Rhesus Monkey, and some other Cercopithecidae
Macaca mulatta

Order: Primates
Family: Cercopithecidae

1) General Zoological Data

The rhesus monkey is the most widely used laboratory primate. An enormous amount of information has been accumulated on its anatomy, physiology, and on pathologic features afflicting this species. While specimens of rhesus monkeys are not commonly carried in zoos, some placental specimens of rhesus placenta were available to me. But I have had considerably more access to specimens from the lion-tailed macac, Macaca silenus. This endangered Indian species has been bred for many years at the San Diego Zoo. In addition, a few related species with very similar placentation are considered here. The term "macaque" is Portuguese for monkey.

Macacs are members of the large group of Cercopithecidae ("apes with tail"). This genus comprises at least 20 species and some additional subspecies. One species, the Kolb's monkey, has been discussed in a separate chapter. Taxonomic revisions are frequently made in this genus (Nowak, 1999). Many of these species hybridize fertilely (Fa, 1989; Gray, 1972). Hybridization is not only true for the macac species but it occurs with related genera, irrespective of chromosome numbers. Thus, assignment of species rank is somewhat problematic in some animals. A complete review of the genus comes from Lindburg (1971, 1980). It needs to be consulted if more data are desired than what is reviewed by Nowak (1999).

The macacs are largely Asiatic species and are related to other cercopithecid members, such as baboon, mandrill, langurs, etc. Many cercopithecids have very similar or even an identical placentation. Macacs are diurnal animals with considerable arboreal ability. They forage on the ground for variable times and, depending on the species, they are hardy animals, good swimmers, can withstand snow and heat, and macacs generally produce a single young. Twins occur, but this is uncommon. Indeed, Geissmann (1990) determined that the estimates often published suffer from a small sample size. If this is taken into consideration, then twinning frequency in macacs is slightly lower than in human populations (0.19-0.35% vs. 0.8%). Estrous cycles are between 28 and 40 days in length, depending on species and authority, and estrus may last for 9 days. Gestation lasts 160-170 days in rhesus monkeys, slightly longer in some other species. There is, however, considerable variation in rhesus monkeys as well. Specifically, prolonged gestation is not uncommon. Newborns weigh between 400 and 500 g and mothers usually nurse for a year. Sexual maturity occurs between two and three years of age. Longevity for some animals in zoos is over 30 years, and rhesus females are said to go into menopause at age 25 years.

Ramsey has made numerous contributions to our understanding of placentation and reproduction in rhesus monkeys. Her contribution in 1972 evaluates the usefulness of the rhesus monkey for studies to understand human reproductive problems. Despite finding differences in depth of implantation, the basal decidua and vasculature, she nevertheless concluded the animal to be useful, so long as its physiology is better understood. Myers (1979) reviewed the history of the establishment of the primate colony in Puerto Rico and advocated the rhesus for studies of abnormal placentation.

2) General Gestational Data

Gestational length in rhesus monkeys is about 160 days. Newborns weigh then between 450 and 600 g and the corresponding placentas are around 140 and 160 g. There is a general correspondence of placental and fetal weights (Bunton, 1986). Singletons are the rule. The primary disk measures around 9 x 0.75 cm, the secondary disk around 6.5 x 1 cm.

The growth of fetus and placenta was also plotted by v. Wagenen et al. (1965). In their experience, the average length of gestation was 168 (+/- 7) days, at which time the neonate weighed around 470 g and had a crown-rump (CR) length of 19 cm. The average weight of the placenta then was 121 g and their cord measured 20 cm in length. I am impressed with the frequency of longer gestations in this extensive study that reported the data in numerous tables. Placentophagy was observed in this study as well.

3) Implantation

Enders & Schlafke (1981) flushed the uteri of cycling, sexually active female rhesus monkeys and collected various preimplantation conceptuses between days 2 and 8 of the estrogen peak. Five of their specimens had blastocysts without zona pellucida (days 7-8). They showed the trophectoderm to possess microvilli and, near the inner cell mass, there are larger protrusion that presumably will subsequently interact with endometrium at implantation. These authors were impressed with the frequency of cell death in the recovered blastocysts and depicted them in a later publication (Enders et al., 1982). They also saw the earliest differentiation of endoderm in late stages of blastocysts.

