Tumor induction by ras and myc oncogenes in fetal and neonatal brain: modulating effects of developmental stage and retroviral dose

Introduction into fetal rat brain cells of a replication-defective retroviral vector harboring v-Ha-ras and v-gag-myc rapidly causes the induction of highly malignant undifferentiated neuroectodermal tumors following transplantation into the brains of syngeneic hosts [Wiestler, et al. (1992) Cancer Res. 52: 3760–3767]. In the present study, we have investigated the modulating effect of the developmental stage of neural target cells and of the dose of the retroviral vector used in the grafting experiments. Exposure of fetal cells from embryonic day (E)12 or E14 produced a 100% incidence of malignant neuroectodermal tumors which led to the death of recipient animals after a median latency period of 32 days. A 100-fold reduction of the virus dose from 2.062×10⁶ to 2.062×10⁴ focus-forming units/ml resulted in a lower tumor incidence of 25%. Of six neural grafts exposed to v-Ha-ras and v-myc at E16, only one showed evidence of tumorigenesis (low-grade astrocytoma and hemangioma). All other transplants were morphologically normal for observation periods of 26 weeks, indicating a marked loss of transforming activity of ras and myc in more advanced stages of brain development. In retrovirus-exposed donor cells which caused the development of neural tumors in recipient rats, malignant transformation was also evident during culture in vitro, usually after 9–12 days. Oncogene complementation was also studied in the newborn rat brain. After microinjection of the retroviral vector into the brain at postnatal day (P)0, P1 and P3, 5 out of 20 animals (25%) developed a total of seven brain tumors. Histopathologically, three of these neoplasms were malignant neuroectodermal tumors which, in contrast to those induced in fetal brain transplants showed evidence of focal glial and/or neuronal differentiation. In addition, we observed one oligodendroglioma, two hemangiomas and a malignant hemangioendothelioma. These data indicate that neural precursor cells and endothelia of the rat brain represent the major target cells for the complementary action of ras and myc and that the use of target cells from later developmental stages (E16 and postnatal) leads to the induction of both primitive and more differentiated neoplasms.These studies were supported by the Fonds zur Förderung der wissenschaftlichen Forschung in Österreich (Erwin Schrödinger fellowship, JO501-MED), by the Swiss National Science Foundation and by the Cancer League of the Kanton of Zürich     

Acoustic rhinometry in pre-school children

Acoustic rhinometry was performed in 35 normal nose-breathing children between 3 and 6 years. The average cross-sectional areas at the nasal valve, at the anterior end of the turbinates, and in the nasopharynx were 0.34±0.06 cm², 0.35±0.08 cm² and 1.37±0.48 cm² respectively. The average minimal cross-sectional area was 0.29±0.06 cm². The minimal cross-sectional area was located at the nasal valve in 14 and at the anterior end of nasal tubinates in 21 of the 35 children. As would be expected, the cross-sectional areas at different sites of the nasal cavity increased with increasing age of the children. But, whereas the minimal cross-sectional area increased by 0.024 cm² per year, the nasopharyngeal cross-sectional area increased by 0.20 cm² per year. No significant differences were found between boys and girls. Measurements of the posterior nasal and nasopharyngeal cross-sectional areas were unreliable, whenever the minimal cross-sectional area was less than 0.2 cm². Furthermore, assessment of the nasopharynx may be difficult because of involuntary movements of the soft palate.     

Location and geometric description of carpal bones in CT images

The carpal regions of ten cadaver extremities were imaged by CT. The images were combined into a 3-dimensional model of the carpus using a technique based on a dynamic programming algorithm to find an optimal estimate of the location of the bone boundaries in the CT images. The resulting set of surface points on each bone was used to compute volumes and principal and antipodal axes for the bones. A spatial coordinate system was established based on the positions of the centroids of three bones in the distal carpal row. The angular orientations of all carpal bones were determined with respect to this system. The principal axes for the same bone among ten wrist specimens proved to be more widely dispersed than the antipodal axes for the same bones. The antipodal axes also correspond more closely to an intuitive notion of the “longest axis” of the bones. We conclude that the antipodal axis is a more reliable and useful measure of bone orientation than the principal axis.     

