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Scalp lacerations are frequently seen in both living trauma victims and at post-mortem examination. In clinical circles, it is well known that even "trivial" lacerations of blood-rich areas such as the scalp may bleed profusely and persistently.It is less well known, however, that hemorrhage even from simple scalp lacerations may be fatal. We present seven cases in which hemorrhage from simple scalp lacerations was considered to be the principle cause of death.Chronic alcohol misuse, alcoholic liver disease, and the co-existence of other pathologies such as ischemic heart disease were frequently contributory factors.

Commotio cordis is a recognised cause of sudden death in which an apparently minor blow to the chest causes ventricular fibrillation and cardiac arrest. It is best known for causing death during games of youth baseball in the United States, but individual cases have been recorded as a result of a wide range of activities, principally sporting. The underlying biochemical and mechano-electric causes have been well documented. However, there are few reported cases where commotio cordis is implicated as the cause of death in homicide cases. We present three cases from the north-east of England where an assault caused death by this mechanism.

The in-vitro pharmacokinetics of vincristine (VCR) in normal rat colonic mucosa were studied. Two complementary approaches were adopted using an explant organ-culture system. Firstly [G-3H]vincristine (3HVCR) accumulation, retention and efflux were characterized under basal conditions and compared with measurements made either under energy-depleted conditions, or in the presence of VRP. Secondly, a histological method--the postmetaphase index (PMI)--was used to compare the sensitivity of explants to VCR in the presence or absence of verapamil (VRP). This latter technique involves the measurement, by counting, of the proportion of mitotic figures escaping from metaphase arrest. The studies yielded the following results: 3HVCR accumulation in colonic mucosa showed no evidence of saturability up to the maximum dose studied (130 nM), at a dose of 52 nM accumulation was enhanced in energy-depleted conditions by a factor of 1.8, and in the presence of VRP (6.6 microM) by a factor of 1.4. In the presence of VRP (6.6 microM) retention of 3HVCR was increased by a factor of 1.3 and efflux was reduced by a factor of 0.8 after 2 hr. VRP (6.6 microM) reduced the PMI of colonic mucosal epithelial cells exposed to 11 nM VCR from 18.8% to 11.4% (i.e. 40% reduction) indicating sensitization of the cells to this property of VCR. These results provide evidence that the sensitivity of normal colonic mucosa to vincristine is, at least in part, regulated by drug transport. Qualitatively our observations resemble those described in multidrug resistance. Given that P-glycoprotein has been demonstrated by several groups in colonic mucosal cells, the results support a normal role for this membrane transport molecule in the protection of intestinal cells from plant alkaloids and other xenobiotic agents ingested in the diet.

Dimethylhydrazine has been used to produce colonic tumours in mice. If sulindac, a non-steroidal anti-inflammatory drug, is administered simultaneously fewer microadenomata and fewer macroscopic tumours are produced. Those which do appear are comparable in size to the ones in the mice which do not receive sulindac. Sulindac therefore appears to exert an anti-tumour influence at the stage between dysplasia and the formation of microadenomata.

Administration of dimethylhydrazine (DMH) to adult rats by two subcutaneous injections each of 120 mg(base)/kg body weight and spaced 10 days apart resulted in the development of renal tumours in over 90 per cent. of treated animals at 30 weeks after injection. The tumours were frequently bilateral and multiple, and had the structure of the "mesenchymal" tumours which occur in a high incidence following treatment with nitrosamines. The incidence of tumours both in the small intestine and in the colon was lower than that experienced using a weekly DMH treatment schedule.

