Spontaneous apoptosis and retinoic acid receptor incidence in neuroblastomas and peripheral neuroectodermal tumors.

Twelve cases of neuroblastoma (NB) (7 boys and 5 girls) and 4 cases of primitive peripheral neuroectodermal tumor (PNET) (3 boys and 1 girl) were investigated for the presence of apoptosis and retinoic acid receptor (RAR) by immunhistochemical method. The apoptotic index in NB was zero or 1% in 8 children and relatively low (2-4.8%) in the other 4 cases, while it was higher (4.1-10.5%) in PNET. The RAR index determined by immunoperoxidase reaction in NB was zero or 3% in 5 cases and 9-34% in 7 children. RAR index in PNET was 16-68% in all the 4 cases. Good correlation (r = .47 according to Pearson-Bravis) was found between the number of RAR and spontaneous apoptosis. These results suggest that the RAR index in untreated NB and PNET shows great individual variation since its determination is necessary for the evaluation of the efficacy of retinoic acid treatment.

A study of children, fathered by men treated for testicular cancer, conceived before, during, and after chemotherapy.

One hundred fifty children of 113 fathers with testicular tumour treated from 1979 on the National Institute of Oncology, Budapest, were studied. Three groups were formed on the basis of the time of conception; 69 children were born before the illness of the fathers, 40 during the 12 pretreatment months, and 41 during or after combined chemotherapy. One hundred fifty control children underwent tonsillectomy/appendectomy, but were otherwise healthy. They were matched according to age, sex, and place of inhabitance with index children. Family anamnesis, perinatal, and gestational data were listed; thereafter, physical, laboratory, immunological, and, if required, radiological examinations were made. No difference was detectable in the somatic and psychiatric status of the three groups, and development was well balanced, corresponding to age. Protocols of the combined chemotherapy applied, and the incidence of anomalies, abnormalities, malignancies, and other diseases was recorded. Incidence was similar in all three groups. Incidence of congenital malformations was not increased in children conceived before and after therapy; however, a complex congenital abnormality, an atrial septal defect with horseshoe kidney, occurred in one young girl, conceived after the end of her father's treatment. The interval between conception and the end of therapy was established in the case of children conceived either during or after therapy. This was shorter in the case of healthy children; the number of healthy children conceived during cytostatic treatment was also remarkable. Further detailed analysis of data and individual evaluation of case reports are recommended.

Children fathered by men treated for testicular cancer conceived before, during and after chemotherapy--examination for evidence of congenital malformations, malignancies and immunological defects.

Hundred children of 64 fathers with testicular tumour treated from 1979 on at the National Institute of Oncology, Budapest were studied. Three groups were formed on the basis of the time of conception. 59 children were born before the illness of the fathers, 19 during the 9 pretreatment months and 22 during or after combined chemotherapy. Family anamnesis, perinatal and gestational data were listed, thereafter physical, laboratory, immunological, psychiatric, and, if required, radiological examinations were made. No difference was detectable in the somatic and psychiatric status of the three groups, development was well balanced, corresponding to age. Protocols of the combined chemotherapy applied and incidence of anomalies, malformations, malignancies and other diseases were recorded. Their incidence was similar in all three groups though frequently this was higher than that of the normal population. Often cumulated incidence of severe congenital malformations was found in the group conceived after concluded therapy where twice as many girls were born as boys. The interval between conception and the end of therapy was established in the case of children conceived during and after therapy. This was shortest in the case of healthy children, the number of healthy children conceived during cytostatic treatment was also remarkable. Further compilation of data and individual evaluation of case reports is recommended.

Monitoring the therapy of acute lymphoid leukemia (ALL) in children--changes induced in clinical, cytological and immunological parameters during treatment of high malignancy ALL with ALL-BFM 88.

The ALL-BFM 88 RF greater than 1.7 treatment of high malignancy ALL patients in remission was monitored at the 4th week of Protocol I. The qualitative and quantitative processing of parameters indicating cellular transformations by light and electronmicroscopy was performed in lymphocytes separated from peripheral blood drawn at scheduled times of therapy. The immunophenotype of sample lymphocytes was determined by indirect immunofluorescent techniques, by listing the percentual level of CD2, CD3, CD4, CD8, CD19 surface antigens. The incidence of infections, confirmed clinically and bacteriologically, was recorded. The parameters of the patients were compared to those of healthy children. In the group of patients with high malignancy in the intensive period of ALL-BFM 88 RF greater than 1.7 therapy the incidence of cells rich in organelles, dense granules and vacuoles was significantly (p less than 0.05) higher compared to the control cells, poor in structures. During the weeks of induction and after the consolidating combination with VM-26+ARA-C the expression of surface antigens of the lymphocytes was reduced. That means that up to the introduction of maintenance treatment the presence of surface antigens remained below the range of normal deviation. These data obtained during monitoring revealed that the morphological and functional integrity of cells was damaged in patients with high malignancy ALL during intensive therapy, though only temporarily.

In vitro effect of antitumor drugs on lymphocytic blastogenesis in childhood acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL).

"In vitro" sensitivity of lectin (PHA, Con A)-stimulated lymphocytes to antitumor drugs (ARA-C, ADR, VM26, MTX, CP, VCR, Vepesid, ACLA) and the clinical efficiency of the complex therapy was compared in 7 patients with ALL and 2 patients with NHL. H3-thymidin incorporation of lymphocytes labelled prior to the drug exposure was used as "in vitro" method. A fairly good correlation was found between the "in vitro" test and the clinical response to the drug administered. These results suggest that this "in vitro" test is useful in choosing the drugs to be administered in case of malignancies of children.

