The mode of cell death in H-358 lung cancer cells cultured with inhibitors of 5-lipoxygenase or the free radical spin trap, NTBN.

The 5-lipoxygenase inhibitors SC41661A and MK886 with different mechanisms of action and the free radical spin trap, NTBN inhibit proliferation of the human bronchiolar lung cancer cell line NCI H-358 (5807 CRL). With continued culture, the agents induced a form of programmed cell death in which DNA laddering was not detected and ultrastructural changes were not characteristic of classic 'type 1' cellular suicide. The changes were more consistent with a type 2 cytosolic, autophagic form of PCD. MK886 induced strikingly abnormal mitochondrial morphology. Since the lipoxygenase inhibitors and NTBN induce classic type 1 PCD in U937 monoblastoid cells, these agents can activate either pathway, depending upon cell type. It is not certain whether activation of type 1 or 2 pathways depends entirely upon cell lineage and/or initiating agent, if all cells retain both pathways, and if type 1 PCD a more effective mediator of the process. These are all relevant questions for assessing the impact of PCD on malignant cell survival and considering ways in which it might be enhanced.

Mesangial lupus nephritis with associated nephrotic syndrome.

Patients with mesangial proliferative lupus glomerulonephritis (World Health Organization class II) are generally believed to have only mild to moderate proteinuria and normal renal function. However, there have been several reports of patients with mesangial lupus with nephrotic-range proteinuria. In this report, we present two additional cases and review the literature. Of seven reported cases, persistent nephrotic syndrome was observed in four, morphologic transformation occurred in three, and all but one presented with varying degrees of azotemia. These cases reinforce the concept that in systemic lupus erythematosus, laboratory findings may not correlate well with the underlying glomerular lesion, and therefore, the renal biopsy is an essential clinical tool in the approach to lupus nephritis.

Biomechanical studies of the anterior spinal fixators after corpectomy in pigs.

An unstable corpectomy porcine spinal model was created for the testing of anterior spinal fixators including: Kaneda device (KD), combination of Polster-Brinckmann prosthesis and Zielke implant (PBZ), and a new prototype device (CH). These spinal implants were examined in a one above/one below corpectomy model to determine the relative stiffness of each construct and the deformation of the adjacent discs under loading. The results indicated that the relative torsion and flexion stiffness were higher for the tested spines fixed with KD and CH. However, the relative compression stiffness of the tested spines was the same for all devices. The rigidity of the spinal constructs, which were measured around the corpectomy region showed the same tendency as above. However, the stiffness of CH and KD constructs were significantly higher than that of the PBZ construct under flexion and torsion. The difference in deformation of the upper and lower adjacent discs was not obvious among the intact spine and the spinal constructs with different devices. Clinical relevances: The corpectomy model represents a "worst case" scenario of spinal instability. In many conditions, spinal reconstructive surgery can restore axial compressive, torsional, and flexural rigidity to normal levels. These experimental conclusions apply to acute restoration of stability, rather than to rigidity after long-term cyclical loading. These three anterior fixators extended to only one cephalad level and one caudal level beyond the corpectomy defect. The new prototype device (CH) has a stability to the Kaneda device. The superior mechanical strength and simpler operative procedure of the new device provide for a potential clinical advantage in restoration of unstable spinal conditions.

Immunocytochemical evaluation of neoplastic and non-neoplastic breast diseases with Mab A-80.

Five hundred breast tissue samples from 404 cases were immunostained with A-80, a murine IgM Mab that recognizes a mucinous glycoprotein associated with exocrine differentiation. Samples included 196 primary breast carcinomas, 30 breast carcinoma metastases, 118 fibrocystic disease (FCD), and a further group of 84 samples of FCD from cases known to have breast carcinoma. These samples represented a broad spectrum of common and rare variants of carcinoma and FCD. Samples of fibroadenomas, lactating adenomas, cystosarcoma phylloides, gynecomastia, and normal breasts were similarly studied. The vast majority of carcinomas, 203/212 (95.7%) were immunoreactive; staining varied in extent and intensity, and was virtually unrelated to histologic type and to the presence or absence of recognizable glands. In samples including in-situ and infiltrating ductal or lobular carcinoma, reactivity was frequently stronger in the infiltrating components. No significant difference in reactivity between primary and metastatic carcinomas was noted. Of the group of 118 FCD, 27 were negative whereas 91 showed focal and weak staining. Seventy-two/84 FCD with associated carcinoma were immunostained; in 13 of those 72, staining was strong and extensive. Fibroadenomas, lactating adenomas, gynecomastia, and normal "resting" and lactating breast samples stained focally or not at all. Our findings indicate that Mab A-80 is an excellent immunohistochemical marker for the overwhelming majority of breast carcinomas whereas it marks weakly or not at all the majority of benign neoplasms and normal breast. Moreover, Mab A-80 recognizes a subset of FCD that includes proliferative variants associated with an increased incidence of carcinoma, and FCD in association with carcinoma. Questions regarding rare breast carcinomas that do not react with Mab A-80 remain unclear; yet, we believe that Mab A-80 is a highly promising marker of malignant and dysplastic breast epithelium.