A method is described enabling the direct measurement of vincristine resistance in intact tissues in vivo by morphological study. Using the metaphase arresting properties of the drug, counts were made of escaping anaphase and telophase mitotic figures at a range of doses. The proportion of post-metaphase mitotic figures is called the post-metaphase index (PMI). In 95 primary intestinal tumours induced by dimethylhydrazine (DMH) in rats, an increase in resistance to vincristine was shown over normal mucosa (P less than 0.001). The data were analysed by computer modelling and a linear relationship is demonstrated between the logit of the post-metaphase index, and log dose of vincristine. To achieve a PMI of 1% the fitted lines show an enhanced vincristine dose requirement over normal mucosa of 6 times in colonic tumours, and 8 times in small intestinal tumours. Non-neoplastic mucosa from the DMH-treated animals requires an enhanced dose of vincristine of 1.5 times, compared with normal mucosa, to achieve a PMI of 1%. Given current interest in the mechanism of vincristine resistance in cell lines this new approach provides a technique for assessing the resistance of solid tumours, both in vivo and in vitro, and for subsequent experimental manipulation.

Carbon fibre patches were inserted as prostheses into the dorsal lumbar fascia of rabbits. Their incorporation into the tissues was observed over a period of 15 weeks, and their mechanical properties were compared with those of implants made of a conventional Mersilene mesh. Although the mechanical properties of carbon fibre patches are initially poor, the development of a superior connective tissue response after several weeks suggests that a layered composite of carbon fibre and Mersilene with the latter giving initial strength may provide a useful material for clinical use as a hernia prosthesis.

This case report describes three case histories and the analytical procedures used for the identification and quantification of triazolam. The levels of triazolam detected in the blood are interpreted with reference to those previously reported in the literature.

We have measured mitotic indices and 3H-thymidine-labelling indices for the colonic epithelial tumours induced in rats by the administration of dimethyl-hydrazine (DMH). The fraction-of-labelled-mitoses (FLM) technique has been used to estimate the duration of the cell-cycle phases. In general, mitotic and labelling indices in the tumours are similar to those in the proliferation zone of the normal crypt epithelium; lesions considered to be least well differentiated on histological grounds appear to have the lowest mean labelling index. Benign tumours and the different types of malignant tumours have mean cell-cycle times about half those of the normal mucosa.

In the long term, administration of dimethylhydrazine (DMH) to rats results in the development of tumours in both small intestine and colon. This study has been undertaken in order to document the sequence of changes occurring in the intestinal mucosa in the first 108 h following a single subcutaneous injection of DMH. After a lag of several hours there is evidence of damage to cells in the proliferation zone of the intestinal crypts, and a brief reduction in tritiated thymidine labelling index. A phase of compensatory regenerative activity emerges from the setting of continuing cell damage, resulting in restoration of the mucosa to normal. The severity of the toxic damage to the intestinal mucosa at various sites mirrors the vulnerability of the mucosa to the long term carcinogenic effects of DMH, suggesting that inherent properties of the mucosa may be of more importance than other cocarcinogenic influences in the ultimate development of tumours.

The parenteral administration of 1,2-dimethylhydrazine to rats caused the development of colonic neoplasms in about 90% of animals by 24--30 weeks of treatment. Usually there were multiple tumours with a mean of 2.7 per rat. The lesions have been classified histologically into adenomata (26% of all tumours) and carcinomata, the latter showing varying degrees of differentiation. No completely anaplastic tumours were seen, and there were none originating in connective tissue. The distributions of the different tumour types along the length of the colon varied. The more benign lesions were situated predominantly in the distal half of the colon, while the poorly differentiated adenocarcinomata were concentrated in the proximal third of the colon. There was good evidence to suggest that adenomata often progressed to frank malignancy in the distal colon. In the proximal part, however, it appeared that tumours frequently developed de novo as poorly differentiated carcinomata. Perhaps regional variations in the kinetic organisation of the normal colonic mucosa somehow influence the nature of the neoplastic change induced by DMH, thus accounting for the differences in tumor distribution. After 24 weeks of DMH treatment there was only a small increase in the mean number of tumours per rat.

During the course of carcinogenesis in the intestinal tract a series of proliferative changes occur which may represent pre-neoplastic abnormalities. These include progressive crypt hyperplasia, expansion of the proliferation zone within the crypt and alterations in the numbers and distribution of proliferating cells. The literature documenting these changes has been reviewed and their significance as pre-neoplastic phenomena assessed. Major problems include the differentiation of coincidental adaptive changes from truly pre-neoplastic ones, and the integration of morphological and kinetic observations.