The implantation of the rhesus blastocyst was first studied by Wislocki & Streeter (1938) and further elaborated upon by Heuser & Streeter (1941). Its superficial similarity has given rise to hopes that its placentation may thus constitute a useful model for human reproductive studies. Ramsey (1972), while agreeing in general with this, is also adamant to point out significant differences that need to be considered. These include the shallow implantation, the formation of a secondary disk as a result, the development of an endometrial plaque, and differences in maternal vascular supply.

Heuser & Streeter (1941) stated that the blastocyst remains in the uterus for about 5 days, that it is sticky and thus adheres readily to the endometrium. Thereafter the epithelial endometrial plaque forms. They likened the plaque to a deciduoma. One half of the implantations they observed were anterior and one half was posterior in the middle of the uterus. A few exceptional blastocysts implanted laterally in the uterus. Implantation occurred on days 8 to 9. Beautiful photographs and diagrams accompany this publication of data that extend to term gestation.

Ramsey et al. (1976) beautifully illustrated the implanting blastocysts in a comparison between human, rhesus and baboon placentations. The rhesus blastocyst does not implant "interstitially" as the human, but remains only superficially attached and thus lacks the usual decidua capsularis of human placentas. A dome of blastocyst protrudes from the endometrial surface into the endometrial cavity (which is then only a slit) and becomes attached to the other side of the uterus. Also the endometrial reaction is much different. In humans, a pronounced decidua is hormonally initiated. In rhesus monkeys, on the other hand, there is a profound proliferation of surface epithelium, the so-called epithelial plaque.

4) General Characterization of the Placenta

The placenta of rhesus monkeys is similar to that of human placentas, except for the predominance of two disks in most rhesus monkey placentas. The rhesus monkey placenta has two disks in about 80% of term gestations; the remainder, however, has a single disk, as is the normal finding in baboons (Myers, 1972; Chez et al., 1972).

Whether there are two disks or only one, this does not appear to have an impact on fetal growth and survival. The actual cause of the development of single disks in about 20% of rhesus gestations, however, is unknown. Perhaps it is the result of slightly deeper implantation. Chez et al. (1972) found no differences in prenatal bleeding or other parameters that might explain this difference in placental forms. They suggested that this is the result of some autosomal Mendelian trait.

This is a cotyledonary, villous placenta. There are between 4 and 24 lobules of the rhesus placenta according to Myers who also found that wild-born animal placentas had more placental lobules and heavier infants than those born in captivity. In contrast to human placentas, fewer septa are found between the individual cotyledons. As in human placentas, these septa are rarely complete and span only for a short distance into the placenta (Ramsey & Harris, 1966). It is believed that some of the septation is due to the contraction of the uterus during expulsion of the human placenta.

Another feature mentioned by Myers and others is the frequency (around 15%) of circumvallation of the placenta. Circumvallation is a condition in which a wall of degenerated fibrin encircles the placenta with a concomitant narrower insertion of the peripheral membranes. While it seems to be a placental "abnormality", I believe its impact on fetal development to be small.

The study of Wislocki & Streeter (1938) laid the foundation for our knowledge of placentation in this species. At that time, however, the mechanism of trophoblastic growth was not understood. The studies by Galton (1962) on DNA content, by Richart (1961) on thymidine incorporation, and later by Pierce et al. (1964) on gonadotropin-producing cells, laid the foundations for the current understanding. The cytotrophoblast (the "Langhans' cell layer") of the villous surface proliferates and, continuously throughout pregnancy, adds nuclei and cellular material to the syncytiotrophoblast that borders the entire intervillous space. The cytotrophoblast of very young placentas is a continuous sheet of cells that is easily identified. Later in gestation, these cells are less apparent. They are, however, readily seen electronmicroscopically and identified by cell markers (vide infra). The syncytial nuclei have lost their replicative ability. Thus, the syncytium is a single, uninterrupted sheet of cytoplasm within which the nuclei are "loose". Protrusions often form (so-called "knots"), and many of these knots detach. They are then swept away by the intervillous circulation. They are transported to the lung and there they deteriorate. The syncytium is the outermost cell layer of villi. It is studded with numerous microvilli that effects transport in and out of the placenta, produces hormones and has other enzymatic activity. None of these functions are available from the villous cytotrophoblast.

