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Objectives: Magnitudes of morphological integration may constrain or facilitate craniofacial shape variation. The aim of this study was to analyze how the magnitude of integration in the skull of Macaca fascicularis changes throughout ontogeny in relation to developmental and/or functional modules., Materials and Methods: Geometric morphometric methods were used to analyze the magnitude of integration in the macaque cranium and mandible in 80 juvenile and 40 adult M. fascicularis specimens. Integration scores in skull modules were calculated using integration coefficient of variation (ICV) of eigenvalues based on a resampling procedure. Resultant ICV scores between the skull as a whole, and developmental and/or functional modules were compared using Mann-Whitney U tests., Results: Results showed that most skull modules were more tightly integrated than the skull as a whole, with the exception of the chondrocranium in juveniles without canines, the chondrocranium/face complex and the mandibular corpus in adults, and the mandibular ramus in all juveniles. The chondrocranium/face and face/mandibular corpus complexes were more tightly integrated in juveniles than adults, possibly reflecting the influences of early brain growth/development, and the changing functional demands of infant suckling and later masticatory loading. This is also supported by the much higher integration of the mandibular ramus in adults compared with juveniles., Discussion: Magnitudes of integration in skull modules reflect developmental/functional mechanisms in M. fascicularis. However, the relationship between "evolutionary flexibility" and developmental/functional mechanisms was not direct or simple, likely because of the complex morphology, multifunctionality, and various ossification origins of the skull., (© 2020 Wiley Periodicals LLC.)

We assessed the variability of spleen and mesenteric lymph node (MLN) microscopic observations and the correlations of these observations with other study data from 478 control cynomolgus monkeys from 53 routine nonclinical safety studies. Spleen weight parameters (absolute and relative to body or brain weights) were highly variable both within a control group on an individual study (up to 5.11-fold) and among animals with the same light microscopic observation. Grades for microscopic observations were also highly variable. The most frequent microscopic observations for spleen were changes in the size and number of germinal centers (58%), acidophilic (hyaline) material in lymphoid follicles (52%), and compound lymphoid follicles (20%). The most frequent microscopic observations in the MLN were eosinophil infiltrates (90%), changes in size and number of germinal centers (42%), and brown pigment (21%). The only meaningful relationships ( r 2 > 0.3) were positive correlations between reticuloendothelial hyperplasia and malarial pigment in the spleen and between each of these observations and spleen weight parameters. We conclude that determination of test article-related effects on the immune system in routine monkey toxicology studies requires careful consideration and a weight-of-evidence approach due to the low numbers of animals/group, the inherent variability in spleen and MLN parameters, and the infrequent correlation among immune system-related end points.

The present study aimed to specify the cerebral sulci developed by cortical expansion in cynomolgus monkey fetuses. The degree of sulcal infolding was evaluated by the gyrification index (GI), which was quantified using ex vivo magnetic resonance imaging. The correlation of cortical volume with the sulcal GI was most frequent during embryonic days (EDs) 100 to 120. Interestingly, the high correlation was marked during EDs 140 to 150 in restricted primary sulci in prefrontal, parietotemporal and medial temporal regions. The present results suggest that cortical expansion is involved in gyral demarcation by sulcal infolding, followed by the sulcal infolding progression in phylogenetically-newer cortices., (© 2017 Japanese Teratology Society.)

Callosal projection neurons (CPN) interconnect the neocortical hemispheres via the corpus callosum and are implicated in associative integration of multimodal information. CPN have undergone differential evolutionary elaboration, leading to increased diversity of cortical neurons-and more extensive and varied connections in neocortical gray and white matter-in primates compared with rodents. In mouse, distinct sets of genes are enriched in discrete subpopulations of CPN, indicating the molecular diversity of rodent CPN. Elements of rodent CPN functional and organizational diversity might thus be present in the further elaborated primate cortex. We address the hypothesis that genes controlling mouse CPN subtype diversity might reflect molecular patterns shared among mammals that arose prior to the divergence of rodents and primates. We find that, while early expression of the examined CPN-enriched genes, and postmigratory expression of these CPN-enriched genes in deep layers are highly conserved (e.g., Ptn, Nnmt, Cited2, Dkk3), in contrast, the examined genes expressed by superficial layer CPN show more variable levels of conservation (e.g., EphA3, Chn2). These results suggest that there has been evolutionarily differential retraction and elaboration of superficial layer CPN subpopulations between mouse and macaque, with independent derivation of novel populations in primates. Together, these data inform future studies regarding CPN subpopulations that are unique to primates and rodents, and indicate putative evolutionary relationships., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The authors examined a large random sample of skulls from two species of macaques: rhesus monkeys and cynomolgus monkeys. The skulls were measured, divided into age and sex groups and thoroughly analysed using statistical methods. The analysis shows that skulls of young rhesuses are considerably more domed, i.e. have better-developed neurocrania, than their adult counterparts. Male and female skulls, on the other hand, were found to be very similar, which means that sexual dimorphism of the rhesus macaque was suppressed. Both of these patterns are known from the human evolutionary pattern. No such parallelism to the development of Homo sapiens was found in the cynomolgus monkeys. The authors conclude that mosaic hominisation trends may have featured in the evolution of all primates. This would mean that apes were not a necessary step on the evolutionary way leading to the development of Homo sapiens, who may have started to evolve at an earlier stage of monkeys.

Testicular volume is one of several parameters that have been used in preclinical toxicology to facilitate the identification of sexually mature male cynomolgus macaques when semen evaluation is unavailable. Furthermore, testicular volume provides additional information to pathologists to aid in the interpretation of microscopic findings. Orchidometry has been proposed as a useful tool for assessing testicular volume. To assess its utility for this purpose, we used orchidometry to measure testicular volume in untreated control male cynomolgus macaques during preclinical toxicology studies. Additional parameters including age, body weight, testicular weight, serum testosterone, and testicular histology were also evaluated. Serum inhibin B and the diameter of histologic testicular sections were assessed to determine whether they might provide any additional corroborative evidence for differentiating stages of sexual maturity in males. Orchidometry was easy to use in sedated or awake macaques and, in combination with testicular histology, enabled the establishment of cut-off values by which sexually mature male cynomolgus macaques can be identified with a high degree of confidence. The relative utility of the parameters examined for discriminating sexually mature and immature males was testicular volume ≥ serum testosterone > body weight > age; for differentiation of sexually mature and peripubertal males the order was testicular volume ≥ body weight > serum testosterone > age. Testicular weight and the diameter of histologic testicular sections provided corroborative information for discriminating stages of sexual maturity. Serum inhibin B was of little value in helping to differentiate the different stages of sexual maturation evaluated in this study.

