Mean Labeling Index Research Articles

Pancreatic acinar cell tumors in rats induced by 3,2'-dimethyl-4-aminobiphenyl.

Pancreatic acinar cell lesions, including foci, nodules, adenomas and in situ carcinomas, were found in male F344 rats given s.c. injections of 3,2'-dimethyl-4-aminobiphenyl (DMAB) at doses ranging from 50 to 167 mg/kg body weight in two 60-week experiments. The pancreatic lesions induced by DMAB were essentially the same as those reported in rats treated with 4-hydroxyaminoquinoline-1-oxide and azaserine. DMAB at high doses induced pancreas acinar cell as well as fat necrosis, and tumorigenicity for the pancreas was most effective at high necrogenic levels of carcinogen exposure. Mean labeling indices in basophilic foci, acidophilic foci, nodules and adenomas assessed by bromodeoxyuridine incorporation were elevated to approximately 0.69, approximately 2.17, approximately 1.43 and approximately 0.96% respectively, in contrast to the value of 0.39% observed for the surrounding normal acinar cells. The increase was significant in the acidophilic foci and nodules and the fact that these lesions had very high labeling indices suggests that they may have potential for progression to tumors.

Comparison of 5-bromo-2-deoxyuridine and [3H]thymidine for studies of hepatocellular proliferation in rodents.

Hepatocyte replication traditionally has been studied by [3H]thymidine (TdR) incorporation into DNA, and more recently using incorporation of 5-bromo-2-deoxyuridine (BUdR), a synthetic analog of thymidine which is measured by immunohistochemistry. In studies to compare TdR and BUdR, mice were given the peroxisome proliferator [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (WY-14643) in the diet (0.1%) for 5 days and either TdR (1 microCi/g) or BUdR (100 mg/kg) on days 2-5. The labeling index (LI) for hepatocytes of WY-14643-treated mice was 4.7% with BUdR and 5.2% with TdR. The LI for control mice was 0.3-0.4% with either label. Partially hepatectomized rats given TdR had a mean LI of 30.0 versus 32.0% in rats labeled with BUdR. Sham-operated controls given TdR had a mean LI of 0.2% and BUdR controls had a mean LI of 0.1%. Hepatectomized rats given TdR and BUdR simultaneously had an LI of 20.1% for TdR and 22.4% for BUdR. In these rats, 94.1% of the labeled cells contained both markers, whereas 1.9% had only TdR and 4.0% had only BUdR. Comparable labeling indices using either TdR or BUdR indicate that the analogs may be used interchangeably in short-term in vivo studies of liver cell proliferation.

A topographical study of the circadian rhythm in labelling index of mouse gingival and floor-of-mouth epithelium, including changes in labelling activity with individual cell position on the epithelial ridges

A continuous strip of epithelium from the mandibular teeth to the ventral surface of the tongue of B6D2F-1 mice was examined autoradiographically after tritiated thymidine flash-labelling. Five areas were defined: area 1, the gingival sulcus epithelium adjacent to tooth enamel; area 2, the free gingival margin epithelium; area 3, the attached gingiva; area 4, the floor of mouth with undulating basement membrane; area 5, the floor of mouth with flat basement membrane. Data for the circadian variation in the proportion of DNA synthetic cells were recorded into a microcomputer, which enabled a large number of cells to be scored. The topographical position of each basal cell along the rete ridges and the incidence of labelling were noted. In each of the five areas a statistically significant circadian variation in labelling index (LI) was demonstrated, with a peak at 04.00–06.00 h and a trough at 20.00 h, although area 1 was slightly out of phase with the rest. The 24-h average LI values were almost double those obtained from a single flash-labelling at 10.00 h. The peak to trough ratio in LI was greatest in area 5 and fell towards area 1. Within the attached gingiva, cells deepest in the epithelial ridges had a larger peak to trough ratio than more superficial basal cells. For a group of mice labelled at 10.00 h the mean LI of the basal epithelial cells in areas 1–5 was 7.5 ± (3.0)% (SD). Various aspects of the distribution of DNA synthesis in relation to topography were examined. Cell labelling was highest adjacent to the teeth and lowest in the floor of mouth. In areas 1, 2 and 3 labelling was greatest in the anterior (first molar) region of the mandible. Where rete ridges were present, labelling was greatest in the most deeply positioned basal cells. These findings indicate heterogeneity in proliferation indices even within specific regions of gingival epithelium, consistent with the concept of a proliferative hierarchy within the basal layer of the epithelium.

