Segmental Arterial Mediolysis in Pigs Presenting With Renal Infarcts.

Segmental arterial mediolysis, a rare arteriopathy first reported in humans, is described in the kidneys of 36 pigs slaughtered in an abattoir in Jutland, Denmark. The kidney changes presented themselves macroscopically as one or more cortical wedge-shaped hemorrhagic or pale lesions. The arterial lesions involved the interlobar and arcuate arteries and exhibited injurious and reparative phases of development. Two types of injurious lesions occurred: (1) a tearing separation of the outer media from the adventitia with fibrin, erythrocytes, and edema fluid filling the formed space, causing collapse of the arterial wall, and (2) outer and mid-medial foci showing irregularly bordered cytoplasmic vacuolar change containing membranous and organelle debris or smooth muscle shrinkage with nuclear loss. In the reparative phase, granulation tissue filled and expanded tear sites and zones of arterial medial muscle loss and extended into the adventitia and through the intima into the arterial lumen. Sequelae, including dissecting hematomas and arterial occlusions causing renal infarcts, were found. Although repartitioning agents widely used in animal husbandry in many countries may potentially cause segmental arterial mediolysis, no such link could be identified. The causation of segmental arterial mediolysis in these pigs is currently unknown but is being further investigated.

Myocardial toxicity in a group of greyhounds administered ractopamine.

Ractopamine, a synthetic ß(2)-adrenoceptor agonist, is widely used as a feed additive in the United States to promote a reduction in body fat and enhance muscle growth in cattle, pigs, and turkeys. It has the potential for illegal use in show and racing animals because it may affect performance via its ß-adrenergic agonist properties or anabolic activities. Nine greyhounds were orally administered 1 mg/kg of ractopamine to investigate the ability to detect the drug in urine. Postdosing, 7 of 9 dogs developed cardiac arrhythmias and had elevated troponin levels indicating myocardial damage. One dog necropsied 4 days postdosing had massive myocardial necrosis, mild to focally moderate skeletal muscle necrosis, and widespread segmental arterial mediolysis. A second dog necropsied 17 days postdosing had mild myocardial necrosis and fibrosis. Scattered arteries exhibited segmental medial and perimedial fibromuscular dysplasia. This is the first reported case of arterial, cardiac, and skeletal muscle damage associated with ractopamine.

T cell subsets, epitope mapping, and HLA-restriction in patients with allergic bronchopulmonary aspergillosis.

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity lung disease characterized by Aspergillus fumigatus (Af) colonization, IgE and IgG anti-Af antibodies, pulmonary infiltrates, bronchiectasis, and pulmonary fibrosis. Little is known regarding T cell responses and their role in the pathogenesis of ABPA. To examine T cell reactivity to Af antigens, T cell clones (TCC) specific to the Asp f 1 antigen, an 18-kD protein of Af, were established from the peripheral blood of three ABPA patients. The majority of TCC isolated from ABPA patients, and specific for the Asp f 1 allergen of Af, are IL-4 producing CD4+ cells of the Th2 phenotype. Further analysis in this study revealed that the majority of TCC reacted to mainly two epitopes of Asp f 1, while the remaining TCC reacted to three additional "minor" epitopes. Blocking studies using monoclonal antibodies specific for class II HLA-D region gene products showed that most TCC, 19/21, were restricted by HLA-DR molecules, and the remaining two clones by HLA-DP molecules. The use of a panel of HLA-matched and mismatched EBV-transformed B cells as antigen presenting cells revealed that the HLA-DR restriction was mediated exclusively by either the HLA-DR2 or HLA-DR5 alleles. Genotyping of DRB1 gene products showed that class II presentation for most clones was not restricted to a single allele, representing DRB1 gene products of either HLA-DR2 or DR5. These studies offer insight into the cellular and molecular determinants which contribute to the immunopathophysiology of ABPA.

Metabolism and fate of neutral lipids of fetal lung fibroblast origin.

