mandible and teeth size, there were some significant differences. In the castrates, (1) the distance between the two rami was narrower than in intact males leading to a relatively narrower and longer face; (2) both the mandibular body and ramus had thinner cortical bone leading to less total bone mass; and (3) the canines and molar teeth were slender with lower and less robust tooth cusps. In addition, the alveolar bone of two geriatric castrates was greatly receded with signs of periodontitis more severe than in intact aged males. Old castrates also had severe temporomandibular joint osteoarthritis. DISCUSSION: The findings suggest the importance of testosterone in craniofaciodental development, and maintenance of skeletal and oral health in male macaques. These results suggest that dental health professionals might want to include in their medical history questionnaires whether or not male patients have taken hormone (testosterone) replacement therapy.

Discovery of a secular trend in Cayo Santiago macaque reproduction.

Reproductive synchrony and the consequent clustering of births are hypothesized to be regulated by seasonal changes in rainfall and food availability. Such climate-related seasonality is, however, questionable in tropical populations occupying temporally invariant habitats year round. Using the long-term data of the Cayo Santiago rhesus macaques from 1973 to 2013, this study distinguishes synchrony (a greater than chance clustering of births) from seasonality (a cluster of births during a period of the year when abiotic conditions are favorable) and shows that females are highly synchronized (>72% of births in a 3-month period) but the effects of environmental zeitgebers on reproduction are overridden by biological factors. Specifically, biotic and abiotic factors including (i) loss of immature offspring; (ii) population density; (iii) age at delivery; (iv) rainfall; and (v) changes in colony management were modeled in relation to the annual onset of births and the median birth date. Females experiencing loss of immature offspring had an interbirth interval of <365 days in average and the proportion of these females increased up to 48% due to changes in colony management overtime, although reproductive synchrony increased with increasing population density. A secular trend in both the onset of births and the median date of birth is documented and the model predicts that the median birth date will advance across all calendar-based seasons by 2050. The secular trend in reproduction appears to be triggered by changes in the age at delivery of females, the absence of physiological constraints from maternal investment due to offspring loss, shorter interbirth interval, and a higher degree of coordination due to increasing population density. This study challenges the reproductive phenology previously described for rhesus macaques highlighting the importance of long-term studies in addressing the ultimate causes of reproductive synchrony.

Genetic studies on the Cayo Santiago rhesus macaques: A review of 40 years of research.

Genetic studies not only contribute substantially to our current understanding of the natural variation in behavior and health in many species, they also provide the basis of numerous in vivo models of human traits. Despite the many challenges posed by the high level of biological and social complexity, a long lifespan and difficult access in the field, genetic studies of primates are particularly rewarding because of the close evolutionary relatedness of these species to humans. The free-ranging rhesus macaque (Macaca mulatta) population on Cayo Santiago (CS), Puerto Rico, provides a unique resource in this respect because several of the abovementioned caveats are of either minor importance there, or lacking altogether, thereby allowing long-term genetic research in a primate population under constant surveillance since 1956. This review summarizes more than 40 years of genetic research carried out on CS, from early blood group typing and the genetic characterization of skeletal material via population-wide paternity testing with DNA fingerprints and short tandem repeats (STRs) to the analysis of the highly polymorphic DQB1 locus within the major histocompatibility complex (MHC). The results of the paternity studies also facilitated subsequent studies of male dominance and other factors influencing male reproductive success, of male reproductive skew, paternal kin bias, and mechanisms of paternal kin recognition. More recently, the CS macaques have been the subjects of functional genetic and gene expression analyses and have played an important role in behavioral and quantitative genetic studies. In addition, the CS colony has been used as a natural model for human adult-onset macular degeneration, glaucoma, and circadian rhythm disorder. Our review finishes off with a discussion of potential future directions of research on CS, including the transition from STRs to single nucleotide polymorphism (SNP) typing and whole genome sequencing.

A 75-year pictorial history of the Cayo Santiago rhesus monkey colony.

This article presents a pictorial history of the free-ranging colony of rhesus monkeys (Macaca mulatta) on Cayo Santiago, Puerto Rico, in commemoration of the 75th anniversary of its establishment by Clarence R. Carpenter in December 1938. It is based on a presentation made by the authors at the symposium, Cayo Santiago: 75 Years of Leadership in Translational Research, held at the 36th Annual Meeting of the American Society of Primatologists in San Juan, Puerto Rico, on 20 June 2013.

Long-term effects of castration on the skeleton of male rhesus monkeys (Macaca mulatta).

