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Effects of caffeine on mitotic index, mitotic aberrations and bimitosis with and without aeration.

The effects of 1 to 3 h 0.2% caffeine treatment on mitosis in lateral roots of Vicia faba with and without aeration have been investigated. During the treatment a marked decrease of the mitotic index followed by strong deviations and changing phase indices can be stated. By means of aeration the number of mitotic aberrations increases with time of treatment, while it decreases without aeration until 3 h treatment. Tetraploid cells are supposed to be formed by spindle aberrations at early anaphase. The number of binucleate and tetraploid cells is affected by aeration during caffeine treatment. During division of the binucleate cells tetraploid nuclei are formed by fusions, so the population of binucleate cells may become smaller.

Air

Analysis of intestinal cell proliferation after guanethidine-induced sympathectomy. I. Stathmokinetic, labelling index, mitotic index, and cellular migration studies.

Guanethidine-induced sympathectomy in the rat during the neonatal period (injection of 20 microgram/g body weight every 48 h from day of birth until day 14) produces an absolute reduction in the number of sympathetic ganglion cells, but no significant alteration of body weight. Superior cervical ganglia show 79.8% fewer cell bodies at 15 days and 92.3% at 45 days; coeliac ganglia exhibit an 81.0% reduction at 15 days and 89.6% at 45 days in guanethidine-treated rats as compared to normal controls. The sympathetic ganglion cells that remain after treatment have an abnormal morphological appearance with distended mitochondria and depletion of endoplasmic reticulum. Sympathectomy produces a prolongation of the generation cycle time (Tc) as measured by the colchicine-induced mitotic arrest technique, and a decrease in labelling, mitotic, and migration indices. In addition, sympathectomy suppresses the amplitude of the circadian rhythm in mitotic activity. The general suppression of this activity in the intestinal epithelium is more pronounced in the jejunum and ileum than in the duodenum. Variation in the effectiveness of sympathectomy on the inhibition of intestinal cell proliferation may be related to segmental differences in cell proliferation, to segmental differences in innervation, and/or to segmental variation in the effectiveness of guanethidine.

Animals

Bursa of Fabricius--mitotic index in the follicles of immunized and non-immunized chicks (Gallus domesticus).

The mitotic index in the cortical compartment of the follicles of the bursa of Fabricius from chicks immunized with sheep red blood cells (SRBC) is always higher when compaired with non-immunized ones. This mitotic index reachs its maximum 6 days after the SRBC injection, coincident with the highest serum antibody titer. The mitotic activity in the cortex of the follicles of the bursa of Fabricius is always higher than that of the medulla during the postembryonic development of chickens (PROCHAZKA, RODAK, KREJCI 1967). Otherwise it is almost established that the cortex is a zone of continuous lymphocyte proliferation, not occuring the same with the medulla. In addition these bursal histological structures are considered as 2 distinct compartments (GROSSI et al. 1974). The purpose of this paper is to study the response in the mitotic index of the cortical and medullary compartments of the follicles of the bursa of immunized and non-immunized chicks. To correlate possible changes in the mitotic index with circulating antibody levels, the serum antibody titer from the same birds was also recorded.

Animals

[Mitotic index modifications in a series of gliomas related to degree of malignancy].

We have measured on semi-thin sections, the mitotic index in 5 benign gliomas and 5 malignant gliomas among a whole of about 80,000 cells in each group, divided into fields of 750 cells on an average. We have differentiated between normal mitoses and abnormal mitoses on one hand, between viable and adequate mitoses and non-viable mitoses on the other. If we take into account the total number of mitoses, the mitotic index is not greatly different between the 2 groups of tumors (about 5 per thousand), although slightly superior in the benign gliomas. If we take into account the viable or adequate mitoses only, the mitotic index is greatly superior among the benign gliomas. These results are discussed according to other data related with the kinetics of proliferation of gliomas and according to the possibility of cellular fusions as a process of a minor spreading of malignant gliomas.

Cell Fusion

Cytosine arabinoside modulation of the mitotic index in treatment of adult acute leukemia.

