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OBJECTIVE To examine the interaction between i.c.v. administration of endothelin and brain natriuretic peptide (BNP) on vasopressin (AVP) secretion in unanesthetized, freely moving rats. METHODS I.c.v. cannulation and femoral artery catheterization were performed 7-8 days and 2 days before the experiment, respectively. Endothelin and BNP were injected into the third ventricle through the guide cannula. One millilitre of blood was collected for AVP measurement 30 min before and 10 min after i.c.v. injection. RESULTS Central administration of endothelin (20 or 40 pmol/2 microliters) dose-dependently evoked the elevation of plasma AVP levels. Preinjection of BNP (0.2 or 1 nmol/3 microliters, i.c.v.) dose-dependently attenuated central endothelin (40 pmol/2 microliters)-induced plasma AVP secretion. CONCLUSIONS We have already reported that BNP attenuated central endothelin-induced pressor response and plasma catecholamine secretion. Taken together, the results indicate that BNP attenuated central endothelin-induced pressor response, at least partially, by suppressing sympathetic nervous system activation and plasma AVP secretion.

A study was carried out in four patients with nephrotic diabetic nephropathy in order to determine if decreased creatinine clearance observed during prostaglandin E1 therapy was reversible on discontinuation of therapy. The patients received 40 μg prostaglandin E1 intravenously twice daily for 4 weeks and creatinine clearance and daily excretion of urinary protein were measured immediately before, during and 2 weeks after therapy. Total serum protein and serum albumin were also determined. There was a significant decrease in creatinine clearance during therapy and after therapy clearance increased but not significantly. It is concluded that decreased creatinine clearance during prostaglandin E1 therapy has a partial reversibility on discontinuation of the treatment.

Senile dementia of the Alzheimer type (SDAT), in contrast to multi-infarct dementia (MID) was associated with delirium and marked increases in the number of walking steps taken during both the day and night. In SDAT patients, plasma ACTH levels in the afternoon and evening were higher but plasma corticotropin releasing hormone (CRH) levels in the evening were lower than in the MID patients. A positive correlation between ACTH levels and walking steps and a negative correlation between plasma levels of CRH and ACTH were found. These results suggest relevance of hyper-kinetic delirium to disruption of diurnal rhythm of the pituitary-adrenal axis, and a possible mechanism of the short feedback suppression of CRH release by increased circulating ACTH.

To examine the effects of aging on the density and distribution of somatostatin receptors (SS-R) in the rat brain, receptor autoradiography for SS-R was carried out in rats aged 3 and 24 months using 125I-labeled Tyr11-SS-14. Autoradiograms were quantitatively assessed by an image analyzer to evaluate changes in the expression of SS-R due to senescence. Statistically significant decreases in SS-R binding were found in specific regions of the brains of senescent rats as compared to young adult rats. The regions affected included the periaqueductal gray matter (73% loss versus young adult rats), the interpeduncular nucleus (73% loss), the pontine nucleus (63% loss), the superior colliculus (46% loss), the ventral tegmental area (46% loss), the temporal cortex (39% loss), the frontal cortex (34% loss), the hippocampus (33% loss), the amygdala (27% loss) and the claustrum (26% loss). There was no significant change in SS-R expression in the spinal cord with aging. Significant reductions in SS-R binding in these brain regions may be involved in the impairment of sensory and cognitive function that can occur with aging.

The autoradiographic localization of α1- and α2-adrenoceptors was identified in 22-week-old Wistar – Kyoto rat kidney, using α1-selective ([3H]bunazosin) and α2-selective ([3H]yohimbine) antagonists. [3H]Bunazosin binding was distributed predominantly over the cortex, less over the outer medulla and was absent from the inner medulla. [3H]Yohimbine binding was distributed predominantly over the medulla, less over the renal cortex and was absent from the inner medulla. In addition, the distribution of renal α-adrenoceptors was investigated in 3-, 7- and 22-week-old spontaneously hypertensive rats (SHRs) using a computerized image analysis system. Renal α-adrenoceptors were both found to be increased in SHRs at all ages tested compared with their respective controls and were increased in both the cortex and the outer medulla. The increase in renal α-adrenoceptors was already present in 3-week-old SHRs whose systolic blood pressures did not differ significantly from those of the controls. The results strongly suggest that these abnormalities of renal α-adrenoceptors may play a critical role in the development of hypertension in SHRs.

Changes in the distribution and densities of somatostatin receptors (SS-R) in young adult and aged rat brain and the effects of chronic administration of bifemelane hydrochloride (bifemelane) on these changes were studied by in vitro quantitative autoradiography of iodinated [Tyr11] SS-14. SS-R was highest in density in the amygdala, followed by the cingulate cortex, temporal cortex, frontal cortex, hippocampus and septal nucleus in the young adult rats. In contrast, SS-R binding was markedly reduced in the frontal cortex, temporal cortex, cingulate cortex, hippocampus, amygdala and septal nucleus of aged rats compared to young adult rats. However chronic administration of bifemelane significantly increased SS-R binding in the frontal cortex, temporal cortex, cingulate cortex, hippocampus and septal nucleus of aged rats without effects on young adult rats. This bifemelane-induced increase in SS-R is considered to have important implications in the mechanism of the therapeutic efficacy of bifemelane.

