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A 40-year-old pregnant woman who had previously been diagnosed with uterine myoma underwent cesarean section. During the operation, a tumor thought to be uterine myoma was found to be an extrauterine tumor arising from the upper abdomen. After the delivery of the fetus, a staging CT scan was performed, which revealed a huge, 18 cm, hepatic tumor in the left lateral segment, a mediastinal tumor with calcification, and multiple lung nodules. She underwent a left hepatic lobectomy and a wedge resection 8 days after the delivery. The initial pathological diagnosis was moderately differentiated neuroendocrine tumor (NET). However, as a primary hepatic NET is extremely rare, further immunohistochemical staining was performed. The tumor was positive for p63, CD5, c-kit, and bcl-2, indicating a diagnosis of thymic carcinoma with liver and lung metastases.

Lymph node lesions in infectious mononucleosis (IM) show a marked histologic diversity. We report here three cases of IM lymphadenitis with histologic findings indistinguishable from those of toxoplasmic lymphadenitis. The histologic findings of the three cases presented here showed a histologic triad of toxoplasmic lymphadenitis, including (i) numerous lymphoid follicles with hyperplastic germinal centers; (ii) small clusters or single epithelioid histiocytes; and (iii) multiple foci of monocytoid B-cells. Moreover, all three lesions contained isolated or small clusters of epithelioid histiocytes within the hyperplastic germinal centers and the periphery of lymphoid follicles, which are the most specific histologic findings of toxoplasmic lymphadenitis. However, serologic findings confirmed EBV infection in all three cases. On in situ hybridization, numerous Epstein-Barr virus (EBV)-encoded small RNA (EBER)-positive cells were demonstrated in the germinal center, as well as in interfollicular areas in all three cases. Toxoplasmosis gondii infection was excluded in at least one case, based on serologic findings. Polymerase chain reaction analysis also demonstrated that there was no T. gondii DNA in the remaining two cases. Two of our three cases showed atypical clinical presentations, including an absence of atypical lymphocytosis in peripheral blood in two cases, age more than 30 years, and an absence of systemic symptoms in one case. It appears that previous descriptions emphasize the differential diagnostic problems between IM lymphadenitis and malignant lymphomas. However, from a therapeutic perspective, it is important to discriminate IM lymphadenitis from toxoplasmic lymphadenitis particularly in patients showing atypical clinical features., (2010 Elsevier GmbH. All rights reserved.)

We evaluated six cases of diffuse large B-cell lymphoma (DLBCL) involving the red pulp of the spleen. All had B symptoms and an aggressive clinical course. The lymphoma cells proliferated diffusely and non-cohesively in the cords of the red pulp. The lymphoma involved the bone marrow in four of the five patients and the liver in all four of the patients examined. However, lymph node (LN) involvement was rare at presentation, and systemic LN involvement was not observed even in the terminal phase. The lymphoma cells infiltrated the intrasinusoidal/intravascular and interstitial spaces of the involved tissues and were detected in the peripheral blood in two of the six patients. CD5-expressing lymphoma cells were detected in four of the five patients examined. Because these cases had some unique clinical features and occurred in distinct splenic sites, we proposed that primary splenic DLBCL manifesting in red pulp is a distinct clinicopathological entity.

Over half of the salmon consumed globally are farm-raised. The introduction of oil-adjuvanted vaccines into salmon aquaculture made large-scale production feasible by preventing infections. The vaccines that are given i.p. contain oil adjuvant such as mineral oil. However, in rodents, a single i.p. injection of adjuvant hydrocarbon oil induces lupus-like systemic autoimmune syndrome, characterized by autoantibodies, immune complex glomerulonephritis, and arthritis. In the present study, whether the farmed salmon that received oil-adjuvanted vaccine have autoimmune syndrome similar to adjuvant oil-injected rodents was examined. Sera and tissues were collected from vaccinated or unvaccinated Atlantic salmon (experimental, seven farms) and wild salmon. Autoantibodies (immunofluorescence, ELISA, and immunoprecipitation) and IgM levels (ELISA) in sera were measured. Kidneys and livers were examined for pathology. Autoantibodies were common in vaccinated fish vs unvaccinated controls and they reacted with salmon cells/Ags in addition to their reactivity with mammalian Ags. Diffuse nuclear/cytoplasmic staining was common in immunofluorescence but some had more specific patterns. Serum total IgM levels were also increased in vaccinated fish; however, the fold increase of autoantibodies was much more than that of total IgM. Sera from vaccinated fish immunoprecipitated ferritin and approximately 50% also reacted with other unique proteins. Thrombosis and granulomatous inflammation in liver, and immune-complex glomerulonephritis were common in vaccinated fish. Autoimmunity similar to the mouse model of adjuvant oil-induced lupus is common in vaccinated farmed Atlantic salmon. This may have a significant impact on production loss, disease of previously unknown etiology, and future strategies of vaccines and salmon farming.

