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Cholesterol granulomas are uncommon pathologic lesions in animals, although they are important intracranial tumors in humans. This report describes cholesterol granulomas associated with multiple organ systems of three captive meerkats. In the most severe case, meerkat No. 1, the pathologic behavior of the cholesterol granuloma was unique in that it appeared to locally invade the cerebrum and calvarium, possibly contributing to neurological deficits observed antemortem. A review of other meerkat necropsies revealed incidental, asymptomatic cholesterol granulomas in organs of two other individuals, meerkat Nos. 2 and 3. Histologically, all lesions were composed of cholesterol clefts admixed with large, foamy macrophages containing hemosiderin, multinucleated giant cells, lymphocytes, plasma cells, and foci of mineralization. Hypercholesterolemia was documented in two of the three meerkats.

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Arthritis is often associated with intestinal diseases, but the etiology is not known. We developed a rat model whereby arthritis was reactivated by experimental small bowel bacterial overgrowth (SBBO). Self-limited monoarticular arthritis was induced by intra-articular injection of 2 micrograms of rhamnose peptidoglycan-polysaccharide derived from group A streptococci into the ankle joints in female Lewis rats. Eleven days after intra-articular injection, when swelling was resolving, experimental SBBO induced by surgical creation of jejunal self-filling blind loops reactivated arthritis, but SBBO induced by creation of self-emptying blind loops, which minimally increases luminal bacteria, and sham operation did not (P < 0.001). Increased joint diameters in rats with self-filling blind loops persisted for at least 56 days after surgery. Reactivation of arthritis due to SBBO was prevented by anti-tumor necrosis factor alpha antiserum and interleukin 1 receptor antagonist (P < 0.001), indicating that these cytokines mediate joint swelling secondary to intestinal injury. Recombinant bactericidal/permeability-increasing protein, an agent which neutralizes endotoxin, and metronidazole, which is active against anaerobic bacteria, prevented arthritis (P < 0.001), but polymyxin B (which also neutralizes endotoxin) and gentamicin had no effect. Mutanolysin, an enzyme which degrades peptidoglycan-polysaccharide from group A streptococci, exacerbated arthritis for the first 6 days but then diminished joint swelling from 12 to 21 days after surgery (P < 0.001). These studies introduce a reproducible animal model of reactivation of arthritis secondary to intestinal injury and demonstrate a role for bacterial products from endogenous enteric organisms.

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After previous observation of increased susceptibility to Clostridium difficile enterocolitis in hamsters fed an atherogenic, high-fat diet, a study was undertaken to examine experimental reproducibility of this disease. Hamsters were fed either the high-fat diet or a control diet, then orally challenged with a toxigenic strain of C. difficile. Hamsters fed the high-fat diet suffered 80% morbidity, which was statistically significant from the 11% morbidity of the control diet group (P < or = 0.05). The disease presented acutely, the most common presentation being sudden death. The most common lesions in the affected hamsters were necrohemorrhagic cecitis and cecal mucosal hyperplasia. Hepatic lipidosis was consistent in all hamsters fed the high-fat diet. Toxigenic C. difficile could be recovered from the cecum of most affected hamsters, and toxins A and B were detected in these ceca. Hamsters that were fed the high-fat diet and orally inoculated with a nontoxigenic strain of C. difficile before experimental challenge with a toxigenic strain were initially protected against disease. The protection decreased with each exposure to the toxigenic strain. Results of in vitro colonization-resistance studies indicated that the cecal flora from hamsters fed the high-fat diet and control diets inhibited C. difficile growth, suggesting that increased disease susceptibility was not the result of altered cecal flora.

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A case of adenocarcinoma of the pancreas and mild lung disease in a 39-year-old man homozygous for the delta F508 cystic fibrosis mutation is presented. Cystic fibrosis is the most common lethal genetic disease in Caucasians, and is most commonly associated with severe obstructive lung disease. To our knowledge, this is only the fifth case of adenocarcinoma of the pancreas in a CF patient to be reported and the first case for which molecular data are available. The rare incidence of this type of malignancy in the general population suggests a possible association of CF with this malignant disease.

