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Hepatic expression of the protooncogenes c-fos and c-myc occurs within 2 h after partial hepatectomy, and these immediate early genes are thought to prime the hepatocytes for subsequent proliferation. To examine whether such gene activation occurred in the setting of hepatocyte proliferation after toxic liver injury, protooncogene expression was examined during the regenerative response following liver injury from carbon tetrachloride (CCl4) or galactosamine (GalN). The pattern of protooncogene expression after CCl4 mirrored that seen after partial hepatectomy, with rises in c-fos and c-myc mRNA content within 2 h, and then a rapid return to baseline levels. In contrast, early c-fos and c-myc expression did not occur after GalN injury. Instead GalN-induced regeneration led to a delayed, and prolonged c-fos and c-myc activation which peaked 24-48 h after injury. Increases in c-jun, jun-B, and jun-D mRNA levels also occurred in both models at times similar to the rises of c-fos and c-myc expression. Although the timing of DNA synthesis was identical after GalN or CCl4 treatment, the proliferative response after GalN injury was significantly less than that of CCl4, and marked by the histologic appearance of oval cells. The coadministration of 2-acetylaminofluorene, an inhibitor of differentiated hepatocyte proliferation, together with CCl4 altered the usual pattern of post-CCl4 protooncogene expression to one resembling that seen after GalN injury. Thus, the timing of protooncogene expression during liver regeneration may vary considerably. These variations may influence the nature of the proliferative response in terms of which cell type(s) proliferates, and the amount of regeneration that ensues.

Disseminated histoplasmosis (DH) and progressive multifocal leukoencephalopathy occur in acquired immunodeficiency syndrome (AIDS). At autopsy, DH patients with central nervous system involvement almost always show extensive involvement of the lungs and reticuloendothelial system in addition to the brain, and progressive multifocal leukoencephalopathy is manifest as multiple demyelinating lesions in several locations in the brain. We describe an AIDS patient with a long history of aggressively treated DH who died with DH in the brain only; fungus was not found elsewhere at autopsy. In addition, there was a papovavirus infection restricted to the cerebellum with predominant involvement of the internal granular cell layer; again, demyelinating lesions were not found elsewhere in the brain. Each of these patterns of brain involvement is rare. As the incidence of AIDS increases and patients are treated aggressively, the frequency of unusual neuropathologic patterns of opportunistic infections may be expected to increase.

While Ito cells appear to be a major source of increased matrix synthesis during hepatic fibrogenesis, the cellular changes that occur in these cells during liver fibrosis have not been well delineated. In this study we examined Ito cell gene expression in isolated cells from normal rats, and rats with carbon tetrachloride-induced fibrosis, in order to better define the changes occurring in these cells during this pathologic process. Specifically, we addressed three questions: (1) which matrix genes are over expressed in Ito cells in fibrotic liver; (2) do these cells increase their expression of the fibrogenic cytokine transforming growth factor-beta 1 (TGF-beta 1); and (3) do Ito cells change their phenotype during hepatic fibrogenesis as reflected by alterations in the expression of their intermediate filament genes? Northern hybridization analysis revealed that Ito cells isolated from fibrotic livers had significant increases in mRNA levels of types I, III and IV procollagen compared to normal cells, while no increases were found in hepatocytes, and Kupffer/endothelial cells had only an increase in type I procollagen mRNA. Analysis of other matrix proteins which increase during hepatic fibrogenesis revealed elevations in laminin B and fibronectin mRNA levels only in Ito cells. Increased Ito cell matrix gene expression was also associated with a 4-fold increase in TGF-beta 1 levels in these cells. No increase in TGF-beta 1 mRNA was found in hepatocytes, and less than a 2-fold increase was found in Kupffer/endothelial cells isolated from fibrotic livers.(ABSTRACT TRUNCATED AT 250 WORDS)