Changes in Bromodeoxyuridine Labeling Index during Radiation Treatment of an Experimental Tumor

Cell proliferation kinetics in a spontaneous mouse fibrosarcoma (FSaII) growing in C3H mice has been studied by in vivo pulse labeling of cells synthesizing DNA with bromodeoxyuridine (BrdUrd). A monoclonal antibody to BrdUrd and flow cytometry were used to quantify these cells. Labeling indices (LI) were measured before and after radiation. Unirradiated 10-mm tumors had a mean LI of 17.5%. After a single dose of 20 Gy there was depression of LI after 1 day followed by a rapid increase to greater than control values after 5 days. Analysis performed after five fractions showed that LI was dependent on the dose per fraction and interval between fractions. After 5 and 7 Gy/fraction LI remained similar to control values during daily fractionation but was significantly depressed after twice daily fractionation. With doses greater than 10 Gy/fraction there was marked depression of LI using both fractionation schedules. These changes in LI correlated well with changes in tumor volume after radiation. Tumors were also biopsied after 5 fractions of a 20-fraction course to see if LI would predict for tumor control. LIs of greater than or equal to 10% were associated with lack of tumor control at 90 days while all controlled tumors had a significant depression of LI. Changes in LI after radiation were a reasonable indication of the amount of repopulation occurring and might be useful in selecting patients for altered fractionation schedules.

Proliferative characteristics of intracranial and spinal tumors of developmental origin.

The proliferative potential of 17 intracranial and spinal tumors (six craniopharyngiomas, four chordomas, three mature teratomas, one immature teratoma, one embryonal carcinoma, one choriocarcinoma, and one dermoid tumor) was assessed. The patients received a 30-minute to 60-minute infusion of bromodeoxyuridine (BUdR) (200 mg/m2 intravenously [IV]) at the time of surgery but before a biopsy of the tumor was performed, to label cells in the DNA synthesis phase. The labeling index (LI) was calculated by determining the percentage of BUdR-labeled cells. The mean LI of the squamous epithelial elements of mature teratomas, craniopharyngiomas, and the dermoid tumor were 3.1 +/- 1.2%, 1.9 +/- 0.9%, and 2.9 +/- 1.9%, respectively. As in normal epithelium, the labeled cells were located in the basal layer. These results and the clinical findings suggest that the proliferation kinetics of these tumors are similar to those of normal skin and differ from those of rapidly growing malignant neoplasms. The other tissue elements (i.e., respiratory epithelium and cartilage) also demonstrated "organized" proliferation patterns similar to those of the corresponding normal tissues. An immature teratoma, an embryonal carcinoma, and a choriocarcinoma each had a high LI (24.6 +/- 5.3%, 32.3 +/- 3.8%, and 17.0 +/- 4.6%, respectively), and no organized pattern of proliferation was observed. In contrast, the mean LI of the four chordomas varied from 1.5% to 5.8%, and there was an even larger variation in the LI of different areas in individual tumors (from less than 1% to 7.5%). This finding suggests that even "slow-growing" chordomas sometimes can be locally aggressive and show a high incidence of recurrence, regardless of morphologic similarities.

Progenitor connective tissue cell populations in the gingival papilla of the rat.