Terminal body weights (TBWs), thymus weight parameters, and thymus morphology were retrospectively evaluated in 453 cynomolgus monkeys assigned to control groups on nonclinical toxicity studies. Morphology of bone, ovary, and testis/epididymis were used to determine maturity status of individual animals. There was no correlation between TBW and thymus weight (absolute and/or relative to TBW or brain weight). Thymus weight parameters and grades of decreased lymphocytes in the thymus were highly variable in immature animals compared to mature animals. There was also high (up to 11-fold) variability of thymus weight parameters within a given control group on the same study (generally 3 or 4 animals per sex). Several parameters evaluated had more pronounced age-related changes in males when compared to females. Our results demonstrate the inherent variability of thymus weight parameters and morphologic observations for cynomolgus monkeys on toxicology studies. Changes in thymus parameters in cynomolgus monkeys are unreliable indicators of immunomodulation or immunotoxicity in the absence of other relevant findings. Therefore, the thymus parameters commonly evaluated in preclinical safety assessments should not be the primary data set used to determine the presence of a direct test article-related effect on the immune system., (© 2016 by The Author(s) 2016.)

Objective: To investigate the infection situation of blood parasitic protozoa in farmed Macaca fascicularis in an animal breeding ground in Nanning, Guangxi Zhuang Autonomous Region, so as to provide the evidence for the prevention and control of human blood parasitic protozoa., Methods: A total of 993 blood samples from farmed M. fascicularis were collected and stored on FTA cards. Among them, 550 thin blood smears were made. Each 10 samples were mixed in groups, and then the Babesia spp . and Plasmodium spp. in the blood of M. fascicularis were detected by Nest-PCR and PCR, respectively. The positive groups were tested individually. The thin blood smears stained with Giemsa were examined microscopically when PCR reported the samples were positive., Results: When detected by Nest-PCR, the positive rate of Babesia. microti was 6.95% (69/993); only 1 positive sample with Plasmodium inui was detected by PCR. Among the 22 positive thin blood smears detected by PCR, 16 were determined with B. microti by microscopic examinations, on which the ring forms could be observed in the erythrocytes, but no hemozoin., Conclusions: The positive rate of B. microti in M. fascicularis in Guangxi Zhuang Autonomous Region is high, and the animal may play a role as a reservoir host in the transmission of B. microti . In the screening of B. microti with low infection density, Nest-PCR has a higher sensitivity.

An important aspect of the enhanced pre- and postnatal developmental (ePPND) toxicity study in nonhuman primates (NHP) is that it combines in utero and postnatal assessments in a single study. However, it is unclear if NHP ePPND studies are suitable to perform all of the evaluations incorporated into rodent PPND studies. To understand the value of including cognitive assessment in a NHP ePPND toxicity study, we performed a power analysis of object discrimination reversal task data using a modified Wisconsin General Testing Apparatus (ODR-WGTA) from two NHP ePPND studies. ODR-WGTA endpoints evaluated were days to learning and to first reversal, and number of reversals. With α = 0.05 and a one-sided t-test, a sample of seven provided 80% power to predict a 100% increase in all three of the ODR-WGTA endpoints; a sample of 25 provided 80% power to predict a 50% increase. Similar power analyses were performed with data from the Cincinnati Water Maze (CWM) and passive avoidance tests from three rat PPND toxicity studies. Groups of 5 and 15 in the CWM and passive avoidance test, respectively, provided 80% power to detect a 100% change. While the power of the CWM is not far superior to the NHP ODR-WGTA, a clear advantage is the routine use of larger sample size, with a group of 20 rats the CWM provides ~90% power to detect a 50% change. Due to the limitations on the number of animals, the ODR-WGTA may not be suitable for assessing cognitive impairment in NHP ePPND studies., (© 2012 Wiley Periodicals, Inc.)

We previously reported on a histological classification of cynomolgus monkey testis into six grades (1, immature; 2, prepuberty; 3, onset of puberty; 4, puberty; 5, early adult; 6, adult) based on spermatogenesis development. In this investigation, the accessory reproductive organs from the same animals underwent histomorphometric examination, in addition to being examined histologically and weighed, to evaluate relationships between these parameters and the six grades. Seminiferous tubule diameter increased corresponding to the testicular maturity grade and was notably increased at grade 6. Beginning from grade 3, increases in the areas of the ductus epididymis were noted, and reserved sperm was visible in the lumen. In the prostate, the glandular lumen area per unit area showed an increase beginning from grade 3 but no clear differences between grades 4 and 6; advanced development of epithelial height was observed at grade 6. In the seminal vesicle, development of the epithelial cell layer was markedly increased at grade 6. It was concluded that development of the male accessory reproductive organs began after reserved sperm was observed in the lumen of the ductus epididymis (grade 3) and that these organs were developed notably when the testis reached sexual maturity (grade 6).

The testes from 136 male cynomolgus monkeys were examined histopathologically in order to investigate the relationship between the development of spermatogenesis and testis weight, age, and body weight. At Grade 1 (immature), Sertoli cells and spermatogonia were the only cell classes in the testis. At Grade 2 (pre-puberty), no elongated spermatids were observed in the testis, although a few round spermatids and small lumen formation were observed. At Grade 3 (onset of puberty), all classes of germ cells were observed in the testis, although seminiferous tubule diameters and numbers of germ cells were small. Slight debris in the epididymis was observed in almost all animals. At Grade 4 (puberty), almost complete spermatogenesis was observed in the seminiferous tubules and it was possible to ascertain the spermatogenesis stage as described by Clermont, although tubule diameters and numbers of germ cells were small. There was less debris in the epididymis than at Grade 3. At Grade 5 (early adult), complete spermatogenesis was observed in the seminiferous tubules. At Grade 6 (adult), complete spermatogenesis in the seminiferous tubules and a moderate or large number of sperm in the epididymis were observed. Moreover, sperm analysis using ejaculated sperm was possible. Logistic regression analysis showed that testis weight is a good indicator of testicular maturity.

Tubular anomalous bones were found in both thighs of a 6-year-old male long-tailed macaque (Macaca fascicularis) bred in captivity. The bones had jagged ends and protruded from the skin. Radiographs showed that they developed in the femurs at the middle and elongated. They were removed with surgery under anesthesia. Histological analysis revealed that these bones had the same histological structure as the femur, though they were composed of primary and secondary osteon regions. This finding indicated that the new bones developed from the old bone piece(s), acquired a tubular shape, and elongated. It is suggested that the anomalous bones were produced not by the congenital deformity but by regeneration from fragments of the fractured femur that were embedded in the bone marrow; these acquired a tubular pattern and elongated.

Cynomolgus CYP2C76, not orthologous to any human cytochrome P450, partly accounts for species differences in drug metabolism between cynomolgus macaques and humans. To discover the CYP2C76 variants, we previously surveyed cynomolgus macaque genomes and found several non-synonymous variants, including a null allele. However, the analysis was limited to cynomolgus macaques, and the number of genomes was relatively small. In this study, therefore, further screening was conducted using 74 cynomolgus and 30 rhesus macaques. A total of 18 non-synonymous variants was found, among which 7 were in substrate recognition sites, important for protein function, and 14 (74%) were shared by both macaque lineages. In cynomolgus macaques, 3 (16%) non-synonymous variants were unique to Indochinese animals, whereas all the variants found in Indonesian animals were shared by Indochinese animals. Among the 18 variants, as compared with the wild type, in progesterone 16α-hydroxylation, L65F, M310L, and N364S variants showed lower metabolic activity and lower intrinsic clearance by kinetic analysis. Molecular modeling indicated that the reduced catalytic activity of the L65F variant in progesterone 16α-hydroxylation possibly resulted from a longer distance of progesterone to the heme in the active site of the CYP2C76 protein. L65F, M310L, and N364S variants might partly influence inter-animal variations of CYP2C76 metabolic activities.