We report the case of a 28-year-old woman who presented simultaneously with superior sagittal sinus thrombosis and thyroid crisis, and was subsequently found to have protein C deficiency. February 3, 2003, she admitted complaining of abdominal pain. The diagnosis of appendicitis was made, and she was operated on under lumbar anaesthesia. Day 7, she developed acute headache and distal weakness of the left lower limb. On examination she was alert, with a temperature of 38 degrees C, a sinus tachycardia of 124/min and blood pressure 164/84 mmHg. Neurological examination revealed neck stiffness and left hemiparesis, predominantly in her lower limb. Gadlinium-enhanced brain MRI revealed extensive superior sagittal sinus thrombosis. CT scan demonstrated infarction in the right frontal cortex, and subarachnoid hemorrhage adjacent to the right cerebellar tentorium. The patient was treated with a free radical scavenger edarabon, and glycerin. No anticoagulant therapy was instituted. Over the next 24 hours, her condition worsened. She became comatose, as well as developing a generalized tonic-clonic seizure. Day 12, laboratory examinations revealed an undetectable TSH-level CTSH (thyroid stimulating hormone) <0.005 mcIU/ml), with a level of free thyroxin 7.77 ng/dl (0.9-1.7), free triiodothyronin 29.6 pg/ml (2.3-4.3), and positive anti-TSH receptor antibodies determined subsequently. Coagulation factor VIII activity was 155% (normal range 60-150). Protein C deficiency (antigen 59%, activity 49%) was also present, suggesting a congenital type I heterozygous deficiency. A diagnosis of thyroid crisis on the basis of Graves' disease was made. The patient remained comatose and died on Day 16, with renal failure. The patient had protein C deficiency, a well-established risk factor for cerebral venous thrombosis (CVT). However, additional risk factors are required in most cases to precipitate CVT. In our case, this trigger was most likely thyroid crisis, suggesting that thyrotoxicosis, probably through hypercoagulability, may be a predisposing factor for the development of CVT.

We report a 13-year-old boy with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) at an early stage. He showed migraine, cognitive deficits, depressive episodes and areas of white matter hyperintensity on MRI. There were no first-degree relatives accompanied with similar symptoms. T2-and fluid-attenuated inversion recovery (FLAIR)--weighted brain MRI revealed areas of apparently symmetric high intensity in the deep white matter and periventicular caps. On ultrastructural studies of the biopsied skin, there were free granular osmiophilic materials (GOM) between vascular smooth muscle cells in the cutaneous vessels. But there were no excavations in the cell membranes that contained GOM. On immunostaining with Notch3 monoclonal antibodies, granular staining was not observed in vessels of the skin. No mutation was detected on DNA analysis of the Notch3 gene (exon 4 and part of exon 5) in peripheral leukocytes. Although the frequencies of migraine episodes and depressive episodes decreased with amitriptyline and ibuprofen, the cognitive deficits (delayed-recall impairment) and areas of white matter hyperintensity on MRI have been unchanged for the past four

We report six cases of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPDs) in middle-aged and elderly patients exhibiting atypical clinical findings. The patients, two males and four females, ranged in age from 52 to 74 years, with a median age of 64 years. Clinically, they were characterized by tonsillar tumor, cervical lymphadenopathy, and absence of atypical lymphocytosis of the peripheral blood. "B"symptoms were recorded in only two cases. Pancytopenia was recorded in one case during the disease course. The clinical course was self-limited. Histologically, all lesions were characterized by effacement of the follicles and expansion of the interfollicular area with proliferation of small vessels, indicating atypical lymphoid proliferation. In the interfollicular area, there was a mixed infiltrate, including small-to-medium-sized lymphocytes, plasma cells, and T-and B-immunoblasts. Immunoblasts resembling Reed-Sternberg cells were observed in four lesions. Three lesions contained numerous mature plasma cells, plasmacytoid cells, and immature plasma cells in some areas. In situ hybridization demonstrated a varying number of EBV-infected lymphocytes in the interfollicular area. The overall histomorphologic findings of the present six cases were similar to those of infectious mononucleosis (IM) in younger patients. However, the clinical findings were quite different from those of IM in the younger age population. To avoid overdiagnosis and overtreatment, we emphasize the need to be aware of the atypical clinical presentation of EBV-related LPDs in middle-aged or elderly patients, and to turn careful attention to these clinical and laboratory findings as well as to the morphologic features.

A 49-year-old man was admitted to hospital for investigation of a mediastinal shadow seen on a chest radiograph. Chest completed tomography revealed a mediastinal mass of 65 x 55mm. At surgery, the mass was found to be contained within the upper mediastinum and adherent to the vertebrae, esophagus, trachea, and superior vena cava. We therefore selected sequential approaches using a lateral incision for the thoracotomy and a modified transmanubrial approach. The lateral incision enabled detachment of the adhesion between the mass and the posterior to median mediastinum, and the modified transmanubrial approach was useful for separating the mass from the upper to anterior mediastinum. The mass had no connection to the cervical thyroid gland. Histological examination revealed a large mediastinal cyst of an ectopic thyroid with small nodules diagnosed as papillary carcinoma. There was no recurrence 14 months after surgery.