Sweet症候群は発熱,白血球増多,有痛性隆起性紅斑を生じ,組織学的には真皮に好中球の浸潤を認めることが特徴とされている.関節痛,隆起性紅斑,発熱,口腔内アフタを主訴とする42歳の男性についてSweet症候群の診断のもとにコルヒチンを投与したところ関節痛,口腔内アフタの消失および炎症所見の改善を得,長期にわたって副作用もなくコントロールすることができた. Sweet症候群の治療にあたってコルヒチンは有用な薬剤であることが示された.

ネフローゼ症候群を合併した慢性リンパ性白血病(以下CLL)の1例を報告する.症例は56歳,男性.昭和61年蛋白尿を指摘され,昭和63年8月より下肢の浮腫,全身倦怠感,盗汗,レイノー現象が出現した.同年11月急性扁桃腺炎を契機にネフローゼ症候群を発症し抗核抗体陽性,抗DNA抗体高値,低補体価よりループス腎炎の疑いにてプレドニゾロン(以下PSL) 30mg/日, dipyridamole 300mg/日投与され,腎生検ではループス腎炎(diffuse proliferative lupus nephritis)に類似の組織学的所見を呈していた.経過中に末梢血リンパ球数(10,560/mm3)の増加と膜表面免疫グロブリン保有細胞(IgM, IgD, κ鎖陽性)が80%を占め,モノクローナルなBリンパ球の増殖が認められた.さらに,骨髄穿刺では同じ表面マーカーを有する成熟小リンパ球が50%を占めCLL (stage 0)と診断した.現在, PSLの投与により蛋白尿の消失,末梢血リンパ球数も減少し,良好な経過をたどっている.

Neuro-Behcet病の神経症状は多彩であるが,複視のみの神経症状で発症し,橋の側方注視中枢に限局した障害をきたした症例を経験した.症例は, 38歳男性. 25歳ころより口腔内アフタ,アクネ様皮疹,外陰部潰瘍が出現しはじめ,その後,眼症状も合併したため, Behcet病としてコルヒチンの投与を受けていた.昭和63年3月,突然発熱,頭痛とともに複視が出現したため当科受診し入院となった.髄液圧の上昇と単核球の中等度の増加が認められるが,精神症状はなく,頭部CTおよびMRIでも異常なく,髄液中にoligoclonal bandが認められることから,多発性硬化症との鑑別が問題となった.しかし4主症状が存在することや,左眼の外転障害以外に右眼の内転障害も認められることから, neuro-Behcet病による橋の側方注視中枢の障害と考え,プレドニゾロンの投与を行ったところ,複視は速やかに消失した.

重篤な心不全のため血液透析 (HD) の施行は困難と判断しCAPDを施行したところ, 良好に尿毒症をコントロールし得た慢性関節リウマチ (RA) に続発したアミロイドーシスの腎不全患者を2例経験したので報告する.症例1は75歳, 女性. 昭和56年にRAと診断され, 昭和58年に蛋白尿が出現した. 昭和62年より腎機能が低下し, 平成元年7月より腎機能が増悪した. 心不全が高度なためHDの施行は困難と判断し, 8月にCAPDへ導入した. 以後, 良好に尿毒症や浮腫, 心不全症状はコントロールし得た. 平成2年3月に胃生検でアミロイドの沈着を認めたが, その頃より心不全が再び増悪し血圧が低下した. 5月1日には徐脈傾向となり7日に死亡した. 剖検の結果, AA型のアミロイドが心臓, 腎臓, 甲状腺, 膵臓, 消化管, 全身の中小動脈に高度に認められた.症例2は72歳, 女性. 昭和57年にRAと診断され, 昭和63年に蛋白尿, 腎機能低下を認めた. 平成元年9月に小唾液腺生検と甲状腺生検でAA型のアミロイドの沈着を認め, 続発性アミロイドーシスと診断した. DMSO (dimethylsulfoxide) の投与によりやや改善傾向を認めたが, 本人が服用を拒否した平成2年2月末より急激に腎機能が悪化した. 重篤な心不全を伴ったため, HDの施行は困難と判断し3月にCAPDへ導入したところ尿毒症や心不全は良好にコントロールし得た. しかし7月より再び心不全が悪化し, 8月より血圧の低下を認め, 9月12日に死亡した.2例共に重篤な心不全が存在したが, CAPDにより良好に尿毒症をコントロールし得た. しかし心不全の悪化のため, 導入後それぞれ8か月と6か月で死亡した. その心不全の主因として心アミロイドーシスの悪化が考えられた. CAPDへ導入した後も, 心アミロイドーシスの進展を予防するための治療を継続して行う必要があると考えられた.