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A specific interleukin-1 (IL-1) receptor antagonist (IL-1ra) was used to examine the roles of IL-1 in an experimental model designed to analyze the reactivation phase of erosive arthritis, induced in rats with peptidoglycan-polysaccharide polymers (PG-APS) isolated from cell walls of group A streptococci. Monoarticular arthritis was initiated by injection of a small dose of PG-APS into an ankle joint, and reactivation was induced by intravenous injection of PG-APS 20 days later. Human recombinant IL-1ra given at a dose of 2 to 3 mg/kg at the time of reactivation of arthritis and at 6-h intervals inhibits the increase in joint swelling by at least 60%. Joint swelling is suppressed 30 to 50% when the initial treatment with IL-1ra is delayed until 6 h after reactivation. IL-1ra is not effective when the initial injection is delayed 12 or 24 h. With an injection schedule of IL-1ra given at the time of reactivation and every 6 h, treatment can be stopped at 24 h and the suppression of swelling is no different from that in rats for which injections are continued for 4 days. The results indicate that IL-1 has a prominent, although not exclusive, role in initiating inflammation in this model and is involved in the amplifying processes in progressive inflammation and chronic erosive disease. An anti-inflammatory function of IL-1 is also indicated from data showing that IL-1ra treatment limited to 6 h or less after the induction of reactivation enhances joint swelling, whereas intravenous injection of human recombinant IL-1 beta 24 h before reactivation suppresses the reactivation of arthritis.

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While acute splenic sequestration and splenic infarction are commonly observed in infants and young children with sickle cell anemia, they are rarely experienced by adult hemoglobin S homozygotes because the recurrent splenic infarction that takes place during childhood is typically followed by scarring, atrophy, and splenic fibrosis. Both acute splenic sequestration and splenic infarction do remain relatively common in adults with the other sickle hemoglobinopathies. These episodes are almost certainly a consequence of the persistently enlarged and distensible spleens that often remain present in these conditions. In this report, the authors describe two adult patients with hemoglobin SC disease: one who developed acute splenic sequestration and one with splenic infarction. In neither case was there a history of recent air travel or exposure to altitude. The clinical course of these two syndromes is presented, and the hematologic, radiologic, and pathologic manifestations are discussed. Because they can sometimes be difficult to distinguish from one another, and because a failure to identify acute splenic sequestration can be catastrophic, these two entities must be included in the differential diagnosis for any hemoglobin SC patient who present with an unexplained fall in hemoglobin, left upper quadrant pain, unexplained fever, or symptomatic splenomegaly.

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Acute edematous responses were induced in Sprague-Dawley rats by the intravenous injection of group-specific polysaccharide (PS) isolated from group A streptococci. Thirty minutes after the intravenous injection of PS there was marked degranulation of subcutaneous and periarticular mast cells in all 4 feet, carbon particle labeling of adjacent venules, and an 8-fold increase in Evans blue dye content of the extremities. This acute reaction to PS was completely blocked by pretreatment with compound 48/80, but the polyarticular relapsing arthritis following the systemic injection of an arthropathic dose of streptococcal cell wall fragments containing large, covalently bound peptidoglycan-polysaccharide (PG-PS) was not blocked.