Gastric choriocarcinoma is a highly aggressive carcinoma, most probably originating from somatic cells in the gastric mucosal layer. We herein investigated the regulatory role of hepatocyte nuclear factor (HNF)-4alpha, a transcriptional regulator expressed in non-neoplastic and neoplastic gastric tissues, on functions of gastric choriocarcinoma cells. HNF-4alpha cDNA was stably transfected to a gastric choriocarcinoma cell line, SCH. Alterations in SCH cell functions such as histology, ultrastructure, proliferation, production of trophoblast-specific proteins, and chemosensitivity to methotrexate (MTX) were examined. Neither in vitro and in vivo proliferations nor HLA-G expression differed significantly between the mock-transfected and HNF-4alpha-transfected SCH cells, while suppressed human chorionic gonadotropin (hCG) secretions, increased human placental lactogen (hPL) and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) immunoreactivity, and decreased chemosensitivity to MTX were seen in HNF-4alpha-transfected SCH cells. General histologic features in xenograft nodules were unaltered, but, ultrastructurally, fascicles of paranuclear filaments were significantly more numerous in HNF-4alpha-transfected SCH cells. These results indicated an HNF-4alpha-rendered functional regulation in SCH cells, suggesting a role of transcriptional factors abundant in gastric but not in trophoblastic tissues/cells on the functional modulation of gastric choriocarcinoma cells.

The regional difference in the contribution of the mucous/glycocalyx layers in rat small intestine, as a diffusional or enzymatic barrier, to the absorption of insulin was investigated by in vitro studies. The mucous/glycocalyx layers from the duodenum, the jejunum, and the ileum in rat were successfully removed without damaging membrane integrity, by exposing them to a hyaluronidase solution in situ. In an in vitro transport experiment, the apparent permeability coefficient (P(app)) of insulin for the hyaluronidase-pretreated group was significantly increased compared to the PBS-pretreated (control) group in all small intestinal regions, and the P(app) of insulin in both PBS- and hyaluronidase-pretreated groups increased in the following order: duodenum < jejunum < ileum. On the other hand, irrespective of small intestinal regions, the P(app) of FD-4 and of antipyrine, respectively the passive para- and transcellular permeation marker, exhibited no significant differences between PBS- and hyaluronidase-pretreated group. In addition, a significant amount of insulin was degraded in the mucous/glycocalyx layers compartment removed by hyaluronidase pretreatment, and the degradation activity in the mucous/glycocalyx layers showed regional differences in the following order: duodenum > jejunum > ileum. These findings suggest that, irrespective of small intestinal regions, the mucous/glycocalyx layers contributed to insulin permeation predominantly as an enzymatic barrier, and not as a diffusional barrier. Furthermore, the variation of the enzymatic activities in the mucous/glycocalyx layers and in the brush-border membrane would be one factor that accounts for the regional differences in the transport of insulin.

Background: Nephrotoxic glomerulonephritis is induced by the administration of antibody against the glomerular basement membrane (GBM). We demonstrated previously that Fc receptors for immunoglobulin G (IgG) (FcgammaR) play crucial roles in the induction of accelerated nephrotoxic glomerulonephritis by using FcRgamma-deficient (-/-) mice. Since FcRgamma-/- mice lack the cell surface expression of two activating FcgammaRs, FcgammaRI and FcgammaRIII. The present study aims to identify the FcgammaR responsible for the induction of nephrotoxic glomerulonephritis., Methods: Accelerated anti-GBM glomerulonephritis was induced in FcgammaRI-/-, FcgammaRIII-/-, and FcRgamma-/- mice by preimmunization with rabbit IgG followed by inoculation of rabbit anti-GBM antibody. Histologic analysis and immunostaining of renal sections were performed., Results: FcgammaRI-/- mice as well as wild-type mice showed severe glomerulonephritis with hypernitremia by the administration of anti-GBM antibody. In contrast, FcgammaRIII-/- mice showed much milder renal involvement, similar to FcRgamma-/- mice. Histologically, FcgammaRI-/- mice showed intracapillary proliferation, glomerular thrombosis, and crescent formation, whereas FcgammaRIII-/- mice showed only glomerular hypercellular changes. The depositions of anti-GBM antibodies, autologous antibodies and complement C3 along the GBM were equally observed among all three FcR-/- mouse types by immunostaining., Conclusions: Accelerated nephrotoxic glomerulonephritis is induced predominantly through FcgammaRIII but not FcgammaRI.

