Hisashi Shimojo

Hydronephrosis associated with retroperitoneal fibrosis and sclerosing pancreatitis

Sclerosing pancreatitis is associated with raised concentrations of IgG4. We treated 22 patients with sclerosing pancreatitis, and identified and followed-up three with concomitant hydronephrosis caused by ureteral mass, later diagnosed as retroperitoneal fibrosis. We histologically examined the ureteral and pancreatic lesions of these patients and noted abundant infiltration of IgG4-bearing plasma cells in both tissues. Treatment with corticosteroids lowered serum concentrations of IgG4. IgG4 might also have a pathological role in a systemic fibrosing process that includes pancreatic and retroperitoneal lesions.

Clinical features of a new disease concept, IgG4-related thyroiditis

Objectives: Immunoglobulin (Ig)G4-related disease is a recently proposed systemic disorder that includes autoimmune pancreatitis (AIP), Mikulicz’s disease, and various other organ lesions. In the present retrospective study, we examined whether thyroid lesions should also be included in IgG4-related disease (Ig4-RD) under the new term IgG4-related thyroiditis. Method: We enrolled 114 patients with Ig4-RD, including 92 patients with AIP, 15 patients with Mikulicz’s disease, and seven patients with IgG4-related cholangitis, and analysed clinical findings, function, serum values of activity markers, computed tomography (CT) images, and histology of the thyroid gland. Results: Among the 22 patients (19%) in our cohort who were found to have hypothyroidism [thyroid stimulating hormone (TSH) > 4 mIU/L], 11 patients had clinical hypothyroidism [free thyroxine (FT4) < 1 ng/dL] and 11 patients had subclinical hypothyroidism (FT4 ≥ 1 ng/dL). Serum concentrations of IgG, IgG4, circulating immune complex (CIC), and β2-microglobulin (β2-MG) were significantly higher in the hypothyroidism group compared with the remaining 92 euthyroid patients, and serum C3 concentration was significantly lower. After prednisolone treatment, TSH values had decreased significantly (p = 0.005) in this group and FT4 values had increased significantly (p = 0.047). CT images showed that the thyroid glands of patients with clinical hypothyroidism had a significantly greater volume than those of the euthyroid and other groups. Pathological analysis of one resected thyroid gland disclosed a focused lesion with infiltration of lymphocytes and IgG4-bearing plasma cells and loss of thyroid follicles. Conclusions: Thyroid lesions associated with hypothyroidism can be considered as a new disease termed IgG4-related thyroiditis. Awareness of this condition should lead to appropriate corticosteroid treatment that may prevent progression to a fibrous state.

Extensive lanthanum deposition in the gastric mucosa: the first histopathological report.

Lanthanum carbonate is one of the new phosphate binders used for the treatment of hyperphosphatemia in patients with chronic kidney disease. It is poorly absorbed from the gastrointestinal tract, forms insoluble complexes within the lumen, and prevents the absorption of dietary phosphate. A 63‐year‐old female with a 7‐year history of peritoneal dialysis, who was treated with lanthanum carbonate for four years, underwent endoscopic submucosal dissection for intramucosal gastric cancer. Resected specimens showed massive accumulation of macrophages containing fine, granular, brown material in the lamina propria. This was confirmed as lanthanum deposition by scanning electron microscopy with energy dispersive x‐ray spectroscopy. Although lanthanum may be poorly absorbed, increased tissue accumulation of lanthanum, particularly in the liver and bone, has been reported in animals with chronic kidney disease. This report indicates enhanced gastrointestinal absorption of lanthanum in some patients or conditions, although its clinical significance awaits further studies.

Diacylglycerol kinase zeta inhibits G(alpha)q-induced atrial remodeling in transgenic mice.

BACKGROUND Our previous study showed that diacylglycerol kinase zeta (DGKzeta), which degenerates diacylglycerol (DAG), inhibits ventricular structural remodeling and rescues activated G protein (alpha)q (G(alpha)q)-induced heart failure. However, whether DGKzeta inhibits atrial remodeling is still unknown. OBJECTIVE This study aimed to elucidate the effects of DGKzeta on atrial remodeling. METHODS A transgenic mouse (G(alpha)q-TG) with cardiac expression of activated G(alpha)q and a double transgenic mouse (G(alpha)q/DGKzeta-TG) with cardiac overexpression of DGKzeta and activated G(alpha)q were created. RESULTS During electrocardiogram (ECG) recording for 10 min, atrial fibrillation was observed in 5 of 11 anesthetized G(alpha)q-TG mice but not in any wild-type (WT) and G(alpha)q/DGKzeta-TG mice (P <.05). All of the ECG parameters measured were prolonged in the G(alpha)q-TG compared with WT mice. Interestingly, in G(alpha)q/DGKzeta-TG mice, although the PR and RR intervals were still prolonged, the P interval, QRS complex, and QT interval were not different from those in WT mice. In Langendorff-perfused hearts, the incidence of atrial tachyarrhythmia induced by rapid atrial pacing was greater in G(alpha)q-TG hearts than in G(alpha)q/DGKzeta-TG hearts (P <.05). Action potential duration prolongation and impulse conduction slowing were observed in G(alpha)q-TG atria compared with G(alpha)q/DGKzeta-TG atria. Dilatation of the left atrium with thrombus formation was observed in 9 G(alpha)q-TG hearts but not in any G(alpha)q/DGKzeta-TG hearts. Moreover, the degree of extensive interstitial fibrosis in the left atrium was greater in G(alpha)q-TG hearts than that in G(alpha)q/DGKzeta-TG hearts (P <.05). CONCLUSION These results show that DGKzeta inhibits G(alpha)q-induced atrial remodeling and suggest that DGKzeta is a novel therapeutic target for atrial fibrillation.