Fetal rat lung fibroblasts characteristically increase their triacylglycerol (TG) stores during development. Both fibroblasts and alveolar type II (TII) cells can synthesize TG de novo, but only fibroblasts can absorb TG from culture medium, and retain the TG in a stable state. When fibroblasts pre-labelled with [3H]triolein are recombined with TII cells in organotypic culture the radiolabel appears in TII cell disaturated phosphatidylcholine (disatPC). When fibroblasts are preloaded with increasing amounts of TG there is a commensurate increase in TII cell disatPC following organotypic culture. Comparison of [3H]triacylglycerol and [14C]glucose incorporation into type II cell phospholipids revealed preferential use of TG for the surface-active phospholipids disatPC (10-fold greater) and phosphatidylglycerol (23-fold greater). These in vitro data suggest that fibroblasts provide lipid substrate for TII cell surfactant phospholipid synthesis.

The Jewish Hospital of St Louis Therapeutic Grand Rounds No. 14. Hypersensitivity pneumonitis.

Two examples of immunologically mediated diseases of the lung have been discussed. The first, extrinsic allergic alveolitis, is caused by sensitivity to inhalation of an organic dust. It is largely a restrictive type of lung disease and is probably caused by a combination of type 3 and type 4 allergic reactions. The second disease, allergic bronchopulmonary aspergillosis, is caused by a type 1 and type 3 allergic response to Aspergillus antigen in a basically atopic, generally asthmatic individual. It is vital to keep the diagnostic index of suspicion high so as to recognize these diseases early enough to prevent irreparable tissue damage. Extrinsic allergic alveolitis may masquerade as idopathic pulmonary fibrosis or Hamman-Rich syndrome. Allergic aspergillosis may be called Loeffler pneumonia or PIE syndrome (pulmonary infiltrates with eosiniphilia). Failure to diagnose properly may result in extensive pulmonary fibrosis or bronchiectasis and condemn the patient to a lifetime as a pulmonary cripple.

A fatal case of theophylline intoxication.

A fatal case of theophylline intoxication is presented in which a number of factors leading to a decrease in theophylline clearance and the patient's death were possibly operative. These included advanced age, chronic lung disease, liver disease, and administration of cimetidine. Since early symptoms of the toxic effects of theophylline can mimic peptic ulcer disease, cimetidine might be prescribed for the gastrointestinal symptoms with subsequent worsening of theophylline poisoning. Theophylline plasma concentration should be determined whenever drugs affecting theophylline clearance are administered simultaneously.

Late generalized tuberculosis: a clinical pathologic analysis and comparison of 100 cases in the preantibiotic and antibiotic eras.

1. The clinical and pathologic findings in 100 patients with late generalized tuberculosis (LGT) are described and a comparison made between the findings occurring in the preantibiotic era with those in the early antibiotic period. The clinical presentation of LGT as seen in a general hospital has changed. Whereas, in the preantibiotic era, LGT was often the primary disease, occurring principally in young adults and frequently associated with pulmonary symptoms, in the antibiotic era, LGT commonly occurred together with and was frequently obscured by other diseases, often afflicted the elderly and was much less frequently accompanied by pulmonary symptoms. Symptoms related to extrapulmonary organ tuberculosis in this era were absent in 30% of patients. 2. Diagnostic difficulties in LGT arose because 20% of patients exhibited no constitutional symptoms prior to hospitalization, a history of tuberculosis often was lacking, fever curves and hematologic findings, with the exception of a left shift, commonly were non-specific, monocytosis frequently was absent, chest x-rays were non-diagnostic in about 50% of the cases, and anergy occured particularly in the elderly. 3. Caseous foci responsible for hematogenous spread generally derived from reactivated old caseous lesions located principally in the lungs, lymph nodes, bone, central nervous system, adrenals, and genito-urinary tract. Simultaneous reactivation of anatomically unrelated foci in multiple organs and lymph nodes occurred in 54% of cases. Although chronic pulmonary tuberculosis commonly was associated with LGT in the preantibiotic era, this association was uncommon in recent times. Chronic pulmonary tuberculosis served as the sole source for hematogenous dissemination infrequently and the pulmonary lesions responsible were acute. 5. Large caseous foci located in lymph nodes, bone, prostate gland, and central nervous system frequently occurred in the absence of clinical symptoms and therefore were undiagnosable. 6. The clinical course of LGT was often rapid, although histologic features indicated that the course in some patients was protracted or even episodic. 7. Miliary tubercles very frequently showed caseation and often they enlarged to cause progressive or complicated lesions. Chest x-rays and culture diagnoses were dependent on the formation of these complicated lesions. 8. Liver biopsy is recommended as a diagnostic procedure since 97% of patients exhibited granulomata in this organ. Of diagnostic importance is the fact that 90% of these granulomata exhibited caseous necrosis. Twenty-two percent of patients with liver granulomatas did not show tubercles in the bone marrow. 9. Multiple pathways rather than an exlcusive lymphangitic route were available for tubercle bacilli to gain access to the blood stream and cause hematogenous dissemination.

