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Induction of islet neogenesis by cellophane wrapping (CW) reverses streptozotocin-induced (STZ) diabetes. Administration of Ilotropin, a protein extract isolated from CW pancreata, causes recapitulation of normal islet ontogeny and reverses STZ diabetes, reducing mortality by 50%. We investigated the hypothesis that a novel gene encoding a constituent of Ilotropin was expressed in the hamster pancreas undergoing islet neogenesis. Islet neogenesis associated protein (INGAP) is a product of a novel gene expressed in regenerating hamster pancreas. Northern blot analysis showed a strong single transcript of 850 bp at 1 and 2 d after CW that disappeared by the 6th day and was absent from untreated control pancreata. INGAP gene is expressed in acinar cells, but not in islets. Western blot analysis demonstrated the presence of INGAP in Ilotropin but not in extracts from control pancreata. A synthetic pentadecapeptide, corresponding to a region unique to INGAP, stimulated a 2.4-fold increase in [3H]thymidine incorporation into hamster duct epithelium in primary culture and a rat pancreatic duct cell line but had no effect on a hamster insulinoma tumor cell line. A portion of human INGAP gene was cloned and appears to be highly homologous to the hamster gene. This data suggests that the INGAP gene is a novel pancreatic gene expressed during islet neogenesis whose protein product is a constituent of Ilotropin and is capable of initiating duct cell proliferation, a prerequisite for islet neogenesis.

Administration of supramaximal doses of cerulein results in acute interstitial pancreatitis. To understand the pathogenesis of this disease, it would be of great importance to elucidate the changes during the early phase of the process. We report changes of gene expression in the pancreas during the first 6 h of cerulein supramaximal stimulation. The expression of genes, including the secretory enzyme amylase, the lysosomal enzyme cathepsin B, as well as the housekeeping genes beta-actin and glyceraldehyde-3-phosphate dehydrogenase (GAPD), was investigated in this study. The most prominent alteration in gene expression is beta-actin messenger RNA (mRNA), which increased continuously after cerulein infusion. Immunostaining for beta-actin was observed along the membrane of large cytoplasmic vacuoles in pancreatic acinar cells. The level of amylase mRNA decreased during the first 30 min of cerulein infusion, recovered to the control level at 1 h and increased twofold at 2 h. An obvious increase in cathepsin B mRNA was observed after 3 h of cerulein infusion and reached sixfold of the control at 6 h. A significant increase of GAPD mRNA level was observed at 6 h of cerulein stimulation. In conclusion, this study provides direct evidence that the changes in gene expression, such as cathepsin B and amylase, after supramaximal cerulein stimulation, are regulated at the transcriptional level. It also suggests that beta-actin is involved in the formation of cytoplasmic vacuoles during supramaximal cerulein administration. Finally, this study indicates that beta-actin and GAPD may not be appropriate as RNA-loading controls for Northern blot analysis of pancreatic tissue.

Solitary intrapancreatic schwannoma is a rare tumor. We present two patients with this tumor and review 13 previously reported cases from the English-language literature. While the final diagnosis was made based on pathological examination of the tumors, both computed tomography scan and magnetic resonance imaging helped establish the benign nature of the lesion, narrow the differential diagnosis, and define the anatomical locations of the small tumors. Both tumors were treated by enucleation from the surrounding pancreatic parenchyma, and both patients, after 2 years of follow-up, are alive and well. It is concluded that multimodality radiologic investigations are useful in the workup of unusual pancreatic masses. In addition, based on the known biologic behavior of schwannomas occurring elsewhere in the body, simple enucleation, rather than more radical resection, is likely to be adequate therapy for these tumors.

The autoimmune syndrome of the BB rat is associated with a marked increase in glutamine (Gln) metabolism in immune system cells of both diabetes-prone (BBdp) and diabetic (BBd) rats. To test whether inhibition of Gln metabolism prevents diabetes, 17 BBdp received acivicin (1 mg/kg) and 17 received saline subcutaneously every 2 days from age 48 days until diabetes onset or age 186 days. Twenty-seven non-diabetes-prone (BBn) rats served as controls. Acivicin caused some growth effects and a macrocytic anemia, but no other clinical or biochemical side effects. Only one acivicin-treated BBdp became diabetic (age 158 days), compared with saline-treated rats, of which 10 became diabetic and 2 became glucose intolerant (p0.001). Insulitis was moderate to severe in 88% of the saline-treated BBdp rats, but minimal in most acivicin-treated BBdp rats. Liver glutamine and glutamate tended to be higher in acivicin- than saline-treated BBdp rats. Acivicin caused no change in the proportions of T or B lymphocytes, NK cells, or macrophage phenotypes in spleen or blood; all BBdp rats were typically lymphopenic. Mitogenic responses of splenocytes in vitro were not affected. The results are consistent with the hypothesis that acivicin, by interfering with Gln metabolism, "targets" activated cells of the immune system and thereby attenuates the process and prevents overt diabetes, without major disturbance of Gln levels or generalized immunosuppression. This prevention is not due to a nutritional-growth retardation effect, as diabetes was prevented in females that showed no such effect.