In a major urinary protein (MUP)-promoter/simian virus 40 (SV40)Tag transgenic mouse line (MT-D2) the liver-directed, androgen-regulated transgene expression leads to synchronized pathology resulting in a stepwise progression to multiple hepatocellular carcinomas. SV40Tag-activated replication gives rise to two different preneoplastic alterations in hepatocytes, which are characterized in detail: 1) dysplasia and finally cell death in the original hepatocyte population and 2) amplification of periportal transitional hepatocytes leading to multifocal hyperplasia and hepatocellular carcinoma. Multifocal hyperplasia, most probably the equivalent of SV40Tag-immortalization, grows confluent and leads to hepatomegaly. SV40Tag-independent, secondary events are necessary for the tumor development from confluent hyperplasia. This allows further investigation of the steps involved in malignant transformation and progression during hepatocarcinogenesis in vivo.

We present a morphologic and molecular comparison of two models of hepatic fibrosis. Immune complexes are the source of insult in one model. In the other model, CCl4 induces fibrosis. For the immune complex model, rats were immunized intraperitoneally over the course of 4 weeks with human albumin, then injected through a tail vein three times a week for at least 5 more weeks with the same albumin. Seventy-five percent of all treated animals developed fibrosis characterized by fine collagen bands. There was a mild degree of hepatocyte trapping and necrosis as well as some bile duct hyperplasia and tissue eosinophilia. However, there was no significant Kupffer cell hyperplasia or inflammatory reaction. Quantification of specific mRNA species was determined by Northern blot hybridization analysis of total RNA. In comparison with CCl4-induced fibrosis in rats, a hepatotoxin-mediated model with a much greater inflammatory response, this immune complex model showed a less pronounced increase in type I procollagen mRNA, but a relatively greater increase in types III and IV procollagen mRNA. Whereas transforming growth factor-beta 1 mRNA levels were markedly increased in CCl4-induced fibrosis, there was only a slight increase in this cytokine, known to stimulate type I collagen synthesis, in the immune complex model. A comparison of the two model systems indicates that a variety of mechanisms may be involved in the process of hepatic fibrogenesis. It appears that an inflammatory response and elevated transforming growth factor-beta 1 levels are associated with a marked increased synthesis of type I collagen in a hepatotoxin model while other, as yet undefined, mediators may be responsible for the increase in types III and IV procollagen mRNA species found in the immune complex model.

Purpose: Patients with the acquired immunodeficiency syndrome (AIDS) frequently have liver dysfunction, which may be due to a number of causes. Determination of the patients who are likely to benefit from liver biopsy, an invasive procedure, is therefore important. In this study, the results of liver biopsy in patients with AIDS were compared to those in human immunodeficiency virus (HIV)-infected patients without AIDS., Patients and Methods: Thirty-six consecutive patients with antibodies to HIV present in the serum underwent liver biopsy from 1984 through 1988 at the Bronx Municipal Hospital. Twenty (56%) of the patients had AIDS diagnosed prior to the liver biopsy. Indications for the liver biopsy were unexplained fever in 83%, and abnormal serum levels of biochemical parameters of liver function in 89%., Results: Liver biopsy was diagnostic in 18 cases (50%), including findings of hepatic infection by mycobacteria in 15, cytomegalovirus in two, and schistosoma in one; these infections had been previously detected at an extrahepatic site in only two cases. Helpful clinical information in 10 others included findings of granulomas of undetermined etiology in four, cirrhosis in five, and chronic persistent hepatitis in one. Patients with a diagnostic biopsy, as compared to patients with a nondiagnostic biopsy, had a statistically significant increase in the frequency of having AIDS diagnosed before the biopsy, longer duration of AIDS (in patients with AIDS diagnosed before the biopsy), greater number of different prior opportunistic infections, and a more elevated serum alkaline phosphatase level. For example, 70% of patients with AIDS, as compared to 25% of patients with serum antibodies to HIV but without AIDS, had diagnostic liver biopsies. Patients with a diagnostic biopsy also had statistically significantly more frequent pulmonary symptoms, possibly due to more frequent occurrence of Pneumocystis carinii pneumonia. In particular, the 15 patients with hepatic mycobacterial infection, as compared to the other patients, had a statistically significant increase in the frequency of having AIDS diagnosed prior to the biopsy, longer duration of AIDS, more frequent prior opportunistic infections, more severe leukopenia, and a more elevated serum alkaline phosphatase level. Liver biopsy was more sensitive than bone marrow aspiration and biopsy at detecting mycobacterial infection., Conclusion: Liver biopsy, when indicated, is useful to detect opportunistic infection in HIV-infected patients who are not known to have AIDS.