The purpose of this study was to demonstrate the presence and anatomical positions of connective tissue progenitor cell populations in the gingival papilla of the rat. Ten male hooded Lister rats aged 4 wk were killed 1 h after flash labelling with tritiated thymidine. Paraffin sections were cut through the molar regions of 19 mandibles parallel to the occlusal plane. Sections immediately apical to the epithelium of the col and just coronal to the crest of the interdental septum (levels 1 and 5) were chosen for autoradiography, as were a further three sections (levels 2, 3 and 4), spaced equidistantly between levels 1 and 5 in a subsample of 10 of these mandibles. Mean labelling indices (LIs) for all 19 specimens were significantly higher within 5 μm of the teeth at levels 1 and 5, and in a zone 15–25 μm from the teeth in level 5. LIs for the subsample of 10 mandibles were also significantly higher within 5 μm of the teeth in levels 3 and 5, and within 15–20 μm in levels 4 and 5. Nuclear densities were highest at all levels within 10 μm of the teeth and at 20 μm (levels 1–3) or 30 Jan (levels 4 and 5) from the teeth. The data are consistent with the existence of ostensible connective tissue progenitor cell populations, one in contact with cementum and junctional epithelium, the other lying in the body of the papilla at its most apical levels, 15–25 μm from the teeth.

Effect of short-term dietary administration of butylated hydroxyanisole on cell kinetic parameters in rat gastro-intestinal tract, assessed by immunocytochemistry and flow cytometry.

Groups of five male Wistar rats weighing 306 +/- 17 g were fed a diet containing 2% 2-(3)-tert-butyl-4-hydroxyanisole (BHA) or basal diet (control group) for 2 weeks. Subsequently, rats received an i.p. injection of 25 mg/kg bromodeoxyuridine (BrdU), a thymidine analogue, and were killed after 4 h. The gastro-intestinal tract was removed and fixed in 70% ethanol. After pepsin digestion of the fixed tissues, labelled cell nuclei were visualized by means of a monoclonal anti-BrdU antibody technique. Cell kinetic parameters were determined by means of bivariate BrdU/DNA analysis using flow cytometry. Mean labelling index and potential doubling time of forestomach cells were significantly increased (P less than 0.002) in the 2% BHA group as compared to control rats. Cell kinetic parameters in other organs--glandular stomach, ileum, caecum and colon--were not affected by short-term consumption of BHA.

膀胱部分切除,偏側尿管結紮,および経尿道生理食塩水注入のラット膀胱粘膜上皮細胞増殖におよぼす影響

The effects of partial cystetomy, unilateral ureteric ligation, and transurethral injection of physiological saline on the induction of DNA synthesis in urinary bladder epithelium were studied in a total of 130 male F344 rats. DNA synthesis was evaluated by autoradiography and by immunohistochemical detection of bromodeoxyuridine labeled cells. DNA synthesis began to increase 12 hours after each treatment and reached a maximum at 24 to 48 hours with a mean labeling index of 15.8% (partial cystectomy; 48hrs), 1.9% (unilateral ureteric ligation; 24 hrs), 2.5% (1 injection of physiological saline; 24 hrs), and 5.2% (2 times injections of physiological saline; 36 hrs). The proliferative activity of bladder epithelial cells returned to normal 2 weeks after partial cystectomy, and 1 week after unilateral ureteric ligation or physiological saline injection.

Regeneration of submandibular gland autografts in sympathectomized rats.