The role of central angiotensin II (AII) in the shaking stress-induced adrenocorticotropic hormone (ACTH), plasma catecholamine secretion and pressor response were investigated using conscious rats. We also studied whether or not vasopressin (VP) is involved in the shaking stress-induced pressor response. The shaking stress caused significant elevations in plasma ACTH, catecholamine, and systolic blood pressure. Intra-third ventricular administration of the AII antagonist, Sar 1 , Ile 8 -angiotensin II (saralasin) significantly attenuated pressor response and plasma noradrenaline elevation but not plasma ACTH elevation. Pretreatment with the vascular-type VP receptor (V1) antagonist, d(CH 2 ) 5 Tyr(Me)AVP, did not attenuate pressor response nor plasma catecholamine elevation. These results indicate that the central angiotensinergic pathway at least partly mediates the shaking stress-induced activation of the sympathetic nervous system without VP involvement, and that central AII does not mediate the ACTH secretion evoked by shaking stress.

The changes in the levels of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) in the neurointermediate lobe of the pituitary (NIL) following hypertonic saline administration were examined in rats. The plasma osmotic pressure in rats receiving 2% NaCl for 8 days was greatly increased. Plasma AVP concentration in rats receiving 2% NaCl for 8 days were significantly higher than in control rats (566% of the control level). Plasma corticosterone was significantly higher in the saline-treated rats than in controls, whereas plasma ACTH was not significantly different. The pituitary ACTH concentration was much higher in the saline-treated rats than in controls. CRH in the NIL was increased significantly by saline treatment (419% of the control concentration), whereas the CRH in the paraventricular nucleus and median eminence of control and saline-treated rats did not differ significantly. The AVP in the NIL fell greatly in saline treated rats. The extract from both control and saline-treated rats showed a major peak for immunoreactive CRH, with a retention time identical to that of rat CRH. However, the peak was much higher in the extract from saline-treated rats. The immunoreactive AVP peak was greatly reduced in saline-treated rats. These results suggest that hypertonic saline administration increases the CRH in the NIL and causes AVP hypersecretion and/or hyperfunction of magnocellular-NIL CRH might be responsible for pituitary-adrenal stimulation in saline-treated rats.

Bucillamine (リマチルR, BU)投与により尿異常をきたした慢性関節リウマチ(RA)患者5例を臨床病理学的に検討した. 5症例は年齢29歳から70歳で,全例女性である. RAの罹病期間は5年から18年, RAのClass, StageまたCRP,赤沈値などにみる活動性はさまざまであった.尿異常としては全例蛋白尿陽性であったが, 5例中4例は顕微鏡的血尿を伴っていた.また2例はネフローゼ症候群を呈していた.尿異常出現までのBU投与期間および投与量はそれぞれ2.5ヵ月から15ヵ月(平均6.1ヵ月), 7.9gから128.0g (平均41.6g)であった.一般検査で肝機能障害など他の臓器障害を示唆する所見は得られなかったが,免疫学的検査にて4例に抗核抗体がspeckled patternを呈し, 2例はBUに対するリンパ球幼若化試験(DLST)が陽性であった.腎機能検査では血清クレアチニンが上昇するような高度の腎不全症例はみられなかったが,尿細管障害を示唆する尿中NAGの上昇, Fishberg濃縮試験の低下をきたす症例が認められた. 4例に経皮的腎生検を施行したが全例膜性腎症の組織所見であり,蛍光抗体法でidiopathicな膜性腎症に比較して補体系の沈着が少ないこと, deposit量が少なくsegmentalな沈着である点が特徴的であった.また,尿細管,間質の変化は認めなかった.ネフローゼ症候群を呈した2例には副腎皮質ホルモンを投与し,他の症例に対してはBU中止のみで経過観察中であるが,現在まで1例を除き蛋白尿は減少傾向であり腎不全への移行例は認めていない. BUは, RA緩解導入剤として開発されたimmunomodulatorであり,腎障害の報告は少ないが,今後その使用に際し,腎障害,とくに膜性腎症の発生に十分な注意を要する.

Tubular injury leading to tubular atrophy and tubular loss is one of the characteristic features of chronic renal failure. To reveal the mechanism of tubular atrophy in chronic renal failure, the involvement of apoptosis was studied byin situ nick end labeling of biotinylated deoxyuridine by terminal deoxy nucleotidyl transferase (TUNEL) as well as by electron microscopy. TUNEL-positive cells and heterophagosomes containing apoptotic body-like structures having nuclear fragments with condensed chromatin were observed in the renal tubular epithelium 8 weeks after nephrectomy. It has become apparent from our study that atrophy of the tubules in chronic renal failure results, to some extent, from cell deletion by apoptosis.

Renal hypertrophy is a characteristic and early manifestation of diabetes in human and experimental animals. We examined the precise distribution of insulin-like growth factor-I (IGF-I) receptor mRNA in the experimental diabetic rat kidney using a nonradioactive in situ hybridization technique. Expression of IGF-I receptor mRNA was rarely seen in the glomeruli of control rats. IGF-I receptor mRNA was detected after induction of diabetes in glomerular mesangial, visceral epithelial, and parietal epithelial cells. The number of IGF-I receptor mRNA-positive cells in a glomerulus increased significantly at 4 weeks as compared with the control rats. Overexpression of IGF-I receptor in glomerular cells may contribute to the glomerular hypertrophy in diabetic nephropathy.

