Neurovisceral and skeletal GM1-gangliosidosis in dogs with beta-galactosidase deficiency.

Beta-galactosidase-deficient siblings in two litters of English springer spaniel puppies showed a progressive neurological impairment, dwarfism, orbital hypertelorism, and dysostosis multiplex. An excess of GM1-ganglioside was found in the brain. Three abnormal oligosaccharides were present in samples of urine, brain, liver, and cartilage. Light microscopy of selected tissue specimens revealed cytoplasmic vacuoles in neurons, circulating blood cells, macrophages, and chondrocytes. Ultrastructural studies demonstrated that these membrane-bound vacuoles were of two types--one containing lamellated membranes and the other, finely granular material. These clinical and pathological findings are similar to those observed in human patients affected by the infantile form of GM1-gangliosidosis.

Age-dependent growth inhibition of estrogen-sensitive rat mammary tumors. Probable role of alpha-fetoprotein.

The growth patterns of estrogen (E)-sensitive mammary tumors (SNMU) and autonomous mammary tumors (ANMU) were compared in normal host F344 and BUF rats of different ages. Both SNMU and ANMU tumors have comparable amounts of E receptors of similar physicochemical properties. The E sensitivity was apparent in SNMU tumors regardless of the age of inoculation. The latency period before tumors became palpable was considerably lengthened when the SNMU tumors were inoculated into newborn hosts. The growth pattern of the ANMU tumor was not affected by the age or sex of the host. Comparable results previously obtained with two hypophyseal cell lines suggest that this growth pattern could now be extended to other E-sensitive autonomous systems and become a generalized principle. These results suggest that: 1) the presence of 17 beta-estradiol (E2) receptors is not sufficient to qualify cells to be considered E-sensitive, 2) E-sensitive cells may be delayed in expressing their malignant growth properties if inoculated during the perinatal period, and 3) alpha-fetoprotein may be the substance responsible for the inhibition of the growth of E-sensitive tumor cells during the perinatal stage.

Growth inhibition of estrogen-sensitive rat mammary tumors. Effect of an alpha-fetoprotein-secreting hepatoma.

The growth and regression patterns of estrogen (E)-sensitive mammary tumors (SNMU) and autonomous mammary tumors (ANMU) were studied in normal, castrated, and alpha-fetoprotein (AFP)-secreting and nonsecreting hepatoma-bearing female BUF rats. Both SNMU and ANMU tumors had comparable amounts of E receptor. SNMU tumors grew faster in female hosts than in male hosts. The latency period of SNMU tumors was lengthened when the tumor was inoculated into newborn hosts. These E-sensitive tumors regressed after castration of the adult hosts. Tumor regression was also observed in SNMU-bearing rats inoculated with AFP-secreting hepatomas. The growth pattern of the ANMU tumor was not affected by the sex or age of the host. Castration and inoculation of hepatomas to ANMU tumor-bearing rats did not result in regression of the ANMU tumors. We suggest that AFP inhibited the growth of E-sensitive cells in newborn and hepatoma 7777-bearing hosts. This inhibitory effect of AFP could not be attributed to a "functional castration" resulting from the trapping of 17 beta-estradiol (E2) by AFP, because the plasma levels of E2 in these animals affect levels of gonadotropins. Moreover, castration of hepatoma 7777-bearing rats resulted in increased plasma follicle-stimulating hormone and luteinizing hormones levels. The results strongly suggested that a) the malignant properties of E2-sensitive cells in adult hosts can be controlled by AFP, and b) the mechanism by which AFP inhibits the growth of E2-sensitive cells is independent of the E2 "trapping" phenomenon. An ontogenetic approach to the mechanism of action of estrogens may account for available results.

Heterogeneous distribution of filipin-sterol complexes in nuclear membranes.

Filipin, a sterol-specific polyene antibiotic, has been shown by electron microscopy to form complexes in membranes of mouse urinary bladder cells. Following instillation of a glutaraldehyde-filipin-dimethylsulfoxide solution into the bladder lumen, filipin-cholesterol complexes appear as membrane corrugations in thin sections and as 20-25 nm protuberances and depressions on PF and EF faces in freeze-fracture replicas. The complexes are observed in plasmalemma, Golgi membrane, rough endoplasmic reticulum and nuclear membrane of five different cell types (urothelial, endothelial, mesothelial, smooth muscle and fibroblasts). In the present report, we direct particular attention to the localization of numerous filipin-cholesterol complexes present in the nuclear envelopes of these cells. Our results suggest that enrichment of cell membranes with cholesterol occurs at an earlier stage in the flow-differentiation process than previously suspected. In addition, the unequal distribution of complexes in favor of the outer nuclear membrane suggests that it has a higher cholesterol content than the inner membrane.