Segmental mediolytic arteritis. A clinicopathologic and ultrastructural study of two cases.

We describe the histopathologic and ultrastructural changes in two cases of segmental mediolytic arteritis (SMA) and summarize the clinical and pathologic findings in previous reports. SMA is initiated by the transformation of the arterial smooth-muscle cytoplasmic contents into a maze of dilated vacuoles containing edema-like fluid. With vacuolar rupture, the smooth-muscle cells are disrupted and the mediolytic process completed. Mediolysis is accompanied by fibrin deposition and hemorrhages at the adventitio-medial junction and within the media. Inflammation is inconstant and limited to the periadventitial tissues. Transmural mediolysis leads to the formation of arterial wall gaps--defects in the vascular wall bridged by a serofibrinous layer. The serosal and intramural arteries and arterioles of the jejunum and the epicardial coronary arteries were the targets of SMA in this report. SMA occurs in two clinical settings: (a) in abdominal muscular arteries and arterioles of predominantly elderly patients presenting either with ischemic bowel disease or shock, and (b) in the coronary arteries of neonates in conditions associated with severe hypoxemia. We conclude that SMA is the result of an inappropriate vasospastic response expressed in a splanchnic vascular bed undergoing vasoconstriction as a response to shock or severe hypoxemia.

Pathology of the lung in Behçet's disease. Case report and review of the literature.

Histopathologic changes in the lung in a patient with Behçet's disease are described and the literature dealing with pulmonary pathologic changes in this disease is summarized. The basic lesion is a lymphocytic and necrotizing vasculitis involving all sized pulmonary arteries, veins and septal capillaries. Complications include aneurysms of elastic pulmonary arteries, arterial and venous thromboses, pulmonary infarcts, and bronchial erosion by pulmonary artery aneurysms. Striking periadventitial fibrosis develops and is believed to be related to repetitive vascular inflammatory insults. Peculiar newly formed collateral vessels, lacking elastic lamellae and derived from smooth muscle metaplasia around arterioles, are found in the periadventitial fibrous tissues around thrombosed arteries and aneurysms. Cases of pulmonary artery aneurysms of obscure origin, including those found in the Hughes-Stoven syndrome, are reviewed and both clinical and pathologic findings in these reports are found to be remarkably similar to those observed in Behçet's disease. It is suggested that such cases represent unrecognized or incomplete expressions of Behçet's disease.

Locally aggressive granular cell tumor causing priapism of the crus of the clitoris. A light and ultrastructural study, with observations concerning the pathogenesis of fibrosis of the corpus cavernosum in priapism.