An indirect immunofluorescent method for localizing specific types of collagen was applied to unfixed cryostat sections of autopsy and biopsy specimens of normal and fibrotic human livers. Monospecific antibodies to Types I, III, and B collagens were raised in goats by injecting collagens extracted from normal and fibrotic human livers. The antibody against B collagen stained the delicate sinusoidal meshwork within the lobule that closely paralleled in distribution the staining of reticulin fibers as seen in classical silver preparations. Antibody to Type III collagen stained at the sinusoidal aspect of the hepatocytes in a pattern similar to anti-B antibody. All three antibodies tested strongly stained the portal tracts and the fibrotic bands in specimens with cirrhosis. These observations indicate that reticulin fibers within the liver lobule contain both Type III and Type B collagen.

A rare case of primary cardiac neurilemoma arising in the right atrium is reported. The patient was a 55-year-old woman who was treated for 20 years with drug and radiation therapy for a metastatic ovarian carcinoma. The cardiac tumor was an incidental finding at autopsy. Both light and electron microscopic examination of the tumor confirmed the Schwann cell origin of the neoplasm. Review of the literature reveals only one other unequivocal report of a primary cardiac neurilemoma.

We have previously shown that dexamethasone increases albumin mRNA and decreases procollagen steady-state mRNA levels in rat hepatocyte cultures. These studies were extended by evaluating an in vivo model of fibrogenesis (murine schistosomiasis) and by determining a more precise level of gene expression responsible for these changes. Control mice and litter mates infected with Schistosomiasis mansoni were evaluated at 8 weeks postinfection when the livers of the infected mice had become fibrotic and their serum albumin levels significantly decreased. The addition of 4 micrograms/mL dexamethasone to the drinking water of half of the infected mice led to a 75% decrease in the liver collagen content as determined by high-performance liquid chromatography. RNA was extracted from the livers of mice under three conditions: control and infected +/- dexamethasone. This RNA was then hybridized with cDNA probes to determine steady-state levels of specific mRNAs. In the infected mice, albumin mRNA levels were decreased compared to control; however, infected mice treated with dexamethasone increased their albumin mRNA content by 3-fold at 8 weeks. Types I and IV procollagen steady-state mRNA levels in infected mice were increased compared to control while dexamethasone suppressed the mRNA level of collagen in infected mice by 50%. The level of gene expression responsible for these steady-state changes was evaluated by nuclear run-on analysis. While the effect of schistosomiasis on these genes was primarily at a transcriptional level, dexamethasone exerted its effect on different genes in the injured liver by diverse mechanisms, i.e., decreasing collagen synthesis at a transcriptional level and increasing albumin by posttranscriptional mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Liver biopsies of four patients with hepatosplenic schistosomiasis, two patients with schistosomiasis and chronic active hepatitis, two patients with chronic active hepatitis and four control patients with no clinical evidence of either disease, were examined by standard light microscopic techniques, electron microscopy and immunocytochemical staining for collagen type I, III and B. Pure schistosomiasis showed the classical "clay-pipe stem fibrosis" and granulomata composed of eosinophils, macrophages and lymphocytes. In that group, the hepatocellular damage was less conspicuous than in the groups with chronic hepatitis and was usually confined to the granulomatous or fibrotic areas. Destruction of the normal architecture and infiltration by macrophages and lymphocytes with severe damage of hepatocytes was found only in the cases of chronic active hepatitis, with or without associated schistosomiasis. Increased collagen deposits were demonstrated in all three groups. Types I, III and B were found in the enlarged portal triads and fibrotic septa. The intranodular or intralobular collagen stained negatively for type I and strongly positive for types III and B.