This morphologic study compares the regenerative response in submandibular gland (SMG) autografts placed in the tongues of previously sympathectomized rats to autografts placed in tongues of sham-sympathectomized rats. We hypothesized that sympathectomy would alter the process of cellular proliferation and inhibit cytodifferentiation in regenerating SMG autografts. Either 1 week, or 8 to 11 weeks following the SMG autografting procedure, the rats were sacrificed and their tongues were removed and sectioned in a cryostat. Frozen tissue sections containing the SMG autografts were either reacted for cholinesterase activity, treated with a glyoxylic acid mixture to induce histofluorescence, or stained for histologic examination. In addition, 3H-thymidine labeled and unlabeled cells were counted in autoradiographs of 1-week autografts, and these counts were used to calculate labeling indices. The 1-week SMG autografts from both the sympathectomized and the sham-sympathectomized rats were similar in histologic appearance, and neither group of autografts contained cholinesterase-positive or monoaminergic nerve fibers. The 8- to 11-week autografts from sympathectomized and sham-sympathectomized rats contained cholinesterase-positive fibers, but monoaminergic fibers were present in the autografts only from the sham-operated rats. Acinar cells were observed in one-third of the 8- to 11-week autografts of both the sympathectomized and sham-sympathectomized rats. This finding suggests that sympathectomy did not prelude cytodifferentiation in the autografts. The autoradiographic data revealed no statistically significant difference between the mean labeling indices of the 1-week autografts from the sympathectomized and sham-sympathectomized rats, which suggests that sympathectomy also did not alter the level of cellular proliferation in the autografts.

Tritiated thymidine labeling index in indian childhood acute lymphoblastic leukemia

Tritiated thymidine labeling index (LI) was determined in 25 unselected children with cytochemically proved ALL, at various stages of the disease. All the cases were treated by a uniform therapeutic protocol. Pretreatment LI determined in 15 cases showed an inverse correlation with the duration of first complete remission. LI was also studied during remission in 23 patients. Six out of these 23 patients relapsed within subsequent 90 days, while the rest continued to be in remission. Mean LI of the nonerythroid cells in later group of patients was found to be significantly higher than that of the patients who relapsed.

Cancer family syndrome: Marker studies

Individuals from kindreds with the cancer family syndrome (CFS) have an increased hereditary risk for the development of adenocarcinoma of the colon in childhood and early adulthood. Previous studies have suggested that this high occurrence of adenocarcinoma may be due to a genetic defect in the control of colonic epithelial proliferation. Others have suggested that these families may have an underlying abnormality in immunologic tumor surveillance. We have investigated these possibilities in 15 cancer-free, at-risk individuals (10 children, ages 3–15 yr, and 5 adults) from two unrelated CFS kindreds. Colonic mucosal proliferative activity was studied by in vitro autoradiography after tritiated thymidine labeling in 7 subjects. The mean labeling index (12.7 ± 0.9%) was comparable to that in controls, as was the distribution of thymidine labeling. Immunologic evaluation revealed depressed lymphocyte culture responses to stimulation by microbial antigens, but not to that by mitogens. Mixed lymphocyte culture responses were depressed in 4 of 8 subjects, but became normal in 2 of these after filtration through a Sephadex G10 column. Natural killer cell cytotoxicity was significantly depressed in 5 of 13 subjects, and borderline normal in another 3 subjects. These data suggest that many cancer-free members of CFS kindreds have a spectrum of in vitro cell-mediated immunologic defects that might interfere in vivo with the recognition or killing of incipient tumor cells.

Effect of heparin, heparin fragments, and corticosteroids on cerebral endothelial cell growth in vitro and in vivo.

Heparin and heparin fragments in combination with corticosteroids have been shown to markedly inhibit tumor angiogenesis. Experiments were performed to test the hypothesis that heparin, heparin fragments, and the combination of heparin and corticosteroids affect DNA synthesis and the proliferation of cerebral microvessel endothelium (ME). In vitro, methyl-3H-thymidine incorporation in the ME cells was measured after a 24 hour pulse. Our results show that heparin, hydrocortisone, and heparin in combination with hydrocortisone had a slight inhibitory effect on DNA synthesis of ME (p less than 0.05), and hydrocortisone in combination with heparin had a slight inhibitory effect on ME cell growth (p less than 0.05). The hexa-, octa-, and deca-saccharide fragments of heparin stimulated DNA synthesis in ME (p less than 0.01). In vivo, DNA synthesis in cerebral endothelial cells at the margin of a freeze lesion to mouse cerebral cortex was assayed by quantitation of labeling indexes from methyl-3H-thymidine autoradiographs in mice treated with heparin, cortisone, or a combination of heparin and cortisone. A mean endothelial cell labeling index (LI) of 6% in the cortisone-treated animals was significantly lower than controls (32%, p less than 0.01). The addition of heparin to cortisone did not significantly alter the endothelial cell LI compared to the cortisone-treated animals, and heparin alone did not significantly alter the LI compared to the controls. These results indicate that cortisone markedly reduces the endothelial proliferation around a cortical freeze lesion in vivo. This effect is independent of heparin.