Surgical thyroparathyroidectomy of the rabbit.

Previous studies in the rabbit suggest resistance to parathyroid hormone (PTH) despite the reported presence of PTH-sensitive adenylate cyclase activity in renal cortical slices and tubules. The lack of response may reflect difficulties with complete parathyroidectomy in this species, which has been reported to possess 32 accessory glands. Aided by systematic histology of tissues extirpated during exploration, we tested the hypothesis that the rabbit possesses only four functional parathyroid glands and that the rabbit kidney is sensitive to the expected physiological actions of endogenous PTH. In all rabbits studied, only four glands could be identified histologically, two within the thyroids and two located in the fascial plane between the sternohyoid and sternothyroid muscles and the carotid artery. Surgical thyroparathyroidectomy markedly reduced serum Ca (6.3 vs. 10.6 mg/dl in sham-operated controls), increased the clearance (C) (3.51 vs. 0.78 ml/min) and fractional excretion (FE) of Ca (44.5 vs. 8.3%) while decreasing CP (1.14 vs. 2.40 ml/min), FEP (14.8 vs. 29.9%) and adenosine 3',5'-cyclic monophosphate (cAMP) excretion (341 vs. 760 pmol/min). These findings demonstrate the feasibility of using the described techniques for complete parathyroidectomy in the rabbit. Furthermore, they document the presence of only four functioning parathyroid glands and the renal sensitivity to endogenous PTH in this species.

Glomerular changes in renal allografts.

The renal allograft is host to a number of injuries and all its structural components are prone to damage. The glomeruli respond to these varied stimuli in many ways. The fibrinoid necrosis, thrombosis, and polymorphonuclear cell exudation that accompany hyperacute or accelerated rejection are well-recognized. The transplant may also be afflicted by forms of de novo or recurrent glomerulonephritis. Apart from these, there are other patterns of reaction. The mesangium is often the site of a rapidly reversible change; it expands readily. Arterial changes initiate ischemia and collapse of glomerular capillary spaces. Glomerulitis accompanies cases of acute rejection, but when seen as a predominant feature, usually antedates chronic rejection. Heavy proteinuria may be associated with profound alterations in the peripheral capillary basal lamina including irregular thickening, interposition of mesangial cell cytoplasm, and lamellation. Allografts with these glomerular changes eventually fail.

Scanning electron microscopy of immune complexes in membranous glomerulopathy.

Scanning electron microscopy (SEM) was done on seven cases of membranous glomerulopathy (MG) in order to describe the morphologic appearance of the immune complexes that are deposited in the glomerular basement membranes, as previous SEM studies on the human glomerulus primarily focused on the changes in the podocytes. The diagnosis of membranous glomerulopathy of idiopathic form or secondary to systemic lupus erythematosus was confirmed by conventional light and transmission electron microscopy and immunofluorescent microscopy. By SEM, the external surfaces of the basement membranes were covered by immune complexes that appeared as a network of "lumpy-bumpy" deposits. They were arranged in anastomosing cords imparting a "swiss cheese" pattern. The immune-complex nature of these anastomosing cords of deposits is confirmed by our preliminary immunoscanning electron-microscopic study. The exact mechanism for immune complexes to be localized on the external surface of the basement membrane remains to be elucidated.

Amphicrine cells, dysplasias, and neoplasias.

The existence of epithelial cells displaying synchronous features of exocrine and endocrine differentiation has been well established. Sporadic descriptions of neoplasms comprising or including such cells have also been recorded. The authors investigated eight carcinomas (lung, two; stomach, two; colon, one; appendix, one; esophagus, one; and pancreas, one). By conventional light microscopy, all eight neoplasms appeared as moderately to well-differentiated adenocarcinomas. Mucosubstance stains showed positive material within well-defined lumina and as intracytoplasmic droplets. Argyrophil stains were positive in seven of the eight neoplasms. The esophageal tumor was a predominantly solid carcinoma; it compromised small to intermediate cells with focal mucosubstance positivity and squamous pearls. By electron microscopy, all these carcinomas including cells displaying variable complements of neurosecretory granules, which were concentrated in the basal pole or in cytoplasmic processes. The granule population was often heterogeneous. The pancreatic carcinoma also showed typical zymogen granules. In all cases, many of the neoplastic cells had true lumina or intracytoplasmic lumina, as well as arrays of filaments; secretory granules were also observed in cells with true or intracytoplasmic lumina. Immunohistochemical studies revealed in all cases either serotonin or one of a spectrum of neuropeptides. Five tumors contained more than one immunoreactive material. The authors conclude that synchronous exocrine and endocrine differentiation may be comparatively frequent in a spectrum of tumors that may be properly termed "amphicrine" carcinomas. This demonstrable heterogeneity of malignant cell populations, however variably expressed, may prove to have considerable significance in the diagnosis and management of these neoplasms.

