Rapid recycling of cholesterol: the joint biologic role of C-reactive protein and serum amyloid A.

Proteins that are highly conserved throughout evolution are presumed to have critical roles in the survival of the species. The two major acute phase proteins, C-reactive protein (CRP) and serum amyloid A (SAA) increase up to 1000-fold during inflammation. Both proteins have been highly conserved phylogenetically for at least the last 500 million years. Thus far the physiologic role and the evolutionary significance of each remains uncertain and their potential interactions have been totally ignored despite a vast and accelerating scientific literature on the involvement of each in human disease. CRP is known to bind to phosphocholine in dead eukaryote and some live bacterial cell walls suggesting that CRP facilitates the phagocytosis of fragmented or intact dead cells and/or enhances host bacterial defenses. SAA has recently been shown to increase the rate of export of cholesterol of phagocytosed cell membranes from macrophages fourfold. We postulate that their combined physiological role is to facilitate the rapid endogenous recycling of cell membrane cholesterol and phospholipids during acute inflammation. CRP promotes efficient phagocytosis of dying cells by macrophages; SAA enhances the export of their free cholesterol/phospholipid for reuse in the membranes of the hundreds of billions of new cells required daily during acute inflammation and repair. The evolutionary conservation of these proteins in species from the horseshoe crab and echinoderms to humans suggests that the rapid endogenous recycling of cholesterol and phospholipids during the highly vulnerable period of acute inflammation is critical for their continual survival.

Promoting, building and sustaining a regional laboratory network in a changing environment.

The Queen's University Department of Pathology and its affiliated hospital laboratories (Kingston, Canada) have operated a successful laboratory outreach program for more than a decade in Southeastern Ontario. The outreach program provides high quality reference testing and technical and professional expertise in laboratory medicine to largely rural and small urban community hospitals. As a consequence of dramatic cuts to the publicly funded health-care system in the Province of Ontario, the environment in which laboratory medicine is practiced has altered irrevocably. This article discusses some of the difficult internal and external challenges faced by the outreach program within the region and how they were effectively managed, not only to maintain but to enhance the program's services. The result has been a continued improvement in the quality of laboratory services in the region with significantly increased cost-effectiveness, largely through reengineering and consolidation.

Integrating academic and community laboratory needs: developing a successful outreach program.

Remarkably few large regional laboratory programs involving academic health centers exist in Canada. We present a model of a successful laboratory outreach program established by the Queen's University Department of Pathology (Kingston, Ontario) and its affiliated hospital laboratories. Community hospitals in small urban and semi-rural areas benefit from a diffusion of specialty expertise in laboratory medicine and technology, which enables them to increase their local testing capabilities and improve turn-around time. Testing and services of a more complex nature are referred to the academic hospitals. The result has been a steady improvement in the quality of laboratory services in the region with increased cost-effectiveness through shared services and focused economies of scale.

Endoscopically removed malignant colorectal polyps: clinicopathologic correlations.

BACKGROUND/AIMS: Treatment options for patients with endoscopically removed malignant colorectal polyps are polypectomy alone vs. polypectomy followed by surgery. The aim of this study was to define histopathologic parameters that can be used for clinically relevant treatment decisions. METHODS: Five pathologists evaluated 140 polyps for the presence or absence of unfavorable histology. Unfavorable histology was tumor at or near (< or = 1.0 mm) the margin and/or grade III and/or lymphatic and/or venous invasion. Adverse outcome was recurrent and/or local cancer and/or lymph node metastasis. RESULTS: Adverse outcome was 19.7% (14 of 71), 8.6% (2 of 23), and 0% (0 of 46) when unfavorable histology was present, indefinite (lack of agreement), and absent, respectively (P < 0.0005, present vs. absent). Four patients with cancer > 1.0 mm from the margin had an adverse outcome (2 with lymphatic invasion and 2 indefinite for lymphatic invasion). Four patients with negative resections later developed distant metastases. Eight patients (6.3%) died of disease, and 2 of 69 without unfavorable histology (both indefinite for lymphatic invasion) had an adverse outcome. Interobserver strength of agreement was substantial to almost perfect for margin, grade, and venous invasion and fair to substantial for lymphatic invasion. CONCLUSIONS: This system is usable clinically. Patients with unfavorable histology are probably best managed by resection postpolypectomy, whereas in the absence of unfavorable histology, they probably can be treated by polypectomy only.

Induction of controlled prostatic tissue necrosis by bacille Calmette-Guérin derivatives.