Effects of Progestins and Glucocorticoids on Deoxyribonucleic Acid Synthesis in the Uterus of the Neonatal Mouse*

The effects of progestins and glucocorticoids on cellular proliferation were examined in the uterus of 5-day-old mice by monitoring either the labeling index (LI) after exposure to [methyl-3H]thymidine ([3H]TdR) in vivo or the mitotic index (MI) after colchicine-induced arrest of cells in metaphase. In untreated 5-day-old mice, epithelial LI was 31%, and stromal LI was 15%. Eighteen hours after a single ip injection of 40 mg/kg progesterone, epithelial LI was reduced to 2.3% and remained low for 48 h. Stromal LI increased transiently, reaching a zenith (40%) 18 h after administration of progesterone and returning to control levels by 24 h. When mitotic activity was assessed 24 h after progesterone treatment, epithelial MI was decreased (control, 3.1%; progesterone, 0.23%) and stromal MI was increased (control, 0.60%; progesterone, 2.1%). Thus, the measured effects on LI were indicative of altered proliferative activity of the tissues. Glucocorticoids also inhibited epithelial LI, but had no effect on stromal LI. Eighteen hours after a single ip injection, dexamethasone inhibited epithelial LI to the same extent as progesterone treatment. Corticosterone did not significantly decrease epithelial LI, while cortisol produced an intermediate inhibitory response. To determine whether the high baseline LI in uterine epithelium of neonatal mice was estrogen dependent, uteri of 1-day-old mice were grafted under the kidney capsule of ovariectomized adult mice. Eight days later, the hosts were treated with either progesterone or vehicle and then killed 18 h later. After labeling the tissue with [methyl-3H]thymidine in vitro, the mean LI of the epithelium of the grafted uteri was 11.5%, while that of the vehicle-treated hosts was 0.10%. Progesterone treatment reduced the LI of the grafted uterine epithelium to 1.0%. These data demonstrate that uterine tissues of the neonatal mouse proliferate rapidly in the absence of gonadal steroids. Progestins and glucocorticoids specifically inhibit this estrogen-independent DNA synthesis of uterine epithelium.

Cell kinetic indicators of premalignant stages of colorectal cancer.

Using an in vitro double labeling technique with two different levels of 3H-thymidine, the duration of the phase of DNA synthesis (S) and the labeling index (LI) were measured in the colorectal mucosa of three groups of patients: patients with colorectal neoplasms (adenomas and/or adenocarcinomas), patients with inflammatory bowel disease, and a control group of patients without gastrointestinal pathology. In those patients with colorectal neoplasms, samples were obtained from both the neoplastic mucosa and from the normal appearing mucosa at various distances from the lesions. One-way analyses of variance were used to test the equality of mean S-phase duration and LI in the various types of tissues. S-phase duration was significantly longer in the tumor than in the unaffected mucosa of patients with adenocarcinoma (18.65 hours +/- 2.3 versus 10.13 hours +/- 1.26 P less than 0.0001). However, S-phase duration was significantly longer in the unaffected mucosa of cancer patients than in the mucosa of patients without gastrointestinal pathology (10.58 hours +/- 1.84 versus 7.91 hours +/- 0.46, P = 0.013). Similarly, LI was significantly higher in the unaffected mucosa of patients with adenoma and adenocarcinoma than in the mucosa of patients without gastrointestinal pathology (19.1% +/- 3.0 versus 9.5% +/- 2.2, P less than 0.0001). There was a highly significant trend to a progressive increase of LI from flat histologically normal appearing mucosas to inflammatory mucosas, adenomas, and adenocarcinomas (P less than 0.0001). These results suggest that increased S-phase duration is specifically related to cancer. In mucosa without histologic sign of malignancy, an increased S-phase duration would indicate that the malignant process has started. An increased LI would appear to relate to the selective advantage that rapidly proliferating cells hold over less proliferating ones.

