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Histamine H2 receptor antagonism by T-593 was investigated in Hepa cells expressing canine histamine H2 receptors. T-593 inhibited generation of cAMP in Hepa cells stimulated by 10(-5) mol/l histamine with an IC50 value of 2.3 x 10(-6) mol/l, (S)-(-)-T-593, one of the enantiomers comprising racemic T-593, inhibited cAMP generation with an IC50 value of 6.1 x 10(-7) mol/l. On the other hand, the other enantiomer (R)-(+)-T-593 exhibited only a negligible effect. Incubation of the cell with (S)-(-)-T-593 for 60 min depressed the maximal response of the concentration-response curve of histamine with a nonparallel rightward shift. The slope of a Schild plot was 1.27. In contrast, (S)-(-)-T-593 caused a parallel rightward shift of the curve, with a Schild plot slope that did not significantly differ from unity, by treating the cells for 15 min. The H2 receptor-blocking action of (S)-(-)-T-593 remained almost unaffected after washing out the drug, whereas the effect of ranitidine was reversible after washing. These results suggest that T-593 possesses a time-dependent insurmountable antagonistic action against histamine H2 receptor. T-593 may interact with the histamine H2 receptor molecule in a slowly associable and dissociable manner.

Advanced glycation end products (AGEs) are formed during non-enzymatic glycation and oxidation (glycoxidation) reactions. AGEs, such as pentosidine and carboxymethyllysine are increased in plasma proteins and skin collagen of uraemic patients several times more than in normal subjects and non-uraemic diabetic patients. However, AGEs do not differ between diabetics and non-diabetics in uraemic patients. The AGE accumulation in uraemia, therefore, cannot be attributed to hyperglycaemia, nor simply to a decreased removal by glomerular filtration of AGE-modified proteins. Recent evidence has suggested that, in uraemia, the increased carbonyl compounds, derived from both carbohydrates and lipids, modify proteins not only by glycoxidation but also by lipoxidation reactions, leading to the increased production of AGEs and advanced lipoxidation end products (ALEs). Thus, uraemia might be a state of increased carbonyl compounds with potentially damaging proteins ('carbonyl stress'). Carbonyl stress in uraemia appears relevant to long-term complications, such as dialysis-related amyloidosis. The increased AGEs and ALEs in uraemic plasma and tissue proteins may indicate alterations in the non-enzymatic chemistry involving both carbohydrates and lipids in uraemia.

The Role of Organ Transplant Network are the encouragement of the organ transplantation and fair organ sharing. Its principled are united, neutral open and nonprofit organization, so as to secure the fair and quick organ sharing based on the uniform allocation policy. Japan Kidney Transplant Network was established in 1995 nad reorganized into multi-organ sharing network, Japan Organ Transplant Network in 1997, when Japan Organ transplant Act was enacted. It consists of transplant coordinators, physicians, transplant surgeons, kidney banks, local administration, academic standings, other organization/associations and others. There are several committee, in which special subjects on organ transplantation and related matters are consulted, and review system in which each case is assessed and judged. And principal and essential items are decided by the board of members and then by the general assembly. The new computer system was introduced and registrants data are renewed every year, and recipient selection is done based on the latest registrants data. Standardized HLA examination tray was introduced and class II antigen was examined by means of DNA typing since 1997, which enabled more precise and accurate search. Hereafter, the education and encouragement of transplant coordinators to raise themselves and the more effective and extended distribution of donor cards are indispensable to promote organ donation/transplantation.

Some epithelial cells have Na+/H+ exchanger (NHE) activity in both apical and basolateral membranes. Amiloride-sensitive NHE-1 is generally identified in the basolateral membrane. The renal cell line, OK7a, targets amiloride-resistant NHE predominantly to the apical membrane. It is controversial whether the transfected NHE-1 is targeted preferentially to the basolateral membrane in OK7a cells, when human NHE-1 is chronically expressed under control of constitutively active promoters. We tried to identify the membranes in which the transfected human NHE-1 could be detected following acute expression in OK7a cells. We have always observed small Na(+)-dependent pH recovery in the basolateral membrane in OK7a cells. It is, however, controversial whether or not OK7a cells express NHE activity in the basolateral membrane. We also characterized Na(+)-dependent pH recovery in the basolateral membrane. It was not inhibited by [4,4'diisothiocyanatostilbene-2,2'-disulfonic acid] (DIDS), [4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid] (SITS), or contralateral amiloride. Li+ but not K+, chol+, or NMG+ could replace Na+. These results are consistent with the presence of the NHE in the basolateral membrane. NHE activities were predominant in the apical membrane and those in both membranes were resistant to amiloride analogs. After stable transfection with human NHE-1 in a vector utilizing the metallothionein promoter, overnight induction with Zn(2+)increased the NHE activity and its sensitivity to amiloride only in the basolateral membrane in OK7a cells. We conclude that the transfected human NHE-1 is exclusively targeted to the basolateral membrane of OK7a cells during acute induction.

A 63-year-old hypertensive and diabetic woman suddenly experienced severe pain in the back and abdomen of the left side. Sensory disturbance and muscle weakness in her left leg and urinary retention followed. Somatosensory evoked potential (SEP) indicated a thoracic cord lesion. Furthermore, MRI showed a focal lesion with a high signal intensity on T2-weighted images in the left posterolateral region of the cord Th4-9. She was diagnosed with posterior spinal artery syndrome (PSAS) due to spinal infarction by clinical presentation and MRI findings. Monoparesis can be caused by PSAS.