A 20-year-old woman was hospitalized repeatedly because of intermittent bouts of intestinal obstruction and the symptoms usually improved with conservative treatments. One year after the first admission the patient was hospitalized in emergency and a laparotomy revealed a circular stricture with a pinhole perforation in the ileum. Histological sections of the stricture showed the characteristic features of microscopic polyangiitis varying from active to resolving stages, which were localized in the ileum. Fibrinoid necrosis, fibroblastic and fibrous proliferation of the intima and fibrous replacement of the media with a variable pan- and perivascular inflammatory cell infiltrate were characteristic in the muscular arteries and arterioles. Vascular occlusion by pale eosinophilic, fibrillar-like materials resembling livedo racemosa of the skin, was noticed in the small arterioles and capillaries. Under no prophylaxis, the postoperative course was uneventful with no recurrence of the illness at an 18-month follow up. The pathological alterations were distributed focally, occasionally segmentally, and haphazardly, and required detailed examination by stepwise sections for the histological diagnosis.

Objective: To determine the role of Fc receptors (FcR), which play crucial roles in antibody and immune complex-mediated inflammation and autoimmunity, including glomerulonephritis (GN), in the development of autoimmune GN and vasculitis in MRL/lpr mice, one of the most widely used lupus-prone mouse models., Methods: FcRgamma(-/-) MRL/lpr mice were generated by backcrossing for 8 generations. The development of GN and vasculitis of various sized vessels was analyzed histopathologically in the kidney, lung, and skin. Autoantibody and immune complex levels were determined biochemically at 16-24 weeks of age and compared with the findings in FcRgamma(+) MRL/lpr mice. The lifespan of the mice was also recorded., Results: Diffuse proliferative GN, with deposition of IgG and C3, developed in both FcRgamma(-/-) and FcRgamma(+) MRL/lpr mice. There was no difference in the survival rate and degree of proteinuria between FcRgamma(+) and FcRgamma(-/-) MRL/lpr mice. Regardless of the level of FcR expression, there were no significant differences in the levels of serum IgG, anti-DNA antibody, or circulating immune complexes between the two types of mice. Necrotizing vasculitis in medium-sized arteries of the kidneys and lungs as well as small-vessel vasculitis in the skin was observed in both in FcRgamma(+) and FcRgamma(-/-) MRL/lpr mice. In contrast, the Arthus reaction was induced in FcRgamma(+) MRL/lpr mice, but not in FcRgamma(-/-) MRL/lpr mice., Conclusion: Unlike (NZB x NZW)F(1), the other strain of lupus-prone mice that develops GN in an FcR-dependent manner, the development of autoimmune GN and vasculitis in MRL/lpr mice was FcR-independent, implying heterogeneity of the contribution of FcR to the development of autoimmune disease.

We experienced a coincidental case of two types of glomerulopathy associated with Graves' disease. A 64-year-old man, who had been treated with propylthiouracil(PTU) for Graves' disease for 15 years, was admitted to our hospital for macroscopic hematuria and rapidly progressive deterioration of renal function. Although his thyroid function had been within the normal range during treatment, the level of thyrotropin receptor antibody(TRAb) gradually increased from a year before admission. Serological tests revealed that he was positive for myeloperoxidase-antineutrophil cytoplasmic antibody(MPO-ANCA). The renal biopsy specimen showed necrotizing and crescentic glomerulonephritis(GN) superimposed on membranous nephropathy(MN). This is a rare case of MN complicated with ANCA associated crescentic GN in a Graves' disease patient. Association of these two renal alterations was not clearly defined. MN involved with Graves' disease also has been rarely reported. Some reports demonstrated deposition of thyroglobulin and other thyroid related antigens in the glomeruli. In the present case, long-term impairment of Graves' disease and elevation of TRAb might have been responsible for the formation and deposition of thyroid-associated immune complex in the glomeruli. As for crescentic GN, PTU might have induced ANCA-associated GN independently of MN. This case is instructive for considering the relation between Graves' disease and renal injury.

MRL-Fas lpr mice spontaneously develop a severe autoimmune disease closely resembling human SLE. To investigate the possible role of RANTES in autoimmune tissue injuries, we have constructed RANTES-deficient MRL-Fas lpr mice by gene targeting. In the RANTES-deficient mice, axillary lymph nodes were significantly reduced in size compared with those of RANTES-intact mice. Flow cytometric analysis revealed that double-negative (DN) T cells were significantly reduced. Image analyzer showed that cell-infiltrated areas in peribronchial lesions were decreased in the lung of RANTES-deficient MRL-Fas lpr mice. Furthermore, we detected continuous expression of RANTES mRNA in the lung of MRL-Fas lpr mice. In contrast, the degree of histological renal injuries and survival rate was similar in both genotypes. We speculate that RANTES is involved in the development of peribronchial pulmonary lesions in MRL-Fas lpr mice. Further studies using RANTES-deficient mice might contribute to the elucidation of the role of RANTES in autoimmune tissue injuries.