Twenty-three unselected adult acute leukemic patients were treated with an initial intravenous pulse of cytosine arabinoside (Ara-C) 5 mg/kg. The mean mitotic index dropped from 7.7/1,000 to 2.8/1,000 at 4 hours after Ara-C pulse and rebounded to 6.7/1,000 at 18 hours. Infusions of Ara-C 7--10 mg/kg were given for 9 or 12 hours, depending on changes in the mitotic index. The group of responders (M1 or M2 marrows) could be predicted by the initial blast count in the marrow and the change in the mitotic index 18 hours after the Ara-C pulse. There were 9 (39%) complete and partial remissions. Six patients remained in remission more than 200 days. Since the changes in the mitotic indices induced by Ara-C were indistinguishable from those of another more successful trial, we infer that factors other than modulation of the cell cycle are critical to the success of this mode of therapy.

Acute Disease

Short term effects of animal venoms on the mitotic index of the duodenal mucosa of albino rats.

Short term administration of the venoms of the snakes Naja haje, Naja nigricollis, and Cerastes vipera and of the scorpion Leiurus quinquestriatus on the mitotic index of the duodenal mucosal cells of the white rat, Rattus rattus, has been studied. All the venoms increased the number of dividing cells of the duodenal mucosa significantly. Naja haje crude venom was fractionated into three fractions. Fraction I had no effect on the mitotic index whereas fractions II and III increased it significantly. Treatment of rats with Naja haje venom fractions II and III after blocking the histamine or the serotonin receptors did not affect the stimulatory action of the two venom fractions on the mitotic index, which it increased significantly. It was suggested that the venoms of Naja haje, Naja nigricollis, Cerastes vipera, and Leiurus quinquestriatus and Naja haje venom fractions possessed a mitogenic activity. Fraction II of Naja haje venom acted through both the muscarinic and adrenergic receptors while fraction III acted on the adrenergic ones.

Animals

The effect of isoprenaline and pilocarpine on mitotic index and goblet cell number in rat respiratory epithelium.

The effect of both isoprenaline (IPN) and pilocarpine (PCP) on mitotic activity and goblet cell number has been studied at 5 levels of the bronchial tree in male and female animals. While both drugs increased mitotic index and goblet cell number at most of the airway levels studied, differences in their effect were detected. After both drugs, nuclei in division were more often superficial within the epithelium than basal but IPN caused a greater increase in mitotic index than PCP. IPN increased goblet cell number at all levels, PCP only in the trachea and larger intrapulmonary airways. The types of goblet cell increased by IPN were particularly those containing acid glycoprotein, whereas PCP increased all types of goblet cell, that is, both those containing neutral and acid glycoprotein. After the drugs, the concentration of cells per unit length of airway epithelium was higher than normal. This is the first study demonstrating the effect of these two drugs on both goblet cell number and cell division. While the two drugs differ in their pharmacological action, the result of their stimulation of airway epithelium is similar. The way in which each effect is produced is discussed.

Animals

Immunohistochemical studies on oncogene products (EGF-R, c-erbB-2) and growth factors (EGF, TGF-alpha) in human breast cancer: their relationship to oestrogen receptor status, histological grade, mitotic index and nodal status.

In this investigation, 83 human mammary carcinomas were examined for the expression of oestrogen receptor (ER), epidermal growth factor receptor (EGF-R), epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha), c-erbB-2, histological grade, mitotic index and nodal status, all of which are reportedly prognostically significant factors (Bloom and Richardson 1957; Baak et al. 1985; Wright et al. 1989). ER expression was biochemically recognized in 43.4% of mammary carcinomas, and EGF-R, EGF, TGF-alpha and c-erbB-2 were histochemically recognized in 25.3, 14.5, 27.7 and 18.0% of mammary carcinomas examined respectively, using conventional sections of buffered formalin-fixed, paraffin-embedded tissue and monoclonal or polyclonal antibodies. There were significant relationships between negative ER and positive EGF-R or TGF-alpha; positive EGF-R and TGF-alpha; positive EGF-R and c-erbB-2; and positive c-erbB-2 and TGF-alpha. The single changes which were the negative ER and the positive c-erbB-2 correlated with histological grade and mitotic index. Co-expression of EGF-R and TGF-alpha correlated with positive nodal status. Therefore, the present investigation indicates that the negative ER, single expression of c-erbB-2 and co-expression of EGF-R and TGF-alpha are important markers which contribute indirectly to prognosis, which reconfirms previous findings on the former two while adding the new finding that immunohistochemical demonstration of expression of EGF-R and TGF-alpha may provide useful information for selecting the appropriate treatment.