Intraprostatic administration of live bacille Calmette-Guérin (BCG) in humans has been found to produce tumor necrosis; unfortunately, the number of severity of complications have made its clinical use prohibitive. Previous studies have shown that soluble and microparticulate components present in the supernatants obtained after centrifugation of a reconstituted BCG preparation exhibit similar immunogenicity to the one shown by live bacteria. The supernatants, however, are not associated with disseminated infection of the progressive regional tissue destruction observed with the use of viable vaccine. Experiments were conducted to determine the effect of intraprostatic injection of BCG and its supernatants. Adult dogs, after positive conversion to protein purified derivative (PPD), were randomly assigned to three groups. Under direct vision and with digital rectal control, intraprostatic injections of various agents were given as follows: group I, normal saline; group II, live BCG; group III, 200 micrograms of BCG supernatants. Two months later the animals were sacrificed, and the prostates removed in toto and submitted for a thorough histological examination. Extensive but variable tissue necrosis was noted in groups II and III. No histological alterations were present in group I. The histological picture of the animals receiving BCG supernatants conclusively demonstrated circumscribed necrosis of the gland. Side effects and complications were present in animals receiving live BCG but conspicuously absent in the ones receiving supernatants. The observed effectiveness and safety of BCG supernatants for intraprostatic administration in an experimental system may lead to a simple, safe, and efficacious therapeutic modality for localized carcinoma of the prostate in humans.

Embolic mesenteric infarction: a unique initial manifestation of renal cell carcinoma.

Renal cell carcinoma is an unpredictable tumor that often has already metastasized when first seen. It can affect many organs before the primary tumor is found. We describe a unique example of renal cell carcinoma first seen as repeated episodes of small-bowel infarction caused by tumor emboli from a metastasis in the left ventricle. Although intestinal ischemia caused by emboli is not uncommon, intestinal ischemia resulting from metastatic tumor emboli occurs in only a small percentage of cases. We suggest that surgeons include the possibility of tumor emboli in the differential diagnosis for mesenteric or peripheral ischemia that cannot be attributed to more common causes.

Bile duct carcinoma and biliary tract dysplasia in chronic ulcerative colitis.

A case of chronic ulcerative colitis with a moderately differentiated adenocarcinoma of the common hepatic duct is described. Throughout the entire biliary tree, there was extensive epithelial dysplasia associated with changes of primary sclerosing cholangitis. The development of primary sclerosing cholangitis in the biliary tract of patients with ulcerative colitis appears to precede dysplasia and may be a marker of patients at risk for developing biliary tract carcinomas.

Response to steroids in Budd-Chiari syndrome caused by idiopathic granulomatous venulitis.

A 31-yr-old man presented with the Budd-Chiari syndrome. A liver biopsy specimen demonstrated noncaseating centrilobular granulomas and an idiopathic necrotizing granulomatous venulitis involving hepatic vein radicles with superimposed thrombotic occlusion. High-dose prednisone therapy produced dramatic clinical improvement with resolution of the hepatomegaly, ascites, and portal hypertension and normalization of the hepatic venous angiogram. A repeat liver biopsy specimen showed resolution of the venulitis and disappearance of the hepatic vein thrombosis. Idiopathic granulomatous venulitis that is reversible with prednisone therapy should be considered in the differential diagnosis of the Budd-Chiari syndrome.

Isotretinoin-associated proctosigmoiditis.

A 17-yr-old boy developed acute proctosigmoiditis after the institution of isotretinoin for the treatment of cystic acne vulgaris. Painless diarrhea, accompanied by mucus and eventually blood, began within days of commencing treatment and persisted while the drug was administered. At sigmoidoscopy patchy mucosal inflammation associated with numerous discrete aphthous ulcers was seen, apparently restricted to the rectosigmoid. Histologic examination of the affected mucosa revealed an acute focal superficial inflammatory infiltrate. Withdrawal of the drug resulted in prompt resolution of symptoms and a reduction in the severity of the inflammation. Rechallenge with isotretinoin induced a second, almost identical, attack of proctosigmoiditis. Withdrawal was again followed by disappearance of symptoms, and a subsequent sigmoidoscopy and mucosal biopsy were normal. The patient has remained clinically well for 16 mo after his initial presentation. Although the pathogenesis of the colonic mucosal inflammation remains unknown, the relationship of the bouts of proctosigmoiditis to the administration of isotretinoin strongly suggests that the drug was directly responsible.

Delayed intestinal perforation after nonpenetrating abdominal trauma.

