Fetal cells in the maternal circulation. Technical considerations for practical application to prenatal diagnosis

We have used electron-microscopic studies, bromodeoxyuridine (BrdU) incorporation and antibody labeling to characterize the development of the Drosophila larval photoreceptor (or Bolwig's) organ and the optic lobe, and have investigated the role of Notch in the development of both. The optic lobe and Bolwig's organ develop by invagination from the posterior procephalic region. After cells in this region undergo four postblastoderm divisions, a total of approximately 85 cells invaginate. The optic lobe invagination loses contact with the outer surface of the embryo and forms an epithelial vesicle attached to the brain. Bolwig's organ arises from the ventralmost portion of the optic lobe invagination, but does not become incorporated in the optic lobe; instead, its 12 cells remain in the head epidermis until late in embryogenesis when they move in conjunction with head involution to reach their final position alongside the pharynx. Early, before head involution, the cells of Bolwig's organ form a superficial group of 7 cells arranged in a 'rosette' pattern and a deep group of 5 cells. Later, all neurons move out of the surface epithelium. Unlike adult photoreceptors, they do not form rhabdomeres; instead, they produce multiple, branched processes, which presumably carry the photopigment. Notch is essential for two aspects of the early development of the visual system. First, it delimits the number of cells incorporated into Bolwig's organ. Second, it is required for the maintenance of the epithelial character of the optic lobe cells during and after its invagination.     

Intraleucocyte malaria pigment in asymptomatic and uncomplicated malaria

While malaria pigment or haemozoin is known to be an end product of haemoglobin digestion by the malaria parasite, its clinical significance is just beginning to be elucidated. We have studied the distribution of intraleucocyte malaria pigment in 92 children, consisting of 32 children with asymptomatic malaria, 32 children with mild or uncomplicated malaria and 28 children with no malaria. Over 90% of children in each of the three groups had pigment-containing monocytes and the numbers of pigment-containing monocytes were not significantly different between the three groups. While over 90% of children in both the asymptomatic malaria and uncomplicated malaria groups had pigment-containing neutrophils, 71.4% of the no malaria group had such neutrophils. The numbers of pigment containing neutrophils was highest in the uncomplicated malaria group, followed by the asymptomatic malaria group with the no malaria group having the least numbers. The pigmented neutrophil: monocyte ratio followed the same pattern. It was concluded that the number of pigment-containing neutrophils and the pigmented neutrophil:monocyte ratio may be a marker of the severity of malaria infection when one considers the conditions: no malaria, asymptomatic malaria and mild malaria. Further work to verify this hypothesis across the full spectrum of the manifestations of malaria infection is needed.     

Mortality and morbidity from malaria after stopping malaria chemoprophylaxis

Gambian children who had received malaria chemoprophylaxis for a variable period of time during their first 5 years of life were followed to determine whether they experienced a rebound in mortality or in morbidity from malaria during the period after chemoprophylaxis was stopped. The risk of dying between the ages of 5 years, when chemoprophylaxis was stopped, and 10 years was no higher among children who had received chemoprophylaxis with Maloprim (pyrimethamine plus dapsone) for some period during their first 5 years of life than among children who had received placebo (21 vs. 24 deaths) and the beneficial effect of chemoprophylaxis on mortality observed during the first 5 years of life was sustained. The incidence of clinical attacks of malaria during the year after medication was stopped was significantly higher among children who had previously received Maloprim for several years than among children who had previously received placebo. However, at the end of this year, there was no significant difference in spleen rate, parasite rate or packed cell volume between the 2 groups of children. Thus, stopping chemoprophylaxis after a period of several years increased the risk of clinical malaria but did not result in a rebound in mortality in Gambian children. However, the number of deaths recorded was small, so a modest effect on mortality cannot be excluded.     

Fetal retinoblastoma

Fetal tumors are sporadic entities and in some cases can be diagnosed prenatally. A team approach, incorporating the skills of obstetricians, radiation therapists, pediatric medical oncologists and hematologists, neonatal surgeons, rehabilitation specialists, and social workers, is imperative to ensure that the patient receives the best treatment. Retinoblastoma is a relatively uncommon tumor of childhood that arises in the retina. The estimated annual incidence is between 1 in 15,000 and 1 in 34,000. Although it may occur at any age, it most often arises in younger children, with 80% of cases diagnosed before the age of 5 years. We report a case of prenatally diagnosed fetal retinoblastoma.     

Fetal echocardiography

From a research programme comparing two photorefractive keratectomy (PRK) methods, Group S using Summit ExciMed UV 200, and Group V using the VisX 20:20 excimer laser system, 10 patients from each group were recruited. They were referred 6-12 months post-PRK for lens fitting to correct resultant ametropia or irregular astigmatism. Ablation zone diameters were: Group S, 4.5 mm; Group V, 4-6 mm. For Group S, best fit rigid gas permeable (RGP) lenses generally had a back optic zone radius (BOZR) 0.10 mm steeper than the mean keratometry reading (K) and overall diameter of 9.20-10.0 mm. For Group V best fit RGP lenses generally had a BOZR of 0.20 mm steeper than the mean K. The lenses often required large diameters to improve lens centration and extra negative power to compensate for the positive power of the central tear pool. Several patients required soft lens fitting to improve comfort and some finally opted for repeat PRK.     

Fetal surgery

Although most fetal defects are best managed after birth, a few with predictable, life-threatening developmental consequences have been successfully corrected in utero. Many technical problems have been solved, but preterm labor remains a significant risk to mother and fetus. Less invasive interventional techniques and fetal stem cell transplantation promise to extend the indications for intervention.     