Study of the effects of dopamine hydrochloride on alpha 1-adrenoceptors in rat kidney

We studied the number and affinity of catecholamine receptors in SD rat kidney by radioreceptor technique. The following conclusions were obtained: 1) By using 3H-prazosin, the numbers of alpha 1-receptor (Bmax) in rat renal cortex were greater than those in rat kidney medulla. As for affinity (Kd), the significance was not recognized between the two. Bmax of the rat renal cortex to 3H-prazosin binding was 96.1 fmol/mg protein, and Kd was 0.17 nM, and for the rat renal medullar these values were 44.5 fmol/mg protein and 0.13 nM, respectively. 2) By measurement of D1-receptor using 3H-SKF38393 in the rat renal cortex in the Scatchard plot analysis, positive cooperativity was observed under the low concentration of hot ligand which was less than 1 nM. But at the concentration of hot ligand over 1 nM, the plots showed a straight line. Bmax of the rat renal cortex to 3H-SKF38393 was 2.5 pmol/mg protein and Kd was 5.3 nM. 3) Based on displacement by dopamine for 3H-prazosin binding to rat renal cortex, it was surmised that high concentration of dopamine had an affinity to alpha 1-adrenoceptors. 4) There was no change in the Kd and Bmax of alpha 1-receptor in the rat renal cortex after incubation of samples with low concentration of dopamine. However, in the case of high concentration of dopamine, a remarkable decrease of the affinity (Kd) of alpha 1-adrenoceptor was observed.     

Premature closure of the physis following diaphyseal fractures

Three patients who experienced premature complete physeal closure of the ipsilateral limb following diaphyseal fractures are reported. The diagnosis was recognized because of unexpected progressive limb length discrepancy following fracture healing. The cause is unknown. This phenomenon should be recognized by those treating fractures in children.     

Electro-encephalographic disturbances due to chronic toxin abuse in young people, with special reference to glue-sniffing

A study was carried out in order to document any abnormalities in the electro-encephalogram (EEG) that might appear in young adolescents who have deliberately inhaled the range of volatile substances loosely referred to as 'glue'. The EEGs of a group of 'street children' being assisted in a Johannesburg shelter were examined. The records were analysed for any clinical abnormalities and also subjected to spectral analysis in order to examine the overall characteristics of frequency, power and spatial distribution. The EEGs clearly revealed that, although at the time of the examination the subjects were ostensibly abstinent, both clinical and normative evidence of continuing brain disturbance was present. It was concluded that glue sniffing is likely to have long term electrocerebral sequelae.     

The in vitro fertilisation programme at Tygerberg Hospital and the University of Stellenbosch. Five years' experience, April 1983-January 1988

The results of the in vitro fertilisation programme at Tygerberg Hospital for the period April 1983 to January 1988 are presented. Of the 1117 laparoscopies performed, 825 patients reached the transfer stage. A live-birth rate of 9.3% was achieved. The pregnancy rate after transfer of 4 embryos was 25.9% compared with 15.4% after 2 embryos and 10.8% after 3 embryos (P = less than 0.0001). The multiple pregnancy rate was 2.8% in the group receiving 2 embryos and 11.7% and 10.4% in those receiving 3 and 4 embryos, respectively. Of the 77 successful pregnancies (90 babies), 1 baby died at 34 weeks' gestation as the result of abruptio placentae due to preeclampsia and 1 cot death occurred. The only congenital abnormality encountered was a cleft palate.     

Dural arteriovenous malformations at the base of the anterior cranial fossa: report of nine cases

Nine men with dural arteriovenous malformations (DAVM) at the base of the anterior cranial fossa are described. Four patients had intracerebral haemorrhage and four had seizures, associated with haemorrhage in two. In three cases the fistula was an incidental finding. In five cases the diagnosis could be made before angiography, on the basis of CT findings. Angiographically, venous drainage was always seen into ascending cortical veins. Five cases demonstrated drainage via the olfactory vein into the basal vein of Rosenthal; in four this way was the principal route of drainage. Five patients underwent surgery, the therapy of choice. One fistula closed spontaneously after angiography. Two patients refused treatment and one was not treated because of his poor general condition. Because arterial supply was usually bilateral, from small branches of the ophthalmic artery, embolisation seemed to be more dangerous. Compared to dural fistulae in other locations the DAVM of the anterior cranial fossa have a higher risk of complications and should be treated even if asymptomatic at the time of diagnosis.     

A new technique for assessing the efferent innervation of the human striated urethral sphincter

A technique is described for recording the electromyographic response of the striated urethral sphincter to transcutaneous magnetic stimulation of the brain and spinal cord. A series of 11 control patients have been studied and 3 examples of patients with neurological disease also are reported. The most reliable response was recorded after facilitated transcranial stimulation of the cerebral cortex, with the mean latency of the electromyographic response in the striated sphincter being 26.4 msec. (standard deviation 2.21). It is concluded that assessment of the latency of the striated urethral sphincter electromyographic response to transcranial magnetic stimulation may be a useful technique in the investigation of patients with disorders of micturition.