Cynomolgus macaques, frequently used in drug metabolism studies, are bred mainly in the countries of Asia; however, comparative studies of drug metabolism between cynomolgus macaques bred in these countries have not been conducted. In this study, hepatic gene expression profiles of cynomolgus macaques bred in Cambodia (mfCAM), China (mfCHN), and Indonesia (mfIDN) were analyzed. Microarray analysis revealed that expression of most hepatic genes, including drug-metabolizing enzyme genes, was not substantially different between mfCAM, mfCHN, and mfIDN; only 1.1% and 3.0% of all the gene probes detected differential expression (>2.5-fold) in mfCAM compared with mfCHN and mfIDN, respectively. Quantitative polymerase chain reaction showed that the expression levels of 14 cytochromes P450 (P450s) important for drug metabolism did not differ (>2.5-fold) in mfCAM, mfCHN, and mfIDN, validating the microarray data. In contrast, expression of CYP2B6 and CYP3A4 differed (>2.5-fold, p < 0.05) between cynomolgus (mfCAM, mfCHN, or mfIDN) and rhesus macaques, indicating greater differences in expression of P450 genes between the two lineages. Moreover, metabolic activities measured using 14 P450 substrates did not differ substantially (<1.5-fold) between mfCAM and mfCHN. These results suggest that gene expression profiles, including drug-metabolizing enzyme genes such as P450 genes, are similar in mfCAM, mfCHN, and mfIDN.

The neural processes that underlie executive function begin to develop in infancy. However, it is unclear how the behavior manifested by these processes are related or if they can be differentiated early in development. This study seeks to examine early emerging executive functioning skills in monkeys (Macaca fascicularis) by using an error analysis approach where traditional measures of the tasks, as well as identification of major error patterns are related. Results show that during the infancy and early juvenile period, two processes that help support set-maintenance could be differentiated: modulation of responses to novelty and persistence despite negative feedback. The results suggest that these two aspects of set-maintenance were largely independent. Modulation of responses to novelty was most prominent in the infancy and early juvenile period. The ability to persist with a response set despite negative feedback emerged in the early juvenile period and was related to task performance until the end of the study., (Copyright © 2011 Wiley Periodicals, Inc.)

Introduction: The identification and use of mature male non-human primates in nonclinical toxicology studies could be important for evaluating candidate drugs for which the profile of toxicity may differ depending on sexual maturity. This investigation sought to establish operational criteria to complement the current standard of histological evaluation for defining sexual maturity in male cynomolgus monkeys (Macaca fascicularis) used for toxicology studies, and to identify a practical non-invasive measure to select mature males for study., Method: Retrospectively, the relationships between body weight, testicular weight and testis histology were established in control males (n=126) used in previous toxicology studies. Prospectively, testicular volumes were measured in-life by orchidometry using comparative scrotal palpation (n=23 males used for study), then compared to testicular weights measured at necropsy., Results: Consistent with previous literature, a weak relationship was observed between body weight and testicular weight. There was, however, a very good relationship between testicular weight and histological maturation level, which was based upon microscopic examination of testes, epididymides and prostates. Orchidometric measurement of testicular volume was found to be a reasonable predictor of testicular weight and served to rapidly select sexually mature males for study, and a total testicular volume (left and right combined) of >20 ml correlated with the histological appearance of maturity., Conclusion: Based upon this preliminary exploratory study, the initial simple measurement of testicular volume by orchidometry may provide a non-invasive alternative approach for assessing the sexual maturity of male cynomolgus monkeys in research colonies or during toxicology studies that will require more thorough validation., (Copyright 2009 Elsevier Inc. All rights reserved.)

Belimumab is a fully human monoclonal antibody antagonist for soluble B-lymphocyte stimulator, and is a potential therapeutic for various autoimmune disorders. To support clinical use, belimumab was administered intravenously to pregnant cynomolgus monkeys every 2 weeks throughout gestation at dosages of 5 and 150 mg/kg. Fetuses were delivered by C-section on Gestation Day 150 from one-half of the mothers, and evaluated for teratologic effects (external, visceral, skeletal, and heart), pharmacodynamics (PD) and toxicokinetics (TK). Remaining mothers delivered their infants naturally, enabling extensive assessment of PD and TK during a 1-year postnatal period. Effects attributed to belimumab were limited to the expected pharmacology, primarily decreased numbers of B-lymphocytes in peripheral blood of mothers and infants, and in fetal lymphoid tissues. Infants demonstrated full recovery upon cessation of exposure. In conclusion, belimumab was well tolerated at pharmacologically active dose levels in pregnant cynomolgus monkeys and their infants after exposure throughout pregnancy.

Antagonists of myostatin, a blood-borne negative regulator of muscle growth produced in muscle cells, have shown considerable promise for enhancing muscle mass and strength in rodent studies and could serve as potential therapeutic agents for human muscle diseases. One of the most potent of these agents, follistatin, is both safe and effective in mice, but similar tests have not been performed in nonhuman primates. To assess this important criterion for clinical translation, we tested an alternatively spliced form of human follistatin that affects skeletal muscle but that has only minimal effects on nonmuscle cells. When injected into the quadriceps of cynomolgus macaque monkeys, a follistatin isoform expressed from an adeno-associated virus serotype 1 vector, AAV1-FS344, induced pronounced and durable increases in muscle size and strength. Long-term expression of the transgene did not produce any abnormal changes in the morphology or function of key organs, indicating the safety of gene delivery by intramuscular injection of an AAV1 vector. Our results, together with the findings in mice, suggest that therapy with AAV1-FS344 may improve muscle mass and function in patients with certain degenerative muscle disorders.

Background: Natalizumab is a humanized monoclonal IgG4 antibody to human alpha4 integrin that blocks the interaction of alpha4beta1 and alpha4beta7 integrins with their ligands, including fibronectin, vascular cell adhesion molecule-1, and mucosal addressin cellular adhesion molecule-1. Because alpha4 integrins and their ligands are widely involved in mammalian development, lymphopoeisis, and hematopoiesis, natalizumab may interfere with these processes., Methods: The effects of prenatal exposure to natalizumab on postnatal development were assessed in cynomolgus monkeys at doses of 0 and 30 mg/kg administered intravenously every other day from gestational day (GD) 20 to 70 or GD 20 to term. Infants were delivered by natural birth and evaluated for general health, survival, development, and immunological structure and function at 12 or 18 months., Results: An increase in abortions was seen in the first cohort of natalizumab-treated dams (39.3 vs. 7.1% in the controls) but not in the second cohort (33.3, 37.5%). Infants in the term treatment group had elevated lymphocyte ( approximately 150%) and nucleated red blood cell counts ( approximately 400%), consistent with the pharmacological effect of natalizumab, and reductions in platelet counts ( approximately 28%), which were reversible following clearance of natalizumab. No anemia was observed. Infants in the term treatment group had significantly increased spleen weights at 12 months but not at 18 months. All other experimental observations in infants from natalizumab-treated dams were comparable with those of controls., Conclusion: Natalizumab had no adverse effects on the general health, survival, development, or immunological structure and function of infants born to dams treated with natalizumab during pregnancy., ((c) 2009 Wiley-Liss, Inc.)

