Mitotic and labelling activity in normal human epidermis in vivo.

Labelling and mitotic indices were studied in the epidermis of twenty-eight young men. A mean labelling index of 5.5% was found from the whole study and a mean mitotic index of 0.06%. Mitotic index particularly was extremely variable; indices between 0.002 and 0.438% were found in individual biopsies. In the first two of three experiments in which mitotic index at 09.00 hours was compared with that at 15.00 hours, significant differences were found (15.00 hours greater than 09.00 hours by a factor of 2.6, P less than 0.001). However, in the third such experiment no such difference was found, suggesting that the timing and occurrence of diurnal rhythms of mitotic activity may not be consistent in normal human epidermis. In the one experiment in which it was investigated, a significantly higher mitotic index was found at 21.00 hours compared to 09.00 and 15.00 hours. Labelling index did not vary significantly at 09.00, 15.00 or 21.00 hours. However, labelling index did show a significant pattern of change over a 12-month period in two groups of subjects; peaks of labelling were seen in July and troughs in January. Very high ratios of labelled: mitotic cells were found, the median ratio for the whole study being ninety-eight labelled: one mitotic cell. This finding supports the possibility that not all labelled cells subsequently go on to divide in normal human epidermis.

"Of mice and men" the cell cycle in human epidermis in vivo.

This article deals with and compares cell cycle information obtained in mouse and in human epidermis in vivo. In order to compare data in mouse and in man, DNA labeling and mitotic index experiments were performed to obtain cell cycle information in normal human epidermis in vivo. Experiments were also performed on genetically inbred and outbred strains of mice--to provide a clue to the differences observed between mouse and man. The article makes the following points: 1. In contrast to mouse epidermis, there are no consistent diurnal fluctuations in and there is no cell kinetic relationship between mitotic and DNA-labeling indices in normal human epidermis in vivo. The variability from individual to individual in human subjects and the lack of cell cycle-related circadian fluctuations, preclude the use of statistical analysis and the use of conventional cell kinetic principles in understanding epidermal cell proliferation in man and may preclude the use of circadian rhythmicity for therapy scheduling. 2. The consistent and intelligible cell cycle information obtained in laboratory mice (as compared to man) is not due to the genetically inbred condition of mice. 3. This report introduces the use of ambient temperature as a potential nontoxic cell cycle tool for manipulating epidermal cell proliferation in the therapy of human proliferative skin diseases.

Circadian rhythms and differences in epidermal and in dermal cel proliferation in uninvolved and involved psoriatic skin in vivo.

Using in vivo DNA labeling procedures, the present study makes a detailed comparative analysis of circadian rhythms in labeling indexes (Is), in mitotic indexes (Im), and in Is/Im ratios in uninvolved and in involved psoriatic epidermis in vivo (12 patients, studied at 6-hr intervals over a 24-hr period). We also provide comparable data on the rates of epidermal DNA synthesis and on the proliferative activity of dermal infiltrate cells. There are no circadian-diurnal variations in epidermal or in dermal infiltrate cell proliferation in either inactive (uninvolved) or in active (involved) lesions of psoriatic skin. The rates of epidermal DNA synthesis were lower at 9 AM and 3 PM; higher at 9 PM and 3 AM in both uninvolved and involved epidermis. The following cell kinetic information was derived from 78 biopsy samples-from epidermal mitotic and labeled nuclei counts in approximately 100 mm unit lengths of epidermis per biopsy. DNA labeling indexes, 6.1 vs. 21.2%; mitotic indexes, 0.13 vs. 0.43%; and Is/Im ratios, 152/1 vs 70/1 in uninvolved vs. involved psoriatic epidermis in vivo. There was an overall 20% decrease in the rate of cycling epidermal cell DNA synthesis involved epidermis; and 5-fold increase in the overall proliferative activity of dermal infiltrate cells in involved psoriatic skin. These results are discussed in relation to the clinical use of circadian rhythms for the "chronotherapy" of proliferative diseases in man, in relation to cell cycle aspects of psoriasis and psoriatic epidermal responses to therapy, and in relation to cell proliferation in human epidermis in vivo.

An attempt to use vincristine and colcemid to measure proliferative rates in normal human epidermis in vivo.

A range of doses of vincristine (0.5-10 micrograms) or colcemid (5-100 micrograms) injected intradermally into normal volunteers failed to yield any significant accumulation of arrested mitoses. This was despite an apparently successful block of cells in metaphase by the highest three doses of each drug. Possible reasons for the failure to see accumulation are discussed. The results suggest that normal human epidermis is not a suitable system for application of the metaphase-arrest technique using intradermal injection.

The cell cycle in psoriasis: a reappraisal.

The current belief that the clinical manifestations of psoriasis (excessive scaling) are due to a twelve-fold speeding up or shortening of the cell division cycle time of the germinative cells in psoriatic epidermis (from 457 to 37-5 h) is shown to be incorrect. A new concept is introduced--that the germinative layer in human epidermis is composed of not one, but three separate and distinct populations of epidermal cells. First, there are cycling cells which are actively moving through the cell cycle. Then there are two categories of non-cycling cells (blocked in the G1 or the G2 periods of the cell cycle) which are capable of moving into the proliferative pool upon specific stimulation. Thus, increased epidermal cell proliferation in active lesions of psoriasis would be brought about mainly by a recruitment or a relase of the two categories of non-cycling cells. The idea that germinative epidermal cells are primarily non-cycling, leads to the suggestion of focusing attention on non-cycling cells (rather than on cycling cells) for the control and treatment of psoriasis. It might be worthwhile considering treating psoriatic patients during periods of clinical remission--with factors to keep the germinative cells in the non-cycling state--rather than during psoriatic flare up--with cancer chemotherapy drugs.

Noncycling tumor cells: mitogenic response to antilymphocytic serum.

After continuous labeling with tritiated thymidine for a period several times the cell generation time, some ELD ascites cells remained unlabeled. Despite continued exposure to tritiated thymidine, unlabeled mitoses appeared promptly after administration of mouse antilymphocytic serum. Immunosuppression released some noncycling G(2) tumor cells into mitosis.