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The arthropathic activity of mouse recombinant IL-1 (mrIL-1) after intraarticular (i.a.) injection into rat ankles was investigated. Nanogram quantities of either mrIL-1 alpha or mrIL-1 beta induced an acute transient arthritis. Arthritis induced by i.a. mrIL-1 developed more rapidly and was more severe in ankles previously injured by i.a. injection of group A streptococcal peptidoglycan-polysaccharide (PG-APS) fragments. In addition, a protracted pain response, as judged by severe limping, occurred 60 to 90 min after mrIL-1 injection into joints previously injured by PG-APS or 4 to 6 h after mrIL-1 injection into naive joints. The severity of arthritis was related to the mrIL-1 dose. Arthropathic activity of mrIL-1 alpha was neutralized by goat anti-mouse IL-1 alpha IgG, and the activity of both the alpha and beta preparations was heat labile. Repeated episodes of acute inflammation were induced by repeated i.a. injection of mrIL-1. In naive ankles this led to chronic synovitis without histologic evidence of erosions. However, in joints previously injured by PG-APS, repeated mrIL-1 injection induced a more severe chronic synovitis with a 50% incidence of early pannus formation and limited marginal erosions of cartilage and subchondral bone. Thus, mrIL-1 induces an acute exacerbation of arthritis in joints previously injured by PG-APS and repeated exposure of these joints to mrIL-1 promotes chronic erosive synovitis. These studies provide evidence for an in vivo function of IL-1 and are consistent with its role as one of the mediators in the local regulation of inflammation in recurrences of arthritis induced by bacterial cell wall polymers.

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Review of the hearts of seven patients in whom hypertrophic obstructive cardiomyopathy had been diagnosed by the usual clinical and morphologic criteria revealed diminished angles between the interventricular septa and ascending aortas in three cases. The angles in these three hearts were 90 to 110 degrees, as compared with a mean value of 145 degrees in the other four hearts with hypertrophic obstructive cardiomyopathy and 140 +/- 14 degrees in 55 control hearts. None of the patients with hypertrophic subaortic stenoses and angled aortic roots died of the heart disease, and none had either asymmetric ventricular hypertrophy or evidence of familial cardiomyopathy. It is proposed that in patients with angled aortic roots and left ventricular hypertrophy, subaortic obstruction may develop due to narrowing of the left ventricular outflow tract, resulting in clinical and morphologic findings of hypertrophic obstructive cardiomyopathy. In hearts with angled aortic roots the top of the ventricular septum is tipped toward the mitral valve, rather than tapered toward the aorta, as in normal hearts. This configuration narrows the outflow tract of the left ventricle and can result in systolic anterior motion of the mitral valve, the illusion of asymmetric septal hypertrophy when studied by M-mode echocardiography, a subaortic pressure gradient, and a subaortic endocardial plaque. This less serious form of hypertrophic subaortic stenosis should be distinguished from other forms of hypertrophic obstructive cardiomyopathy.

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Amiodarone is a potent new antiarrhythmic drug that has multiple effects on thyroid function, including inhibition of extrathyroidal triiodothyronine production and rarely, iodine-induced hypothyroidism. This report describes a man with recurrent ventricular tachycardia in whom hypothyroidism developed during amiodarone therapy and who died of probable myxedema coma. Parenteral and oral thyroxine therapy promptly reduced serum thyroid-stimulating hormone concentrations without increasing the patient's very low serum triiodothyronine concentration. This response to thyroxine suggests that thyroxine itself may have biologic activity and participate directly in regulation of thyrotropin secretion. Because amiodarone-induced hypothyroidism may be life-threatening, thyroid function should be monitored before and during amiodarone therapy, and the drug discontinued or appropriate therapy instituted if hypothyroidism develops.

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Although premature closure of the foramen ovale has been proposed as a possible cause of hypoplastic left heart syndrome, very few such cases have been described. We have seen two examples of the combination and no associated malformations. In both the foramen was firmly closed on its left atrial aspect and the dimensions of the left sided structures were well below normal values.

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The following clinical and pathologic features were evaluated in 170 patients with electron microscopically documented membranous glomerulopathy: age, sex, race, American Rheumatism Association lupus criteria, serum ANA, serum complement, glomerular hypercellularity, stage of subepithelial dense deposits, endothelial tubuloreticular inclusions, tubular basement membrane deposits, tissue ANA, glomerular deposition of IgG, IgM, IgA, C3, C4, and Clq. At the time of biopsy 148 patients had no clinical evidence for lupus, and 22 had a clinical diagnosis of lupus. Six additional patients eventually developed overt lupus after an average of 12 months. Incidences of serologic and pathologic features in lupus as compared with nonlupus membranous glomerulopathy were determined. These data were used to calculate sensitivity, specificity, positive and negative predictive values, and overall efficiency of each parameter in differentiating between lupus and nonlupus membranous glomerulopathy. In general, serologic, morphologic and immunohistopathologic features are more accurate at ruling out lupus than making the diagnosis of lupus. However, a number of features are significantly more frequent in lupus membranous glomerulopathy. Therefore, identification of these features, especially more than one, warrants a high suspicion of lupus rather than nonlupus membranous glomerulopathy even in patients without clinically overt systemic lupus erythematosus. The positive/negative predictive values of some of the pathologic features studied are as follows: mesangial dense deposits 63/99, subendothelial dense deposits 77/93, tubuloreticular inclusions 61/96, intense C1q deposition 47/95, tubular basement membrane deposits 100/87, and glomerular hypercelularity 26/86.