A patient presented with a three-year history of diarrhea and was found to have a monoclonal gammopathy (IgM lambda) and a malabsorption syndrome with dilatation of the small bowel. Small-intestinal biopsy revealed a homogeneous eosinophilic granular material between the epithelial cells. On electron microscopy this material was shown to consist of an electron-opaque background mixed wit radiolucent lipid sheres. Immunofluorescent studies showed the accellular material to consist entirely of IgM-reactive material. The patient's course and a review of the literature is presented.

Two unusual carcinomas of the breast are described, containing nests of infiltrating neoplasm situated within stromal lacunar spaces, and surrounded by numerous benign appearing multinucleated giant cells. Within the stroma, there was extensive hemorrhage, hemosiderin pigment deposition, and large numbers of mononucleated inflammatory cells. The morphology of both tumors resembled the giant cell tumor of bone. Although a similar giant cell reaction has recently been described in association with a uterine leiomyosarcoma, we are aware of only two other examples of this entity in the breast, both reported over 40 years ago in the French literature. This is the first report in which electron microscopy confirmed the benign histiocytic nature of the giant cells. These cells had many of the ultrastructural features of multinucleated giant cells described in tissue culture, skeletal osteoclastomas, and foreign body granulomas. We propose that the giant cells arise from fusion of mononucleated stromal cells, and most likely are reactive histiocytic elements which are in some way related to the tumor cell nests. Further studies of these unusual neoplasms are needed to determine if the giant cell reaction in any way affects the prognosis of the patient.

Mitral valve, coronary arteries, cartilage, and liver were studied by light and electron microscopy in a 15 year old boy with Morquio's syndrome, a genetic mucopolysaccharidosis, in which a deficiency of lysosomal hexosamine sulfatase is associated with accumulations of keratan sulfate in various organs. Coronary artery intimal sclerosis was a prominent feature of this disorder. Ultrastructural examination revealed numerous intimal smooth muscle cells containing storage vacuoles consistent with lysosomes. This was associated with marked interstitial deposition of collagen, elastin, and basement membrane material. Recent studies of human and experimental atherosclerosis have demonstrated the accumulation of cholesterol within vascular smooth muscle cell lysosomes. Intralysosomal accumulation of substrates other than cholesterol is also associated with vascular intimal sclerosis in genetic lysosomal disorders such as Fabry's disease and Hurler's syndrome. Lysosomal storage of undegraded substrate may be an important pathogenetic mechanism in the development of sclerotic vascular lesions.

The accumulation of excessive amounts of copper in the livers of toxic milk mice results in gross morphologic, histologic, and ultrastructural changes that are progressive with age even though the concentrations of copper tend to decrease in mice older than 6 months. Striking differences in morphologic integrity between regenerative nodules and the intervening parenchyma were observed. Profound changes in mitochondria, endoplasmic reticulum, and nuclei as well as accumulation of microvesicular lipid droplets were observed in injured hepatocytes. By contrast, the hepatocytes of regenerative nodules appeared well preserved. Comparisons with other inherited mammalian disorders associated with hepatic copper toxicosis indicate that copper causes species specific organelle injury.

Bile duct carcinoma is a relatively uncommon lesion that usually presents in the 6th to 7th decade. The only prior reported cases under the age of 20 were two patients with diseases known to predispose to the development of this tumor. We report a case of a 17-year-old girl with a bile duct tumor without any known predisposing factors.

A case of Hurler's disease in a mentally retarded, six year old boy is reported. In Hurler's disease a lysosomal hydrolase, l-iduronidase, is deficient, and consequently undegradable mucopolysaccharide accumulates within lysosomes in many tissues. Severe occlusive coronary artery disease and sclerotic aortic lesions are common in very young patients, although their serum lipid and blood pressure levels are normal. Vascular collagen and elastin is increased, but little or no stainable lipid is present. Electron microscopy shows that aortic smooth muscle cells are distended by vacuoles, appearing empty in formalin fixed tissues, that identify them as the "gargoyle" cells in the proliferative lesion. The presence of a basic lysosomal defect and the absence of other contributing metabolic factors suggest that accumulation of an excess of undegradable substrate within smooth muscle lysosomes may be an initiating event in the development of proliferative sclerotic vascular lesions.

Tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta 1 (TGF-beta 1) have a number of in vitro functions that could be important in vivo in acute liver injury and repair. Therefore, we investigated these two cytokines in acute liver damage. Northern blots of RNA isolated from rats sacrificed at various time intervals after a single oral dose of CCl4 revealed that TNF-alpha mRNA levels were elevated within 6 hr of CCl4 administration and returned to control values by 24-32 hr. In contrast, TGF-beta 1 mRNA levels started to rise significantly at 24 hr, peaked at 48 hr, and approached baseline levels by 72 hr. Identical changes in TNF-alpha and TGF-beta 1 mRNA levels were also seen with D-galactosamine-induced hepatotoxicity. Immunohistochemical analysis using a TGF-beta 1 antibody demonstrated increased hepatic staining in CCl4-treated rats, at times corresponding to the increases in TGF-beta 1 gene expression. Therefore, there is a differential expression of these cytokines in acute CCl4 and galactosamine hepatotoxicity with an early rise in TNF-alpha, suggesting that this cytokine may affect inflammation and cell toxicity, while TGF-beta 1 peaks later, when it may regulate hepatocyte proliferation and extracellular matrix repair.

Since interferons have been shown to affect the synthesis of matrix proteins such as collagen in several in vitro systems, the potential role of gamma-interferon in inhibiting hepatic fibrosis was investigated. Hepatic cells, consisting primarily of hepatocytes, were treated with recombinant gamma-interferon for 24 hr. Northern blot hybridization showed that gamma-interferon treatment caused a profound decrease in pro-alpha 2(I)collagen mRNA levels but an increase in beta-actin mRNA content. The effects of gamma-interferon were then studied in an in vivo model of hepatic fibrogenesis, murine schistosomiasis. Schistosoma-infected mice were treated with daily i.m. injections of gamma-interferon for a 4-week period starting 4 weeks after the initial infection. gamma-Interferon treatment decreased collagen deposition as determined by histologic evaluation and measurement of total liver collagen content. Northern blots showed Types I and III procollagen mRNA levels for treated, infected animals to be only 32 and 29% that of infected controls, but beta-actin mRNA levels were significantly elevated. These results indicate a potential role for gamma-interferon as an antifibrogenic agent in vivo.

We have shown previously that an increase in tumor invasion and metastases occurred concurrently with a decrease in collagen content of the extracellular matrix surrounding the C3H mouse mammary adenocarcinoma borne by C3H/HeJ mice. In this paper we report the production of collagenase and elastase activities by the primary tumor cultures and three types of cloned C3H mouse mammary adenocarcinoma cell cultures. The primary tumor cell cultures and tumor-associated stromal cultures produced large amounts of collagenase and elastase activities. On the other hand, the primary tumor capsule cultures produced little or no collagenase and elastase activities even though they produced type I collagen. The production of proteases by the primary tumor cultures decreased along with time and with an alteration in the morphology of cell populations and/or passage of the cultures. The three clones of tumor cell cultures produced variable amounts of collagenase in response to induction by phorbol myristate acetate, an agent that stimulates maximal collagenase production. In contrast, all three cloned cultures elaborated significant amounts of elastase that degraded insoluble ligamental elastin, and most of the elastase production was increased further in response to induction by phorbol myristate acetate. Each cloned cell population exhibited differences in their production of collagenase and elastase in parallel with their difference in growth kinetics, yet these cells still possess the distinctive properties of the tumor. However, a unit amount of collagenase produced by each of the cloned cultures, with or without induction by phorbol myristate acetate, was less than that of the primary tumor cultures. Results suggest that some cell types or combination of cell types in the heterogeneous cell population of the tumor and/or their products appear to be responsible for the increased production of collagenase and elastase activities and for the invasiveness of a malignant tumor.