In diabetic nephropathy there is accumulation of matrix proteins. Overproduction of these matrix proteins considered to be due to the phenotypic change of mesangial cell. In order to detect the phenotypic change of the mesangial cell, renal biopsy specimens from patients with diabetic nephropathy were stained with antibodies against various types of collagens and contractile-associated protein, caldesmon. Type III collagen was not stained in the glomerulus and type VI collagen showed mesangial pattern from normal controls. In diabetes, mesangial staining of type III collagen and increases in type VI collagen were observed in the mesangium. Increased mesangial staining of caldesmon was noted in the glomerulus from diabetic nephropathy in contrast to only vessel staining from normal controls. These results indicate that phenotypic changes are noted in the mesangium in diabetes. Expression of contractile-associated protein such as caldesmon, would serve as a useful marker to predict glomerulosclerosis.

Advanced glycation endproducts (AGE) have been proposed as a major mediator in the development of various diabetic complications. In order to evaluate the involvement of AGE in the development of diabetic nephropathy, we examined the localization of AGE in the kidney of the streptozotocin-induced diabetic rats immunohistochemically using a monoclonal antibody directed to AGE. In the diabetic rats, glomerular hypertrophy, thickening of the glomerular basement membrane, and expansion of mesangial matrix were observed. AGE was detected in expanded mesangial area and glomerular basement membrane in the kidneys of diabetic rats. The present results suggest that AGE may participate in the development of diabetic nephropathy.

Recently, we have developed a tissue-negative staining method, and successfully visualized fine meshwork structure of the glomerular basement membrane (GBM). To clarify the mechanism of proteinuria in active Heymann nephritis, we performed tissue-negative staining and investigated the ultrastructural alterations of the GBM. Active Heymann nephritis, the animal model of human membranous nephropathy, was induced in Lewis rats by the injection of proximal tubular brush border antigen, i.e. Fx1A. Urinary protein excretion was measured and histological studies were performed over 15 weeks following the Fx1A injection. Proteinuria developed at 10 weeks after injection (38.2 ± 7.4 mg/day) and progressively increased (160.2 ± 20.6 mg/day at 15 weeks). Capillary fine deposits of IgG and C3 were seen by immunofluorescence, and subepithelial electron dense deposits (EDD) by transmission electron microscopy (TEM). Using the tissue-negative staining method, regular meshwork structure consisted of fine fibrils and pores (2.5 ± 0.7 nm in short dimension) was observed in the GBM of control rats. At 10 and 15 weeks after injection, the GBM, directly facing the endothelial side of EDD, contained enlarged pores and nephrotic tunnels. Mean values of the short dimension of enlarged pores were 2.9 ± 0.5 nm at 10 weeks and 3.1 ± 0.4 nm at 15 weeks, which were significantly larger than that of control rats (p < 0.01). The rest area of the GBM, including newly produced GBM covering the epithelial side of EDD, had no significant difference in size of the pores from control GBM and no tunnels. Although there was no significant difference in the size of enlarged pores between 10 and 15 weeks, the percentage area of GBM with impaired size barrier increased at 15 weeks (51.4 ± 8.1%) compared with 10 weeks (24.0 ± 8.3%) and related to severity of proteinuria. The density of the tunnels also increased at 15 weeks. In conclusion, immune deposits may affect the GBM biosynthesis and induce the defect of size barrier of the GBM, which is responsible for proteinuria in active Heymann nephritis.

Background/Aims: Glomerular basement membranes (GBM) and tubular basement membranes (TBM) consist of a fine meshwork composed mainly of type IV collagen. Each segment of tubules has specialized physiologic functions, and thus we investigated the ultrastructure of various basement membranes in rat kidneys. Methods: Since purifying basement membranes from different tubule segments is technically challenging, we employed tissue negative staining rather than conventional negative staining to compare the ultrastructures of proximal and distal TBM and GBM in normal rats. We also assessed the distribution of extracellular matrix components including type IV collagen, laminin, heparan sulfate proteoglycan, and fibronectin in the basement membranes by immunohistochemistry. Results: TBM and GBM of normal rats showed a fine meshwork structure consisting of fibrils forming small round to oval pores. Short- and long-pore diameters in proximal tubules were 3.3 ± 0.5 and 3.9 ± 0.6 nm, respectively, and in distal tubules 3.5 ± 0.7 and 4.3 ± 0.8 nm, respectively. For GBM the respective diameters were 2.5 ± 0.5 and 3.0 ± 0.5 nm. Immunohistochemical analysis showed no significant difference in distribution of extracellular matrix components between proximal and distal TBM. However, immunofluorescence scores of α1 chain of type IV collagen, fibronectin, and laminin were higher in the TBM than in the GBM. On the other hand, heparan sulfate proteoglycan was higher in the GBM. Conclusion: Ultrastructural differences in renal basement membranes may be related to differences in physiologic function in each segment.