Prior to the knowledge of these details, investigators also considered that the trophoblast may produce the connective tissue, even the vasculature of the villi. I consider this now to be erroneous for many reasons. Importantly, none of the choriocarcinomas that are composed of these two trophoblastic cell types ever produces connective tissue or vessels. This has been studied extensively in human neoplasms and is also true of the few tumors of rhesus monkeys. The mesenchymal elements of the placenta arise from mesodermal precursors (see section of membranes below).

Another topic of concern has been an understanding of the villous structure, especially when the villi were compared with those of other primate placentas. Considerations of this kind have been used to understand the developmental relationships among primates and especially, to understand the possible relationship between platyrrhine and catarrhine primates. Did they have a common ancestor, and when did they separate; and can the placental structure be useful in understanding this evolutionary complexity? These are the principal reasons for such considerations.

It is true, the appearance of the platyrrhine (South American) monkeys' villi differs; they have a trabecular structure (please see chapter on Tamarins). Although cercopithecids have in their final form some similarities with those villi, their villi form quite differently as was pointed out by Starck (1959). In the development of platyrrhines there is much more initial trophoblastic growth, while implantation of cercopithecids is much "thinner" and the growing connective tissue pushes the trophoblast ahead, thus producing the villous outgrowths. Starck also pointed out that the typical longitudinal connecting villi of platyrrhines (that go from chorionic plate to the floor) are very uncommon in cercopithecids, as for instance in the rhesus monkey.

5) Details of fetal/maternal barrier

A superior electronmicroscopic study of rhesus monkey placenta villi was published by Luckett (1970). This animal's placental details are similar to those of human trophoblast. The syncytium contains large amounts of rough endoplasmic reticulum, a Golgi complex, and numerous transport vesicles. The syncytial surfaces are studded with microvilli and at their bases that connect them to the villous mesenchyme, they are complex and infolded. The cytotrophoblast beneath the syncytium is discontinuous. The villi have large, active-appearing macrophages, so-called Hofbauer cells. The trophoblast layer is exposed to the intervillous space within which maternal blood circulates, and the syncytium has the appearance of being the most active cellular component.

8) Extraplacental membranes

The rhesus monkey placental membranes are very similar to those of apes and humans with the exception of having virtually no decidua and no atrophied villi. The inner surface of the sac in lined by a flat, single-layered amnionic epithelium that is placed on an avascular connective tissue layer. The amnion is pressed passively against the chorionic connective tissue membrane. The fetal vessels that connect the fetal circulation of the two lobes are carried in this membrane. These two layers also contain numerous macrophages and connective tissue cells. Peripheral to the chorionic connective membrane is a layer of trophoblast that is composed principally of extravillous trophoblast ("X-cells"). It often makes small cysts. Peripheral to this trophoblast may be some decidua capsularis. This is minimal in most bilobed placentas and also absent in the baboon (Hendrickx, 1971). Only when there is some adhesion of the membranous dome to the parietal decidua exists, some decidua is delivered with the placenta. When decidua should be present, it is vascularized by maternal blood vessels. This is then a good location in which to find maternal vascular disease, either secondary to hypertension or from pre-eclampsia (especially so-called atherosis). Contrary to the observations of human membranes, there are no atrophic villi in the membrane rolls that I have examined, nor are any present in the baboon (Hendrickx, 1971). This, however, is contrary to the statements by Torpin (1969). He alleged to have found presence of atrophic villi and drew significant conclusions from this without adequately depicting or documenting these structures. In a detailed study of the structure of the rhesus monkey placental chorion, King (1981) did not mention villous remnants either, nor did he include them in his drawing of the placenta. He pointed out that the adjacent trophoblast ("X-cells") is angular and often vacuolated with glycogen content.

King (1980) published a detailed study of the developing amnion in rhesus monkeys. It shows the development of microvillous surface, basal folds and an apparent absorptive capacity. Mitoses are virtually never seen in amnionic epithelium but, when special stains (Ki-67) are used to demonstrate replicative cellular activity, this is found in occasional amnionic epithelial cells. The amnion also contains numerous macrophages.

Enders & King (1988) studied the origin of the mesoderm of rhesus monkey placentas. They were also of the opinion that it does not derive from trophoblast. The earliest differentiation of the extraembryonic mesoderm (that ultimately gives rise to the "membranes" and villous cores) occurs between the primitive endoderm and trophoblast. It can be seen even earlier than the formation of the embryonic disk. These authors indicated that the mesenchyme is likely to commence as a reticulum from the endodermal cells and that, a few days later, this differentiates into proper mesodermal cells. Later still, the extraembryonic mesoderm initiates the formation of villous capillaries. Trophoblast and embryonic disk do not participate in the derivation of mesoderm.