While osteopenia (OPE) and osteoporosis (OPO) have been studied in various species of aging nonhuman primates and extensively in ovariectomized rhesus and cynomolgus macaques, there is virtually no information on the effects of castration on the skeleton of male nonhuman primates. Most information on castrated male primates comes from a few studies on the skeletons of eunuchs. This report used a subset of the Caribbean Primate Research Center's (CPRC) Cayo Santiago (CS) rhesus macaque skeletal collection to qualitatively and quantitatively compare the bone mineral density (BMD) of castrated and age-matched intact males and, thereby, determine the long-term effects of castration (orchidectomy) on bone. Lumbar vertebrae, femora, and crania were evaluated using dual-energy X-ray absorptiometry (DEXA or DXA) and digital radiography augmented, when fresh tissues were available, with autoradiography and histology. Results confirmed physical examinations of long bones that castration causes changes in the skeleton of male rhesus macaques similar to those found in eunuchs, including OPE and OPO of the vertebrae and femora, thinning of the skull, and vertebral fractures and kyphosis of the spine more severe than that caused by normal aging alone. Also like eunuchs, some castrated CS male rhesus monkeys had a longer life span than intact males or females. Based on these results and the effects of castration on other tissues and organs of eunuchs, on behavior, hormone profiles and possibly on cognition and visual perception of human and nonhuman primates, and other mammals, castrated male rhesus macaques should be used with caution for laboratory studies and should be considered a separate category from intact males. Despite these caveats, the castrated male rhesus macaque should make an excellent animal model in which to test hormone replacement therapies for boys and men orchidectomized for testicular and prostate cancer.

Long-term effects of tetanus toxoid inoculation on the demography and life expectancy of the Cayo Santiago rhesus macaques.

Tetanus was a major cause of mortality in the free-ranging population of rhesus monkeys on Cayo Santiago prior to 1985 when the entire colony was given its first dose of tetanus toxoid. The immediate reduction in mortality that followed tetanus toxoid inoculation (TTI) has been documented, but the long-term demographic effects of eliminating tetanus infections have not. This study uses the Cayo Santiago demographic database to construct comparative life tables 12 years before, and 12 years after, TTI. Life tables and matrix projection models are used to test for differences in: (i) survival among all individuals as well as among social groups, (ii) long-term fitness of the population, (iii) age distribution, (iv) reproductive value, and (v) life expectancy. A retrospective life table response experiment (LTRE) was performed to determine which life cycle transition contributed most to observed changes in long-term fitness of the population post-TTI. Elimination of clinical tetanus infections through mass inoculation improved the health and well-being of the monkeys. It also profoundly affected the population by increasing survivorship and long-term fitness, decreasing the differences in survival rates among social groups, shifting the population's age distribution towards older individuals, and increasing reproductive value and life expectancy. These findings are significant because they demonstrate the long-term effects of eradicating a major cause of mortality at a single point in time on survival, reproduction, and overall demography of a naturalistic population of primates.

Demographic variability and density-dependent dynamics of a free-ranging rhesus macaque population.

Density-dependence is hypothesized as the major mechanism of population regulation. However, the lack of long-term demographic data has hampered the use of density-dependent models in nonhuman primates. In this study, we make use of the long-term demographic data from Cayo Santiago's rhesus macaques to parameterize and analyze both a density-independent and a density-dependent population matrix model, and compare their projections with the observed population changes. We also employ a retrospective analysis to determine how variance in vital rates, and covariance among them, contributed to the observed variation in long-term fitness across different levels of population density. The population exhibited negative density-dependence in fertility and the model incorporating this relationship accounted for 98% of the observed population dynamics. Variation in survival and fertility of sexually active individuals contributed the most to the variation in long-term fitness, while vital rates displaying high temporal variability exhibited lower sensitivities. Our findings are novel in describing density-dependent dynamics in a provisioned primate population, and in suggesting that selection is acting to lower the variance in the population growth rate by minimizing the variation in adult survival at high density. Because density-dependent mechanisms may become stronger in wild primate populations due to increasing habitat loss and food scarcity, our study demonstrates that it is important to incorporate variation in population size, as well as demographic variability into population viability analyses for a better understanding of the mechanisms regulating the growth of primate populations.

Tetanus antibody titers and duration of immunity to clinical tetanus infections in free-ranging rhesus monkeys (Macaca mulatta).

Prior to 1985 tetanus was a major cause of mortality in the free-ranging colony of rhesus monkeys on Cayo Santiago, accounting for almost a quarter of annual deaths. In 1985 and 1986 all animals (except infants) received primary and booster doses, respectively, of tetanus toxoid. In subsequent years primary immunizations were given to all yearlings, and boosters were administered to all 2-year-old animals during the annual capture of the colony. The main objectives of the tetanus immunization program were to reduce the pain and suffering caused by tetanus infections and to decrease mortality in the colony. Other objectives were to evaluate the efficacy of the two-dose tetanus toxoid immunization protocol and to determine whether additional boosters might be required to provide adequate long-term protection against tetanus infections. The immediate effect of the mass immunization program was the elimination of clinical tetanus infections in the population and a 42.2% reduction in the overall mortality rate. Since the immunization program began, no cases of tetanus have been observed in the colony, except in two unimmunized infants, and it has not been necessary to give tertiary injections of tetanus toxoid to maintain protection against infection. A sample collected in 2004 of the original cohort of monkeys immunized in 1985 and 1986 showed that 93.3% (14/15) had protective tetanus antibody titers (>0.01 IU/ml) at the ages of 20-23 years, which is close to the life expectancy of the Cayo Santiago rhesus macaques. Two intramuscular doses of tetanus toxoid provided long-term, if not lifelong, protection against tetanus for rhesus monkeys living in a tropical clime where tetanus is enzootic and the risk of infection is great.