A case of focal priapism of the clitoris caused by a microscopic granular cell tumor (GCT) is described. This neoplasm is considered locally aggressive because it invades the lumens of peripheral cavernous sinuses of the crus of the clitoris. Caverns adjacent to those invaded by tumor exhibit stasis, telangiectasia, and necrosis of the smooth muscle of the trabecular wall. These alterations lead to telescoping collapse and compression of the cavernous spaces and culminate in fibrosis. Ultrastructurally, replicated basal lamina is found surrounding clusters of granular cells. We suspect that the multilayered lamina, in addition to being produced by tumor cells, is derived from the trabecular endothelium surrounding the caverns invaded by the GCT. The replication of the basal lamina may be provoked by cycles of injury and repair to these vessels caused by repeated episodes of prolonged vascular stasis. A peculiar large vein with perforating branches was observed in the center of the cavernous spaces of the crus. This vein is not found in normal crura and, therefore, represents a morphologic adaptation created to drain the cavernous spaces.

Familial tumoral calcinosis. A clinical, histopathologic, and ultrastructural study with an analysis of its calcifying process and pathogenesis.

We describe histopathologic and ultrastructural changes in tumoral calcinosis (TC) occurring in seven siblings from a single family. Tumoral calcinosis appears to be triggered by bleeding followed by aggregation of foamy histiocytes. These in turn are transformed, with participation of collagenolysis, into cystic cavities lined by osteoclast-like giant cells and histiocytes--the lesion resembling adventitious bursae. Movement and friction, forces generated from the periarticular location of the TC lesions, putatively are key to this transformation. Concomitantly, two calcifying events develop, possibly driven by concurrent hyperphosphatemia or endogenous hypervitaminosis D. One occurs on membranous fragments in antiprotease-containing large cytoplasmic vesicles within osteoclast-like giant cells and mononuclear cells lining the TC cavities; the second, in the TC locules on membranous and cellular debris derived from cavity-lining cells and erythrocytes. The TC cavities ultimately fill with calcified material, losing their synovial-like lining, become encapsulated by fibrous tissue, and ossify. Hydroxyapatite may gain entrance to capillary lumens and embolize to the lung. We conclude that TC represents a disordered reparative process that often is exaggerated because episodes of bleeding, caused by TC-induced vascular injury, provoke development of new lesions. The capricious response of TC to treatment is correlated with its morphologic features.

Characterization of bovine surfactant for infants with respiratory distress syndrome.

Exogenous surfactant treatment of surfactant-deficient disease states is now under study in a number of centers, using a variety of surfactant preparations. We have chosen one preparation because of its current and potential clinical usefulness, and we have characterized it using selected tests and assays that we thought would be necessary (although not necessarily sufficient) to justify extended clinical use. We found its lipid composition to resemble that of other surfactants derived from lung mince. There is little variation among several batches with regard to lipid composition or surface tension-lowering capability. Morphologic heterogeneity occurs in individual samples of pelleted material studied by electron microscopy. Arterial oxygenation is improved when the material is administered to animals depleted of surfactant. A low molecular weight protein was identified that reacted with antibody that specifically binds nonserum surfactant proteins in a number of animal species (including human and cow). The characteristics of this surfactant preparation should be useful for comparison as newer and simpler products become available.

Aberrant commissural positioning, hooding, and thrombotic occlusion of right and left coronary ostia in the left sinus of valsalva associated with small coronary arteries: a newly described anomaly and a cause of sudden death in an adolescent.

Reported is a triad of coronary artery anomalies associated with sudden and unexpected death in an adolescent occurring 10 hours after elective surgery. The abnormalities consisted of (1) the anomalous origins of both left and right coronary orifices in the left sinus of Valsalva, behind and through the commissure; (2) formation of a triangular septum between the upper portion of the commissure and the aorta, delineating a cul-de-sac which partially surrounded the coronary ostia; (3) small proximal coronary arteries. Development of a thrombus, putatively elicited by turbulence in the cul-de-sac, acted as a flutter valve to occlude both coronary ostia causing extensive acute myocardial infarction.

Endometriosis-associated intestinal tumors: a clinical and pathological study of 6 cases with a review of the literature.