In a population of cells that proportion which is actively engaged in the proliferative cycle is often estimated from the ratio of the observed labelling index to an expected labelling index, calculated, on the basis of all cells being in cycle, from the cell cycle phase durations and the age distribution. Ignoring the variability in cell cycle times may lead to large overestimates or underestimates in the expected labelling index. A method is given of obtaining a more accurate estimate of this variable, and hence of the proliferative proportion.

Mucosal explants were prepared from the colons of normal rats and from the non-neoplastic colonic mucosa of rats which had been treated chronically with the intestinal carcinogen dimethylhydrazine. They were maintained in an organ culture system which permitted survival up to at least 25 days. Morphological preservation of the mucosa was excellent up to 6 days in culture and thereafter changes began to occur. But even at 25 days normal crypt structures were still evident. The hyperplastic and dysplastic changes seen in pre-culture samples of DMH-treated mucosae remained recognisable during the first two days in culture. They were no longer seen in explants examined after this time however and, indeed, there appeared to be no difference in the morphology and survival of control and DMH-treated mucosae. It is possible that our culture system does not permit further neoplastic progression, but an alternative explanation is that the system discriminates specifically against the survival of neoplastic elements.

Two patients with benign chondrolipomatous tumours of the breast were subjected to mammography. In one case this was as part of the investigation of a breast lump detected clinically, while in the other the lesion was detected during routine follow-up of a woman with long-standing cystic hyperplasia. The mammographic appearances were similar in the two cases and were unusual, each lesion showing as a circumscribed lobulate area of radiolucency containing tiny dense flecks of opacification. Mammographic and pathological findings are presented and the significance of the diagnosis discussed. Benign chondrolipomatous tumours of the breast are rare but with increase in mammography it is possible that they will present more frequently than hitherto.

A formula is given, and proved, for the expected position of the highest labelled cell in an individual crypt column, if the labelling index distribution is known.

A case of visceral Kaposi's sarcoma occurred in a patient with adult celiac disease. A search of the literature has failed to disclose any previous case showing this association, although Kaposi's disease has been reported to occur in a variety of situations in which immunological abnormalities have been manifest. Conversely, celiac disease has been shown to predispose to the development of a variety of malignant neoplasms.

The present study was undertaken in order to try to define some of the kinetic parameters in the colonic mucosa of normal Wistar rats. Preliminary observations showed considerable morphological differences in the mucosa from site to site along the length of the colon. In particular the height of the crypts (measured in cells) was variable. In addition labelling index studies demonstrated dramatic variations in the distribution of labelling along the length of the crypts from site to site in the bowel. A single site in the descending colon was selected for more detailed study using a stathmokinetic agent, vincristine, and the continous labelling technique with tritiated thymidine. The results of these investigations suggest that there exists at the base of the crypt a subpopulation of cells cycling more slowly than the cells in the rest of the proliferative compartment. Growth fraction appears to fall with rising cell positions within the crypt.

Using a system designed to preserve, in vitro, both the epithelial and the connective tissue elements, we have maintained adult colonic mucosa in organ culture for up to 336 hours and have investigated the sequential morphological changes which occur. During the first 48 hours, normal micro-architecture is preserved, but there is progressive loss of cytoplasmic mucin from crypt cells. Subsequently, accelerated degenerative changes develop; cells are lost from the crypts and, because cell proliferation in the crypt is reduced, these lost cells are not replaced. For a time, the crypts are represented by discrete acinar formations or clusters of cells in the lamina propria, apparently discontinuous with the intact surface epithelial layer. These remnants manifest intense proliferative activity during the period between 72 and 96 hours after explantation, leading to the restoration of well formed crypts lined by columnar epithelial cells between 120 and 144 hours; differentiation of goblet cells ensues and this state of virtually normal structure persists until the termination of culture between 186 and 336 hours. It is concluded that the determination of normal crypt structure and of crypt-cell differentiation is governed by intrinsic control mechanisms although these may be subject to extrinsic modulation. Whether or not the degeneration phase can be eliminated, it is clear that long term culture of adult human colonic mucosa is possible. Such a system may be useful in the study of mucosal function and of mucosal response to drugs, carcinogens and trophic factors.