The incidence of hollow-organ injury has increased steadily since the use of seat-belts was introduced. It has become apparent that the clinical manifestations of intestinal injury may be delayed considerably. Delayed perforations can pose a diagnostic challenge to the attending surgeon. The authors report four patients who suffered delayed intestinal perforation 6 or more days after sustaining nonpenetrating abdominal trauma in motor vehicle accidents while wearing passive seat-belt restraints. All patients had low severity of injury (scores ranging from 4 to 13) but had persistent vague abdominal pain before perforation occurred. Three of the four patients suffered spinal trauma as their major initial injury. Such patients appear to be at higher risk for delayed perforation and should be monitored carefully.

Indwelling cardiac catheters. An autopsy study of associated endocardial lesions.

An autopsy study was carried out to assess the relationship between indwelling intracardiac catheters and hemorrhagic, thrombotic, and infective lesions of the right heart endocardium and valve. Intracardiac catheters cause such lesions frequently, with a spectrum from uncomplicated valvular hemorrhage through nonbacterial thrombotic endocarditis to infective endocarditis. Pulmonary emboli were associated with the thrombotic, infective lesions. Endocardial lesions are more commonly seen with Swan-Ganz (SG) catheters; with these, lesions are more common and severe, with longer periods of catheterization. Pulmonic-valve lesions were only seen with SG catheters. However, not all hemorrhagic lesions in the right heart endocardium were associated with catheters, because a few inpatients without catheters had small subendocardial valvular hemorrhages; the cause of these hemorrhages is obscure because they were not seen in the hearts of patients who died outside the hospital.

Actinomycosis complicating Crohn's disease.

A case of secondary infection of Crohn's disease by Actinomyces is reported. Clinically, Crohn's disease and actinomycosis may be difficult to differentiate. The distinguishing histopathological features of secondary actinomycosis include multiloculated abscesses, sulfur granules, typical organisms seen with Gram stain, and rarely, necrotizing granulomata. As actinomycosis may be cured by surgery and/or antibiotics, a careful search for Actinomyces including anaerobic culture is recommended in Crohn's disease with abscess formation.

Immunohistochemical evaluation of prostatic carcinoma before and after radiotherapy.

Immunohistochemical procedures were applied to the examination of human tissues for prostatic acid phosphatase. With antisera against purified human prostatic acid phosphatase 173 normal and neoplastic tissues were tested. Samples of 45 non-prostatic carcinomas and their respective normal tissues were negative. Of 4 seminal vesicles studied 2 showed weak reactivity. The epithelial cells of normal prostatic acini were uniformly positive in 25 patients studied. In contrast to normal prostatic tissue the malignant acini in 53 of 55 patients with prostatic carcinoma had variable but positive reactivity. Of 27 patients receiving radiotherapy for adenocarcinoma of the prostate variable staining was observed in the neoplastic cells of 24, 8 to 52 months after treatment. The continued production of prostatic acid phosphatase in the malignant cells after radiotherapy suggests that they also may maintain metabolic activities necessary for growth and metastasis.

Distribution of storage iron as body stores expand in patients with hemochromatosis.

The relative distribution of storage iron between bone marrow and liver has not been adequately studied in patients with iron-loading disorders. To help clarify this we assessed iron metabolism in patients with iron overload and in control subjects with cirrhosis but no excess body iron. In 4 patients with advanced iron overload studied late in the course of their illness, excess hemosiderin was present in both bone marrow and liver, as expected. In contrast, 2 patients with idiopathic hemochromatosis whose excess iron had been depleted by phlebotomy subsequently developed progressive hepatic parenchymal and reticuloendothelial (RE) deposition of iron, yet marrow hemosiderin remained sparse. Moreover, surface radioactivity over the liver after an oral dose of 59Fe. These results suggest that during the initial stages of hemochromatosis there is a dissociation in the rate of iron accumulation between the bone marrow and liver. Excess hemosiderin appears to be deposited predominantly and preferentially in hepatic storage sites until the later stages of the disease.

A demonstration of several deoxyribonuclease activities in mammalian cell mitochondria.

Extracts of purified mitochondria from adult rabbit liver and kidney have been prepared by lysis with Triton X-100. Such extracts contain deoxyribonuclease activity demonstrable at alkaline pH. Studies utilizing the effects of substrate variation, differing ionic strength, nucleoside di- and triphosphates, and SH-group inhibitors reveal the existence of at least five distinguishable deoxyribonuclease activities in these extracts. Assay of lysosomal and mitochondrial enzyme markers indicates no significant lysosomal contamination of the mitochondrial extracts. Further studies also suggest that the alkaline deoxyribonuclease activity is specifically located in or in association with mitochondria.