Physiological parameters of laboratory animals used for biomedical research is crucial for following several experimental procedures. With the intent to establish baseline biologic parameters for non-human primates held in closed colonies, hematological and morphometric data of captive monkeys were determined. Data of clinically healthy rhesus macaques (Macaca mulatta), cynomolgus monkeys (Macaca fascicularis), and squirrel monkeys (Saimiri sciureus) were collected over a period of five years. Animals were separated according to sex and divided into five age groups. Hematological data were compared with those in the literature by Student's t test. Discrepancies with significance levels of 0.1, 1 or 5% were found in the hematological studies. Growth curves showed that the sexual dimorphism of rhesus monkeys appeared at an age of four years. In earlier ages, the differences between sexes could not be distinguished (p < 0.05). Sexual dimorphism in both squirrel monkeys and cynomolgus monkeys occurred at an age of about 32 months. Data presented in this paper could be useful for comparative studies using primates under similar conditions.

In macaque monkeys the foveal depression forms between fetal day (Fd) 105 and birth (Fd 172 of gestation). Before this, the incipient fovea is identified by a photoreceptor layer comprising cones almost exclusively, a multilayered ganglion cell layer (GCL), and a "domed" profile. Vessels are absent from the central retina until late in development, leading to the suggestion that the GCL in the incipient fovea may be transitorily hypoxic. Vascular endothelial growth factor (VEGF), expressed by both glial and neuronal cells and mediated by the hypoxia-inducible transcription factor (HIF)-1, is the principal factor involved in blood vessel growth in the retina. We examined VEGF expression in macaque retinas between Fd 85 and 4 months postnatal. Digoxygenin-labeled riboprobes were generated from a partial-length human cDNA polymerase chain reaction fragment, detected using fluorescence confocal microscopy, and quantified using Scion Image. High levels of VEGF mRNA were detected in astrocytes associated with developing vessels. We also detected strong expression of VEGF mRNA in the GCL at the incipient fovea prior to Fd 105, with peak labeling in the incipient fovea that declined with distance in nasal and temporal directions. By Fd 152 peak labeling was in two bands associated with development of the inner nuclear layer (INL) capillary plexus: in the inner INL where Müller and amacrine cell somas are located, and in the outer INL where horizontal cells are found. The findings suggest that at the incipient fovea the GCL is hypoxic, supporting the hypothesis that the adaptive significance of the fovea centralis is in ensuring adequate oxygen supply to neuronal elements initially located within the avascular region., (Copyright 2003 Wiley-Liss, Inc.)

In pharmaceutical drug safety testing, sexual maturity is an important experimental parameter. Histologic immaturity of the tissues of the reproductive system can interfere with the interpretation of compound-related effects on the reproductive organs. In female cynomolgus macaques, determination of sexual maturity is simplified by the presence of a menstrual cycle. For male cynomolgus macaques, predicting maturity is much more difficult. In this study, we evaluated methods that would reliably predict sexual maturity in male cynomolgus macaques. The results of histologic examination of testes of control male cynomolgus macaques used for drug safety studies were examined retrospectively for evidence of sexual maturity. These data were compared with age and body weight determinations to establish statistical models for determining the probability that a male cynomolgus macaque is sexually mature. This model presents a simple prospective method of predicting sexual maturity in male cynomolgus macaques.

This research examined between-species variation in the development of hand preference among Macaca. Specifically, we examined hand preference using juveniles and adults of three macaque species that differ in social and reactive tendencies in order to examine whether the correlation between temperament and handedness that has been noted within Macaca mulatta occurs between closely related species. Each of the species studied exhibited a different pattern of hand preference development. Both juvenile and adult M. mulatta exhibited group-level left-hand bias. Juvenile Macaca nemestrina were not biased towards either hand at the group-level, whereas adults exhibited a group-level left-hand bias. Neither juvenile nor adult Macaca fascicularis exhibited manual bias at the group-level. Analysis of variance indicated statistically significant main effects of species and age class on hand preference measures. Post-hoc analysis indicated greater use of the left- versus right-hand, and greater hand preference strength independent of direction, among M. mulatta and M. nemestrina than among M. fascicularis, and among adults than among juveniles. These results indicate significant between-species variation in the development of hand preference within the genus Macaca, and are inconsistent with any one single-factor theory yet offered to explain the etiology of primate laterality. We hypothesize that the relationship between handedness and temperament that has been shown within M. mulatta may generalize across closely related primate species.

The age-related expression of testosterone and 3beta-HSD in the testes of cynomolgus monkeys was detected using light-microscopic immunocytochemistry. Intense deposits of immunoreactive testosterone were labeled in parts of Leydig cells in neonatal, late infantile, pubertal, and adult testes, and only a few Leydig cells in early infantile testes. The immunoreactive 3beta-HSD was labeled in parts of Leydig cells and in all Sertoli cells in neonatal, late infantile, pubertal, and adult testes, whereas only a few Leydig cells, but no Sertoli cells, were labeled in early infantile testes. The fluctuations of testosterone and 3beta-HSD expression in testes correlated well with those already observed plasma testosterone levels during postnatal development in cynomolgus monkeys.

Macaca monkey and humans have three cone types containing either long-wavelength (L), medium-wavelength (M), or short-wavelength (S)-specific opsin. The highest cone density is found in the fovea, which mediates high visual acuity. Most studies agree that the adult human fovea has a small S cone-free area, but data are conflicting concerning S-cone numbers in the adult Macaca monkey fovea, and little evidence exists for how either primate fovea develops its characteristic cone pattern. Single- and double-label in situ hybridization and immunocytochemistry have been used to determine the pattern of foveal S cones in both the fetal and adult Macaca and human. Both labels find a clear difference at all ages between monkey and human. Adult humans have a distinct but variable central zone about 100 microm wide that lacks S cones and is surrounded by a ring in which the S-cone density is 8%. This S cone-free zone is detectable at fetal week 15.5 (Fwk15.5), shortly after S opsin is expressed, and is similar to the adult by Fwk20.5. Adult monkey foveas have an overall S-cone foveal density of 10%, with several areas lacking a few S cones that are not coincident with the area of highest cone density. A surrounding zone at 200-microm eccentricity has an S-cone density averaging 25%, but, by 800 microm, this has decreased to 11%. Fetal day 77-135 monkeys all have a distribution and density of foveal S cones similar to adults, although the high-density ring is not obvious in fetal retinas. Estimates of the numbers of S cones missing in the fetal human fovea range from 234 to 328, whereas no more than 40 are missing in the fetal monkey. These results show that, in these two trichromatic primates, S-cone distribution and the developmental mechanisms determining S-cone topography are markedly different from the time that S cones are first detected.