9) Trophoblast external to barrier

Extravillous trophoblast infiltrates diffusely into the basal endometrium and its arterioles (not the veins). In retrospect it is interesting to read about the confusion that existed initially regarding the origin of the large cells that appear to completely plug the endometrial arterioles and subsequently alter the walls of the endometrial vessels. At one time these cells were thought to be endothelial proliferations. This conclusion was rectified when Beck & Beck (1967) studied the distribution of Barr bodies (the expression of the inactivated second X-chromosome of females) in these cells. They found them to correspond to the fetal component and concluded that they are indeed trophoblast. Later investigators supported this conclusion (see Ramsey et al., 1976).

This is now the accepted concept. Extravillous trophoblast (the "X-cells") infiltrates the maternal arterioles early in gestation, appears to completely plug these channels and, later, alters the musculature of the vessels in such a manner as to create a non-contractile blood vessel. This trophoblast may even infiltrate in the blood vessels somewhat beyond the endometrium, the superficial myometrial vessels. This modification of the blood vessels is thought to be essential for normal blood flow to ensue. It has been discussed extensively for human placentation and the reader is referred to our text for further details (Benirschke & Kaufmann, 2000). In that publication we discuss the evidence that through this trophoblastic plugging of vessels, the circulation of the primitive intervillous space is effected by a serum filtrate. It thus also reduces the pressure gradient of the maternal circulation. There is no infiltration of trophoblast into myometrium or beyond the endometrial implantation site except within some blood vessels.

The extravillous trophoblast, the "X-cells", plays an important role in human and simian placentation. For a long time it was unknown whether they were fetal or maternal cells, hence they were referred to as X-cells. They are now known to be a trophoblastic element that differs substantially from the villous trophoblast. It initiates implantation and infiltration into the arterioles. It produces islands within the villous portion of the placenta and lines the membranes. In the X-cell islands of the placenta, the cells produce occasional cysts with proteinaceous content. These cells are also responsible for the production of fibrinoid of the placenta; this is not the coagulation product fibrin but a distinct entity. The regulation of these cells is completely unknown. Indeed, it was only recently that Maddox et al. (1984) and Wasmoen et al. (1989) identified this trophoblast to produce a specific protein, "MBP" (major basic protein), that had been believed to be specific for eosinophilic granule protein. Blood levels during pregnancy are elevated and fall immediately after delivery. Interestingly, this protein from eosinophils is toxic to parasites. In subsequent studies, Wasmoen et al. (1987) identified the same features to exist for simian placentas.

10) Endometrium

The rhesus monkey and other cercopithecids make a fairly good decidua during early pregnancy that it is only somewhat similar to that of human gestations. Although it is readily possible to induce decidualization that becomes similar to deciduomata by the administration of provera (see below), the intense modification of the stroma seen in human decidua differs in rhesus gestations. In general, the development of decidua of rhesus uteri during pregnancy is less prominent than in humans. That is readily apparent when looking at the illustrations of Bartelmez' paper (1951) on the normal rhesus endometrium. There is much less swelling of the stromal cells and the glands do not atrophy as much as is seen in human gestations. Moreover, these illustrations indicate the earlier reduction of the endometrial response in rhesus monkey gestations and the occurrence of focal decidual bleeding, the "decidual sign". Despite these findings, the report by Ramsey (1972) suggested that the animal was still a useful model for human placentation. This difference in decidualization has also been studied by King (1981) who also found some similarities with human placental "membranes".

11) Various features

There is no subplacenta in higher primates. The base is composed of some decidua basalis with extensive infiltrating trophoblast and fibrinoid deposits. Endometrial glands are generally less atrophied than in humans. Some retain thickened secretion.

12) Endocrinology

The endocrine performance and regulation of fetal growth, and the differentiation of these regulatory events are very complex. They have been studied in considerable detail, especially in rhesus monkeys and baboons. Numerous hormones are produced in the placenta and fetus, as well as in the mother, and these have interactions that undergo changes as pregnancy proceeds. Moreover, numerous specific enzymes interact and alter these hormonal profiles. Good evidence also exists to show that hormones modulate vascularization of the placenta and regulate blood flow. The complexity is exceedingly well reviewed by Pepe & Albrecht (1995).