Organ culture, using human colorectal mucosa and tumours, is a good system in which to test a new stathmokinetic agent such as vindesine. Using this system we have found that vindesine has similar metaphase-arresting properties to vincristine, including at least a 6-fold dose response difference in its ability to arrest mitosis in mucosa and tumour, mucosa being the more sensitive. Vindesine is a satisfactory stathmokinetic agent, but in view of its greater cost offers no particular advantages over vincristine.

This study was undertaken in order to compare cell proliferation at different sites along the length of the large bowel of the mouse. Simple morphometry has been used along with 3HTdR labelling studies and metaphase arrest with vincristine. Differences have been described in the shape and size of crypts, the distribution of proliferating cells, the duration of the cell cycle, as well as in the rate of cell production by the crypts. The findings explain some of the apparent inconsistencies in the literature.

A case of rheumatoid disease with localised granulomatous involvement of the leptomeninges is described. This meningeal disease apparently caused a symptomatic epilepsy. This is thought to be only the second reported case of rheumatoid granulomatous involvement of the leptomeninges.

In this study using a panel of anticytokeratin antibodies and an indirect immunoperoxidase method, we examined cervical squamous epithelia including mature stratified epithelium, immature squamous metaplasia, CIN 1, 2 and 3, wart virus infection and squamous carcinoma. Changes from the normal patterns of staining were inconsistently seen in CIN 1 and 2, but in CIN 3 the changes were more marked, and consisted of a loss of stratification of the staining pattern and a patchy reduction in staining. Invasive carcinomas showed a similar staining pattern to CIN 3 lesions.

At eight time points over a period of 24 hours, crypt length (in cells) and crypt cell birth rate were measured by the stathmokinetic method with vincristine and evaluated at two sites in the small intestine and two in the colon in Wistar Porton rats. Normal animals were compared with animals which had received 24 injections, at weekly intervals, of the intestinal carcinogen 1,2-dimethylhydrazine. In the treated animals, crypts were significantly longer at sites prone to tumour formation but not at those sites known to be resistant to the effects of the carcinogen. In neither group of animals was there any significant fluctuation in mean crypt length over a 24 hours period. Crypt cell birth rates showed a considerable fluctuation. No difference was noted between normal animals and those treated with dimethylhydrazine and statistical analysis failed to confirm the presence of any true periodic fluctuation.

Sulindac, a non-steroidal anti-inflammatory drug, has been reported to lead to tumour regression in cases of human polyposis coli. We have investigated the effects of this drug on the growth of 1,2-dimethylhydrazine (DMH)-induced mouse colonic tumours. In one experiment, DMH and oral sulindac were administered concurrently to a group of mice for a period of up to 24 weeks, while a control group of animals received DMH only for the same period. Sulindac caused a significant reduction in both the number of mice with colonic tumours and the number of tumours per mouse. In a second experiment, two groups of mice which had already been treated with DMH for 17 weeks received either sulindac or not for 78 days. In this experiment sulindac had no effect. These results demonstrate that sulindac has a protective effect against the chemical induction of colonic tumours in mice, but does not cause the regression of established tumours.

The successful development of a long-term organ culture system has made it possible to perform experiments on rat colonic mucosa in vitro. However, the effect of trauma or the withdrawal of trophic influences in culture may result in the disturbance of proliferation within the tissue. In this paper we describe an investigation designed to characterise the culture system by a comparison of the proliferative parameters in vitro with those in vivo. Stathmokinetic experiments were performed in vivo and in vitro to estimate cell birth rate. Mitotic indices were also calculated. The in vivo birth rate (7.8 +/- 0.8 cells/1000 cells/hour) and the in vitro birth rate for the whole explant (7.7 +/- 0.5 cells/1000 cells/hour) were found to be similar. A study of crypts in the centre and at the edge of the cultured explants, however, indicated that proliferation at the two sites differed markedly, the birth rate at the edge (7.5 +/- 0.9 cells/1000 cells/hour) being approximately twice that at the centre (3.2 +/- 0.9 cells/1000 cells/hour). Provided that this topological difference in proliferation within the explant is recognised the in vitro model, in particular the basal level found at the centre, may still be regarded as a valid system for studying tissue responses to carcinogens and trophic factors.

