Futoshi Yoshida

Age-related changes in BDNF protein levels in human serum: differences between autism cases and normal controls.

Accumulating evidence suggests the possible association between the concentrations of serum brain‐derived neurotrophic factor (BDNF) and psychiatric disease with impaired brain development. Yet the reasons remain unclear. We therefore investigated the characteristics of serum BDNF as well as its age‐related changes in healthy controls in comparison to autism cases. BDNF was gradually released from platelets at 4 °C, reached a maximal concentration after around 24 h, and remained stable until 42 h. At room temperature, BDNF was found to be immediately degraded. Circadian changes, but not seasonal changes, were found in serum levels of BDNF existing as the mature form with a molecular mass of 14 kDa. In healthy controls, the serum BDNF concentration increased over the first several years, then slightly decreased after reaching the adult level. There were no sex differences between males and females. In the autism cases, mean levels were significantly lower in children 0–9 years old compared to teenagers or adults, or to age‐matched healthy controls, indicating a delayed BDNF increase with development. In a separate study of adult rats, a circadian change in serum BDNF was found to be similar to that in the cortex, indicating a possible association with cortical functions.

A Case of Nephrotic Syndrome with Glomerular Lipoprotein Deposition with Capillary Ballooning and Mesangiolysis

A 33-year-old man with nephrotic syndrome and rapid deterioration of renal function showed curious glomerular morphological abnormalities. Ballooning of the glomerular capillaries due to a substance accumulated in the capillary lumina and mesangiolysis were prominent histological features. The deposits in the capillary lumen were positive for Sudan III staining, and also for beta-lipoprotein, apoprotein B and apoprotein E by immunofluorescent technique. The staining of beta-lipoprotein in a flower leaf pattern was a striking characteristic, while such staining was negative when studied in 20 patients with nephrotic syndrome who were used as controls. Based on these findings, the morphological abnormalities in this case were considered to be related to lipoprotein deposition in the glomeruli. This case is thought to be the first reported in a complete form in the literature which could be classified as a new kind of disease related to lipoprotein metabolism abnormalities.

A Case of POEMS Syndrome Showing Elevated Serum Interleukin 6 and Abnormal Expression of Interleukin 6 in the Kidney

A 46-year-old female presented with POEMS syndrome. Hemodialysis was initiated to control severe anasarca and declining renal function. Corticosteroids were effective in treating renal insufficiency and other symptoms. Serum interleukin 6 (IL-6) was elevated before the corticosteroid therapy but returned to the normal level under the therapy. Immunostaining for the kidney tissue obtained by a renal biopsy showed a diffuse distribution of IL-6 in the glomeruli; thus, in contrast to normal, IL-6 was detected not only in mesangial cells but also in endothelial cells. IL-6 was also distributed in capillaries in the interstitium. While these results suggest a pathogenic role of IL-6 in POEMS syndrome, other factors may be necessary for the full expression of symptoms. Furthermore, it is suggested that chronically stimulated glomerular endothelial cells are capable of producing IL-6.

A case of angiotropic large cell lymphoma manifesting nephrotic syndrome and treated successfully with combination chemotherapy.

A 52-year-old female had a nephrotic syndrome without neurological or dermatological manifestations. Renal biopsy revealed that glomeruli were filled with tumor cells which bore leukocyte common antigen and pan B cell marker. These cells occupied the capillary lumen and invaded into the mesangial area. Morphological alteration of endothelial cells and glomerular basement membrane were also noticed. The interstitium was well preserved. After five cycles of a combination chemotherapy, CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone), the second biopsy revealed that tumor cells disappeared from glomeruli showing mild sclerosis. Proteinuria became absent. This is the first report of an angiotropic large cell lymphoma manifesting a nephrotic syndrome and treated successfully by CHOP therapy.

Acute renal failure and degenerative tubular lesions associated with in situ formation of adenovirus immune complexes in a patient with allogeneic bone marrow transplantation

We describe the development of acute renal failure and degenerative tubular lesions associated with local immune deposits in a patient with allogeneic bone marrow transplantation. A 21-year-old man with an acute myelocytic leukemia received a bone marrow graft from a cousin mismatched for a single HLA-DR locus antigen. Hemorrhagic cystitis due to adenovirus type 11 infection occurred 26 days after transplantation, and 17 days later the patient developed acute renal failure. A study of renal tissue obtained by needle biopsy showed degenerative and necrotic lesions, especially in the distal part of the nephron. By electron microscopy adenovirus type 11 particles were found in the nuclei of tubular cells and in cellular debris in tubular lumina. By immunofluorescence technique, granular immune deposits containing adenovirus type 11 related antigen(s), immunoglobulins, C3, and membrane attack complex (MAC) C5b-9 of the complement system were detected along the tubular basement membranes but not in glomeruli. The patients IgG did not bind to normal human kidneys. These findings suggest that adenovirus type 11 directly induced acute tubular damage, and that the tubular immune deposits were formed “in situ” by viral antigens and circulating viral antibody.

Unique glomerular lesion with spontaneous lipid deposition in glomerular capillary lumina in the NON strain of mice.