The placenta of rhesus monkeys and related simians produces chorionic gonadotropin. Since this hormone is deemed necessary for the initial maintenance of the corpus luteum and thence its progesterone support of pregnancy, it has attracted many studies. One such study was undertaken to ascertain the need for the presence of a fetus in order to assure pregnancy continuation. Initially, studies showed that fetectomy leads to the delivery, many months later, of the normal placenta. Renewed investigations by Lewis and Hertz (1966), however, clearly demonstrated that this is not the case. The villi atrophy or degenerate after fetectomy and progesterone support did nothing to enhance survival. Contrary to their expectations, however, no hydatidiform moles developed either. Now it is recognized that hydatidiform moles of human gestations have an androgenetic origin (two male sets of chromosomes only) and such change is not expected any longer from fetectomy. No hydatidiform moles have been reported in rhesus monkeys. Other investigators have subsequently made similar observations on the sequelae of fetectomy, namely that the living fetus is needed for normal parturition to occur (the most recent paper summarizes others - Nathanielsz et al., 1992).

In a related study by Novy et al. (1981) it was found that fetal hypohysectomy or interruption of the inter-disk blood vessels did not change the monkey chorionic somatomammotropin (sMC) levels. [sMC is also called placental lactogen]. This vascular ligation merely led to atrophy of the secondary disk and to hypertrophy of the primary placental disk. Placental endocrine function was not changed, and the normal mCS rise continued throughout pregnancy.

All simians produce some chorionic gonadotropin during pregnancy but its length of secretion and the nature of the glycoprotein structure are incompletely known for most species. Macacs produce mCG during the first 35 days of gestation and the amounts then fall to immeasurable levels (Atkinson et al., 1975). Estrogens and progesterone are also produced during pregnancy and the levels for various gestational ages can be found in Hobson (1971), and Hodgen et al. (1972). An exhaustive review of all endocrine functions of placenta and fetus of primate pregnancies is found in Pepe & Albrecht (1995).

In efforts to understand the macac chorionic gonadotropin (mCG) production, Wilken et al. (in press) investigated the expression of mCG genes in cynomolgus monkeys (Macaca fascicularis). They demonstrated the existence of a single gene for the alpha-subunit, but multiple genes for the beta-subunit and put this into an evolutionary context.

13) Genetics

Rhesus monkeys have 42 chromosomes. Numerous cytogenetic studies have been undertaken, including all staining methods. Stock & Hsu (1973) have discussed the possible rearrangements that are the basis for such marked differences in the karyotypes of cercopithecids, specifically between rhesus (2n=42) and African green monkey (2n=60). Indeed, there is a great deal of variability of chromosome number and structure among cercopithecine monkeys. Therefore, hybridization while perhaps possible among many forms, it may lead to fertile offspring. Ruppenthal et al. (2004) reported trisomy 16 (homologous to trisomy 13 of humans) in a pigtailed macac (M. nemestrina) that had many anomalies but lived to age 3 years.

At least one chromosomal error has been recorded, a 41,X animal, monosomy-X. This is the human Turner-syndrome equivalent (Weiss et al., 1973). Perhaps some of the abnormal blastocysts that have been studied in the past were chromosomally abnormal. This warrants further study.

The rhesus monkey, of course, has been a vital model for the detection of the "rhesus factor" (Landsteiner & Wiener, 1940). Through this study and the large number of subsequent developments in immunogenetics, erythroblastosis or "Rh-incompatibility" in gestations has been made a harmless entity in human pregnancies. Socha (1986) and Wiener et al. (1964) provided further insight into blood groups of rhesus and other simians.

14) Immunology

The expression of major histocompatibility loci (MHC complex) in the placentas of rhesus monkeys is beyond the scope of this chapter. Nevertheless, many studies have been done to understand the possible antigenicity of this "graft" and its possible role in selection of fitness. The reader is referred to recent publications by Knapp et al. (1997, 1998), and Boyson et al. (1997). Insight into cytotoxic lymphocyte population in rhesus pregnancies can be obtained from the publication by Kuroda et al. (1998).

The fact that the syncytium is apparently non-antigenic has evoked much interest. The recent identification of the incorporation of a viral envelope gene into the simian genome and its effect of cell fusion ("syncytin") are the most important advances made in understanding primate placentation. The reader is referred to the discussion on Genetics in the chapter on Ateles (Spider monkey).

