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.

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.

Opioids accelerate fetal rat lung maturation in vitro.

Infants born to heroin- and cocaine-addicted mothers have been reported to have a lower incidence of respiratory distress syndrome (RDS) compared with nonaddicted infants. However, it is not known whether these are direct drug-mediated effects or secondary phenomena. We therefore investigated the effect of opioids and cocaine on fetal rat lung maturation in vitro. Using 18- to 20-d fetal rat lung explants and 20-d fetal type II cells, we measured the effect of varying concentrations (1 x 10(-8) to 1 x 10(-3) M) of heroin, morphine, methadone, and the nonopioid cocaine on the rate of choline incorporation into phosphatidylcholine (PC) and disaturated PC. We also analyzed the morphology of 19-d explants after exposure to opioids. Significant increases in rate of choline incorporation were noted in 19- and 20-d explants using 1 x 10(-3) M heroin, 1 x 10(-3) M morphine, and 1 x 10(-4) M methadone (P < 0. 005). No acceleratory effect was seen with cocaine. Morphologic analysis of the three opioid-treated groups revealed a significant (192 to 251%) increase in type II pneumocytes and lamellar bodies per alveolar lining cell (P < 0.01). Choline incorporation into PC by type II cells was also significantly increased by opioids (P < 0. 01); lactate dehydrogenase release and cell viability were not affected by opioid treatment. These data indicate that high-dose opioids have an acceleratory effect on biochemical and morphologic parameters of fetal lung maturation in vitro. The lack of in vitro acceleration with cocaine suggests that any cocaine-related reduction in the incidence of RDS is a secondary effect.

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.

Segmental arterial mediolysis: a precursor to fibromuscular dysplasia?

We describe five cases of segmental arterial mediolysis (SAM), formerly known as segmental mediolytic arteritis. SAM occurs in epicardial coronary arteries and in the abdominal splanchnic arteries. Patients with abdominal SAM are generally elderly, whereas coronary SAM presents in neonates, children, and young adults. SAM is initiated by mediolysis of the outer media, which can expand to involve the mid- and inner media. Accompanying alterations include fibrinous linear deposits at the medial adventitial junction and replacement of the lysed muscle fibers by fibrin, erythrocytes, and granulation tissue. Transmural mediolysis results in arterial wall gaps frequently complicated by dissecting hematomas and aneurysms. Abdominal hemorrhages stem from these complications. SAM involving abdominal splanchnic arteries clinically presents with abdominal pain and distension, falling hematocrit, and shock. Simultaneous involvement of more than one abdominal artery is frequent, and branches of the celiac axis are most commonly affected. Various disease states that provoke pathologic stimuli for endothelial mediated vasoconstriction occur in the immediate clinical background of patients with SAM. Certain morphologic features of SAM suggest that this arterial lesion is due to vasospasm, which we putatively ascribe to focal endothelial paracrine dysfunction. Organization of uncomplicated SAM lesions could resemble certain types of fibromuscular dysplasia, suggesting that the genesis of such arterial lesions is related to vasospasm.

Cardiac angiosarcoma arising in a coronary artery: angiographic and pathologic findings.

We discuss a unique case of an angiosarcoma which arose in an atherosclerotic coronary artery. It was widely metastatic. We describe the angiographic findings and their differential diagnosis, and briefly discuss this relatively common cardiac malignancy.

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.

Culture of a prostatic cell line in basement membrane gels results in an enhancement of malignant properties and constitutive alterations in gene expression.

Interaction of a transformed rat prostate epithelial cell (NbMC-2) with basement membrane gels (Matrigel) has been evaluated using a long-term matrix culture system. NbMC-2 cells, and single-cell clonal derivatives, formed spheroidal multicellular structures (aggregates) on Matrigel surfaces and were weakly invasive or noninvasive during a 1 week period. During subsequent 2-4 week periods, invasive cells originating from the aggregates and exhibiting a fusiform morphology became evident and increased in number in the matrix cultures. This biphasic pattern of behavior did not occur on laminin, type I or type IV collagen, or fibronectin substrates, but it did occur on Matrigel in serum-free medium. Characterization of sublines enriched in fusiform cells indicated that they maintained their distinct morphology with continuous culture. Further, they exhibited significantly greater invasive potential, saturation density, and random motility (chemokinesis) than the parent cell line. Steady-state levels of fibronectin mRNA were highly elevated in the fusiform variants, demonstrating a constitutive alteration in patterns of gene expression coinciding with the altered morphology. These results indicate that clonal NbMC-2 cells differentiate at a reproducible frequency into a more aggressive cell type in response to culture in the basement membrane-like matrix. The altered phenotypic properties appear to be stable since they can be inherited by daughter cells and because they are evident in the absence of matrix. These observations suggest a cell-specific mechanism for promotion of malignant growth by matrix-mediated induction of novel cell properties.

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.

Mixed müllerian tumors of the uterus: a clinicopathologic study.

Forty-seven cases of mixed müllerian tumors of the uterus were analyzed clinically and pathologically. All patients but one were postmenopausal. Vaginal bleeding was the most frequent presenting symptom, followed by abdominal mass and pelvic pain. Long-term survival was found only in those cases in which the tumor was localized to the uterus (surgical stage I), particularly if it arose from a benign endometrial polyp. No correlation could be established between survival and tumor size, depth of myometrial invasion, or histologic type of sarcoma. Tumors arising after previous irradiation had a poor prognosis. Treatment included surgery, radiation, and chemotherapy. The cumulative probability of 5-year survival was 35%.

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.

Mixed mesodermal tumors of the ovary: a clinicopathologic study of 14 cases.

Fourteen cases of mixed mesodermal tumor of the ovary are presented. The actuarial survival of patients with these tumors was 2.5 months. Eighty-six percent of patients were stage III or IV at the time of diagnosis. The stromal or carcinomatous component of the tumor could not be correlated with survival. Both our two longest survivors, 14 and 27 months, were treated with surgery and radiotherapy, one patient with and one without chemotherapy.

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.

Feulgen DNA content and mitotic activity in proliferative breast disease. A comparison with ductal carcinoma in situ.

Nuclear Feulgen DNA content was measured by cytophotometry and the number of mitoses per 40 high power fields was determined in hyperplastic and atypical hyperplastic lesions of fibrocystic disease in 18 patients, in ductal carcinoma in situ in 14 patients and in ductal carcinoma in situ associated with infiltrating carcinoma in 11 patients. These parameters were also investigated in the hyperplastic lesions accompanying ductal carcinoma in situ and ductal carcinoma in situ associated with infiltrating carcinoma. The nuclear Feulgen DNA content could not discriminate between atypical hyperplasia and ductal carcinoma in situ. Although differences in the mitotic count between hyperplastic and atypical breast lesions were not statistically significant, there was a statistically significant greater mitotic count in ductal carcinoma in situ alone or associated with infiltrating carcinoma. These findings suggest that the mitotic count is useful for the differential diagnosis between atypical hyperplasia and ductal carcinoma in situ. In addition, hyperplastic lesions associated with ductal carcinoma in situ, with or without infiltrating carcinoma, exhibited a statistically significant higher mitotic count than those in benign fibrocystic disease. Hyperplastic breast lesions exhibiting high mitotic counts may indicate the presence of a neighbouring ductal malignancy and suggest an increased proliferative activity in breast tissue in the neighbourhood of malignancy.

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.

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.