Biomarkers, Tumor

Mitotic index of the bronchial and alveolar lining of the normal rat lung.

Cell turnover in the rat airway epithelium has been studied at 5 levels of the bronchial tree after administration of either colchicine or tritiated thymidine, and in male and female rats of 3 age groups. This is the first study to include all these features of the same species. In the young animals the Mitotic Index (number of cells in division per 1,000 nuclei) decreased progressively to the periphry and was higher in the male than in the female, although the rate of weight gain was the same for both. In the oldest animals no difference was observed between the various airway levels or between the sexes. In the intermediate group the proximal to distal decrease was apparent but the difference with sex was not. The concentration of cells per unit length of airway is higher in the trachea and main bronchus than in intrapulmonary airways. (In the intrapulmonary airways virtually no basal cells are present.) This means that a given Mitotic Index represents replacement of a larger area of epithelium in small airways than in large ones.

Age Factors

Prognostic factors in WHO grade 2 transitional-cell bladder cancer (TCC); a novel two-grade classification system for TCC based on mitotic index.

A retrospective histological analysis has been carried out on 537 cases of transitional-cell bladder carcinoma, followed-up over a period of 9 years. In the first part of the study WHO grade 2 tumours were analysed and a number of independent factors predictive for survival identified. In a multivariate analysis the T category and M/V index (number of mitotic figures/mm2 neoplastic epithelium) were the most important prognostic factors. In a subsequent analysis of the whole series of 537 cases, overall the M/V index was not as important in predicting survival as the stage of the tumour. However, in superficial tumours (Ta-T1) subsequent analysis showed that the M/V index alone could be used to predict survival.

Aged

Mitotic index and cell nuclear volume of zona fasciculata externa in processes of postnatal growth of rat adrenals.

Mitotic index and nuclear volume of the zona fasciculata externa have been studied using male and female Wistar rats weighing 20, 50, 100, 250 and 300 g. Adrenal weight of females was greater than of males. Early postnatal growth of adrenals was attained at the expense of intensity of mitotic division. With age mitotic division decreased but cell hypertrophy developed. Cell hypertrophy in females began at an early age and was more marked than in males.

Adrenal Glands

Diagnostic and prognostic significance of the mitotic index in endometrial adenocarcinoma.

The aim of current study was to evaluate the diagnostic as well as the prognostic significance of the mitotic index (MI) in endometrial adenocarcinoma. We compared the MI in normal endometrium, endometrial hyperplasia, and endometrial adenocarcinoma. The mean MI in normal proliferative endometrium (4.35 +/- 3.4) was not significantly different from those in glandular hyperplasia (4.19 +/- 6.0) and well-differentiated adenocarcinoma (4.01 +/- 4.2). A significantly higher MI (10.7 +/- 8.2) was found only in poorly differentiated adenocarcinoma (P less than 0.05). Results of our work indicate that the MI cannot be used as a discriminating factor in the differential diagnosis of borderline cases of endometrial hyperplasia and endometrial adenocarcinoma. We examined the usefulness of the MI, grade of differentiation, and depth of invasion as the prognostic factors in endometrial adenocarcinoma. The significantly higher 5-year mortality rate was associated with an MI greater than 5, grade III of differentiation, and neoplastic invasion penetrating to the outer third of the myometrium. All of the patients with MI greater than 5 had tumors with the highest grade of differentiation and/or invasion involving the mid and outer third of myometrium. This suggests that the higher mortality of patients with an MI greater than 5 reflects the presence of anaplastic and/or highly invasive tumor.

Adenocarcinoma

Radioprotective effect of a protein free parathyroid extract on the mitotic index of rat bone marrow cells.

The protective efficacy of an orally administered bovine protein-free parathyroid extract (PF-PTE) was studied on rat bone marrow cells in vivo with the mitotic index after 850 R irradiation. A remarkable decrease was found in the mitotic activity of bone marrow cells after irradiation in the non-protected animals. However, in the animals treated with PF-PTE after irradiation, a significantly smaller decrease and a faster recovery were found in the mitotic activity of the bone marrow cells.

Animals

Effect of chronic ethanol consumption on mucosal morphology and mitotic index in the rat small intestine.