The intraperitoneal administration of large doses of quinacrine in rats results in a state of enteromegaly affecting mainly the distal small bowel, caecum and proximal colon. This enteromegaly is associated with mucosal crypt hyperplasia, and hypertrophy and hyperplasia of the Muscularis propria. In order to investigate the changes in the intestinal mucosal crypts, morphometry and a metaphase-arrest experiment with vincristine were undertaken on a group of rats given 12 mg of quinacrine hydrochloride by intraperitoneal injection daily for 5 days 2 weeks previously, and comparisons drawn with a group of control animals. In the quinacrine-treated animals there was marked enteromegaly affecting the distal small bowel, caecum and proximal colon, and in these segments there was clear crypt hyperplasia. Proximal and distal to the dilated bowel hyperplasia was not seen. No consistent pattern of change in crypt-cell birth rate was evident. The mechanisms by which quinacrine may effect kinetic and morphometric changes in the intestinal crypts are considered.

The development of an organ-culture system for rat colonic mucosa has enabled a direct assessment of the effect of epidermal growth factor (EGF) on cell division. An augmented mitotic index (AIm) has been employed to identify changes in cell proliferation. Explants of colonic mucosa from four animals were maintained in a medium containing serum for five days. On the fifth day of culture, half of the explants received fresh medium containing EGF (40 ng/ml) and the remainder (controls) fresh medium only. At 6, 12, 24 and 48 hr thereafter groups of both experimental and control explants received the metaphase-arresting drug vincristine (4 micrograms/ml) for 3 hr prior to fixation. The proportions of vincristine-arrested metaphases within the explants were determined. Analysis of the data indicates that when serum is present exogenous EGF exerts a trophic effect which increases with time (P less than 0.001). In a second experiment colonic explants from four animals were maintained for five days in a serum-free medium and were then divided into groups, each of which received one of a range of concentrations of EGF. The AIm was determined for each group after 36 hr. It was found that increasing concentrations of EGF produce a small but significant increase in cell proliferation (P less than 0.01). This effect, however, was less pronounced than that seen when serum was present. These results suggest that EGF has a trophic action on the colon and interacts with additional factors found in serum.

This paper describes the progressive effects of severe copper depletion on pancreatic weight, structure, amylase content and responses to secretin and caerulein, as well as a number of general body parameters (appearance, body weight and blood indices). Copper depletion was produced by feeding young rats a copper-deficient diet alone or together with either of the two chelating agents D-penicillamine or triethylene tetramine (Trien). After 6 weeks, the copper-deficient diet alone had relatively little effect on general body parameters but reduced gland weight and the secretory response to caerulein. Addition of D-penicillamine ductal and islet tissue relatively intact; gland weight was markedly reduced, and gland amylase was reduced virtually to zero; and the secretory response to caerulein was almost abolished while that to secretin was reduced. The effects of Trien on general body parameters were less severe; the secretory response to secretin was also less affected, while acinar cell atrophy, gland amylase and the secretory response to caerulein were affected to the same extent as with D-penicillamine. The effects of severe copper depletion on the pancreas were largely irreversible after 13 weeks on a copper-supplemented diet.

This study was carried out to determine whether stainable copper accumulates in the hepatocytes of patients with alcoholic liver disease. Liver sections from 44 cases of alcoholic cirrhosis and 32 cases of non-cirrhotic alcoholic liver disease were stained by the rubeanic acid, rhodanine and orcein methods. Intrahepatocytic copper granules were found in 13 cases of cirrhosis (30%), but in none of the non-cirrhotic livers. The abundance of granules did not appear to be related either to the activity of the cirrhotic process or to the presence of cholestasis. It may well be that alcoholic cirrhosis is the most common disease associated with excess of intrahepatocytic copper.