The generation of autoantibodies and deposition of immune complexes (ICs) in tissue play a primary role in autoimmune diseases. However, the IC-triggered response consists of complex mechanisms that make it difficult to identify the pathogenesis and develop specific therapy. We clarified here a sequential mechanism for the induction of hypersensitivity angiitis by analyzing the responsible Fc receptor (FcR), effector cells, and mediators in an animal model using FcR-deficient mice. In this model, rheumatoid factor-mediated skin vasculitis was induced in wild-type mice, whereas FcRgamma-deficient mice did not develop the vasculitis. Adoptive transfer of various FcR(+) cells into FcRgamma-deficient mice showed that mast cells but not macrophages derived from wild-type mice triggered skin vasculitis. Mast cells derived from either FcgammaRIII-deficient or tumor necrosis factor (TNF)-deficient mice did not possess the inducibility of skin vasculitis. These results indicate that triggering of vascular inflammation was induced by mast cells through IC binding on FcgammaRIII. TNF produced by such activated mast cells was mainly responsible for the pathogenesis of autoantibody-mediated vasculitis. These findings illustrate the clinical significance of mast cells, Fcgamma receptors, and TNF in IC-induced vasculitis syndrome.

A case of nephrotic syndrome complicated by acromegaly is presented. The first renal biopsy specimen showed minor glomerular abnormalities with glomerular hypertrophy, corresponding with minimal change nephrotic syndrome. Corticosteroid therapy led to a partial remission, followed by frequent relapses after reduction of the drug. A diagnosis of atypical focal segmental glomerulosclerosis (FSGS) was made based on the second renal biopsy results 6 months after the first. We combined steroid therapy with the administration of an anticoagulant, cytotoxic agents, angiotensin-converting enzyme inhibitor, and low-density lipoprotein adsorption. Except for the angiotensin-converting enzyme inhibitor, these medications were not effective in terms of allowing a reduction in the high dosage of steroid, which in turn threatened progressive osteoporosis and lumbar vertebrae fracture. Administering the steroid at a moderate dosage, treatment was focused on the complicating acromegaly from pituitary microadenoma. Subcutaneous injections of octreotide acetate, a somatostatin analogue, reduced proteinuria and increased urine volume. Subsequent transsphenoidal microsurgery of the adenoma resulted in the normalization of the elevated creatinine clearance and the further reduction in steroid dosage while maintaining a remission state. This is the first reported clinical case with acromegaly followed by FSGS, and it is suggested that hypersecretion of growth hormone participates in the development and progression of glomerular disease.

Aneurysms, mostly saccular, of the medium-sized muscular arteries are frequently encountered in classic polyarteritis nodosa, whereas their occurrence in smaller arteries is unclear. The objective of this study is to clarify the three-dimensional morphology of the small-sized muscular arteries involved in microscopic polyangiitis (MPA). Six autopsy cases of MPA of the acute inflammatory stage were chosen. Using serial paraffin-embedded sections of the kidney, vasculitic lesions observed in the interlobular arteries were three-dimensionally reconstructed. All of the 19 lesions showed microaneurysms, of which 18 were sausage-shaped and the other was saccular. In the former type, average outer diameter at the most expanded point was 235.4 +/- 83.8 microm (mean +/- SD), which was 2.78 +/- 0.73 times that of an uninvolved adjacent arterial diameter. The major axis-minor axis ratio in a cross-aneurysmal section was 1.17 +/- 0.16, indicating rather regular centrifugal expansion of the aneurysm. The aneurysmal length was 742.7 +/- 254.8 microm. These sausage-type aneurysms showed whole circumferential vasculitic involvement, whereas the saccular-type aneurysm contained an uninvolved arterial portion. In both types, the luminal spaces showed similar three-dimensional features to the outer surface of microaneurysms It was concluded that the interlobular arteries of the kidneys in MPA were characterized by formation of microaneurysms, most of which were sausage-shaped

This clinicopathologic study aims to clarify routes of hepatic metastasis of gallbladder carcinoma. Nineteen liver specimens obtained by extensive hepatectomy performed for the treatment of advanced gallbladder carcinoma were analyzed. We defined hepatic metastasis as a discrete hepatic lesion separate from the primary tumor and paid special attention to portal tracts at the margins of direct hepatic invasion. Eleven early metastatic foci were demonstrated histologically in 6 cases, most commonly in segments adjacent to the gallbladder. All cases with hepatic metastasis had direct hepatic invasion. Nine of the 11 metastatic lesions were located within the portal tracts or accompanied by invasion into the portal tracts. Because they are in continuity with areas of direct hepatic invasion, the portal tracts at the invasive margin often were involved by cancer cells that spread along these tracts. These results suggest that the most important route in development of hepatic metastasis from gallbladder carcinoma is along the portal tracts after direct hepatic invasion.