This clinicopathologic study of primary Mullerian tumors of the bowel arising in foci of endometriosis is based on six new cases and an analysis of 17 previously reported cases. Varieties of Mullerian tumors occur in the bowel; the most common types are endometrioid carcinoma, followed by various mixed Mullerian tumors and stromal sarcomas. Seventy-eight percent develop in the rectosigmoid colon, the remaining in the cecum or ileum. Those in the latter area tend to be sarcomas or mixed Mullerian tumors. Certain architectural growth characteristics, derived from precursor endometriosis, are common to most endometriosis-associated intestinal tumors (EAITs). Seventy percent of EAITs occur in the outer bowel wall. Transmural tumors tend to form luminal polyps and assume an hourglass shape. Metachronous or synchronous Mullerian tumors occur in 39% of cases. Seventy percent of women with EAITs are in their mid 30s to early 50s. Common presenting symptoms are abdominal or pelvic pain, melena, and an abdominal or pelvic mass. Documented in 26% of patients is a history of prolonged unopposed estrogen therapy. Only 28.5% of cases die of their tumors, but follow-up is less than 5 years in all but 2 patients.

Ectopic gastrinoma and Zollinger-Ellison syndrome.

In Zollinger-Ellison syndrome (ZES), the discovery of gastrinomas in unusual locations, such as a lymph node, poses a diagnostic problem centered on whether the neoplasm is primary or metastatic. The clinical, gross, microscopic, immunocytochemical, and ultrastructural features of ectopic gastrinomas were studied in four patients with ZES, and reports of 14 similar cases were reviewed. These extragastroenteropancreatic (EGEP) gastrinomas have many of the morphologic features of gastrinomas in conventional locations. However, the centrifugal expansile growth pattern, characterized by a thick fibrous capsule, hyalinized fibrous septa, and, frequently, cystic degenerative changes in EGEP gastrinomas should alert the pathologist to the probability that these neoplasms are primary. Additional evidence for the primary nature of these EGEP gastrinomas is derived from the postoperative normalization of high serum gastrin levels and the correction of the abnormal gastrin response to secretin challenge or to calcium infusion tests. Increased awareness of the occurrence and features of these EGEP gastrinomas is crucial for both pathologists and surgeons to ensure proper evaluation and treatment of patients with ZES.

Pathology of high dose intermittent cyclophosphamide therapy.

Pathologic changes induced by high dose intermittent cyclophosphamide therapy are described in 39 patients with solid tumors, lymphohematopoietic malignant disease, and bone marrow transplants. Patients receiving 50 to 120 mg. per kg. daily for one to four days showed transmural bladder injury affecting all component tissue; toxic vasculitis involving small arteries, capillaries, and venules; and interstitial, myocardial, and vascular changes in the heart. Myocardial necrosis with heart failure was the dose limiting factor of very high dose therapy. Patients receiving 15 to 30 mg. per kg. for four days showed variable degrees of bladder injury limited to the mucosa and lamina propria and vascular changes consisting only of telangiectasia. Both groups showed atypia of transitional urinary and esophageal epithelia as well as of mesenchymal cells in the lamina propria of the bladder, persistent and total ablation of spermatogenesis, and long lasting absence of ovarian follicular maturation. Bone marrow hypoplasia and lymphoid depletion developing after cyclophosphamide therapy completely disappeared an average of 3.5 weeks after the last dose.

Lead arthritis and lead poisoning following bullet wounds: a clinicopathologic, ultrastructural, and microanalytic study of two cases.