Partial obstruction of the pancreatic duct in hamsters leads to new islet formation and reversal of streptozotocin diabetes. The purpose of this study was to delineate the mechanism by which endocrine cell proliferation and differentiation is mediated in this model. Six pairs of parabiotic hamsters were established and partial duct obstruction was inducted in 1 parabiont from each pair. At 6 weeks, the pancreatic weight (mg/100g bw); DNA (microgram/100g bw) and protein content (mg/100g bw) showed 28% (167 +/- 21 vs. 130 +/- 17), 32% (1,052 +/- 206 vs. 795 +/- 159), and 20% (25.4 +/- 6.6 vs. 21.2 +/- 1.9) increases (p0.05), respectively, over the non-wrapped parabionts. Morphometric analysis demonstrated the presence of new islets in the wrapped pancreata with a 100% increase in the number of islets/mm2 compared with non-wrapped controls (0.90 +/- 0.5 vs. 1.8 +/- 0.7, p0.01). A cytosol extract was prepared from duct-obstructed pancreases, and 4 microliters/g bw injected i.p. twice daily for 2 d produced significant increases in pancreatic weight and DNA content of 12% and 40%, respectively. Cytosol extract from non-wrapped pancreata had no effects compared with saline. When wrapped cytosol extract was injected for 21 d, the labeling index of ductular and islet cells (% cell nuclei labeled with 3H-TdR) was increased 10- and 6-fold respectively over controls (2.42 +/- 0.28 vs. 0.23 +/- 0.01 and 1.17 +/- 0.01 vs. 0.25 +/- 0.04, respectively, p0.01). The trophic effects observed in this model of islet cell proliferation and differentiation did not appear to be mediated by a humoral mechanism because the changes induced by partial obstruction were not observed in the non-operated parabiont. Control of pancreatic endocrine cell growth in this model appears to involve paracrine and/or autocrine regulatory mechanisms.

A case of minimal change nephropathy occurring in association with a renal cell carcinoma is presented and discussed. The case was unusual in that it was associated with acute renal failure necessitating hemodialysis for five weeks. The renal failure resolved but the nephrotic state persisted in spite of therapy with prednisone then cyclophosphamide. The literature on nephrotic syndrome causing acute renal failure and its association with solid tumors is briefly reviewed.

The purpose of this study was to demonstrate that the pancreas of the hamster contains a growth factor(s) that can induce cells associated with the ductular epithelium to differentiate along an endocrine pathway and thereby provide a means of regenerating a functioning islet cell mass. We have shown previously that partial obstruction of the pancreatic duct leads to the induction of nesidioblastosis. A cytosol extract prepared from the partially obstructed hamster pancreas was injected at a dose of 4000 microliters intraperitoneally twice a day for 2 days and produced significant increases in pancreatic weight, protein, and deoxyribonucleic acid of 18%, 18% and 42% respectively, over saline-treated control animals. To assess the effects of this extract on morphology, 150 microliters intraperitoneally twice a day was administered for 21 days. Tissue was processed for histologic, morphometric, and autoradiographic analysis. Budding of endocrine cells from cells of the terminal ductules was observed in cytosol-injected animals and the number of islets per square millimeter was determined to be increased by 100% compared with saline-treated controls (p less than 0.01). Tritiated thymidine uptake by ductal and islet cells was increased tenfold and sixfold, respectively, over that of control animals (p less than 0.01). Cytosol extract was also administered to hamsters rendered diabetic by streptozocin. Survival in these animals was 100% compared with only 60% for saline-treated control animals (p less than 0.05). Furthermore, the blood levels of glucose in cytosol-treated animals was significantly less than the levels in saline-treated controls (p less than 0.05). We conclude that the pancreas does indeed contain a growth factor(s) responsible for the induction of nesidioblastosis and the new islet tissue is functionally capable of stabilizing a diabetic state.

A case of post-biopsy renal arteriovenous fistula causing high output cardiac failure was diagnosed one year after the start of maintenance hemodialysis, confirmed by radionuclide studies, and successfully treated with nephrectomy. Management was complicated by superimposed digitalis intoxication. It is suggested that the presence of the renal arteriovenous fistula might account for the accelerated deterioration in renal function observed in this patient.

The histologic changes which occur in the human adrenal cortex in conditions of stress are attributed to the liberation of endogenous corticotropin (ACTH). The effect of exogenous corticotropin on the adrenal gland is well known in animals, but only recently has it been possible to study the changes which take place in the human adrenal cortex as a result of such stimulation. Variations occur in lipid pattern, cytology, enzyme content and ribonucleic acid content of the cells. A comparison of the changes during stress with those found during administration of corticotropin forms the basis of this paper.