Malignant tumor, of the gastrointestinal stromal tumor type, in the greater omentum.

We report herein a rare case of gastrointestinal stromal tumor (GIST) type, arising from the greater omentum. A 65-year-old man who had a large abdominal tumor was referred to our hospital. Ultrasonography (US) and computed tomography (CT) scans showed a mass occupying almost the entire abdomen anterior to the bowel loops. Abdominal angiography showed that the main feeding artery of the tumor was the right gastroepiploic artery. The preoperative diagnosis was suspected gastric leiomyosarcoma. Laparotomy revealed a large mass arising from the greater omentum, and the tumor seemed to be completely excised. Histopathological and immunohistochemical studies indicated the tumor had the same characteristics as GIST. Twelve months after the operation, the tumor recurred in the peritoneal cavity at the site of the stomach, and was associated with multiple liver metastases. The patient died of hypovolemic shock. Necropsy revealed that rupture of one of the metastatic liver tumors had resulted in a massive intraperitoneal hemorrhage.

Renal involvement in bone marrow transplantation

SUMMARY:  Bone marrow transplantation (BMT) is an effective therapeutic strategy for leukaemic malignancies and depressed bone marrow following cancer. However, its side effects on kidneys have been reported. Some drugs and irradiation are also suggested to be nephrotoxic. It is well known that haemolytic uraemic syndrome (HUS) after BMT develops as late‐onset BMT nephropathy. Cyclosporine A (CsA) is a possible cause. Radiation nephropathy shows changes that are similar to the histology of HUS. These findings suggest that endothelial damage is closely associated with the pathogenesis of post‐BMT nephropathy. Recently, some patients have developed glomerulonephritis accompanied by graft‐versus‐host disease (GVHD) after BMT. In these patients immune deposits are found mainly in subepithelium and mesangium equal to those of secondary membranous glomerulonephritis. A murine experimental model of GVHD manifests similar symptoms and histological changes to those of actual patients and may suggest the pathogenesis of glomerulonephritis.

Mature teratoma of the placenta

A rare case of a mature teratoma of the placenta is reported. The tumor lay between the amnion and the chorlon and contained skin and its appendages, bone, cartilage, fat and ganglia, without organization. There was no evidence of a recognizable umbilical cord. We concluded that the tumor was a mature teratoma of the placenta. The distinction between a teratoma and a fetus acardius amorphus, and the possible origin of the tumor in this site, are discussed with a brief review of the literature.

Preexisting Membranous Nephropathy in Allograft Kidney

A case of membranous nephropathy, preexisting in a donor kidney, will be reported. A 41-year-old man underwent a cadaver renal transplantation. An allograft biopsy specimen obtained during the operation showed spike formation on periodic acid-silver methenamine staining and deposition of IgG along the glomerular capillary loop on immunoperoxidase staining. Immunofluorescence staining for IgG remained in the specimens obtained on day 11 and after 4 weeks, but markedly decreased in the specimen obtained 7 weeks after transplantation. Electron-dense deposits also decreased in amount, but irregular thickening of the glomerular basement membrane with spikes, electron-lucent washout lesions, and small amounts of electron-dense deposits remained 20 months after the transplantation. These findings suggest that membranous nephropathy, as well as IgA nephritis and diabetic nephropathy, resolve after renal transplantation and that deposition of IgG markedly decreases within a few months after transplantation, but that complete histological restoration of the basement membrane needs at least a few years.

Adaptation and distortion of podocytes in rat remnant kidney

A sequence of alterations of podocytes as well as the development of glomerulosclerosis was analyzed in a five‐sixths nephrectomy rat model. Morphometric measurements showed a gradual enlargement in glomerular size without any increase In the number of podocytes in the glomerulus. Structural changes of podocytes appeared as early as 4 weeks after operation, and increased their degree and extent with time. In electron microscopic studies, changes of podocytes In the early stage consisted of foot process stretching and thinning, and cell body attenuation accompanied by pseudocyst formation. As weeks passed, these changes became prominent and were occasionally associated with podocyte detachment from the glomerular basement membrane followed by tuft adhesion and the development of segmental sclerosis. In parallel to the structural changes, Immunohistochemical staining demonstrated a marked Increase of desmin expression in the glomerulus with Intense staining in podocytes. Podocyte alterations were Identified as an adaptation to the enlargement of the glomerulus and, consequently, the podocytes seemed to fail to adapt to the structural changes of the glomerulus. The present study supports the hypothesis that podocyte defects are responsible for both the Initiation and progression of glomerular damage. Furthermore, the findings may provide the hypothesis that the native disposition of podocytes in the glomerulus participates In the development of glomerular lesions in a focal and segmental fashion.

Reduced Glycosylation of α-Dystroglycans on Carcinoma Cells Contributes to Formation of Highly Infiltrative Histological Patterns in Prostate Cancer

α‐Dystroglycan (DG) carries glycan chains that bind to laminin and thus function in homeostasis of not only skeletal muscle but also of various epithelial cells. Loss of glycosylation has been suggested to play important roles in tumor development, particularly in detachment and migration of carcinoma cells. We previously reported that glycosylation of α‐DG, but not levels of α‐DG core protein itself, is reduced in prostate carcinoma. In this study, we investigate the association between reduction of laminin‐binding glycans on α‐DG and the degree of tumor cell differentiation and/or infiltrative properties, as assessed by the Gleason grading system.