Fundus pigment distribution in rhesus monkeys.

There is growing evidence for an interaction among fundus pigmentation, character, geography and the function and structure of the outer retina. We examined three inbred groups of rhesus macaques (132 eyes) including all ages. One was a smaller (18 eyes) group. Coat colors were variations of brown-tan however, the smaller group had lighter 'golden' coats and colors. Fundus images were classified for pigmentation and its geographic distribution. In golden-coated animals there was bias toward nasal fundus hypopigmentation with the optic disk as a watershed demarcation zone, which extended in the superior-inferior direction. Temporal fundus hypopigmentation did not occur in the absence of nasal hypopigmentation. More common, darker coated samples showed a characteristic diffuse fundus pigmentation. There was no evidence for albinism or large variations in macular pigmentation. Rhesus monkeys can exhibit geographically controlled genetic development of fundus pigmentation. Hypopigmentation provides for access to the choroidal infrastructure.

Free-ranging Cayo Santiago rhesus monkeys (Macaca mulatta): II. Passive joint mobility.

Recent studies on the effects of caging on joint mobility and the correlations between joint mobility and use of the extremities have pointed out the need for baseline values that are readily available in the literature. This report provides normative data on the passive mobility of the major joints of free-ranging Cayo Santiago rhesus monkeys (Macaca mulatta). The sample in this cross-sectional study is large (661 animals including 315 males, 346 females), and it spans the entire age spectrum (24 hours to 25 years) of the population. Included are data on motion in the sagittal plane at six joints: shoulder, elbow, wrist, hip, knee, and ankle. Results indicated that passive joint mobility changes in a nonlinear fashion throughout the life cycle. The apparent rapid decline in mobility from birth through puberty parallels rapid changes in body size and proportions in young animals. Joint mobility is relatively stable in prime-age adults, whereas it is generally more restricted in older monkeys. Both genders follow a similar pattern, but timing differs somewhat. Although the primary purpose of this paper is to present numerical data on the Cayo Santiago population, the results are compared with previous, more limited studies of both captive and free-ranging rhesus macaques.

Free-ranging Cayo Santiago rhesus monkeys (Macaca mulatta): I. Body size, proportion, and allometry.

This paper presents comprehensive baseline data on body size and proportion of 661 (315 male, 346 female) free-ranging Cayo Santiago rhesus monkeys (Macaca mulatta) ranging in age from 24 hours to 25 years. All animals were born and raised in the free-ranging colony on Cayo Santiago, and exact ages were known for all. Tabular data from this cross-sectional study are provided to enable comparisons with data from laboratory, wild, and other captive populations of rhesus monkeys, as well as with other species. Despite the extensive literature on rhesus monkey behavior and biology, to date published accounts of its morphometrics have been limited to only a few measurements from animals of unknown age, small sample sizes, or caged colonies. Results of this study showed a distinct intraspecific pattern for body proportions throughout the life cycle. Relative linear increases in overall body proportions of maturing animals appeared to be from greatest to least in the trunk, hindlimb, and forelimb, respectively. Within the limbs, allometric scaling appeared to be fastest in the proximal segment and slowest in the distal segment. Males and females differed in the duration of growth, and gender dimorphism was associated primarily with differences in size rather than proportion. Although the primary purpose of this paper is to present numerical data on the Cayo Santiago colony, the results are compared with previous studies of both laboratory and free-ranging rhesus monkeys.

Induction of experimental myasthenia gravis in Rhesus monkeys: a model for the study of the human disease

Experimental autoimmune myasthenia gravis (EAMG) was induced in thesus monkeys using purified acetylcholine recptor (AChR) from Torpedo california. A single dose of 80 µg induced antibody formation two weeks after injection. Two subsequent doses at two-week intervals caused clinical signs (anorexia, fatigability, weight loss, ptosis and dysphagia) which initially responded to treatment with neostigmine. Histologic examination of post-mortem tissues revealed lesions characteristic of myasthenia gravis in man: musuclar atrophy, fibrous degeneration and lymphocytic infiltration. Antibodies were quantitated in the sera of three other monkeys which received only 60 µg of purified AChR. Abnormally high titers persisted for two years (60-200µg/ml versus 0-10µg/ml for controls). A monkey injected with 60µgAChR as part of reconstituted membrane vesicles had lower titers (30-50µg/ml) than those which received purified receptor. Only those monkeys with antibody titers exceeding 800 µg/ml developed overt disease. These titers were 4-100 times higher than those reported for myasthenic humans. The antibody-antigen molar ratios were higher for monkeys with disease than for asymptomatic animals. These data suggest that the diversity of antibody molecules synthesized by the sensitized monkeys determined the appearance of clinical signs, and that the cross reaction of tanti-torpedo antivodies with monkey receptor was primarily responsible for the development of EAMG