A case is reported of neurotropic melanoma developed from a superficial spreading melanoma with minimal cytological deviation, situated in the right temple. The nine-year course was clinically characterised by local recurrences, involvement of the orbit and the parotid region via neurogenic invasion, and systemic metastases to lung, seventh rib, and the brain. The histopathology was characterised by fascicles of dysplastic spindle cells, neuroid arrangement in loose fibrillary matrix, and peri- and intraneural permeation of the nerve trunks. Despite minimal atypism the neoplasm metastasised and had a fatal outcome. The spindle cell component of the neurotropic melanoma lacked melanogenesis; Fontana stains were negative. As previously demonstrated, the histogenesis of the neurotropic melanoma is possibly a Schwann cell differentiation of the dysplastic atypical melanocytes, as shown by the positive reactions to Bodian's stain.

Orbital involvement as the initial manifestation of primary extramedullary plasmacytoma is rare. The case presented in this article illustrates several interesting aspects of the disease. The neoplastic process involved monoclonal B-lymphocytes that produced IgG-lambda chains.

Chronic renal failure was induced in mice using bilateral electrocoagulation of the renal cortex. Thermal injury via an angled point cautery was applied to the fully exteriorized right kidney. Following a 10-day interval the left kidney was injured in a similar fashion. The incidence of local complications was negligible and because of the limited blood loss, very small laboratory animals can be used. By restricting trauma to varying proportions of the visible cortex graded levels of injury were obtained. Thus this model can produce a uniform pattern of renal failure and will therefore facilitate the acquisition of information on the biological consequences of chronic uraemia.

We reviewed the long-term results of management of 38 patients with carcinoma in colorectal polyps. Of these, 16 patients demonstrated malignant invasion of the lamina propria but not the muscularis mucosa (group I), and 22 patients showed malignant invasion of the muscularis mucosa (group II). Primary therapy for group I patients consisted of polypectomy in 12, local excision in one, and colonic resection in three. One patient had a subsequent abdominal-perineal resection and was found to have no residual disease and no lymph node involvement. Follow-up of the group I patients showed that 11 were alive and well (mean 5.8 years) and five died of unrelated causes (mean 5.2 years). Of group II patients, 12 underwent polypectomy, six local excision, and four colectomy. Of these 22 patients, 11 underwent further operation, including nine major bowel resections and two local re-excisions. None of these 11 patients had either residual tumor or lymph node metastases. One patient died of complications after abdominal-perineal resection. Follow-up showed that 18/22 group II patients were alive and well 5 to 15 years later (mean 7.5 years); four died of unrelated causes (mean 3.2 years). We then reviewed another group of 220 patients who had undergone resection for invasive colon cancer to relate the presence or absence of lymph node metastases to the depth of malignant invasion in the bowel wall. We found that 44% of this entire group had lymph node involvement. Of 36 patients with tumor confined to the bowel wall, nodal metastases occurred in only 22%. Of eight patients with malignancy superficial to the muscularis propria, only one had nodal involvement. We conclude that colon cancer tends to progress in an orderly fashion and the risk of nodal metastases increases with the depth of invasion. Carcinoma in a polyp represents a very early stage of colon cancer. We therefore recommend polypectomy as primary treatment for pedunculated polyps containing carcinoma either superficial to or invading muscularis mucosa. If histologic review demonstrates incomplete excision, lymphatic invasion, or poor differentiation, patients with lesions invading the muscularis mucosa should undergo formal colonic resection.

SUMMARY.– The variability of dosage of dapsone required to control dermatitis herpetiformis is well known but unexplained. As a first step in the investigation of this problem this paper describes the results of estimations of serum levels and urinary excretion levels after a single oral dose of 100 mg. 35S dapsone given to patients with and without dermatitis herpetiformis. For comparison the levels were measured by radio-activity and by chemical methods. Radiochromatographic studies were also carried out to determine the form in which dapsone circulates and is excreted. Autoradiographs of biopsies are also discussed.

THE hydroxylation and secretion of steroids by the adrenal cortex has been studied extensively in animals (1, 2), and there is a marked species difference in the quantitative and qualitative nature of the secretion. The perfusion of surgically removed human adrenals with media containing adrenocorticotropic hormone (ACTH) yielded only traces of cortisol 11β, 17α, 21-trihydroxy-4-pregnene-3, 20-dione) and corticosterone (11β, 21-dihydroxy-4-pregnene-3, 20-dione) (3), yet these are the principal substances obtained on perfusion of ox adrenals (4) and are two of the major steroids found in human adrenal venous blood. Pincus and Romanoff (5) isolated crystalline cortisol, corticosterone and 11β-hydroxy-4-androstene-3, 17-dione from human adrenal venous blood. Hudson and Lombardo (6) observed wide variations in the amount of cortisol and corticosterone in the adrenal venous blood of 3 women with breast cancer. When corticotropin (ACTH) was administered to 1 of these patients during the collection of blood the ...

A patient is described who passed from a clinical state consistent with Hashimoto's thyroiditis to Riedel's thyroiditis over a period of 6 months. Serum levels of thyroid antibodies were high and there was a family history of Hashimoto's thyroiditis. A good therapeutic response to steroids was observed but these were without effect in a further patient with Riedel's thyroiditis of 10 years' duration. It is suggested that Riedel's thyroiditis is an uncommon variant of Hashimoto's thyroiditis.