Nephrotic syndrome in two patients with cured Hodgkin's disease.

Two cases of lipoid nephrosis (minimal change glomerulonephritis) in patients cured of Hodgkin's disease are reported and the literature is reviewed. Cases reported to date have shown a close temporal relationship between this renal lesion and the presence of Hodgkin's disease. The patients reported are 11 and 9 years without evidence of active malignancy after successful treatment for Hodgkin's disease. Each had abnormal immunologic parameters, depressed T4 (helper) cells and increased T8 (suppressor) cells, which may predispose to the development of the nephrotic syndrome. However, the advent of this complication is not necessarily a harbinger of recurrent lymphoma.

Paragangliomas of the head and neck: ultrastructural and immunohistochemical analysis.

Eighteen head and neck paragangliomas were studied by light microscopy and light microscopic immunohistochemistry by the peroxidase technique for the presence of NSE (neuron-specific enolase), serotonin, and a battery of neuropeptides. Seven of these tumors were also studied by electron microscopy. All 18 cases demonstrated immunostaining for NSE; 10 of the 11 carotid body tumors had immunostaining for multiple hormones. Considering all 18 cases, the most frequently demonstrated hormonal substances were in order: serotonin, leu-enkephalin, gastrin, substance P, vasoactive intestinal polypeptide (VIP), somatostatin, bombesin, calcitonin, and alpha MSH. In several tumors, adjacent-step sections stained for different hormonal substances strongly suggested reactivity for more than one hormone in given tumor cells. By electron microscopy, all 7 cases studied displayed considerable heterogeneity of the neurosecretory granules with respect to size, shape, and electron density. This demonstrated that branchiomeric paragangliomas are capable of producing a spectrum of neuropeptides in addition to their known amine content. The presence of immunoreactive serotonin in most of these neoplasms was confirmed. In addition to these findings, neurofibrils within the substance of carotid body paragangliomas demonstrated immunoreactivity for somatostatin and a gastrinlike neuropeptide. The significance of the neuropeptides in these neoplasms and their possible presence and role in normal and hyperplastic paraganglia remain to be defined.

Cytopathologic diagnosis of extracolonic amebiasis.

Extracolonic amebiasis must be distinguished from bacterial abscesses and neoplastic disease. Newer technology in diagnostic and interventional radiology permits such lesions to be aspirated more accurately for both diagnostic and therapeutic purposes, often averting an open surgical procedure. Paracecal and hepatic masses of one patient, who presented with fever and abdominal pain, were shown to be amebic abscesses by cytopathologic examination of material obtained by ultrasonically guided percutaneous fine needle aspiration. Another patient, who was thought to have metastatic carcinoma, died, with clinically unrecognized extensive pulmonary and hepatic amebiasis proven at autopsy. A review of this patient's sputum cytology smears showed numerous trophozoites of Entamoeba histolytica that were not recognized earlier. Cytopathologic studies of sputum and fine needle aspirates is an important means of detecting extracolonic amebiasis and distinguishing these lesions from neoplastic disease.

Large-cell calcifying Sertoli cell tumor of the testis: a case report with ultrastructural study.

Large-cell calcifying Sertoli cell tumor (LCCSCT) is a rare histologic variant of Sertoli cell tumor. Recently we observed a case of LCCSCT of the testis with no associated endocrine abnormality. Our ultrastructural findings of rows of tight junctions, numerous intracytoplasmic filaments, and abundant rough endoplasmic reticulum in whorled formations support the Sertoli cell origin of this neoplasm.

Myeloid bodies in drug-induced acute tubular necrosis.

A growing list of drugs, metals, and chemicals has been implicated as the cause of functional and structural damage specifically to the proximal tubular epithelium. Renal biopsies were obtained from three patients who had developed nephrotoxic agent-related acute renal failure. Two of the patients had received gentamicin and viomycin; the third patient had heavy exposure to chromium. All three biopsies showed acute tubular necrosis (ATN) on light microscopy. Electron microscopy revealed that the proximal tubular cells and, to a lesser degree, the distal tubular cells, contained abundant, variably sized myeloid bodies. In our previous experimental study of viomycin-induced ATN in rats, similar ultrastructural findings of a gradual increase in the number of myeloid bodies in the proximal tubular cells were also observed. The constant presence of myeloid bodies in the tubular epithelial cells following drug-induced tubular necrosis suggests that they may represent lysosomal isolation of drug-bound cytoplasmic structures, as a cellular mechanism to degrade toxic substances and, therefore, may serve as an ultrastructural marker of cellular drug uptake and drug disposition.