A large number of sequence-related, cysteine-rich membrane proteins containing metalloproteinase-like and disintegrin-like domains (the MDC protein family) have been identified in mammalian tissues from a variety of species. Previous studies in the macaque (Macaca fascicularis) have led to the cDNA cloning and sequence analysis of a number of MDC proteins which are abundantly expressed in the male reproductive tract. We now describe the distribution of seven of these macaque MDC transcripts in a range of different tissues. This description includes a novel macaque testis-derived MDC, tMDC III, whose full-length sequence is reported for the first time. In addition, polyclonal antisera have been used to localize a number of these MDC proteins to spermatogenic cells in testis sections, and to demonstrate their processing on the sperm surface during epididymal transit.

Although it is established that developmental methylmercury exposure produces severe motor and sensory impairment, the effect on cognitive function is less clear. To explore this issue, monkeys with robust methylmercury-induced deficits in visual, auditory, and somatosensory function were tested on a series of tasks assessing central processing speed, which is highly correlated with intelligence in humans. Five monkeys (Macaca fascicularis) were dosed from birth to 7 years of age with 50 micrograms/kg/day of mercury as methylmercuric chloride. Blood mercury levels were stable at 0.8-1.1 micrograms/g until cessation of dosing. When they were 20 years old, these monkeys and four age- and rearing-matched controls were tested on a series of simple and complex reaction time tasks. The monkey sat in a primate chair with a stainless steel bar centered at waist height. Four push buttons equidistant from the steel bar were mounted on a vertical Plexiglas panel in front of the monkey. The monkey was required to make contact with the bar, then release the bar and push the appropriate button in response to a change in stimulus conditions. For the first task (simple reaction time), the monkey was required to respond on a button when it changed from unlit to red. The monkey then performed a sequence of complex reaction time tasks: two-button, four-button, and several tasks of increasing complexity using four buttons and multiple colors. For each task, the latency to release the bar after the stimulus change (central processing speed) and to move the hand from the bar to the button (motor speed) were determined. Lastly, the monkey was required to make the quickest possible motor response on the simple reaction time task. There were no differences between groups on any aspect of the experiment. These data provide further evidence for absence of cognitive impairment in monkeys exposed developmentally to methylmercury.

Postnatal development of the corticospinal system was investigated in 13 macaques using noninvasive transcranial magnetic stimulation (TMS) of the motor cortex and direct electrical stimulation of corticospinal axons in the medullary pyramid and spinal cord. The latency of antidromic corticospinal volleys evoked from the pyramid and recorded from the motor cortex decreased dramatically during the first postnatal months. Our data predict that conduction velocity (CV) of the fastest corticospinal neurons over their cranial course would reach adult values at approximately 11 months. The CV of corticospinal neurons in the spinal cord increased with age but with a slower time course. In the neonate, the fastest spinal CV was estimated at 7.8 m/sec, approximately 10 times slower than in adults (mean 80.0 m/sec). Our data predict that full myelination of corticospinal axons in the spinal cord would not occur until approximately 36 months. No short-latency EMG responses were elicited in arm and hand muscles by TMS until 3 months of age; TMS thresholds were high initially and then fell progressively with age. When corrected for body size, relative latencies of EMG responses showed an exponential decrease during the first postnatal months. Our data are consistent with the hypothesis that fine finger movements are not observed before functional CM connections are well established and that rapid changes in the physiological properties of the corticospinal system coincide with the period in which precision grip is known to mature (3-6 months). However, corticospinal development continues long after simple measures of dexterity indicate functional maturity, and these changes may contribute to the improved speed and coordination of skilled hand tasks.

In experiments combining retrograde tracers and histochemistry, we have looked at the prenatal development of the cortical pathway linking areas V2 and V4. Transient expression of acetylcholinesterase in fetal area V2 reveals the separate compartments that project to V4 (temporal directed pathway) and V5 (parietal directed pathway). During early stages of pathway formation, V2 neurons projecting to area V4 are clustered in the appropriate compartments. During the phase of rapid axonal growth, there is a selective increase of connections originating from the appropriate compartments leading to a strongly clustered organization at the peak of connectivity. During this phase, injections involving the white matter also showed clustering, but this was somewhat reduced in comparison to that of gray matter injections. The growth phase is followed by an elimination phase during which there is a tendency for a preferential loss of intercluster connections, which may sharpen the early formed pattern. These results demonstrate the primary role of axonal guidance and target recognition mechanisms followed by a limited extent of selective elimination during the formation of functional cortical pathways in the primate isocortex. Compared to previous findings, these results suggest that the developmental restriction of callosal connections is not a universal model of cortical development. In the present report, the directed growth and early specification of feed-forward connections contrast with the prolonged remodelling of monkey feedback projections, suggesting two distinct developmental strategies of pathway formation in the monkey.

Growth is coupled to physiological modifications of the immune system which reaches the functional capabilities according to age-related milestones. Few data are available on the circulating immunoglobulin levels and no data exist on total immunoglobulin light chains in infant macaques. Therefore we studied by a nephelometric assay, the age-dependent variations of kappa and lambda serum light chains in the experimental animal model Macaca fascicularis during the first 20 months of age. Both kappa and lambda showed a marked increase in their concentrations during the first 7-8 months of life. Infants' light chain levels were anyhow significantly lower than those of the nursing dams and of the control group, never attaining, even at the 20th month, the same concentration as the adult, although the value of the kappa/lambda ratio was apparently the same.

Bilateral enucleation was performed at different fetal ages during corticogenesis, and the brains were prepared for histological examination. Early-enucleated fetuses (operated prior to embryonic day 77) showed morphological changes at the level of the thalamus and the cortex. In the thalamus, there was a loss of lamination and a decrease in size of the lateral geniculate nucleus. There was a decrease in the size of the inferior pulvinar, but there was no change in the lateral pulvinar. The border of striate cortex was as sharp in the enucleates as it was in the normal monkeys. In three of the four early enucleates, we observed an interdigitation of striate and extrastriate cortex. In three of the early enucleates, we observed a small island of nonstriate cortex near the striate border that was surrounded entirely by striate cortex. Enucleation led to an age-related reduction of striate cortex. This reduction was greater in the operculum than in the calcarine fissure. The reduction of striate cortex was accompanied by an increase in the dimensions of extrastriate visual cortex, so that the overall dimensions of the neocortex remained invariant. The extrastriate cortex in the enucleated animals presented a uniform cytoarchitecture and was indistinguishable from area 18 in the normal animal. There were changes in the gyral pattern that were restricted mainly to the cortex on the operculum. A deepening of minor dimples as well as the induction of a variable number of supplementary sulci led to an increase in the convolution of the occipital lobe. These results are discussed with respect to the specification of cortical areas. They demonstrate that the reduction in striate cortex was not accompanied by an equivalent reduction in the neocortex; rather, there was a border shift, and a large volume of cortex that was destined to become striate cortex appears to be cytoarchitectonically normal extrastriate cortex.