正常血圧の維持透析患考19名を, その基礎疾患から, 3群-慢性糸球体賢炎 (CGN)・糖尿病 (DM)・嚢胞腎 (PCK) に分け, 透析時の血圧変動と, その際の血漿レニン活性 (PRA), 血漿アルドステロン濃度 (PAC) の変動を検討した. DM群では, 透析中に他の2群に比較し, 著明な血圧下降 (43.7±19.3mmHg) がみられた. CGN群とPCK群には, 両者の問に, 血圧下降度において, 有意な差はみられなかった. また, DM群では, PRA基礎値は0.74±0.15ng/ml/hrと他の2群に比べ著しく低値 (p

Platelet-derived growth factor (PDGF) is an important mitogenic factor for various cells. In order to elucidate the role of PDGF in the development of human glomerulonephritis, we examined the gene and protein expression of the PDGF-B chain (PDGF-B) and PDGF-beta receptor (PDGFR-beta) in renal biopsy specimens from patients with various forms of glomerulonephritis using a nonradioactive in situ hybridization and an immunohistochemical technique. The mRNA expression of PDGF-B and PDGFR-beta was significantly increased in the glomeruli of patients with mesangial proliferative glomerulonephritis (IgA nephropathy, Henoch-Schönlein purpura nephritis, and lupus nephritis) compared with those in normal glomeruli. In cases with increased protein expression of PDGF-B and PDGFR-beta, each mRNA expression was also increased. The degree of glomerular injury was positively correlated with the number of mRNA-positive cells for both PDGF and PDGF receptor. There was also a positive correlation between the number of mRNA-positive cells for PDGF-B and PDGFR-beta. PDGF-B and PDGFR-beta were also expressed on cells of the capillary wall, cellular crescents and infiltrated cells in the interstitium. The results suggest that PDGF acts as an important and common mediator for the development of various forms of human mesangial proliferative glomerulonephritis. Furthermore, PDGF may participate in crescent formation and tubulo-interstitial injury.

Apoptosis is a distinct form of cell death that is observed under various physiologic and pathologic conditions, and it is thought to be important in regulating the number of glomerular cells. This study investigated the possible role of reactive oxygen species in the induction of apoptosis in cultured human mesangial cells. Fragmented nuclei with condensed chromatin, a morphologic characteristic of apoptosis, were observed by electron microscopy in mesangial cells exposed to 0.02 mM hydrogen peroxide for 4 h. Nuclear DNA extracted from mesangial cells that had been incubated with hydrogen peroxide (2 to 20 mM) or with xanthine (0.05 mM) and xanthine oxidase (5 to 100 mU/mL) showed the ladder pattern on electrophoresis that is a biochemical marker for apoptosis. Hydrogen peroxide (0.02 to 20 mM) decreased the number of viable cells, as determined by trypan blue exclusion, in a dose-dependent manner. Hydrogen peroxide or xanthine and xanthine oxidase increased the lactate dehydrogenase release from mesangial cells in a dose- and time-dependent manners. The release of lactate dehydrogenase was prevented by treatment with a free radical scavenger, catalase. Hydrogen peroxide (2 mM) also significantly increased the number of mesangial cells with fragmented DNA as detected by in situ nick end-labeling Results indicate that reactive oxygen species induce apoptosis in cultured human mesangial cells. Furthermore, apoptosis of mesangial cells induced by reactive oxygen species may contribute to the loss of such cells observed in glomerular disease.

We describe a case of diabetes insipidus (DI) due to a pituitary tumor in a 33-year-old pregnant woman who developed a sudden onset of polyuria (over 8 l/day) and polydipsia at 30 weeks of gestation. Her plasma concentration of vasopressin (AVP) was low compared with high serum osmolality (298 mOsm/kg), and her urine output was well controlled by treatment with desmopressin acetate (DDAVP). Cranial magnetic resonance imaging (MRI) demonstrated a 1.8 x 1.2-cm pituitary tumor, but she did not have any disturbance in the release of anterior pituitary hormones. The serum concentration of cystine aminopeptidase (CAP) was within the normal range for a woman at 34 weeks of gestation. After an uncomplicated delivery of a healthy girl, her polyuria gradually resolved. The size of the pituitary tumor gradually decreased in parallel to a reduction in her urine output, but a silent hemorrhage was detected in her pituitary gland 4 weeks after the delivery. Although pregnancy is sometimes associated with central DI, the occurrence of DI due to pituitary tumor under pregnancy is rare. The basal AVP recovered to within the normal range, but the low response of AVP secretion to high osmolality persisted. In this case, pregnancy may affect the manifestation of subclinical DI. This case may therefore enhance our understanding of the mechanisms of DI during pregnancy.

Schmidt syndrome consists of adrenal insufficiency and Hashimoto's thyroiditis, which are probably caused by an autoimmune process. We encountered a patient who manifested severe generalized fatigue due to Schmidt syndrome recurrently. The endocrinological examination tests on the patient showed that the increase in thyroid stimulating hormone (TSH) and ACTH concentrations were not remarkable, despite hypo-function of the peripheral glands. Subsequent cranial magnetic resonance imaging (MRI) exhibited the existence of a pituitary tumor. The pathological findings on the resected tumor and endocrinological stimulation tests proved that the tumor was a FSH-producing adenoma. Although involvement of the pituitary region in Schmidt syndrome on rare occasions presents as hypophysitis, no pituitary adenoma has previously been reported in association with this syndrome. We present a patient with Schmidt syndrome and an accompanying FSH-producing pituitary adenoma. The coexistence of these disorders suggests that the functioning pituitary tumor might be considered as a pituitary lesion in Schmidt syndrome.