In organ culture tissues undergo adaptive changes which complicate the assessment of proliferative indices. In the present study, a technique devised to preserve collagen metabolism and mesenchymal stroma in tissues of mixed origin was employed to investigate the kinetic behaviour of human colorectal mucosa over the first 24 hours in culture. During this period the structural preservation of tissue is good. The mitotic index in mucosa is profoundly depressed throughout the explants during the first 2-6 hours in culture. During this same period, however, heavy uptake of tritiated thymidine, indicating DNA synthesis, is observed within 150 micron of the cut edge of the samples but not centrally. This phenomenon has been described previously and assumed to be the result of inadequate diffusion of oxygen into the tissue. The 'edge labelling' phenomenon is followed by a wave of mitosis in the tissue edge at 8-18 hours in culture. This delay between tritiated thymidine uptake and the appearance of mitoses in the tissue edge may simply represent the duration of the S + G2 phase of the cell cycle, but is more likely to be due to cells in G1 moving into the S phase followed by cells hitherto blocked in G2 being stimulated into the M phase. After 18 hours the mitotic and labelling indices become more uniform throughout the samples suggesting that 'edge labelling' is partly due to local stimulation of cell proliferation by trauma rather than central inhibition due to diffusion problems. These results suggest that in this organ culture system, assessment of proliferative indices should be carried out after these adaptive changes have settled.

Gastric hyalinization is an unusual abnormality that has in the past been regarded by some authorities as a postmortem artifact. We describe a 69-year-old patient who presented with symptoms due to the condition, and who was treated by surgical resection of the diseased stomach. To our knowledge, no other case presenting in life has been identified in the literature, which we reviewed in the light of the present case. The cause of the condition remains unknown.

The prognostic significance of tumour infiltration by inflammatory cells in squamous cell carcinoma of the vulva was examined in a cohort of 34 patients surviving without recurrence for at least 5 years after radical surgery, and a comparative cohort of 35 patients who died of their diseases. Overall, heavy inflammatory infiltration correlated with a good prognosis and light infiltration with a poor one, independent of other indices such as differentiation, tumour size and nodal status. IgA-containing cell infiltration also correlated with a good prognosis but the presence of IgA-containing cells did not alone account for all the inflammation in the good prognosis group. An immunological response to the tumour may be influencing prognosis. At a practical level, the extent of inflammation appears, at least in this material, to be as useful a prognostic index as many more conventional ones.

Short-term organ culture, using a technique to preserve epithelial/stromal interaction and metabolism, is a useful technique for carrying out kinetic studies on human colorectal carcinoma and adjacent normal mucosa, providing initial perturbations of proliferative indices are allowed to settle. Tumours require 3.0 micrograms/ml vincristine for complete metaphase arrest compared with mucosa, which needs 0.5 microgram/ml, a 6-fold difference. Using a stathmokinetic technique, the birth rate of tumour cells is 10.21 cells/1000 cells per hr, compared with 7.73 cells/1000 cells per hr for mucosa, a statistically significant difference (P less than 0.01).

Administration of 1,2 dimethylhydrazine (DMH) to rats by weekly s.c. injections causes the development of multiple epithelial tumours of the large bowel. These appear to arise as localized dysplastic abnormalities in hitherto apparently morphologically normal crypts. This study was undertaken in order to examine cell proliferation in such apparently normal crypts of DMH-treated animals. A number of proliferative abnormalities are evident, including changes in the size of the crypts, changes in the disposition of proliferating cells within them and reduced cell-cycle times. The nature and the extent of the abnormalities vary from site to site along the length of the bowel, and reflect the vulnerability of the different segments of the bowel, not only to the carcinogenic effects of DMH, but also to short-term toxicity.

When symmetrical 1,2 dimethylhydrazine was administered to rats by weekly s.c. injection, 37% of the animals had developed small intestinal carcinomas after 21-27 weeks. These lesions were largely localized to duodenum and upper jejunum. At the same time there was a diffuse crypt hyperplasia in the jejunum which affected all the treated animals, not just those with neoplasms. This marked hyperplasia was preceded by a modest sustained crypt elongation which was seen soon after DMH injections began. In these hyperplastic jejunal crypts the absolute size of the proliferative compartment was increased, but the growth fraction calculated from labelling studies appeared to fall, probably by reduction in relative size of the proliferating population within the proliferative compartment. No convincing alteration in actual cell-cycle time was observed in the abnormal crypts. There was a slight (25%) increase in cell-production rate in the abnormal crypts.