The excimer laser: gross, light microscopic and ultrastructural analysis of potential advantages for use in laser therapy of cardiovascular disease.

Excimer lasers are pulsed gas lasers that use a mixture of a rare gas and halogen as the active medium to generate pulses of short wavelength, high energy ultraviolet light. A krypton-fluoride gas mixture was used to achieve an excimer emission at a wavelength of 248 nm. A total of 30 atherosclerotic coronary artery segments were irradiated over a range of pulse energies (250 to 750 mJ), repetition rates (2 to 25 Hz), average powers (1.9 to 18.8 watts) and cumulative exposures (3 to 12 seconds). In no case was there gross, light microscopic or ultrastructural evidence of the pathologic injury typically associated with continuous wave laser irradiation of coronary artery segments. Similar results were achieved after excimer laser irradiation of 30 samples of myocardium. Excimer irradiation of calcified aortic valve leaflets accomplished focal debridement without pathologic tissue injury; when total debridement was attempted, however, gross charring was observed. The paucity of pathologic alterations observed after excimer irradiation of cardiovascular tissue may prove beneficial in precisely controlling laser ablation of pathologic tissue without injury to the surrounding normal tissue. Clinical application of excimer laser irradiation requires resolution of several issues, including the development of suitable fiber optics and laser coupling, evaluation of potential ultraviolet toxicity, and demonstration that ultraviolet light can be transmitted through a blood-filled system.

Streptozocin-treated Verner-Morrison Syndrome: plasma vasoactive intestinal peptide and tumor responses.

A patient with watery diarrhea, hypokalemia, hypochlorhydria, and a non-beta islet cell carcinoma of the pancreas (Verner-Morrison syndrome) was found to have an elevated vasoactive intestinal peptide (VIP) concentration in the plasma as well as in the tumor. Treatment with streptozocin resulted in a dramatic subjective and objective tumor response in this patient. Plasma VIP concentration fell into the normal range after four courses of treatment, diarrhea ceased after the third course of therapy, and measurable tumor mass markedly decreased during that same period of time. The patient remains in clinical remission with no evidence of tumor regrowth 18 months after the beginning of treatment. In this patient, plasma VIP measurements were an excellent marker of tumor activity and correlated well with objective disease measurements and clinical response.

Identification of glycoprotein storage diseases by lectins: a new diagnostic method.

The specific diagnosis of glycoprotein storage diseases is made by demonstrating a deficiency in enzyme activity or an elevation of undegraded oligosaccharides in cells or body fluids. Prospective sampling and expensive specialized biochemistry, which is also time consuming, are required for such studies. We used lectin reagents on paraffin-embedded tissue sections to identify the specific sugars in undegraded stored substances. We studied 22 cases of glycoprotein storage diseases and differentiated histochemically between alpha- and beta-mannosidosis, fucosidosis, and sialisidosis. Cells affected with alpha-mannosidosis stained with Concanavalia ensiformis (Con A), Triticum vulgaris (WGA), and succinyl-WGA (S-WGA), while beta-mannosidosis cells did not stain with any of the lectins used. In fucosidosis the affected cells stained with Ulex europeus-I (UEA-I), while sialisidosis-affected cells stained with WGA, and in three cases with Arachis hypogea (PNA). This study indicates that lectin histochemistry provides a reliable specific diagnostic pattern for some glycoprotein storage diseases using a simple and inexpensive method.

Lectin histochemistry of glycolipid storage diseases on frozen and paraffin-embedded tissue sections.

Lectin histochemical studies were performed on frozen and paraffin-embedded brain tissue sections from six cases of galactosylceramide lipidosis (i.e., globoid cell leukodystrophy, or Krabbe's disease) in Twitcher mice and one case of canine infantile GM1-gangliosidosis. The globoid cells in Krabbe's disease stained with Ricinus communis agglutinin-I (RCA-I), peanut agglutinin (PNA), and Bandeirea simplicifolia agglutinin-I (BS-I) in frozen sections. However, paraffin sections and frozen sections pretreated with chloroform-methanol or xylene, from the same animals, stained with Concanavlia ensiformis agglutinin (ConA), wheat germ agglutinin (WGA), and succinylated-WGA (S-WGA), in addition to staining with RCA-I, PNA, and BS-I. The affected neurons of canine infantile GM1-gangliosidosis stained only with RCA-I in frozen sections. In paraffin sections, however, these cells were negative with RCA-I but positive with BS-I, ConA, Dolichos biflorus agglutinin (DBA), soybean agglutinin (SBA) and Ulex europaeus agglutinin (UEA-I) in paraffin sections. These results indicate that in paraffin processing of glycolipid storage disease tissue, some lectin receptors are lost and others are unmasked. The retained receptors can be stained with specific lectins and could serve as markers to characterize and differentiate among the various glycolipid storage diseases.