During liver regeneration induced by CCl4 administration to rats, changes in the relative transcription rates of albumin and alpha-fetoprotein genes have been measured in conjunction with other liver-specific and general cellular function genes. Within 24 h following CCl4 administration, albumin gene transcription decreases by 85%, whereas alpha-fetoprotein transcription increases from undetectable levels to 50% of that observed for albumin. These changes precede maximal [3H]thymidine incorporation into DNA which peaks at 48 h. Other genes related to liver-specific functions, such as ligandin, alpha 1-antitrypsin, and cytochrome P-450's, as well as general cellular genes pro alpha 1- and pro alpha 2-collagen, beta-actin, and alpha-tubulin, respond in kinetic patterns often distinct from each other and from albumin and alpha-fetoprotein. Changes in the steady-state levels of albumin and alpha-fetoprotein mRNA correlate with changes in transcription, but there is a lag in alpha-fetoprotein mRNA accumulation, which peaks at 72 h following CCl4 administration. These studies indicate that reciprocal changes in albumin and alpha-fetoprotein gene transcription occur during CCl4-induced liver regeneration, leading to changes in the level of these specific mRNAs. These changes precede DNA synthesis and would appear to represent an alteration in differentiated function of hepatocytes in conjunction with the liver regenerative process.

In efforts to understand mechanisms of liver dysfunction in cirrhosis, transcription of specific genes important to liver function has been measured in the rat model of CCl4-induced hepatic fibrosis. The relative transcription rates of albumin, alpha-fetoprotein and pro-alpha 1-collagen genes were studied during development of fibrosis and after fibrosis was established. During the initial phase of CCl4 administration, there was a decrease in albumin transcription associated with increased alpha-fetoprotein transcription, indicative of active liver regeneration. However, later during development of fibrosis, the response pattern of these genes was different, as albumin gene transcription was normal or increased and alpha-fetoprotein gene transcription was no longer increased. Three weeks after completion of CCl4 treatment (fully established cirrhosis), albumin genes responded normally or hypernormally to an acute regenerative stimulus, but the alpha-fetoprotein gene was again not measurably responsive. Pro-alpha 1-collagen gene transcription increased during the entire fibrogenic process and remained elevated after cirrhosis was established. These studies suggest that a switch from albumin to alpha-fetoprotein gene transcription can serve as a marker of liver regenerative capacity, and that this process is altered during and after development of hepatic fibrosis. The fibrogenic process is also associated with elevated transcription of collagen genes.

Distinctive globular bodies, ranging in diameter from 0.2mu to 1.5mu, were encountered in the cytoplasm of epithelial cells of human rectal mucosa. These profiles, surrounded by a unit membrane, contained a uniform population of electron-dense rods 50 nm wide and 100 to 250 nm long. Although neither the origin nor the relationships of these rod-containing bodies (R-bodies) to other cytoplasmic organelles could be established, morphologic and cytochemical studies demonstrated clear differences from multivesicular bodies.

A case is reported in which hypodense linear structures on postcontrast computed tomography were not intrahepatic biliary dilatation but periductal extension of pancreatic carcinoma.

A recent case of myeloma kidney disease was studied to determine the cellular origin of the syncytial multinucleated giant cell. Light, immunofluorescence, and electron microscopy of the giant cells revealed features characteristic of histiocytes. This finding contradicts the generally accepted conclusion that the giant cell represents a syncytial mass of degenerating or reactive tubular epithelial cells. We conclude that the giant cells arise in the interstitial tissues, migrate through breaks in the tubular basement membrane, and engulf and surround intratubular protein casts.