Pulse-labelling with tritiated thymidine and a fraction of labelled mitoses experiments have been performed in order to investigate the proliferative changes induced at various sites in the hyperplastic small-intestinal mucosa of rats previously subjected to resection of 70% of the small intestine. Proliferative activity in the colon was also studied. In the distal ileum there is a significant reduction in cell cycle time (Tc) of cells at all levels within the crypt and the growth fraction falls. In the jejunum and proximal ileum the crypts contain an increased number of proliferating cells, but as the size of the maturation zone is also increased, there is no significant alteration in the relative number of proliferating cells per crypt. Nor does the distribution of proliferating cells in these crypts seem to alter. There is no general reduction in Tc at these sites, but there does appear to be a significant reduction in Tc on the part of the cells in the stem-cell zone at the crypt base. In neither proximal nor distal colon was there any significant proliferative change apparent after small-intestinal resection.

When a segment of small intestine is transplanted to the external abdominal wall in rats adaptive changes occur in the exposed mucosa. These probably represent an extreme example of a physiological response to one type of trophic influence--the effect of mechanical trauma. The nature of the changes has been studied at 7 weeks after externalization using simple morphometry and a number of cytokinetic techniques (thymidine labelling, vincristine-induced metaphase arrest and the fraction-of-labelled-mitoses method), and comparisons drawn with the normal ileum. The exteriorized mucosa showed marked villus atrophy and hyperplasia of the crypts to three times normal size as a result of increases both in crypt length and crypt circumference. Neither metaplastic nor dysplastic epithelial abnormalities were observed. Crypt-cell production rate doubled in the hyperplastic crypts due to an increase in the size of the proliferation zone within the crypt, and the distribution of proliferating cells within the crypt changed. But cell cycle times were prolonged and more maturing cells were retained in the hyperplastic crypts. The potential usefulness of this model, particularly in carcinogenicity studies is considered.

3H-thymidine labelling studies and a computer simulation have been employed to assess proliferative status and cellular organisation in colonic explants maintained in culture for 5 to 7 days. The one-hour flash labelling index (Is) for crypts within the middle region of explants (5.2%) was considerably lower than that observed in vivo (8.8%). Crypt length and the distribution of labelled cells appeared similar for both situations. A computer simulation program for crypt-cell proliferation was devised, facilitating the modulation of a number of parameters including the cell-cycle time (Tc) and its component phases, the cut-off position, and cell loss at mitosis. This simulation was employed to model continuous labelling (72 h) data obtained in vitro and provided an estimate of various kinetic parameters. Data for the middle region of explants was fitted with a Tc of 62 h, an S phase of 8 h and a cell loss factor (20%) which was consistent with histological findings. A fit to the experimental data obtained in vitro could be achieved by a model based upon a mode of cellular organisation known to occur within crypts in vivo. Therefore in vitro, the dynamic processes of crypt-cell proliferation and migration appear to be organised in the same manner as seen in vivo.

Twenty eight patients with colonic cancer, who were asymptomatic after intestinal resection and anastomosis, underwent colonoscopy as part of their routine follow up, and biopsies were obtained from the anastomosis and several other sites. Sections were stained by haematoxylin and eosin, several methods for mucin, and by the peroxidase-antiperoxidase method for carcinoembryonic antigen. Non-specific inflammatory changes were seen at the anastomosis in 11 of the 28 cases, apparent in several two years after operation; focal surface ulceration was seen in over half these samples. Neither dysplastic nor adenomatous change was detected, but at seven anastomoses the so called transitional change, which has been regarded as a preneoplastic change, was apparent. There was no consistent alteration in carcinoembryonic antigen reactivity. It is concluded that there is morphological evidence of a continued stimulus to regenerative activity at some anastomoses and that this may represent a promoting factor enhancing further carcinogenesis.