Changing incidence of glomerular diseases in adults.

Studies performed at large metropolitan medical centers have reported an increasing incidence of idiopathic focal segmental glomerulosclerosis (FSGS) in adults. To determine whether a similar trend occurs in small urban and rural communities and to determine the role of race in these observations, we reviewed the patient records of all adults who underwent renal biopsies at our institution over the 20-year period from 1974 to 1994. The patients were grouped for analysis in 5-year intervals, 1975 to 1979, 1980 to 1984, 1985 to 1989, and 1990 to 1994, for the following diagnoses: FSGS, membranous nephropathy (MN), minimal change nephropathy (MCN), membranoproliferative glomerulonephritis (MPGN), immunoglobulin A (IgA) nephropathy, chronic glomerulonephritis, diabetic nephropathy, hypertensive nephrosclerosis, and chronic interstitial nephritis. Patients with secondary causes for these lesions were excluded. The relative frequency of FSGS increased from 13.7% during 1975 to 1979 to 25% during 1990 to 1994 (P < 0.05). The relative frequency of MN decreased from 38.3% during 1975 to 1979 to 14.5% during 1990 to 1994 (P < 0.01). There were no changes in the frequencies of MCN, MPGN, IgA nephropathy, chronic glomerulonephritis, diabetic nephropathy, hypertensive nephrosclerosis, or chronic interstitial nephritis over the 20-year period. However, there was a significant increase in the percentage of blacks with FSGS, from 0% in 1975 to 1979 to 22.6% in 1990 to 1994, and an increased percentage of Hispanics with FSGS, from 0% in 1975 to 1979 to 21.3% in 1990 to 1994 (P < 0.05). The modest increase in whites with FSGS did not reach statistical significance. The incidence of MN in blacks and whites decreased over the 20-year period. In the last 5 years, 15 patients per year had FSGS compared with 7 patients per year with MN (P < 0.05). No changes in age or sex between groups or over time accounted for these results. We conclude that FSGS is now diagnosed twice as often as MN and is the most common idiopathic glomerular disease at our hospital. Reasons for this increase include the emergence of FSGS in both Hispanics and blacks, with a modest increase of FSGS in whites. The increase in FSGS in the three most common races in our community suggests that factors other than genetic, perhaps environmental, have a role in the pathogenesis of FSGS.

Biliary cystadenocarcinoma arising in a congenital cyst.

The case of a biliary cystadenoma containing foci of cystadenocarcinoma is reported, along with the first electron microscopic description of this lesion. Both neoplastic and congenital origins have been implicated in the pathogenesis of biliary cystadenomas. In this case hamartomatous bile ducts were found, supporting a congenital origin for at least some biliary cystadenomas. Careful pathologic evaluation is emphasized since malignant degeneration can be detected only after thorough sectioning.

Squamous carcinoma in situ of the skin containing premelanosomes, with melanocytic colonization of the tumor.

Premelanosomes in nonmelanocytic epithelial neoplasms and "colonization" of nonmelanocytic tumors by melanocytes are two phenomena rarely documented in the literature. We report a squamous carcinoma-in-situ of skin displaying both phenomena. Light microscopy showed clusters of tumor cells in the epidermis, some of which contained melanin. Dendritic melanocytes were admixed with the tumor cells. No ulceration was present. Immunoperoxidase stains for keratin showed no staining of tumor cells. Some nondendritic cells stained for HMB-45, consistent with a melanocytic lesion. Electron microscopy showed two cell types, one with desmosomes, tonofilaments, and premelanosomes and a second dendritic type with only premelanosomes. Premelanosomes were also present free in the intercellular space. These findings suggest that premelanosomes may first be discharged by melanocytes into the intercellular space and are then phagocytosed by the neoplastic cells. Thus the presence of premelanosomes in a tumor cell is not pathognomonic for melanoma or other neural crest tumors.

Villous adenoma of the urinary bladder: a morphologic or biologic entity?

Villous adenomas in the urinary bladder are rare neoplasms whose malignant potential is unclear. A case of a morphologically benign non-invasive mucin producing papillary neoplasm of the urinary bladder associated with cystitis glandularis is presented. Absence of A tissue isoantigen from the neoplastic and metaplastic cells and the presence of H tissue isoantigen in both neoplastic and metaplastic cells is observed in a patient whose blood type is A, indicating incomplete maturation of surface coat constituents. The histologically benign appearance of this lesion may belie a malignant potential.

A distinctive perivenular hepatic lesion associated with heart failure.