A 45-year-old woman with rheumatoid arthritis(RA) who developed nephrotic syndrome and acute renal failure was reported. She first noticed polyarthritis in June 1990, and was diagnosed as RA. Since her RA was not controlled with nonsteroidal anti-inflammatory drugs (NSAID), she started taking prednisolone 10 mg daily and received 100 mg of D-penicillamine from October 1990 with improvement of the RA. In March 1991, she noticed edema of the face and legs, at which time massive proteinuria and hematuria were first noted. Because of her nephrosis, she was referred to our hospital for further evaluation. Laboratory investigations revealed 24-hour urine proteinuria of 37 g, serum creatinine, 2.7 mg/dl, blood urea nitrogen, 43.5 mg/dl, total protein, 4.1 g/dl, albumin, 1.5 mg/dl, and total cholesterol, 600 mg/dl. The rheumatoid factor and anti-nuclear antibody were positive. Renal biopsy showed focal segmental glomerulosclerosis (FSGS). Her nephrotic syndrome and renal dysfunction recovered after the administration of prednisolone at 60 mg/day. The possible pathogenesis of FSGS in patients with RA was discussed.

Objectives: To determine the incidence of necrotizing alveolar capillaritis, to elucidate its histopathogenesis and the most reliable histopathologic features for its detection, and to explore its relationship with systemic vasculitis in microscopic polyangiitis., Methods: Twenty-five autopsy cases of microscopic polyangiitis were examined. Double staining with periodic acid-silver methenamine and trichrome was used., Results: Periodic acid-silver methenamine and trichrome staining proved to be a useful and convenient method for the detection of necrotizing alveolar capillaritis. Capillaritis was detected in 10 (40%) of the 25 cases studied. Of 18 cases that exhibited the early degenerative stage of systemic vasculitis, capillaritis was seen in 10 (56%). Fibrinoid necrosis of the alveolar wall was the most reliable histopathologic feature for detecting necrotizing alveolar capillaritis in microscopic polyangiitis. The early stage of capillaritis displayed very little neutrophil exudation, and conspicuous accumulation of neutrophils developed after fibrinoid necrosis. Statistical analysis revealed that alveolar capillaritis had a statistically significant correlation (P < .05) with necrotizing vasculitis of the pulmonary circulatory system. Capillaritis tended to occur when systemic vasculitis of microscopic polyangiitis was in its early degenerative stage., Conclusion: Necrotizing alveolar capillaritis was detected in about half of the microscopic polyangiitis autopsy cases that exhibited the early degenerative stage of systemic vasculitis, and results based on earlier reports of clinical observations may have been too conservative.

Werner syndrome is a rare premature aging syndrome accompanied by severe atherosclerosis. The etiology of atherosclerosis is suspected to be due to its complications, namely diabetes mellitus, hyperinsulinemia and hyperlipidemia. But from an autopsy case we found that some other risk factors may be involved in the mechanism of atherosclerosis in this syndrome. Previously we revealed that the plasminogen activator inhibitor-1 (PAI-1) gene was being overexpressed in skin fibroblasts from a patient with this syndrome. PAI-1 is a potent inhibitor of tissue plasminogen activator and a possible risk factor of atherosclerosis. This led us to assess the plasma concentration of PAI-1. Our working hypothesis was that the PAI-1 gene was upregulated or not fully suppressed in cells responsible for the production of PAI-1 in plasma as well as in fibroblasts. The results show a high concentration of plasma PAI-1. One of the well-known physiological substances that induce the PAI-1 gene is tumor necrosis factor-alpha, which also induces other possible risk factors of atherosclerosis, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1. We found the serum concentrations of ICAM-1 to be elevated in patients with this syndrome. We conclude that high concentrations of PAI-1 and ICAM-1 in blood may be one of the potent causes of severe atherosclerosis in Werner syndrome.

A 31 year-old man treated with sulfasalazine for ulcerative colitis, developed nephrotic syndrome, photosensitivity, alopecia, lymphopenia and hypocomplementemia. Anti-nuclear antibody (speckled) and antibodies to single-stranded DNA and SS-A were positive, while those against native DNA and histon were negative. Renal biopsy revealed diffuse proliferative lupus nephritis. His nephrotic syndrome partially improved with corticosteroid therapy combined with cessation of sulfasalazine. His complement level became normal, however it decreased again during the gradual reduction of corticosteroid dosage. In conclusion, we diagnosed the patient's illness as an idiopathic syntemic lupus erythematosus rather than sulfasalazine-induced lupus.

In order to obtain a useful index that can predict the effectiveness of steroid therapy in IgA nephropathy, we investigated the relationship between steroid therapy and extracapillary change. We analysed 51 cases consisting of a group of 24 cases in which steroid was administered (initial dose: prednisolone 20-60 mg/day orally, or pulse therapy), and a group of 27 cases in which steroid was not administered. First of all, we compared these two groups in terms of a clinical improvement rate over 3, 12 and 60-month-periods after the therapy, respectively. It was found that steroid therapy led to a higher improvement rate (p < 0.01-0.05), indicating that steroid is effective for IgA nephropathy. Among the group undergoing steroid therapy, the frequency of cellular crescents (C) was significantly higher (p < 0.05-0.01) in the cases in whom steroid was effective and that of fibrous crescents or adhesion (F) was significantly lower (p < 0.05-0.01). We then assessed C/F in each case of the steroid-administered group, and studied its relationship with the improvement rate. As a result, the improvement rate was below 50% in the group of C/F < 0.25, over 50% of the group of 0.25 < or = C/F < 0.75, and 100% of the group of 0.75 < or = C/F. Accordingly, we concluded that C/F could be used a parameter for predicting the effectiveness of steroid therapy in IgA nephropathy and for determining indications for steroid therapy.