Fetal growth

Fetal growth requires the correct balance of nutrients, oxygen, and growth factors operating under the direction of a genetic plan modified by maternal factors. The classic hormones of postnatal growth play differing roles with alternative controls compared to those after birth. The study of conditions of abnormal fetal growth illuminates the mechanism of normal fetal growth. It is now apparent that abnormal birth weight leads to long-term consequences.     

Fetal hydrocolpos

This work studies the role that nitric oxide (NO) plays in ischemia/reperfusion (I/R) of the rat kidney. Sprague-Dawley rats, weighing 250-300 g, were subjected to 75 min of warm ischemia and contralateral nephrectomy. The animals were divided into six groups (n = 12 per group): ischemic control (IC) with normal saline, L-NG-mono-methyl-arginine (L-NMMA) 50 mg/kg, L-arginine (L-Arg) 300 mg/kg, Na-nitroprusside (Na-NP) 2.5 mg/kg, the combination of L-NMMA+Na-NP at the doses used before, and the sham group. All animals received the drug intravenously 60 min prior to ischemia. Survival was evaluated at seven days. Renal damage was assessed by kidney function tests (serum creatinine and blood urea nitrogen) and light histology. Lipid peroxidation was measured in renal tissue using the thiobarbituric acid assay. Significantly better survival was seen in the Na-NP group, as compared to the rest of the study. Serum creatinine at 24 and 48 hr showed a significant difference between the Na-NP group and the other groups. Histological damage was minimal in the Na-NP group. Clearly, the Na-NP had the most beneficial effect in survival and histological structure. Lipid peroxidation was significantly different, with the lower levels seen in the L-NMMA group and the higher levels in the Na-NP group. In base to these results, we conclude that exogenous NO has a beneficial and protective effect of the ischemically damaged rat kidney. This protection is independent of lipid peroxidation. Endogenous NO production does not play a role in I/R injury in our model.     

Fetal tachyarrhythmias

Fetal tachyarrhythmias are uncommon but are associated with significant perinatal mortality and morbidity. Fetal echocardiography permits the accurate determination of the nature of the arrhythmia. Transplacental or direct fetal therapy with anti-arrhythmic drugs can successfully cardiovert the fetus in utero with a subsequent reduction in perinatal problems. The investigation and management of these unusual conditions is reviewed.     

The placenta and malaria

Placental malaria is recognized as a common complication of malaria in pregnancy in areas of stable transmission, and is particularly frequent and severe in primigravidae. Many hypotheses, based on a systemic or local failure of the immunological response to malaria, have been proposed to explain the 'preference' of the parasites for replication in the placenta. Some of the hypotheses are briefly reviewed here, with a particular focus on the discovery of an uncommon subpopulation of Plasmodium falciparum which can adhere and massively sequester in the placenta. Histologically, placental malaria is characterized by the presence of parasites and leucocytes within the intervillous spaces, pigment within macrophages, fibrin deposits and trophoblasts, proliferation of cytotrophoblastic cells and thickening of the trophoblastic basement membrane. The exact mechanisms leading to placental changes and determining the observed impairment of materno-foetal exchange are incompletely understood. Parasites are unlikely to be directly responsible for the placental pathology, but leucocytes, through the production of non-chemotactic cytokines, might be associated with the thickening of the trophoblastic basement membrane, and might cause a mechanical blockage of oxygen and nutrient transport across the placenta. There is sound epidemiological evidence that placental malaria determines low birthweight, mainly mediated by intrauterine growth retardation, and increases the risk of death and disease during the first year of life. Antimalarial chemoprophylaxis significantly reduces placental malaria and prevents the development of low birthweight. It is likely that, in areas of high endemicity, the placenta is where the drama of maternal malaria is mostly played. A deeper understanding of the mechanisms involved in this process is of key importance in the design of protective interventions which are effective and acceptable during the gestation period.     

Clinical pharmacology and malaria

The role of clinical pharmacology in improving the prevention and treatment of malaria is reviewed. A series of general and specific issues is discussed, concentrating on risk-benefit and cost-effectiveness. The techniques of clinical pharmacokinetics play an important role in the optimal use of drugs and this is illustrated by studies on quinine and proguanil. In discussing amodiaquine toxicity, the role of the pharmacologist and the chemist in designing out drug toxicity lends hope for producing a new generation of antimalarial drugs.     

Fetal acidemia and neonatal encephalopathy

A 33 years old woman presented with cramp-like abdominal pain. Ultrasound examination revealed multiple lesions in the liver of hyper- and hypoechoic echogenicity which in accordance to subsequently performed computed tomography and dynamic hepatobiliary scintigraphy were considered to be a focal nodular hyperplasia (FNH). A severe increase of the serum lipase concentration, suspected to be an acute pancreatitis, was treated conservatively and led to a short improvement of symptoms. Some months later, a severe progression of the pain symptoms occurred, along with a measurable expansion of the abdominal circumference and palpable tumors of the liver. The dynamic hepatobiliary imaging and the static liver scan showed a decreased perfusion and function of the nodes as well as a reduced RES activity, respectively. A subsequently performed Positron Emission Tomography (PET) with F-18-Fluorodeoxyglucose (FDG) showed a massively increased glucose metabolism of the liver tumors. The histologic result of several biopsies of the tumors revealed metastases of an acinus cell carcinoma of the pancreas. Under systemic and local chemotherapy, a temporary remission could be obtained that was clearly detectable in a second FDG-PET. Nevertheless, during the further course of the disease, a progression occurred being detectable in an additional control PET-study by an increase in tumor size as well as in tumor glucose metabolism. The patient died in liver coma 15 months after the histologic diagnosis was obtained.