Hepatic morphologic changes in seven patients in heart failure who were initially thought to have hepatitis are reported. In each instance, percutaneous liver biopsy or post mortem tissue examination disclosed a striking lesion involving all perivenular areas, with replacement of hepatocytes by erythrocytes. Four patients were in pure left-heart failure, while three were in biventricular failure. Upon treatment of the heart failure, the conditions of all patients improved clinically, and liver-function tests returned to normal or near normal. In two patients who later had refractory heart failure and died, there was no evidence of hepatic-vein thrombosis or occlusion post-mortem. A hypothesis is offered for the pathogenesis of this lesion, and its clinico-pathologic differential is discussed.

Nephrogenic adenoma and embryonic kidney tubules share PNA receptor sites.

Nephrogenic adenoma a rare bladder, ureter, or urethral lesion, is of disputed pathogenesis, metaplastic and congenital etiologies both being implicated in its development. Since light and electron microscopy have been unable to fully resolve the lesion's pathogenesis, the authors used biotinylated lectins as probes and avidin-biotin peroxidase complex (ABC) as a visualant to study cases of nephrogenic adenomas and compared their lectin binding patterns with those of normal transitional epithelium, human embryonic kidneys, and cases of cystitis cystica and glandularis and squamous metaplasia of the bladder in an effort to clarify this issue. Only the epithelial lining of the luminal surface and tubuli in nephrogenic adenoma and tubules in embryonic kidney exhibited free PNA receptor sites. The striking staining similarities between the epithelial components of nephrogenic adenomas and mesonephric and metanephric tubules complement previous findings concerning the origin of nephrogenic adenoma.

Bladder detrusor endometriosis mimicking interstitial cystitis.

Endometriosis involving the muscular wall of the bladder may cause symptoms similar to those of interstitial cystitis. Vesical endometriosis should be considered in the differential diagnosis of interstitial cystitis, especially in patients with a history of prior gynecologic or pelvic surgery.

Renal immunoblastic sarcoma complicating immunosuppressive therapy for Wegener granulomatosis.

A renal tumor developing in a patient receiving cyclophosphamide (Cytoxan) therapy for Wegener granulomatosis is reported. The tumor was similar histologically to the "immunoblastic" sarcoma that develops in renal allograft recipients as a complication of immunosuppressive therapy. This case report strengthens the cause and effect relationship between immunosuppressive drug usage and the subsequent development of neoplasia.

Multicentric angiomyolipoma: renal and lymph node involvement.

A retrospective review of 6 patients with renal angiomyolipoma treated surgically revealed regional lymph node involvement in 2--an incidence of 33 per cent. The clinical behavior in these patients suggests that nodal involvement is an expression of multicentricity rather than metastatic disease.

Computed tomographic findings in renal angiomyolipoma: an histologic correlation.

Accurate preoperative diagnosis of renal angiomyolipomas is essential if conservative resection or angiographic embolization is to be used. Computed tomographic (CT) scanning failed to diagnose angiomyolipoma preoperatively in 2 patients, and this led to a retrospective review of 6 patients to define the limits of CT scanning in preoperative diagnosis. The CT findings were correlated with the histology of the tumors. Two tumors with positive attenuation coefficients suggestive of renal adenocarcinoma had significant amounts of immature "fetal" fat, and one of these had a virtual absence of mature fat. The relative inability of CT scanning to identify immature "fetal" fat, especially in the presence of abundant vessel and muscle elements, is a limitation to its use in the preoperative diagnosis of angiomyolipoma. A negative attenuation coefficient is highly characteristic of renal angiomyolipoma with mature fat elements. A positive attenuation coefficient, although suggestive of renal cell carcinoma, may be found in angiomyolipomas with paucity of mature fat or high proportions of immature fat.

Testicular microlithiasis occurring in postorchiopexy testis.

Testicular microlithiasis occurring in a postorchiopexy testis is described. The histologic characteristics of this uncommon entity are presented, and its etiology and clinical significance are briefly reviewed.

New matrix material for potential use in "reversible" vasectomy. Preliminary animal biocompatibility studies.

The biocompatibility of a new elastomeric-hydrogel matrix biomaterial for use as an intravasal occlusive device was assessed by inserting it into the vas deferens of dogs. The vas was removed and examined histologically after varying periods of time. The biomaterial resulted in total occlusion of the vas. Epithelial changes were limited to squamous metaplasia in areas adjacent to the implant. Changes in the subepithelium were minimal. This new material is biocompatible with the dog vas, and it has potential as an occlusive device for "reversible" vasectomy in men. Semen analysis studies are needed to assess the completeness and reversibility of the vasal occlusion achieved with this implant.