The effect of adding a very low dose of a sulphonylurea (tolbutamide) to the treatment of 10 patients with non-insulin-dependent diabetes mellitus (NIDDM) was investigated. Patients took 0.1 mg tds of an α-glucosidase inhibitor orally for 8 weeks, and 50 mg tds of the sulphonylurea, tolbutamide, for the last 4 weeks of this period. The glycosylated haemoglobin level was significantly reduced during the combined treatment period compared with the level after treatment with α-glucosidase inhibitor alone ( P = 0.035), although not compared with the pretreatment level. There were no significant changes in postprandial blood glucose, serum lipid levels or connective peptide immunoreactivities. These preliminary results indicate that the addition of a very low dose of tolbutamide to a recommended diet and treatment with an α-glucosidase inhibitor, may improve glucose metabolism without raising insulin secretion or influencing lipid metabolism.

Studies were carried out to assess various ways of improving glycaemic control and lipid profiles of patients with non-insulin-dependent diabetes mellitus (NIDDM) in whom glucose metabolism was poor. Part or all of the dose of the sulphonylurea that had been used to treat patients in Group 1 ( n = 8) was replaced by an α-glucosidase inhibitor. Symptoms related to hypoglycaemia disappeared and the postprandial blood glucose level was significantly increased ( P < 0.043) but serum lipid levels were not significantly altered and the mean glycosylated haemoglobin level was unchanged. In Group 2 ( n = 10) patients, a large part of the insulin dose was replaced by an α-glucosidase inhibitor. Hypoglycaemia-related symptoms disappeared but there were no significant changes in lipid profiles, postprandial blood glucose or glycosylated haemoglobin levels. The third group of patients ( n = 9) had been treated with insulin alone and were given additional α-glucosidase inhibitor without changing their insulin dose. This did not significantly change their lipid profiles, postprandial blood glucose or glycosylated haemoglobin levels. In Group 4 ( n = 9) the addition of an α-glucosidase inhibitor to the initial sulphonylurea did not produce any significant changes in mean postprandial blood glucose or glycosylated haemoglobin levels. The results for individual patients indicated that the glycosylated haemoglobin levels had improved after the change of treatment only in those patients whose connective peptide immunoreactivity was > 6.0 ng/ml.

Both ulcerative colitis and Takayasu's arteritis are though to be organ-specific immune-mediated inflammatory diseases. We present the rare case of a 23-year-old woman with a 4-year history of ulcerative colitis who developed Takayasu's arteritis one month after giving birth. She was found to carry the human leukocyte antigens (HLA)-B52 and DR2, which were previously noted to be associated with these inflammatory conditions in the Japanese population. The pathogenic relevance of this haplotype to the concomitant development of these two conditions is discussed.

To assess the relationship between the glomerular injury induced by immune complex deposition and proteinuria, ultrastructural changes of the glomerular basement membrane (GBM) were investigated in Heymann nephritis. Active Heymann nephritis was induced in rats by injecting them with tubular brush border antigen, known as Fx1A, emulsified in complete Freund's adjuvant (CFA). Measurement of urinary protein excretion and histological examinations were carried out for up to 15 weeks after immunization. Proteinuria developed in rats within 10 weeks of immunization and coincided with the development of subepithelial deposits with minimal spike-like basement membrane protrusion. Acellular glomeruli were prepared by detergent treatment and were subjected to tannic acid-osmium conductive staining prior to examination with an ultrahigh resolution scanning electron microscope (HSEM). HSEM of the acellular GBM prepared from control rats injected with CFA alone revealed a meshwork structure, with pores of about 9 nm in diameter. Proteinuric rats immunized with Fx1A showed a loosened meshwork structure, with pores of about 15 nm in the acellular GBM adjacent to the deposits. The newly formed GBM overlying the deposit consisted of a meshwork structure associated with unorganized thin fibrils. Ultrastructural changes were never seen in GBM devoid of deposits. These findings indicate that subepithelial deposits are closely involved in the development of proteinuria by injuring the size selectivity of the GBM.

The phenotypic change of the mesangial cell is considered to play a pivotal role in the accumulation of extracellular matrix in diabetic nephropathy. This investigation was undertaken to evaluate the expression of the various isoforms of contractile proteins in the streptozocin (STZ)-induced diabetic rat kidney and in renal biopsy specimens from patients with diabetic nephropathy. Specific antibodies to myosin heavy chain isoforms (SM1, SM2, SMemb), caldesmon, and α-smooth muscle actin and cDNAs for SMemb were used. Increased expression of SMemb at the mRNA and protein levels was demonstrated at 1 week after STZ administration in the rat. Both levels were increased at 4 weeks. Mesangial staining of caldesmon was observed at 4 weeks and that of α-smooth muscle actin at 24 weeks. Immunohistochemical mesangial staining of the contractile proteins was pronounced in patients with diabetic nephropathy in contrast to the trace mesangial staining in normal control subjects. These results indicate that the phenotypic change in mesangial cells occurs in the early stages of diabetes and that several stages in phenotypic changes may exist. Expression of the contractile protein isoforms, especially SMemb, should serve as a new marker for the subsequent glomerular hypertrophy and sclerosis.