15) Pathological features

Many pathologic features have been described regarding the reproductive physiopathology of rhesus monkeys, baboons and related species. Many of the common lesions have been detailed by Scott (1992) or reference to them can there be found. For instance, the reports on ectopic pregnancy, or cervical cancer, ovarian teratoma, and infections are given. The macac and baboon have been long-term research animals for a variety of diseases. For instance, initially the cause of cerebral palsy was attacked with this "animal model". Infectious diseases, transplacental chemical teratogenesis, and so on have been studied. Effects of drugs on placental blood perfusion have been a specific target, and transplacental transfer of nutrients and chemicals have been studied.

In the Japanese macac (Macaca fuscata) best known for its ability to endure ice and snow, a terrible series of outbreaks of phocomelia occurred all over Japan. The animals shown below are from a troop of these animals in Awaji Island where 30% of newborns suffered phocomelia, some of much greater degree than those shown. This was traced to insecticides. Likewise, Wilson (1972) showed that a single dose of 19 mg thalidomide given on day 27 of pregnancy led to phocomelia. This single finding convinced Society of the culpability of this agent in causing human phocomelia.

Spontaneous abortions occur but are perhaps not so common as seen in human gestations. This is particularly so in breeding colonies of Primate Research Centers. Wilson (1972) reviewed this topic extensively. Around 10-15% of gestations that occurred in Primate Research Centers abort spontaneously or end in premature delivery. Many more do so when the females were freshly imported. Similarly, Hertig et al. (1971) reported that nearly one half of newly imported pregnant animals had either abortions or premature deliveries. Most were due to common infections and/or measles infection. In contrast to human studies of abortions, a majority of which are due to trisomies or other chromosomal errors, such investigations have apparently not been done in rhesus monkey colonies.

Placenta previa, abruptio placentae, infarcts and stillbirths with fetus papyraceus all have been recorded in rhesus monkeys (Myers, 1972). Indeed, Myers asserted that most of the anomalies or pathologic conditions seen in human placentas may be observed in rhesus monkeys. Endometriosis, adenomyosis and endometrial anomalies are some other pathologic features studied in rhesus monkeys.

Structural abnormalities of neonatal primates have been studied by Wilson (1972). A variety of congenital anomalies have been identified, but apparently fewer than found in humans. Importantly, the same author clearly identified the cause of phocomelia following a single dose of thalidomide. Several of those animals are depicted in his report.

Several extrauterine choriocarcinomas have been reported, even in juvenile catarrhine monkeys. They may have arisen from germ cells or stem cells; alternatively they are associated with a teratoma. Their apparent relative frequency is nevertheless surprising and they can be quite destructive. The last-cited authors have used very modern tools for their exploration. (Farman et al. 2005; Giusti, et al. 2005; Marbaix et al., 2008; Moore et al., 2003; Toyosawa et al. 2000; Yamamoto et al. 2007).

16) Physiologic data

Physiologic data on blood pressure and pulse rate of fetus and mother in pregnant rhesus monkeys under anesthesia were reported by Misenhimer & Ramsey (1970. In addition to that report, a wealth of information has been accumulated in fetal and placental physiology of rhesus gestations. Access to this literature can be achieved through the comprehensive book of Ramsey and Donner (1980). Some information on the vasculature is summarized above.

17) Other resources

The Regional Primate Research Centers of the USA, several foreign research centers, and industrial companies have large holdings of rhesus monkeys. Most are now bred in captivity, very few are being imported. And the zoological parks of the world, of course, house large numbers of these animals and more commonly some of the related species. There is much expertise in breeding and pathology in these agencies.

18) Other remarks - What additional Information is needed?

One of the more interesting future studies should be on the regulation of the "X-cells", the extravillous trophoblast. Not only does it achieve the implantation but also, it modifies the blood vessels of the endometrium and produces a specific protein whose function is unknown so far. The means by which MHC is modulated so as to prevent rejection, the exploration of syncytin and syncytium formation will be of interest. Observations on intrauterine mobility and its effect on spiraling (not described in rhesus) of the cord should be made. Do MZ twins occur and how is their placenta structured.

Acknowledgement

Most of the animal photographs in these chapters come from the Zoological Society of San Diego. I appreciate also very much the help of the pathologists at the San Diego Zoo.

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