The in vivo effect of transforming growth factor-beta 1 (TGF-beta 1) was studied in a model system in which arterial intimal thickening was induced by injury of rabbit arteries with a balloon catheter (BCI). Intimal area and its ratio to medial area in carotid arteries after BCI were significantly higher in rabbits treated with 10 micrograms/kg TGF-beta 1 and 10 mg/kg aspirin i.v. QD (TGF-beta 1 group) than in those treated with 10 mg/kg aspirin i.v. QD only (control group). Intimal cell numbers in the TGF-beta 1 and control groups were not significantly different from each other, but matrix volume in the intimal layer was significantly higher in the TGF-beta 1 group. By immunohistochemical and Northern blot analyses, the fibronectin content in carotid intimal and medial layers was greater in the TGF-beta 1 group compared with that in the control group. Thus, in intimal thickenings induced by BCI. TGF-beta 1 mainly enhanced the formation of matrix containing fibronectin. Moreover, the mRNAs of TGF-beta 1 and type II receptors were detected in carotid arteries 7 and 14 days after, but not before, BCI. Thus, TGF-beta 1 influences the process of intimal thickening induced by BCI through a receptor-mediated mechanism in vivo. The significance of this fact is discussed in relation to the development of atherosclerosis.

Out of 21 autopsy cases of microscopic polyarteritis (MPA), six cases that died of acute respiratory failure are described. All of these six cases exhibited pauci-immune necrotizing glomerulonephritis. Of these six cases, systemic vasculitis and respiratory failure occurred almost simultaneously in two, whereas respiratory failure developed when vasculitis recurred in the other four. Pathologically, pulmonary changes were diffuse and almost uniform in each case. Interstitial inflammatory cells (alveolitis), hyaline membrane, restructuring, and fibrosis were observed. The degrees of these changes differed from case to case; four cases showed predominantly exudative changes and two cases exhibited proliferative or organizing ones. Clinical and pathological features were consistent with acute interstitial pneumonia (AIP). Immunofluorescent and ultrastructural studies did not suggest deposition of immune complexes at the lesions of alveolitis. An etiologic agent could not be identified in these cases. Some lung lesions including pulmonary hemorrhage have been described in association with MPA; however, cases such as those presented here have rarely been reported. It was considered that AIP could be one of the pulmonary disorders in MPA. Furthermore, the possible pathogenetic role of antineutrophil cytoplasmic antibodies (ANCA) in the evolution of present lung lesion is discussed. Although ANCA were not examined in the present cases, these antibodies should be investigated in future cases.

A case of low-grade fever developing about a month before the discovery of gastric carcinoma is reported. No findings of infection or collagen disease were revealed. The fever continued for about 3 months, but promptly disappeared after surgical removal of the tumor. A superficial spreading mucosal carcinoma with minimal invasion to the submucosa was seen in the antrum, showing the features of poorly differentiated adenocarcinoma. In addition, unique venous inflammation was recognized beneath and around the neoplasm. Arteries and lymph vessels did not exhibit any inflammatory changes. It was presumed that the gastric carcinoma had induced phlebitis, which subsequently brought about the fever. As to the pathogenetic mechanism, it was suggested that a substance produced by the carcinoma cells flowed into nearby veins to induce the phlebitis.

Duplex Doppler sonography (ultrasonic equipment: Toshiba SSA-270A) were performed in the patients with various renal disease (male 44, female 32) admitted to our hospital between June 1990 and August 1991. Interlobar arterial blood flow velocity was measured at the side of renal pyramid through a longitudinal scan. Both the maximum blood flow velocity (Vmax) and the minimum blood flow velocity (Vmin) were measured quantitatively and resistive index (RI: defined as (Vmax-Vmin)/Vmax) were calculated. Vmax and Vmin correlated well with the creatinine clearance (Ccr) (r = 0.56, r = 0.66 respectively), whereas RI, by which we can detect Doppler waveform changes, correlated weak with Ccr (r = 0.39). We found twenty-nine patients (40%) with an elevated RI (greater than or equal to 0.70). They had severe renal dysfunction and active pathologic findings in the tubulo-interstitial or vascular compartment of the kidney. Doppler examination of renal blood flow velocity was valuable not only to estimate renal function but also to assess pathophysiology of renal disease.