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The effects of a single 17 beta-estradiol (E2) injection on cell proliferation were studied in 3 groups of 30 mice transplanted with the MXT ovary-dependent mammary tumor. In group A, all animals were castrated prior to tumor implantation; groups B and C had intact ovaries at the time of transplantation, but group B was left intact throughout the experiment, while group C underwent castration 4 weeks later. On day 40 in groups B and C and on day 80 in group A, in which tumor development was significantly delayed, the same procedure for testing the effects of E2 was applied: Ten controls received 0.1 ml saline ip and were killed on the next day; 4 lots of 5 mice received 0.25 micrograms E2 ip and were killed one by one at 12-hour intervals. Exactly 1 hour prior to sacrifice, each animal received 25 microCi [methyl-3H]thymidine ip. Histologic sections of tumors and uteri were processed for autoradiography, and nuclear thymidine (dThd) labeling indices (LI) were determined. All tumors of group A grafted under unfavorable hormonal conditions were poorly differentiated, and E2 injection induced no appreciable changes in their dThd LI. Tumors B and C were well-differentiated adenocarcinomas, in which E2 induced significant modifications of cell proliferation. In group B, complex changes in dThd LI occurred in tumors as well as in uteri, probably due to interferences with the ovarian hormonal production. In group C, E2 produced a marked rise in dThd LI in tumors, lasting from the 12th to the 36th hour after its injection. Stimulation was maximum at the 24th hour, representing a 2.8-fold increase over mean basal dThd LI. It is concluded that the presence of an intact ovarian function at the time of transplantation is critical for maintaining the properties of hormone dependence in MXT tumors. In mice castrated after tumor implantation, a single E2 injection induces a marked and partially synchronous proliferation of neoplastic cells. The hypothesis that such hormonal manipulation might amplify the killing effect of cell cycle- or phase-specific cytotoxic drugs could be adequately tested with this model.

Analysis of proliferative compartments in human tumors. II. Seminoma.

Growth pattern and cell kinetics of 12 human seminomas were determined by means of vascular organ perfusion after orchiectomy. The arteria testicularis of the tumor-bearing testis was perfused up to 5 hours with dextran-diluted blood under normothermic and normotonic, simulated physiologic conditions. At defined periods, the specimen was exposed to tritiated and/or carbon 14-labeled thymidine. Autoradiograms prepared of whole tumor sections revealed a dependence of growth pattern on the stage of development. A homogeneous distribution of DNA synthesizing seminoma cells was found in small tumor foci. With increasing size, the zone of proliferation shifted to the periphery of the nodule giving rise to nodular subpopulations of high proliferative activity. In nodules of a diameter of more than about 2 cm the growth compartment consists of a highly proliferating invading cell layer at the edge of the tumor and intratumoral patches of proliferating cells near the vascular stroma. The largest part of the tumor remains at this stage in a quiescent state (G0). The mean labeling index of the seminoma cells was 11.6 +/- 1.4%, with the highest values found immediately adjacent to tumor vessels. High mitotic activity in an anaplastic seminoma was coupled with maximum labeling indices up to 41.9%. DNA synthesis time ts was 15.9 +/- 2.0 hours. The potential population doubling time for the proliferating fraction was in the range of 5 days. Lymphocytic infiltration reduced the proliferative activity in some parts, but was without effect in other areas of the seminoma. The seminoma is an example of a malignant human tumor with a rather regular growth pattern: The distribution of the proliferating compartment appears less dependent on cytologic or histologic structure, but more on tumor geometry and size.

