RESUMEN
Term placentas collected surgically from seven Plasmodium coatneyi-infected rhesus monkeys, one abortion, and five controls were evaluated histopathologically. The placentas from Plasmodium-infected dams had more significant pathologic changes than those from controls for six parameters (P < 0.05) and higher numbers of activated (LN5 + Zymed) macrophages in the intervillous space (IVS) (P = 0.0173). Total parasite load (TPL) was defined as the sum of all weekly peripheral infected red blood cell counts for each trimester and for the entire pregnancy. High first trimester PLs were more likely to result in fetal demise (P = 0.0476) or increased placental damage in surviving infants. As trimester 2-3 TPL increased, so did the number of activated macrophages (P < 0.05) and the total malaria pigment scores (P < 0.05). Low birth weight (LBW) and intrauterine growth retardation (IUGR) were associated with high pigment scores and high numbers of activated macrophages in the IVS. High placental damage scores were not associated with IUGR, LBW, or early infant mortality.
Asunto(s)
Malaria/parasitología , Placenta/parasitología , Plasmodium/fisiología , Complicaciones Parasitarias del Embarazo/parasitología , Animales , Modelos Animales de Enfermedad , Femenino , Inmunohistoquímica , Macaca mulatta , Malaria/sangre , Malaria/patología , Placenta/patología , Plasmodium/aislamiento & purificación , Embarazo , Complicaciones Parasitarias del Embarazo/sangre , Complicaciones Parasitarias del Embarazo/patología , Resultado del EmbarazoRESUMEN
Pregnant women with Plasmodium falciparum infection are at increased risk for complications such as anemia and cerebral malaria. In addition, the infants of these women suffer intrauterine growth retardation (IUGR), low birth weight (LBW), congenital infection, and high infant mortality. Although much has been learned from studies of malaria during human pregnancy, progress has been limited by the lack of a suitable animal model. Nonhuman primates are of particular interest because, other than the armadillo, they are the only animals with a discoidal, villous, hemochorial placenta like that of humans. We have established a model of malaria during human pregnancy by inoculating pregnant rhesus monkeys (Macaca mulatta) with Plasmodium coatneyi (a sequestering parasite) during the first trimester. In our initial experiment, four monkeys were inoculated with a fresh inoculum containing 10(8) viable parasites from an infected donor monkey. All four monkeys became parasitemic seven days postinoculation (PI) and three monkeys aborted 7-10 days PI coincident with high peak parasitemias (41,088-374,325 parasites/mm3). Although abortion is one of the outcomes observed in Plasmodium-infected women, the intent of this study was to examine the effects of Plasmodium infection throughout gestation. Since the rapid onset of high parasitemia may have been responsible for the abortions, a decision was made to reduce the size of the effective inoculum. Six additional pregnant monkeys were inoculated with a frozen isolate taken from the same donor containing 10(6) parasites. These six animals became parasitemic by 14 days PI and, along with monkey E412, carried their infants to term. These seven infants weighed significantly less at term than the infants of uninfected mothers (P = 0.0355). Symmetrical IUGR was detected by ultrasound in one fetus with an LBW of 334 g. Another LBW infant (300 g) had asymmetrical growth retardation, which has been associated with uteroplacental insufficiency and was consistent with the lower placental weights found in infected dams compared with controls (P = 0.0455). The infant with symmetric IUGR died at five days of age, while the other is alive but congenitally infected. The IUGR, LBW, congenital infection, postnatal infant mortality, and early abortions observed in these animals suggest that P. coatneyi in pregnant rhesus monkeys is a valid model of malaria in human pregnancy. This model should provide the opportunity to study questions about malaria in pregnancy that have been difficult to study in humans.
Asunto(s)
Modelos Animales de Enfermedad , Macaca mulatta , Malaria/etiología , Parasitemia/etiología , Complicaciones Parasitarias del Embarazo/etiología , Aborto Veterinario/parasitología , Anemia/parasitología , Animales , Animales Recién Nacidos , Femenino , Retardo del Crecimiento Fetal/parasitología , Humanos , Malaria/complicaciones , Malaria/fisiopatología , Parasitemia/complicaciones , Parasitemia/fisiopatología , Placenta/patología , Embarazo , Complicaciones Hematológicas del Embarazo/parasitología , Complicaciones Parasitarias del Embarazo/fisiopatología , Resultado del EmbarazoRESUMEN
Globoid cell leukodystrophy, or Krabbe disease, is a severe disorder of the peripheral and central nervous system myelin caused by deficient galactocerebrosidase (GALC) activity. This autosomal recessive disease affects humans and animals including dogs, mice, and rhesus monkeys. Cloning of the human and animal GALC genes opened opportunities for therapeutic trials using animal models. We describe the clinical, pathologic, and biochemical features of the affected rhesus monkey. Affected monkeys had very low GALC activity and a two base pair deletion in both copies of the GALC gene. Clinical signs of tremors, hypertonia, and incoordination led to humane euthanasia by 5 months of age. At necropsy, peripheral nerves were enlarged. Microscopically, the cerebral, cerebellar, and spinal cord white matter was infiltrated with periodic acid-Schiff-positive multinucleated globoid cells, and there was a striking lack of myelin. Peripheral nerve fibers were decreased in number and separated by Alcian blue- and safranin O-positive material. Myelin sheaths were greatly diminished. Lipid analysis of brains of 12-day-old and 158-day-old affected monkeys revealed a great excess of psychosine in white matter. The rhesus monkey model will be especially useful for exploring treatment options, including prenatal bone marrow transplantation and various approaches to gene therapy.
Asunto(s)
Galactosilceramidasa/genética , Eliminación de Gen , Leucodistrofia de Células Globoides/veterinaria , Macaca mulatta , Enfermedades de los Monos/genética , Animales , Encéfalo/patología , Química Encefálica , ADN/análisis , Enfermedades Desmielinizantes/patología , Femenino , Riñón/química , Riñón/patología , Leucodistrofia de Células Globoides/enzimología , Leucodistrofia de Células Globoides/genética , Leucodistrofia de Células Globoides/patología , Masculino , Enfermedades de los Monos/enzimología , Enfermedades de los Monos/patología , Conducción Nerviosa/fisiología , Linaje , Psicosina/análisis , Nervio Ciático/patología , Médula Espinal/patologíaRESUMEN
The hypothesis that fibrin type fibrinoid deposition on villi is unique to the term human placenta was tested. Bright-field microscopy was used to examine sections of first and second trimester human placental villi and tissues from three animal species that have villous haemochorial placentae similar to the human: the armadillo, the baboon and the rhesus. Sections stained with haematoxylin and eosin showed fibrin type fibrinoid deposits were hypocellular, eosinophilic masses attached to the surface of villi examined from both the human and the animal species. The deposits were located at discontinuities in the syncytiotrophoblast layer, and the fibrinoid provided a matrix for trophoblast re-epithelization of the villous surface. It is concluded that fibrin-type fibrinoid is not unique to the term human placenta. The presence of the syncytiotrophoblast discontinuities associated with the fibrinoid deposition must be considered in models of maternal-fetal exchange in the villous haemochorial placenta.