Effect of sustained norepinephrine infusion on local cerebral blood flow in the rat.

In order to elucidate the possible role of noradrenergic hyperactivity in producing disturbances of cerebral circulation during hemorrhagic shock, the effect of prolonged norepinephrine infusion on local cerebral blood flow was studied in anesthetized and artificially ventilated rats. Intravenous infusion of 20 micrograms/(kg.min) norepinephrine for 2 hr produced circulatory shock characterized by progressive hypotension and acidosis. As a result, local cerebral blood flow, which was determined by autoradiography employing 14C-labeled iodoantipyrine in 79 different anatomical structures, decreased substantially in many areas. The most pronounced reductions were found in the regions supplied by the internal carotid artery, whereas the blood flow of the vertebral territory remained close to control. The blood supply of the cerebral cortex exhibited extreme heterogeneity with flow values below 0.10 ml/(min.gm). When either the intensity or the length of the infusion was reduced, no signs of circulatory breakdown could be observed. Variation of the infusion parameters demonstrated the dose-dependent nature of the cerebral blood flow response. Preinfusion blockade of alpha-receptors with 5 mg/kg phenoxybenzamine prevented the development of circulatory shock and reversed the decrease in cerebral blood flow induced by norepinephrine. The experimental results support the hypothesis that high concentration of norepinephrine in the vicinity of cerebral vessels produced by sympathetic hyperactivity might be an important factor in the etiology of blood flow deficiencies.

Local effect of anaesthesia on cerebral blood flow in the rat.

Local blood flow was measured in 81 cerebral structures of the paralysed rat during nitrous oxide, sodium pentobarbital and glucochloralose anaesthesia. With a ventilatory mixture of 75% nitrous oxide and 25% oxygen the flow values in comparable structures were slightly lower than those reported in awake animals. Pentobarbital and chloralose depressed the local flow by an average of 32 +/- 2% and 39 +/- 2%, respectively, as compared to values measured during nitrous oxide administration. In some areas the flow was reduced below 40% of the control, whereas other regions showed no significant change at all. Based on the coefficients of correlation, the distribution of local flow values is similar under pentobarbital and chloralose, but differs considerably from the pattern observed during nitrous oxide anaesthesia. The results indicate that the effect of anaesthesia on cerebral blood supply depends a great deal on local factors, and experimental data collected under different types of anaesthesia are not directly comparable.

Effect of autonomic blocking agents on local cerebral blood flow in the rat.

The local effect of autonomic blocking agents on the resting cerebral blood flow of anaesthetized rats was investigated in 78 anatomical structures. The existence of an alpha-adrenergic vascular tone was indicated by the average flow increase of 28 +/- 3% and 17 +/- 3% after the administration of the alpha-receptor blocking agents phenoxybenzamine (56 mg/kg i.p.) and phentolamine (1 mg/kg i.v.), respectively. The injection of atropine (1 mg/kg i.v.) increased the average blood flow by 19 +/- 2%, whereas the overall effect of the beta-blocking agent propranolol (1 mg/kg i.v.) was statistically not significant. The magnitude of local blood flow changes in specific cerebral areas exhibited considerable variation in all experimental groups. The comparison of individual and overall flow changes suggests that some of the discrepancies among different investigations could have resulted from the intraindividual heterogeneity of evoked flow changes.

"Dot-17 alpha-hydroxyprogesterone" radioimmunoassay for identification of congenital adrenal hyperplasia in young infants.

Using a simplified radioimmunoassay method for the determination of 17-hydroxyprogesterone (17-OHP) concentration in blood dried on filter paper seven untreated cases of congenital adrenal hyperplasia were identified among newborns and infants at risk for congenital adrenal hyperplasia (CAH) having ambiguous genitalia and/or failure to thrive with electrolyte disturbances. In three additional cases the diagnosis of congenital adrenal hyperplasia was confirmed by high 'dot-17-OHP' values even after glucocorticoid therapy had been started. Capillary blood samples taken in a local hospital on a filter paper routinely used for the screening of phenylketonuria can be sent by mail into a central laboratory for performing the analysis. Assays of 'dot-17-OHP' are clearly of diagnostic value in the C21-hydroxylase form of CAH and permit a rapid diagnosis of this condition in the newborn period.

Interneurons: an electron microscopic study of the cat's hippocampal formation, II.

The ultrastructure of interneurons was studied in the cat and it was found to differ from that of the pyramidal and granule cells. The size, shape and topographic situation of the cell body of interneurons were the criteria for approaching their identification with the cells found in Golgi material. Some interneuron dendrites are also described. The varicose and spindle-shaped dendritic profiles belonging to interneurons are different in size. In Golgi material the interneurons have beaded (varicose) or spindle-shaped dendrites. The arrangement of synaptic terminals on the interneuron dendritic surface seems to be their characteristic feature.

Efferent connections of the nucleus lateralis posterior-pulvinar complex in the cat.

The nucleus lateralis posterior-pulvinar complex of the thalamus displays an integrative function. The efferent connections of this nuclear group were examined by the authors in the cat. In their work, they utilized also the earlier observations on the afferent connections of the nucleus. The nuclear complex projects to the associative fields encompassed by the visual- and the acoustic cortex without intruding into the primary cortical areas. On the other hand, its afferent connections are, apart from the associative field, also yielded by the primary visual and acoustic cortex. All this is completed by the reciprocal connections of the LP-pulvinar complex with the visual- and acoustic system, as well as between the associative areas of the cortex.