Bullet wounds causing lead synovitis in the wrist and knee are reported in two patients, one of whom also developed clinical plumbism. Very high lead levels in the synovial fluid are believed to be responsible for toxicity changes that occurred in the synovium and bone. Ultrastructurally, these alterations included the formation of nuclear lead inclusions, dilation, and degranulation of the rough endoplasmic reticulum and deposition of crystalline precipitates in the matrix of the mitochondria in macrophages, osteoclasts, and synoviocytes, as well as the development of cytoplasmic lead inclusions in osteoclasts. Energy-dispersive x-ray elemental analysis (EDXEA) indicated that the nuclear inclusions contained only lead, whereas precipitates within the mitochondria and elsewhere in the cytoplasm were composed of complexes containing lead, calcium, and phosphorus. Similarly constituted extracellular complexes were incorporated into newly formed trabecular bone laid down as a physiologic response to the bullet lodged within the wrist bones. This bone subsequently exhibited defects in bone resorption, which were characterized by depressed osteoclastic function and a unique lesion termed incomplete osteocytic osteolysis. The genesis of this latter lesion is uncertain. The sequestration of the partially degraded bone fragments containing lead complexes into the marrow and eventually into the joint spaces and synovium permitted the recycling of bone lead, and this may have played an important role in inducing clinical plumbism in one of the patients in this study.

Extrapulmonary silicosis: a clinical, morphologic, and ultrastructural study.

A variety of silicotic lesions derived from thoracic silicosis via lymphohematogenous spread to the liver, spleen, bone marrow, and extrathoracic lymph nodes are described. The morphologic features of these lesions depend on the extent of macrophage aggregation, the occurrence of fibrogenesis, and the development of necrosis and degradative changes in macrophages and adjacent extracellular matrix, presumably caused by lysosomal enzymes released from macrophages. Ultrastructurally, the degenerative alterations of matrix material include longitudinal splitting and breakage of collagen fibrils into segments one and three quarters the length of the original fibrils and deposition of flocculent electron-dense material either focally or diffusely around collagen fibrils. The corresponding changes viewed light microscopically are those of fibrinoid necrosis. The sclerohyaline nodule, the characteristic lesion of silicosis, includes all of these features as it evolves through nodular histiocytic and subsequent fibrohistiocytic phases. Its ultimate morphology appears to be determined by the reassembly of the degraded matrix into non-native, fibrous long-spacing collagen via a spiny collagen intermediary. The sclerohyaline nodule occurs infrequently in the spleen and liver, although less typical lesions caused by silica alone or admixed with other dusts seem to occur more commonly in these organs. These lesions appeared as loose or nodular histiocytic or fibrohistiocytic aggregates. Nonspecific fibrous nodules or more extensive fibrosis, as seen in portal triads, may represent advanced stages of such lesions. Acute or healed focal segmental glomerulonephritis occurred in 40 per cent of the cases, suggesting that it may be an important remote effect of silicosis. Continuous destruction of lymphocytes adjacent to silicotic nodules may be an antigenic source of the high concentration of autoimmune reactants described in silicosis.

Best evidence synthesis: an intelligent alternative to meta-analysis.

Research review has long been one of the most important scholarly activities in all branches of science. While there is sometimes a single study so well-designed, well carried out, and difficult to replicate that its findings are accepted as conclusive, more often there are many studies on a given topic, no one of which clearly supersedes the others. These studies may be done by different investigators using different methods or different populations. They may arrive at different conclusions. When this is the case, there is a need for reviewers to carefully consider the evidence and to put forth conclusions or hypotheses about where the weight of the evidence lies.

Passive smoking. Effects on bronchial asthma.

Ten patients with bronchial asthma and ten control subjects were exposed to sidestream cigarette smoke (passive smoking) for one hour in an environmental chamber. All subjects showed the same increase in carboxyhemoglobin as a result of the exposure: 0.40 percent. The asthmatic group demonstrated a significant linear decrease in pulmonary function during this exposure. After one hour of smoke, FEV1 decreased 21.4 percent, FEF25-75% decreased 19.2 percent, and FVC decreased 20.0 percent in the asthmatic patients. These alterations were readily reversible in all subjects when given inhalations of metaproterenol following the exposure. The control subjects showed no change in pulmonary function when exposed to identical conditions. These data show that nonsmokers with bronchial asthma are at risk when exposed to sidestream cigarette smoke in an environmental chamber.