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The mechanism for syncope during pulmonary embolism is not well understood. We describe two patients with transient sinus bradycardia and atrioventricular (AV) block during syncope from recurrent pulmonary embolism. Consciousness was regained each time the rhythm returned to normal. We believe that the syncope and bradyarrhythmia was caused by a parasympathetic reflex, since simultaneous slowing of the sinus rate with concomitant AV block is a common manifestation of increased vagal tone. Such a reflex is consistent with known cardiac reflexes, may occur frequently, and may be one of the mechanisms for syncope in patients with pulmonary embolism.

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The clinical histories, risk factors, and autopsy findings were reviewed for five deceased hemophiliacs over the age of 40 years to determine the prevalence and severity of arteriosclerosis. The presence of a severe, congenital, hypocoagulative state did not prevent these five men from displaying typical arteriosclerotic vascular disease. One patient actually died of severe, multivessel, coronary artery disease.

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Chronic, remittent, erosive arthritis was produced in rats by a single intraperitoneal injection of an aqueous suspension of cell wall fragments isolated from group A streptococci. Arthritis could be induced in rats which had been immunologically compromised by neonatal thymectomy. Delayed hypersensitivity to cell wall peptidoglycan could not be elicited in these rats, although progressive joint disease was obvious by clinical and radiological measurements. A delayed skin test was elicited with peptidoglycan in non-thymectomized rats at 6 to 14 days after injection of low doses of cell wall fragments. Between 2 to 4 weeks after cell wall injection the skin test could not be elicited and these rats could not be sensitized again with peptidoglycan. After a high dose of cell wall the skin test could not be elicited at any time. These non-thymectomized rats which had been injected with cell walls remained hyporesponsive to peptidoglycan for at least 3 months. Lymphocytes from non-thymectomized cell wall-injected rats also showed a non-specific depression of lymphocyte response to phytohaemagglutinin in vitro, but this function was recovered between 2 to 4 weeks after cell wall injection. We conclude that cell-mediated immunity against bacterial cell wall antigens is not a pathogenetic factor in this experimental model of arthritis.

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The intraperitoneal injection of peptidoglycan-carbohydrate fragments from Group A streptococci produces a chronic, polyarticular, erosive synovitis in rats. The cell wall material accumulates rapidly in the liver, spleen, and lymph nodes, where it causes little injury. At the same time, selective localization and persistence of the material in the synovial and periarticular tissues occurs. Its presence in the joint is associated with acute and recurrent inflammation with focal synotivitis, pannus formation, joint destruction, and ankylosis. Cell wall fragments become localized in the synovial and periarticular tissues at a time when there are leukocytes in the bloodstream, which appear to contain the material. During this early phase vascular lesions appear in the synovium and in periarticular tissues with collections of fibrin, neutrophils, macrophages, and cell wall fragments near the venules and capillaries. Recurrent episodes of inflammation and joint injury, associated with persistent cell wall antigen within macrophages, were observed over a period of 90 days.

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A retrospective analysis of 12 patients with the diagnosis of thrombotic thrombocytopenic purpura was undertaken with a review of pathological material. The gingival biopsy was found to be a poor method of diagnosing thrombotic thrombocytopenic purpura. Pathological review also verified chronicity of disease. The pancreas was found to be the most severely involved organ, although serum amylase values did not always reflect pancreatic disease.

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