Effects of restricted feeding on the growth of laboratory-bred male cynomolgus monkeys (Macaca fascicularis) aged between one year and four years were studied morphometrically. A series of 11 variables representing physical elements were measured. Before 2.5 years of age, the amount of commercial diet (Type AS, 382kcal/100g and 28.1% of crude protein, Oriental Yeast Co. Ltd.) per day was restricted to 50g (group A), 30g (group B) or 20g (group C) and increased to 100g (group A), 50g (group B) or 40g (group C) respectively at 2.5 years old. Throughout the experimental period ca 100g of apples and oranges per day were provided. Significant differences in body weight between group A and C were detected excepting the early period of the experiment. Although the slight suppression in weight gain was observed in group B during the second trimester of the experiment, body weight increased gradually after increasing the amount of food and no significant difference from A was observed at four years of age. The minimum requirement of diets is judged to be 30g/day before two years old and 50g/day over two years old in the laboratory-bred male cynomolgus monkey. Moreover, the suppressive effects of restricted feeding were most significant on the growth of the limbs and, secondarily, on the growth of the trunk. Practically no effect on the growth of the head was observed.

The mechanism(s) that drives preantral and early antral follicle growth in the primate ovary is poorly understood. We previously reported that estrogen does not stimulate preantral or early antral follicle growth in juvenile primates. The purpose of the present study was to determine whether estrogen priming may play a role in enhancing FSH-stimulated follicle growth. Eight juvenile monkeys received implants on Day 1 of silastic capsules containing estradiol (or vehicle) to elevate circulating estradiol levels. Daily FSH injections were initiated on Day 4 and continued for up to 12 days. The left ovary was removed on Day 8 and served as a control. Ovulation was induced, and a luteal phase followed. On the first day of menses, the estradiol (vehicle) capsule-FSH protocol was repeated. The remaining ovary was removed on Day 8 of the second cycle. The number and size of all follicles in both ovaries were evaluated by light microscopy. Results indicate that estrogen priming in the first cycle did not enhance growth of preantral or antral follicles, but did result in fewer developing follicles > 1.0 mm in diameter, this was accompanied by an increase in early atretic antral follicles of similar size. In the second cycle, an even further reduction in number and size of developing antral follicles > 1.0 mm in diameter was observed. These data suggest that pretreatment with exogenous estrogen has an anti-follicular action on follicle growth in these primates.

Developmental biology holds keys to our understanding of morphological pattern formation whether these patterns are expressed in the fossil record or among extant species. Though much is known about osseous growth at the cellular level (e.g. Hall, 1991), we have minimal understanding of the coordinated processes that combine to produce a complex, three-dimensional form. We have proposed a framework for the coordinate-free representation of form, a statistical method for comparing and modelling growth trajectories for complex morphologies, and a means for the eventual elucidation of the role of growth in the evolution of morphology. Our method uses the coordinate locations of biological landmarks to represent form as a matrix of all possible linear distances between landmarks, the form matrix. When two forms are expressed in this way, comparison of these forms is accomplished by computing the ratios of like linear distances, the form difference matrix. When the forms being compared are from a growth series, the matrix of ratios is called a growth matrix. Patterns of growth for two groups can be compared by computing the growth difference matrix. We applied growth difference matrix analysis to the study of sexual dimorphism of ontogeny in the M. fascicularis craniofacial skeleton. Growth matrices describing growth in male and female M. fascicularis were presented along with the growth difference matrix that describes sexual dimorphism of growth to underscore the detailed information available from this analytical technique. The method is quite general and can be applied to two- or three-dimensional data sets of landmark coordinates (cross-sectional or longitudinal) collected from almost any developing structure. The methods that we propose enable us to go beyond a mathematical summary of the comparison of forms and the comparison of growth patterns. We provide examples of how growth patterns might be used in the study of phylogenetic relationships. Our plans for use of this method in the study of evolutionary change assumes that morphological change in the craniofacial skeleton results from evolutionary change in developmental units (as defined by Atchley & Hall, 1991) that underlie morphological structure. We believe we have the basic tools to ultimately propose informed phylogenies based solely on developmental data. This task requires the identification of 'growth features' and the polarization of these features as primitive or derived. It is also advisable to determine a set of primitive growth features for the groups of interest. This will necessitate the inclusion of outgroups in our growth analysis.(ABSTRACT TRUNCATED AT 400 WORDS)

Physical growth was studied longitudinally in laboratory-bred cynomolgus monkeys (Macaca fascicularis) aged from birth to 6.0 years in females and to 6.5 years in males. An allometric formula was applied to morphometrical growth data and the relative growth of each morphological site to anterior trunk length was analyzed. The growth patterns of all of the measurement sites in females and most of the sites in males showed monophasic allometry; while those of head length, head breadth and morphological upper face length in males were judged to show diphasic allometry. The growth patterns of morphological total face length, upper arm length and lower arm length in some males showed diphasic allometry. Morphological measurements with negative allometry were head length, head breadth, morphological total face length, total head height, biacrominal breadth hand length and foot length, while the other morphological measurements revealed isometry in both sexes. However, the values of the relative growth coefficient to anterior trunk length were larger in males than in females, except for in the case of biiliac breadth. These differences in growth patterns may cause the morphological differences between genders after sexual maturation in this primate species.

Physical growth was studied longitudinally in laboratory-bred cynomolgus monkeys (Macaca fascicularis) aged between zero and 6.0 years (females), and between zero and 6.5 years (males). A series of 17 variables representing physical elements were measured in 12 females and 10 males. Rates of increase in morphological total face length and morphological upper face length were somewhat larger than rates of increase in head length and head breadth. Trunk traits showed relatively high growth rates compared to those of leg and arm traits. Growth functions (Gompertz, logistic and quadratic equations) were applied to the growth data. The quadratic equation had the closest fit to the morphometrical growth data in this primate species.

Postnatal development of the neuro- and viscerocranium with special reference to the maxillodental structures was studied morphometrically by analyzing computer tomograms and radiograms of human and monkey heads of different age groups. The following parameters were used: the prognathic angle, the clivus angle, the palate-incisivus angle, the interincisival angle and the viscerocranial quotient. In the newborn primates including man, all parameters measured were relatively similar; postnatally, however, characteristic differences in the growth pattern between man and monkey were developing. In monkey, a marked prognathic growth of the viscerocranium was found associated with characteristic positional changes of the frontal teeth, whereas the growth of the neurocranium was retarded. Here, unlike the human, a flattening of the skull base was observed. In contrast, the human skull showed no major proportional changes during its postnatal development compared with the original spherical skull form of the newborn.