A case of malignant thymoma with pure red cell aplasia (PRCA) complicated by syndrome of inappropriate secretion of antidiuretic hormone (SIADH) following intrathoracic cisdichlorodiammine platinum (CDDP) administration is reported. A 59-year-old Japanese woman who presented with severe general fatigue was diagnosed with PRCA associated with a thymoma, based on the findings of a bone marrow biopsy, computed tomography of the chest, and the existence of anti-acetylcholine receptor antibodies. She underwent a thymectomy after frequent blood transfusions. This was followed by intrathoracic CDDP administration, because of pleural dissemination. Nine days following chemotherapy, her serum sodium concentration was found to be 104mM, while her consciousness was drowsy with severe fatigue and vomiting. This hyponatremic state was diagnosed as SIADH induced by CDDP infusion into the thoracic space, based on the hypo-osmolality of her serum, the hyper-osmolality of her urine, and an inappropriate level of plasma vasopressin.

Bronchiolitis obliterans organizing pneumonia (BOOP) is a pathologic entity characterized by the formation of fibrous tissue plugs within terminal bronchioles and alveolar ducts. Although BOOP has been associated with several connective tissue disorders, there are rare reports of BOOP in patients with systemic lupus erythematosus (SLE). We present a patient with SLE accompanying antiphospholipid antibody who developed recurrent respiratory symptoms and radiographic abnormalities. The diagnosis of BOOP was confirmed by transbronchial lung biopsy. This case suggests that not only SLE, but also the presence of antiphospholipid antibody, may be associated with the development of BOOP.

The relationships between cardiac autonomic neuropathies, diabetic somatic neuropathy, metabolic parameters, general parameters (such as age and duration of illness) and diabetic microangiopathy and macroangiopathy were investigated in 103 patients with non-insulin-dependent diabetes mellitus (NIDDM). Spearman's correlation coefficients were calculated for the comparisons of all the parameters of the neuropathies with all the other parameters. Variables were selected using a stepwise procedure and multiple regression analysis was carried out using these variables. The results of the regression analysis show that diabetic neuropathy is correlated with vascular parameters including blood pressure and pulse-wave velocity, as well as with parameters of sugar and lipid metabolism. The results confirm the diversity of the clinical characteristics of the neuropathies in patients with NIDDM and confirm that these neuropathies do not always occur in parallel.

Available data indicate that the development of diabetic nephropathy is linked to hyperglycaemia. Glucose reacts nonenzymatically with proteins to form Schiff base and Amadori products. Further incubation of these early products leads to the formation of advanced glycation end-products (AGEs). AGEs seem to play a central role in the progression of diabetic nephropathy. Immunohistochemically, AGEs were also detected in an expanded mesangial matrix, especially in nodular lesions from patients with diabetic nephropathy. AGEs staining was noted in the Bowman's capsule, periglomerular fibrosis in sclerosing glomeruli. In our ultrastructural study of mesangial matrix from patients with diabetic nephropathy by high-resolution scanning electron microscopy after cellular removal, the meshwork structure was evident at higher magnification. In nodular lesions, the loose meshwork structure appeared to be composed of various sized strands, ranging from 6 to 24 nm (mean +/- SD: 11.4 +/- 3.8 nm). The pore sizes were variable, ranging from 4 to 70 nm (mean +/- SD: 23.6 +/- 12.3 nm), and were statistically larger than those of normal controls. As the AGEs are localized most notably in nodular lesions, advanced glycations play a role in the progression of diabetic nephropathy through impairment of the assembly of matrix proteins in vivo. Because type V and type VI collagens are the major components of nodular lesions, increases in these interstitial and fibril or microfibril collagens may contribute to the formation of wider strands in the mesangial matrix of a nodular lesion. As no metalloprotease that is specific for type VI collagen has been identified thus far, AGEs formation might occur preferentially in type VI collagen-rich nodular lesions, which are sites of slow turnover.

Renal hypertrophy is a characteristic and early manifestation of diabetes in humans and experimental animals. We examined the precise distribution of insulin-like growth factor-I (IGF-I) mRNA and IGF-I receptor mRNA in the experimental diabetic rat kidney using a nonradioactive in situ hybridization technique. No significant difference in the distribution of IGF-I mRNA was found between the diabetic and control rats. IGF-I mRNA-positive cells were found in the collecting ducts and in scattered single cells in the distal tubules. The number of IGF-I mRNA-positive cells was very low in the glomeruli. Expression of IGF-I receptor mRNA was rarely seen in the glomeruli of control rats. IGF-I receptor mRNA was detected after induction of diabetes in glomerular mesangial, visceral epithelial, and parietal epithelial cells. The number of IGF-I receptor mRNA-positive cells in a glomerulus increased significantly, peaking at 4 weeks as compared with the control rats. Overexpression of IGF-I receptor in glomerular cells, especially mesangial and visceral epithelial cells, may contribute to glomerular hypertrophy in diabetic nephropathy.