We found a strain of nonobese, nondiabetic (NON) mice which has spontaneous lipid deposition in glomerular capillary lumina. This strain was developed together with a diabetic strain of nonobese diabetic (NOD) mice for the generation of mouse models of diabetes mellitus. In the NON strain, contrary to the name, impaired glucose tolerance (IGT) was observed in about half of the mice. Meanwhile, peculiar glomerular abnormalities which remotely resemble those of diabetic nephropathy were observed in the NON strain. The lesions were characterized by massive lipid accumulation with proteinaceous material within the glomerular capillary lumina. In addition, positive staining for immunoglobulins, especially IgM, was observed by immunofluorescence microscopy. The overall frequency of this lesion was 91%. Mesangiolysis, capillary ballooning with many small lipid vesicles were the striking features by electron microscopy. Histochemical analysis revealed the presence of various lipids in these lesions. However, as far as we examined, these lesions did not correlate with hyperlipidemia or IGT. Lymphoid follicle-like structures were seen around the renal arterioles. The cellular components of these lymphoid follicles reacted with monoclonal antibodies to L3T4. High levels of serum immunoglobulins were observed in this strain. We suppose that the immunological disorders may have some bearing in the evolution of this lesion in NON mice. We believe that this model may be of use in studying the role of lipid derangements in renal diseases.

A new spontaneous animal model of NIDDM without obesity in the musk shrew

The EDS (early-onset diabetes in suncus) colony has been developed as a new closed breeding colony of the musk shrew (Suncus murinus, Insectivora) exhibiting a high incidence of spontaneous diabetes mellitus. We investigated the characteristic features of diabetic shrews in this colony. All diabetic shrews are characterized by glycosuria (Tes-tape value > or = 3+), hyperglycemia (23.3 +/- 0.8 mmol/l) and polyuria, and they were affected by the age of 3 months. Cumulative incidence (64.1% in males and 27.8% in females) was kept intact after the age of 3 months. The growth pattern of diabetic shrews was similar to that of non-diabetic shrews, and obesity was not consistent in diabetic shrews. The intraperioneal glucose tolerance test revealed both impaired glucose tolerance and impaired insulin secretion in diabetic shrews. Insulin sensitivity of diabetic shrews decreased in the intraperioneal insulin tolerance test. Neither severe hypertrophy nor lymphocytic infiltration was observed in pancreatic islets of diabetic shrews. These facts suggested that diabetic shrews in the EDS colony should be classified as early-onset non-insulin dependent diabetes mellitus (NIDDM) without obesity. Early-onset of severe hyperglycemia with impaired glucose tolerance is a distinctive character compared with other non-obese NIDDM models in rodents. We concluded that the diabetic shrews in the EDS colony are a new animal model of human NIDDM without obesity.

Renal Lesions of the FGS Strain of Mice: A Spontaneous Animal Model of Progressive Glomerulosclerosis

The strain of FGS/Nga mouse is reported to develop proteinuria and progressive glomerulosclerosis. We studied the renal pathology of that strain periodically for 1 year. Focal and segmental glomerulosclerosis was observed 3 months after birth and the lesion progressed to the glomerular obsolescence in a year. Electron microscopic study revealed electron dense deposits (DD) in the mesangium and the splitting of glomerular basement membrane. Studies using immunofluorescence and immunoelectron microscopy revealed that these DD were contained IgA, IgM, C3 and the retroviral envelope antigen (gp70). Clinically, proteinuria began at the age of 3 months and the renal function was decreased on time course. No other organs were involved. We studied the renal lesions of FGS mice by the histological and immunohistochemical methods and concluded that this mouse strain provides the tool for studying the mechanisms of the progression of glomerulosclerosis.

Overexpression of Calmodulin in Pancreatic β Cells Induces Diabetic Nephropathy

Recently, endothelial dysfunction induced by an uncoupling of vascular endothelial growth factor (VEGF) and nitric oxide has been implicated in the pathogenesis of diabetic nephropathy (DN). Investigating the pathogenesis of DN has been limited, however, because of the lack of animal models that mimic the human disease. In this report, pancreatic beta cell-specific calmodulin-overexpressing transgenic (CaMTg) mice, a potential new model of DN, are characterized with particular emphasis on VEGF and related molecules. CaMTg mice developed hyperglycemia at 3 wk and persistent proteinuria by 3 mo. Morphometric analysis showed considerable increases in the glomerular and mesangial areas with deposition of type IV collagen. Moreover, the pathologic hallmarks of human DN (mesangiolysis, Kimmelstiel-Wilson-like nodular lesions, exudative lesions, and hyalinosis of afferent and efferent arteries with neovascularization) were observed. In addition, increased VEGF expression was associated with an increased number of peritubular capillaries. Expression of endothelial nitric oxidase synthase was reduced and that of VEGF was markedly elevated in CaMTg mice kidney compared with nontransgenic mice. No differences in VEGF receptor-1 or VEGF receptor-2 expression were observed between CaMTg mice and nontransgenic kidneys. In summary, CaMTg mice develop most of the distinguishing lesions of human DN, and the elevated VEGF expression in the setting of diminished endothelial nitric oxide synthase expression may lead to endothelial proliferation and dysfunction. This model may prove useful in the study of the pathogenesis and treatment of DN.

Ultrastructural observation of glomerular lesions in a new mouse strain manifesting high proteinuria and progressive glomerulosclerosis

Renal pathology of the FGS/Nga strain of mice, which has been known to develop proteinuria and progressive glomerulosclerosis, was studied by light and electron microscopy. Sclerotic changes had increased by 6 months and most of the glomeruli were totally obsolescent by 10 months. By electron microscopy, electron dense deposits were seen in the mice by 3 months and thereafter. Splitting or the irregular thickening of the glomerular basement membrane (GBM) was observed, and some mice showed reticulation in the GBM. The fixed negative charges detectable with polyethyleneimine (PEI) were decreased in the mice with massive proteinuria.