A total of 52 monkeys (Macaca fascicularis) were dosed orally with vehicle or 1.5 mg/kg/day of lead according to one of four dosing regimens (13 monkeys/group): Group 1, vehicle only; Group 2, dosed with lead continuously from birth; Group 3, dosed with lead from birth to 400 days of age and vehicle thereafter; Group 4, dosed with vehicle from birth to 300 days of age and lead thereafter. Blood lead concentrations averaged 3-6 micrograms/dl when monkeys were not dosed with lead, 32-36 micrograms/dl when being dosed with lead and having access to infant formula, and 19-26 micrograms/dl when being dosed with lead after weaning from infant formula. When monkeys were 8-9 years old, they were tested on two sets of concurrent discrimination tasks, each consisting of 6 stimulus pairs. Group 2 required more sessions on Task 1 for 5 of the 6 pairs to reach a criterion of 90% correct, while Groups 3 and 4 required more or marginally more sessions on 4 of the 6 pairs. On Task 2, Group 2 required more sessions to reach criterion for most pairs, Group 4 was marginally impaired, and Group 3 was unimpaired. All three treated groups made more perseverative errors than controls on Task 1, but not on Task 2. There were no differences between groups for response latency or position bias. This extends previous research with these monkeys, in which impairment was observed on spatial and nonspatial discrimination reversal, and spatial delayed alternation.

The relative growth was examined in laboratory-bred cynomolgus monkeys (Macaca fascicularis) aged from zero to 9 years. The principal component analysis and multivariate allometry were applied to the biometrical data. As the result of the principal component analysis, the cumulative contribution ratio of the 1 st (PC 1) and 2 nd (PC 2) principal components accounted for 99.0 percent. According to the eigen vector values of each morphological site (14 sites), PC 1 was acceptable not only as a size factor but also as a shape factor of the morphological growth changes from birth to the 3rd year of life in both sexes. PC 2 was acceptable as a shape factor of the morphological differences between sexes after the 3rd year of life. As the result of the multivariate allometric analysis applied to the same data, proximate sites of the trunk showed relatively high growth rates compared to distal ones of the trunk. The head, limbs and arms grew slowly in contrast to the trunk. Thus, we could demonstrate the relative growth of cynomolgus monkeys morphometrically.

A total of 52 monkeys (Macaca fascicularis) were dosed orally with vehicle or 1.5 mg/kg/day of lead on one of four dosing regimens (13 monkeys/group): Group 1, vehicle only; Group 2, dosed with lead from birth onward; Group 3, dosed with lead from birth to 400 days of age and vehicle thereafter; Group 4, dosed with vehicle from birth to 300 days of age and lead thereafter. Blood lead concentrations averaged 3-6 micrograms/dl when monkeys were not being dosed with lead, 32-36 micrograms/dl when being dosed with lead and having access to infant formula, and 19-26 micrograms/dl when being dosed with lead after weaning from infant formula. When monkeys were 7-8 years old, they were tested on three spatial discrimination reversal tasks: no irrelevant cues, irrelevant form cues, and irrelevant form and color cues. Fifteen reversals were run for each task. Only Group 2 was impaired in the absence of irrelevant cues, while all three treated groups were impaired in the presence of irrelevant cues. These results are in contrast to results from a series of nonspatial discrimination reversal tasks in these monkeys in which Groups 2 and 4 were impaired and Group 3 was unimpaired. The present results are in agreement with results from another spatial task, delayed alternation, in which all three treated groups were impaired.

An enzyme immunoassay for nerve growth factor was developed to determine the regional distribution and ontogenic change in the macaque (Macaca fascicularis) CNS. The standard curve of mouse nerve growth factor paralleled the dilution curves of extracts from the primate CNS at the adult and pre-natal stages. Furthermore, the nerve growth factor immunoreactive material comigrated with mouse nerve growth factor by means of carboxy methyl cellulose chromatography. These findings suggest that the immunoreactive material extracted from the primate CNS is mouse nerve growth factor-like molecules. At the adult stage, the highest level of nerve growth factor was in the hippocampus, with relatively high levels also in the hypothalamus, the cerebral cortex, the amygdala, the basal nucleus of Meynert, the septal nucleus, the cerebellum and the caudate nucleus. No detectable amounts were observed in the spinal cord, the substantia nigra or the dentate nucleus. In addition to the CNS, the pituitary gland contained about four times the level found in the hippocampus. At embryonic day 120, a high level of nerve growth factor already existed in the occipital cortex (80% of the level at the adult stage) and in the hippocampus (70% of the level at the adult stage). Between embryonic day 120 and the newborn stage in the occipital cortex and between embryonic day 120 and postnatal day 60 in the hippocampus, nerve growth factor levels increased about 1.7-fold, and after that, they gradually decreased until the adult stage was reached. In contrast, in the cerebellum, the level was quite high during the pre-natal period and declined to one-third at postnatal day 60. The developmental changes in nerve growth factor and choline acetyltransferase activity in the hippocampus were well correlated (r = 0.963) between embryonic day 120 and postnatal day 60. Our studies reveal that nerve growth factor is present in the primate CNS. The high level of nerve growth factor during embryonic stages and the good correlation with choline acetyltransferase activity suggest a physiological role for nerve growth factor in the development of the primate CNS.

A double-blind study with six cynomolgus monkeys (mean age, 2.0 years) was carried out. All animals received immunosuppression therapy with 16 mg/kg/day of cyclosporin A or G (Norvaline cyclosporine), given intramuscularly in two divided daily dosages. All animals received a small dosage of steroids (0.1 mg/kg/day). After 14 months the dosage of cyclosporin G was increased to 20 mg/kg/day. During the first study year, weight velocity was normal in the cyclosporin G group and impeded in the group receiving cyclosporin A. During the second year of the study, the weight velocity was impeded in both groups. The weight gain was significantly less in the cyclosporin A group than in the group receiving cyclosporin G (p = 0.001). The results suggested that cyclosporine impeded weight gain in primates during the pubertal period. The effect was dosage-related and was less with cyclosporin G than with cyclosporin A. The mechanism is unclear, but the possible effect on the growth hormone merits further studies.

A breeding colony utilizing a harem mating system was established to study the feasibility of breeding cynomoglus monkeys, Macaca fascicularis, in Malaysia. Two groups consisting of 10 females and one male each were evaluated over a 3 period. Forty births were recorded; one was stillborn, 11 died while nursing, and 28 were weaned. The average time to wean offspring was 230 days with an average weight at weaning of 0.858 kg. The average time for conception to take place after weaning was 50 days. Of the 20 breeder females, six produced three offspring each, nine produced two offspring each, four produced one offspring each and one remained barren throughout the project. Three different weaning systems were evaluated. The best method was caging the mother-infant pair within or adjacent to the breeding room followed by a two-part cage system which allowed the infant to continue nursing and also obtain solid food inaccessible to the mother.