Rats were maintained 16 weeks on a well-balanced semisynthetic solid diet supplemented with ethanol which comprised 35% of total calories. A control group was pair-fed the same basic diet with sucrose replacing ethanol isocalorically. Striking changes in mucosal morphology and mitotic index were observed in the jejunum and ileum of ethanol-fed rats in comparison to pair-fed controls. Furthermore, it is significant that these changes were more pronounced in the ileum than in the jejunum. Since ethanol is almost completely absorbed in the stomach and upper intestine, under the conditions of this study, we propose that, apart from a possible topical toxic effect of ethanol, there appear to be other separate possible causes of the extensive small intestinal changes found in ethanol-fed rats. The first is that the changes are due to injurious effects of blood-borne ethanol; secondly, the changes could be a functional adaptation due to altered luminal nutrition as a consequence of the introduction of ethanol in the diet.

Alcoholism

Presence of circadian rhythm in the mitotic index of the ruminal epithelium in sheep.

Mitotic indices of the ruminal epithelium of two castrated male sheep fed at 11:00 h were determined at 00:00, 04:00, 08:00, 12:00, 16:00 and 20:00 h. The schedules were repeated in four trials done in December 1975, February, March and June 1976 respectively. The indices ranged from 0.13 to 0.92 per cent, both animals showing a similar tendency in these fluctuations. The mean rate of cell division was low in the morning, high in the afternoon and in the evening, and declined at about midnight. Another pair of male castrated sheep were fed at 07:00, and rumen samples were biopsied six times in three days. The mean rate of epithelial cell division in the rumen was low at 08:00, but high at noon, suggesting that the rate possibly was affected by the food intake of the experimental animals.

Animals

Mitotic index of the Langhans' cells in the normal human placenta from the early stages of pregnancy to the term.

The mitotic index of the Langhans' cells of the normal human placenta has been evaluated from the 6th week of pregnancy until the term. The index is very high from the 6th to the 10th week, and afterwards it decreases quickly. However, some dividing cells are present also in placentas of 30-32 weeks. The high number of mitotic cells is considered to be related to the increase of the syncytial layer more than to the HCG production. This latter would be independent of the proliferative activity of the Langhans' cells and is probably affected by some humoral factors.

Chorionic Villi

[Critical reflections to the problem of timing in the synchronization therapy of human malignant tumors. Mitotic-index determination, cytophotometric and radioautographic studies (author's transl)].

Formerly (1969) we have been able to demonstrate that during a lengthy inhibition of the DNA synthesis with 5-fluoro-uracil (FU), cells assemble just before, at the outset of, and within the S-phase. By taking off the inhibition, these cells start off together for the rest of the life cycle and pass the S, G2 and M phase like a wave. By the experimental condition given, the time required for passing the S phase was rather constant for all tissues. It generally took about 8 h. The sensitivity of cells to radiation depends on the current phase of their life cycle. Normally they are highly radiosensitive during the transition from G1 to S phase and within the G2 phase. Therefore we tried to improve the effectiveness of radiotherapy by radiating the synchronized cell population in the G2 phase. In clinical treatment we give an infusion with 1 g FU in 1000 ml 5.4% Glucose for 12 h. 8--9 h after the end of the infusion radiation will be applied (Betatron, individual doses: 500 rad). This treatment will be repeated until a total dose of 5000--6000 rad. Until now nearly 300 cases of patients treated in this way have been published. The 5 year-results show only in about 60% of the patients a fast reduction of the tumor. The long term results are unsatisfactory. Beside many other points the most important reason for these clinical results might be the individual length of the S phase of the tumors which prevents that radiation can be given exactly in G2 phase in each case. With mitotic-index determination, with cytophotometric investigations and the double labelling technique (3H- and 14C-Thymidine) we therefore tried to find an answer to the following questions: 1. How long is the DNA synthesis time in the individual case of human ENT tumors? 2. Does the application of FU influence the length of the S phase? 3. Will the synchronization-degree become higher by using other methods of cell cycle inhibition? With the above mentioned experimental methods we found that the length of the S phase in human tumor spreads from about 8--16 h in the individual case. The application of FU has no influence on DNA synthesis time. By using FU the degree of synchronization is about 2.5 in according to former experimental work and that of other authors. These results will be discussed in detail as well as the conclusion we draw from our experiments: to give radiation not in G2 but in G1/S of the cell cycle. Long-term observation of the patients and further animal experiments shall demonstrate whether this technique of synchronization therapy will improve the clinical results.

Autoradiography