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.

Epithelial Cell Proliferation in Duodenal Ulcer

Epithelial cell proliferation in the duodenum was investigated in 50 patients by incubating mucosal biopsy samples with tritiated thymidine, followed by autoradiography. Fifteen patients had a normal duodenum, 15 duodenal ulcer undergoing elective surgery, 10 perforated duodenal ulcer, and 5 severe non-ulcer-associated duodenitis. The mean crypt cell labelling index in the duodenal bulb of controls was 8.8 +/- 0.4% (mean +/- SEM), at the edge of perforated ulcers 19.1 +/- 2.0%, at the edge of elective ulcers 18.6 +/- 1.4%, and in biopsy specimens from non-ulcer-associated duodenitis 14.0 +/- 1.2%. The mean labelling index in the distal first part of duodenum of control patients was 9.1 +/- 0.8 similar to the values found in histologically normal specimens distal to ulcer or duodenitis. The results indicate active epithelial cell proliferation in both duodenal ulcer and duodenitis. There was no evidence of impairment of epithelial cell proliferation in duodenal ulcer patients.

Cell Proliferation in Normal Epidermis

A detailed examination of cell proliferation kinetics in normal human epidermis is presented. Using tritiated thymidine with autoradiographic techniques, proliferative and differentiated cell kinetics are defined and interrelated. The proliferative compartment of normal epidermis has a cell cycle duration (Tc) of 311 h derived from 3 components: the germinative labeling index (LI), the duration of DNA synthesis (ts), and the growth fraction (GF). The germinative LI is 2.7% +/- 1.2 and ts is 14 h, the latter obtained from a composite fraction of labeled mitoses curve obtained from 11 normal subjects. The GF obtained from the literature and from human skin xenografts to nude mice is estimated to be 60%. Normal-appearing epidermis from patients with psoriasis appears to have a higher proliferation rate. The mean LI is 4.2% +/- 0.9, approximately 50% greater than in normal epidermis. Absolute cell kinetic values for this tissue, however, cannot yet be calculated for lack of other information on ts and GF. A kinetic model for epidermal cell renewal in normal epidermis is described that interrelates the rate of birth/entry, transit, and/or loss of keratinocytes in the 3 epidermal compartments: proliferative, viable differentiated (stratum malpighii ), and stratum corneum. Expected kinetic homeostasis in the epidermis is confirmed by the very similar "turnover" rates in each of the compartments that are, respectively, 1246, 1417, and 1490 cells/day/mm2 surface area. The mean epidermal turnover time of the entire tissue is 39 days. The Tc of 311 h in normal cells in 8-fold longer than the psoriatic Tc of 36 h and is necessary for understanding the hyperproliferative pathophysiologic process in psoriasis.

Age-related changes of epidermal cell kinetics in the hairless mouse.

Cell kinetic variables in normal untreated hairless mice were studied in order to observe possible age-related changes. Generally, groups of 4 male and 4 female mice were subjected to study at various ages from one to 115 weeks. The number of basal and suprabasal cells per microscopic field was observed, and after injection of tritiated thymidine the mean labelling index, the average specific activity and the mean grain count were scored. After injection of Colcemid, the average number of Colcemid-arrested mitoses was counted. With flow cytometry the fraction of cells in S and in G2 + M was also observed. In general, both the number of suprabasal cells and the proliferative variables were significantly lower in the very young mice. They increased to slightly above normal values at about 20-22 weeks of age, and then fluctuated a little with two additional possible peaks at 40-50 and around 80 weeks, respectively, and two troughs some weeks after the peaks. However, this rhythmicity was slight and not significant. Thus the only significant age-related pattern was that very young mice have a thin epidermis and low proliferative variables. These values increase up to the age of 20 weeks, and from then on there are no obvious and significant alterations, only slight rhythmic undulations almost within normal limits. The importance of cell kinetic changes with age for epidermal carcinogenesis is discussed in relation to these observations.