This paper describes the results of the artificial nursing of 8 infant cynomolgus monkeys (Macaca fascicularis) weighing 230-350 g at birth. The infants were separated from their mothers just after or 2 days after birth and were kept in a specially deviced small cage (Photo 1 & 2). They were fed on 6.4-16.6% solution of a commercially available powdered milk for the human baby. Apple juice also was given to them from the 3rd or 4th week on. In about the 6th week, the infants received solid foods such as small pieces of apple, biscuit and monkey chow. The main part of the dietary regimen was changed to the solid diet around the 12th week. The volume of milk taken was recorded every day, and the daily intake ff three major nutrients was estimated with the milk intake (Fig. 1,2,5,6). The body weights were between 600 and 750 g on the day of weaning, that is at about 12 weeks of age, except No. 2 infant showing a slight growth retardation (Fig.4). Their physical growth can be judged as normal as that of breast-nursed infants of the saame species from our laboratory. On the basis of these results, an example of the artificial feeding schedule for the infant cynomolgus monkeys was introduced (Fig. 7).

The structural development of the normal monkey lung (Macaca fascicularis) from 61 days of gestation to 14 days postnatal age has been described using quantitative morphometric techniques. The lung of the adult monkey has also been studied. The airway and arterial branching pattern has been traced using serial sections. The alveolar number and size have been estimated and the structure of the arteries after postmortem arterial injection has been assessed. Comparison of lung morphology in monkey and man shows that there are similarities in segmental arrangement, structure and branching pattern of airways, in arterial structure and in changes in the arteries after birth. Although there are differences in the number of lobes, the number of generations of different types of airways and the number and size of alveoli, the overall structure in the monkey is more similar to that in man than is the structure of the lung in species such as sheep, pig or rat. During fetal life the monkey lung passes through the same stages of development as the human fetus but at birth the monkey has a full complement of airways and mature alveoli. Postnatal growth of airways and alveoli is due to increase in size rather than to multiplication. In man there is an increase in the number of alveoli and alveolar ducts after birth as well as an increase in size. Despite the differences between the species it seems appropriate to use the monkey in experimental studies on the lung.

Eight condyles of four growing monkeys (Macaca fascicularis) of estimated ages between 1.6 and 3.6 years (minimum and maximum) were analyzed using radioautographic, histometric, and stereologic techniques. The aim of the study was to examine the relationship between intracondylar variations in structure and growth activities. The animals received 3H-proline (1 mCi/kg body weight) and 3H-thymidine (0.5 mCi/kg body weight) 24 and 3 hours, respectively, prior to sacrifice. The perichondral and chondral layers of the condylar articular covering as well as the subchondral zone of erosion were examined at different sampling sites distributed systematically in the antero-posterior and lateromedial dimension of the articulating surface. Intracondylar variations observed with respect to morphometric and radioautographic parameters suggest the following biologic mechanisms contributing to mandibular growth in a superior-posterior direction. Greater mitotic activity at the central and posterior sites of the condylar perichondrium generates a population of progenitor cells that is larger in these than in other regions. On the other hand, the rate of differentiation of these progenitor cells into chondroblasts and chondrocytes, i.e., the "migration" into and through the chondral layers of the articulating covering, seems to be enhanced in the same superior and posterior areas. Additionally, while "migrating" faster, these cartilage cells become larger and produce greater amounts of extracellular matrix than those in the anterior parts of the condyle. Finally, enhanced resorptive activities in the superior and posterior regions of the subchondral zone of erosion provide an increased "loss" of degenerated chondrocytes, thereby establishing the basis for a cartilaginous drift in the superior-posterior direction.

As in all mammals studied to date, primate retina contains morphologically distinct classes of retinal ganglion cells (Polyak: The Retina. Chicago: University of Chicago Press, '41; Boycott and Dowling: Philos. Trans. R. Soc. Lond. [Biol.] 225:109-184, '69; Leventhal et al.: Science 213:1139-1142, '81; Perry et al.: Neuroscience 12:1101-1123, '84; Rodieck et al.: J. Comp. Neurol. 233:115-132, '85; Rodieck: In H.D. Steklis and J. Erwin (eds): Comparative Primate Biology, Volume 4: Neurosciences. New York: Alan R. Liss, Inc., pp. 203-278, '88). We have now studied the morphologies, central projections, and retinal distributions of the major morphological classes of ganglion cells in the normal adult monkey, the newborn monkey, and the adult monkey in which restricted regions of retina were depleted of ganglion cells at birth as a result of small lesions made around the perimeter of the optic disc. Both old-world (Macaca fascicularis) and new-world (Saimiri sciureus) monkeys were studied. Our results indicate that, at birth, the major morphological classes of monkey retinal ganglion cells are recognizable; cells in central regions are close to adult size whereas cells in peripheral regions are much smaller than in the adult. As in the adult (Stone et al.: J. Comp. Neurol. 150:333-348, '73), in newborn monkeys there is a very sharp division between ipsilaterally and contralaterally projecting retinal ganglion cells (nasotemporal division). Consistent with earlier work (Hendrickson and Kupfer: Invest. Ophthalmol. 15:746-756, '76) we find that the foveal pit in the neonate is immature and contains many more ganglion cells than in the adult. In the adult monkey in which the density of retinal ganglion cells in the central retina was reduced experimentally at birth, the fovea appeared immature, and an abnormally large number of retinal ganglion cells were distributed throughout the foveal pit. The cell bodies and dendritic fields of ganglion cells that developed within cell-poor regions of the central retina were nearly ten times larger than normal. In peripheral regions the effects were smaller. The dendrites of the abnormally toward the foveal pit. They did not extend preferentially into the cell-poor region as do the abnormally large cells on the borders of experimentally induced cell-poor regions of cat central retina (Leventhal et al.: J. Neurosci. 8:1485-1499, '88) or, as we found here, in paracentral regions of primate retina.(ABSTRACT TRUNCATED AT 400 WORDS)

This study concerns the development of the primary visual pathway of the primate. The lateral geniculate nucleus (LGN) is the principal thalamic relay to the visual cortex (area 17), and its neurons have similar morphological characteristics in both monkey and man, as identified by Golgi impregnation. The commonest neuron is the multipolar with a radiate or tufted dendritic tree; next is the bipolar neuron with two or three diametrically opposed dendritic trunks. Less frequent are neurons with beaded dendrites and others with fine, axon-like dendritic processes, possibly interneurons. The dendritic tree of all neurons remains generally within a lamina, but some dendrites cross interlaminar zones. LGN neurons are identifiable before birth and differ from their adult form by the presence of immature features, especially numerous dendritic and somatic spines, most frequent at birth in monkeys and at about 4 months postnatally in man. They disappear almost completely by 3 months in monkeys and 9 months in man. The human LGN has reached its 'adult' volume by this age. Two stages in the development of the human area 17 can be defined. The first is marked by a rapid growth to its 'adult' volume by about 4 months, and by intense synaptogenesis beginning in the foetus and reaching a maximum around 8 months. The second stage is one of stabilization in the volume of area 17 and loss of synapses to reach 'adult' synaptic density around 11 years, at about 60% of the maximum values.