Tubulointerstitial alterations were studied in 18 biopsy cases of systemic vasculitis. To evaluate the changes more objectively, two indexes, the number of interstitial inflammatory cells and tubulitis percentage, were used. The group means of both of these indexes were statistically higher than those of the autopsy control group, while 14 of the cases (77.8%) showed a significant difference (P less than 0.01) between individual means and the control group means. On the other hand, tubulointerstitial changes in systemic vasculitis seemed to be less prominent than drug-induced tubulointerstitial nephritis (TIN) according to these indexes. However, comparing these indexes with those of drug-induced TIN, six cases (33.3%) of systemic angiitis could be regarded as having developed pathologic changes similar to TIN. Statistical difference was not shown in the indexes between those patients with histologic evidence of necrotizing angiitis and those without it. Clinically, urinary N-acetyl-beta-D-glucosaminidase (NAG) was abnormally high in all three examined cases, reflecting the damage of renal tubular epithelial cells. Not only the vascular and glomerular lesions, but also tubulointerstitial changes, should be evaluated in the renal biopsy specimen of systemic vasculitis.

In order to evaluate the clinical implication of experimental studies on halothane-induced liver damage in phenobarbital-treated rats, we studied the clinical records of 315 consecutive patients who underwent brain surgery with halothane anesthesia. After exclusion of subjects with a history of alcoholism or antecedent chronic liver disease, clinical data of 279 patients with normal preoperative transaminase activities were analyzed. The incidence of halothane-induced liver injury was significantly higher in the subjects given phenobarbital than in those with no phenobarbital medication (7/100 vs. 1/179, p less than 0.01). To determine if other anticonvulsant compounds can influence halothane-induced liver injury, rats were pretreated with diphenylhydantoin or valproic acid prior to exposure to halothane under hypoxic conditions for comparison with phenobarbital. The degree of halothane hepatotoxicity assessed from ALT activities and morphological alterations was of the decreasing order of phenobarbital greater than controls = diphenylhydantoin greater than valproic acid, and a similar order was observed in the extent of reductive metabolism of halothane. These results indicate that patients pretreated with phenobarbital may be at a greater risk of halothane-induced liver damage, and that treatment with valproic acid and diphenylhydantoin lead to the production of toxic intermediates of halothane to a lesser extent than treatment with phenobarbital does.

Ultrastructural cytochemistry for nonspecific esterase (NSE) was performed on normal and nephritic rabbit kidneys. In normal glomeruli distinct reaction deposits appearing as electron-dense granules were present in visceral epithelial cells (podocytes) and epithelial cells of Bowman's capsule, but only a few small or minute deposits were seen in some endothelial and mesangial cells. In acute proliferative glomerulonephritis (Masugi nephritis), many reaction deposits occurred in mononuclear cells accumulating in glomerular tufts which presented the characteristic features of monocytic cells. Macrophages which had migrated into subendothelial space as well as epithelioid cells and multinucleated giant cells, all of which are known to be derived from monocytes, also exhibited the reaction product. The NSE granules in mesangial and endothelial cells were much smaller and fewer in number than those in monocytic cells. The present method may contribute to the more precise differentiation of monocytic cells from mesangial and endothelial cells in proliferative glomerulonephritis.

A case of necrotizing angiitis is reported. After acute inflammatory changes had subsided, the patient developed the nephrotic syndrome. Postmortem examination disclosed a unique sclerotic glomerular lesion with deposition of eosinophilic material which contained IgM, IgA, C1, and C3. The lesion was distributed in rather selective areas perfused by some of the arcuate arteries.

Three cases of amyloidosis occurring in the later course of idiopathic myelofibrosis were studied at autopsy. In these cases, the amyloid deposition was seen only in the renal glomerulus, which had caused proteinuria. Although their exact nature could not be determined by immunohistochemistry, the amyloid deposits in the three cases were permanganate resistant and exhibited the same organ distribution, indicating a similarity in their character. These cases suggest that amyloidosis might be a complication of idiopathic myelofibrosis, implying that idiopathic myelofibrosis could be a disorder underlying amyloidosis.

Renal tubular dysfunction was induced in Hartley guinea pigs by injection of sodium aurothiomalate (gold) as manifested by excretion of tubular basement membrane (TBM) antigen and renal tubular epithelial (RTE) antigen in urine and tubular proteinuria. Following the tubular dysfunction, autoimmune tubulointerstitial nephritis (TIN) and/or immune complex nephropathy (ICN) developed in a large proportion of animals. TIN was associated with anti-TBM antibodies, and the histological features were characterized by tubular lesions with interstitial mononuclear cell infiltration, destruction of tubules, and interstitial fibrosis. In ICN, the glomerular lesions consisted of partial thickening of capillary walls and mesangial cellularity, and granular immune deposits were seen in the mesangial area and on capillary walls. Furthermore, electron-dense deposits were demonstrated in the mesangial area and in the glomerular basement membrane (GBM) by electron microscopy. Anti-RTE antibodies were detected in the sera and eluates from the kidney of animals with ICN. RTE antigens were also detected in the glomerular deposits by indirect immunofluorescence using anti-guinea pig RTE antibody. These results suggest that TBM and RTE antigens released from renal tubules damaged by a direct toxic action of gold may lead to antibody formation against these antigens and induce TIN and/or ICN.