Collagenases and other neutral proteases in tumors may facilitate tumor extension, invasion, and subsequent metastasis. We report the effects of vitamin A and dexamethasone, known inhibitors of collagenase production in vitro, on the collagen metabolism of mouse mammary adenocarcinoma and its capsule, borne by C3H/HeJ mice. The weight of the capsule was about 4% of the tumor, yet the total collagen content of the capsule was about 10-fold greater than that of the tumor tissue; tumor cells had no detectable collagen. With tumor growth, the collagenase and other neutral protease activities were increased in the tumor tissue; a negative correlation existed between collagenase activity and collagen content of the capsule. The protease activities of the tumor borne by vitamin A-treated hosts were about 50% lower than those of the controls; this coincided with a slight increase in the collagen content of the capsule. In contrast, the collagen content of the capsule borne by dexamethasone-treated hosts was 50% less than that of the controls; the protease activities were similar to the controls and occurred with tumor invasion and metastasis. Results suggest that the collagen metabolism of the capsule may be an indicator of proteolytic events within the tumor and the metastatic potential of the tumor that, in turn, suggests the possibility of preventing metastasis by inhibiting the production of collagenases and other neutral proteases, thereby localizing the tumor cells within the capsule. Vitamin A could be used for that purpose.

We determined collagen synthetic rates and utilization of key amino acid precursors of collagen in slices of wedge liver biopsy specimens obtained at required surgery from 9 patients with hepatosplenic schistosomiasis and from 4 control patients. The liver specimens from the patients with schistosomiasis showed advanced fibrosis, with histologic evidence of schistosomiasis alone in four, and both schistosomiasis and chronic active hepatitis in five cases. Liver slices were incubated with radioactive proline, arginine and glutamine, using quantitative assay conditions validated earlier for murine schistosomiasis. Collagen peptide synthesis in slices from all nine fibrotic liver specimens was 4- to 25-fold greater than normal and correlated positively with liver collagen content, which was 2- to 5-fold greater than normal. Free proline, an amino acid that may contribute to regulation of collagen peptide synthesis, was increased in six of the nine fibrotic liver specimens, and proline was actively formed from arginine in liver slices from all specimens. These measurements of the initial steps of collagen biosynthesis in fibrotic human liver are quantitatively similar to those previously made of the same processes in experimental animals.

A 41-yr-old homosexual male had cytomegalovirus infection localized to the terminal ileum as his initial and sole evident opportunistic infection due to the acquired immune deficiency syndrome. The symptoms, signs, roentgenographic findings, and appearance at surgery were suggestive of Crohn's disease. The pathogen was identified only by microscopic examination of bowel resected during a second laparotomy. The terminal ileum had profound mucosal ulceration and transmural fibrosis without granulomas. This novel report suggests that cytomegalovirus infection should be carefully searched for in immunocompromised patients presenting with clinical features suggesting Crohn's disease.

Intralysosomal accumulation of lipid has been implicated as an important mechanism in the pathogenesis of atherosclerosis. Although atherosclerosis develops frequently in organ transplants maintained on a long-term basis, to our knowledge no studies to date have demonstrated the intracellular localization of the lipid in this setting. Light and electron microscopic study of a renal artery branch from a transplanted kidney maintained for 3 1/2 years demonstrates that the lipid is sequestered within intimal smooth muscle cell lysosomes. The features of the atherosclerotic plaque in long-term transplantation appear to be identical to spontaneous lesions or those induced experimentally.

Ligandin (GSH-S-transferase B), an abundant intracellular soluble protein in rat proximal tubules, hepatocytes, and small intestinal mucosal cells, is believed to be a component of an organic anion transport system. Its presence in urine was determined immunologically and catalytically in adult, female, Sprague-Dawley rats that were given mercuric chloride or potassium dichromate. These nephrotoxic agents produce severe renal failure, with epithelial necrosis in the proximal tubule. Mercuric chloride perferentially injures the terminal part of the proximal tubule, while potassium dichromate damages more proximal segments. Ligandinuria was consistently detected immunologically and catalytically from 6 to 24 hr following injection of mercuric chloride. Potassium dichromate administration did not result in immunologically detectable liganduria; however, GSH-S-transferase activity, which provides a more sensitive assay, was frequently detected. The findings are consistent with immunofluorescent localization of ligandin in the proximal tubule. Immunologic or enzymatic measurement of ligandin in urine may provide a sensitive index of acute injury to the proximal tubule.