We are actively seeking methods to prevent and to limit the progression of angiopathy in patients with non-insulin-dependent diabetes mellitus (NIDDM). In the present study, we conducted a clinical and epidemiological survey to clarify the clinical factors responsible for the development and progression of diabetic microangiopathy (MI) and macroangiopathy (MA). A total of 107 patients (58 female and 49 male) were randomly selected from 145 NIDDM patients. Twenty-four patient variables were selected for analysis. We identified PWV, UAI, RETINOP, MCV-T, SCV-S, MCV-P, SBP, and DBP as responsible factors and carried out stepwise multiple regression analyses. The following explanatory variables were found to be significant: age > SCV-S (P < 0.0001) for the criterion variable PWV, BUN > HbA1c > MCV-P > HT-drug > HDL-C ( P < 0.0001) for loge UAI, DM-thera > SBP ( P < 0.0001) for RETINOP, MCV-P ( P < 0.0001) for MCV-T, IRI > SBP > MCV-P > S-CR ( P < 0.0002) for SCV-S, MCV-T > SCV-S > DM-thera ( P < 0.0001) for MCV-P, DBP > HT-drug > BUN > MCV-P ( P < 0.0001) for SBP, and SBP > PWV > sex ( P < 0.0001) for DBP. In summary, responsible factors for MI and MA in NIDDM had metabolic and blood pressure factors in common. Moreover, MI was a responsible factor for MA, which becomes a responsible factor for MI because it is a responsible factor for blood pressure factors. Thus, all the responsible factors for MA represented by MI and PWV had metabolic and blood pressure factors in common. The results of this study suggest that metabolic and blood pressure factors must be controlled to prevent and to limit the progression of diabetic MI and MA in NIDDM patients.

To understand the regulation of vasopressin receptors in an animal model of hypertension, localization and age-related changes in renal arginine vasopressin (AVP) receptors in spontaneously hypertensive rats (SHR) were investigated using in vitro (macro) autoradiography and a radiolabeled receptor assay. Autoradiography localized renal AVP V2 receptors to the distal tubules and collecting ducts in the medulla. We also found small numbers of AVP-binding sites within glomeruli, possibly representing V1 receptors in the mesangium. The radiolabeled receptor assay of the medulla membrane fraction revealed that the binding affinity of renal V2 receptors did not differ significantly between SHR and control Wistar-Kyoto rats in any age group. However, the binding capacity (Bmax) for V2 receptors in 12-week-old SHR was significantly increased (p < 0.025) as compared with that of age-matched control rats. The Bmax values for V2 receptors in 3- and 7-week-old SHR were not significantly different from those of age-matched controls. There was no significant change in urine volume between SHR and control rats at the age of 12 weeks. The mean plasma AVP concentration in SHR increased at 7 and 12 weeks of age. These findings suggest that SHR have different developmental changes in kidney AVP receptors and that renal V2 receptors play a role in maintaining fluid homeostasis in SHR with established hypertension.

The effects of treatment with an α-glucosidase inhibitor and a reduced dose of sulphonylurea were investigated in patients with non-insulin-dependent diabetes mellitus who had previously been treated with sulphonylurea compounds but who were hypoglycaemic at times. Treatment with a daily dose of 0.6 mg α-glucosidase inhibitor and a reduced dose of the previously used sulphonylurea compound for 4 weeks did not significantly affect the glycosylated haemoglobin level. The post-prandial blood-glucose concentration of the patients was unchanged after treatment compared with its value immediately before treatment but differed significantly compared with the value 4 weeks before treatment ( P < 0.03); it was considered likely that this change was due to a seasonal increase in calorie intake at the end of the treatment period. Symptoms related to hypoglycaemia disappeared in all of the treated patients.

The effects of administration of an α-glucosidase inhibitor and a sulphonylurea compound on lipid profile were investigated in patients with non-insulin-dependent diabetes mellitus, (NIDDM) previously treated with sulphonylurea compounds alone, but in whom metabolic control was inadequate. A group of patients ( n = 10) were treated with the α-glucosidase inhibitor at a dose of 0.2 mg, three times daily, for 4 weeks. Treatment significantly reduced the post-prandial glucose level and the serum total cholesterol level. In addition, there were non-significant reductions in the triglyceride and very low density lipoprotein levels. These preliminary results suggest that administration of α-glucosidase inhibitors might improve the lipid profile of patients with NIDDM.

The factors that influence the severity of large vessel pathology in patients with non-insulin-dependent diabetes mellitus (NIDDM) were investigated in 154 randomly selected patients. Measurements of aortic pulse-wave velocity were used to quantify the severity of large vessel pathology. The results showed that of the 20 variables considered, age, systolic blood pressure, duration of disease and serum creatinine were all significantly correlated with pulse-wave velocity. Multiple regression analysis with pulse-wave velocity as the criterion variable showed that age, systolic and diastolic blood pressures were all significant explanatory variables, with age carrying the greatest weight. The findings suggest that controlling blood pressure is most important as a means of containing large vessel pathology in patients with NIDDM.