Dialysis-related amyloidosis is recognized as a serious bone and joint complication in long-term dialysis patients. Beta2-microglobulin has been demonstrated to be a major constituent of the amyloid fibrils. However, the molecular pathogenesis of this disorder remains unknown. Recent biochemical and immunohistological studies have identified a new modification of beta2-microglobulin in the amyloid fibrils, i.e., the advanced glycation end products (AGEs). AGEs are formed by non-enzymatic glycative and oxidative (glycoxidation) reactions. The levels of AGEs, such as pentosidine and carboxymethyllysine (CML), are elevated in both the plasma proteins and skin collagen of non-diabetic dialysis patients several times more than in normal subjects. The AGE accumulation in uremia cannot be attributed to hyperglycemia, nor simply to their decreased renal clearance. Recently, gathered evidence has suggested that, in uremia, an increase in carbonyl compounds, derived from both carbohydrates and lipids, modifies proteins, leading to the augmentation of the production of not only AGEs, but also the advanced lipoxidation end products (ALEs). Uremia might thus be a state of carbonyl overload with potentially damaging proteins ('carbonyl stress'). Immunohistochemical studies, with antibodies specific to AGEs and ALEs, identified carbonyl stress in long-lived beta2-microglobulin amyloid deposits. Furthermore, proteins modified by carbonyl stress exhibit a variety of biological activities towards several types of cells, which might partially account for dialysis arthropathies.

By thoracoscopic surgery, we confirmed pulmonary noncancerous lesions in two patients with metastatic nonseminomatous testicular germ cell cancer. The purpose of thoracoscopic surgery was complete resection of postchemotherapeutic residual tumour in one patient or a biopsy for new lesions during chemotherapy. Histological findings were normal lymph node and pulmonary fibrosis. We demonstrated CT findings of these lesions and made some discussion on management of disseminated testicular cancer.

We report a 55-year-old man with impending neuroleptic malignant syndrome who showed a remarkable dysautonomia such as dysuria and was treated with L-dopa under the diagnosis of Shy-Drager syndrome. The patient demonstrated fever, leukocytosis and elevated serum creatine kinase by a decrease in L-dopa dose. Probably, he developed impending neuroleptic malignant syndrome, induced by urinary tract infection as well as decrease in L-dopa dose. Since Shy-Drager syndrome is often treated with antiparkinsonian drugs, neuroleptic malignant syndrome can possibly develop after the change in dosage of catecholaminergic drugs. The imbalance of neurotransmitters and receptors in the central autonomic nervous system may participate in the development of neuroleptic malignant syndrome. Accordingly, Shy-Drager syndrome can easily be associated with neuroleptic malignant syndrome because of its severe disturbance in the autonomic nervous system. However, autonomic nervous dysfunction, a major sign of neuroleptic malignant syndrome, might be masked by symptoms of Shy-Drager syndrome. Therefore, diagnosis of neuroleptic malignant syndrome is often delayed. Careful observations of patients with Shy-Drager syndrome related with an antiparkinsonian drug are necessary, especially when the dose of drugs is changed or the general condition deteriorates.

We investigated the effect of age on nerve conduction parameters to establish a diagnostic validity in demyelinating neuropathies of the aged. We evaluated 257 subjects (age 10-76 years old) with no history or signs of peripheral neuropathies. The CMAP amplitude ratio (proximal CMAP/distal CMAP), duration ratio, and area ratio were almost the same throughout the second to eighth decades. The respective lower limits of the normal CMAP amplitude ratio (mean-3 SD) were 0.79 (median nerve), 0.75 (ulnar nerve), 0.57 (peroneal nerve), and 0.45 (tibial nerve). The upper limits of the normal CMAP duration ratio (mean +3 SD) were 1.21 (median nerve), 1.22 (ulnar nerve), 1.37 (peroneal nerve), and 1.35 (tibial nerve). The lower limits of the normal CMAP area ratio (mean-3 SD) were 0.81 (median nerve), 0.78 (ulnar nerve), 0.60 (peroneal nerve), and 0.57 (tibial nerve). No age-related changes were observed in the amplitude ratio or duration ratio SNAP, although the standard deviation increased with age. Since the amplitude, duration and area ratios are easily calculated and age-independent, they can provide useful and reliable information on aged patients with demyelinating neuropathies by conventional nerve conduction studies.

We report the high-resolution CT (HRCT) and MR findings in a case of pulmonary alveolar microlithiasis. HRCT revealed that the black pleural line on a chest radiograph was caused not by subpleural cysts but by a fat-dense layer between ribs and the calcified parenchyma. MRI showed both lower zones with diffusely increased signal intensity on T1-weighted images. We speculated it was caused by the accumulation of small-sized calcific particles.

It has been demonstrated that cultured mesangial cells (MC) express latent transforming growth factor (TGF)-beta binding protein (LTBP) mRNA, and that LTBP might be essential for the extracellular matrix (ECM) accumulation stimulated by TGF-beta in cultured MC. We performed a study to test the pathophysiological role of LTBP in mesangial ECM accumulation in human glomerulonephropathies. The expression of LTBP in 64 renal biopsies of patients with renal diseases was examined by immunohistochemical staining with the specific antibody raised against human LTBP. The biopsy specimens were divided into three groups: Group 1, IgA nephropathy; Group 2, IgA negative mesangial proliferative glomerulonephritis, which mainly consisted of diabetic nephropathy and lupus nephritis; and Group 3, non-proliferative nephropathy, which consisted of minimal change and membranous nephropathy. Immunohistochemical staining of LTBP was significantly detected in mesangial/paramesangial area of glomerulus in Group 1, but not observed in Group 2 or Group 3. The intensity of staining was well related to the grade of mesangial ECM accumulation in Group 1. These findings suggest that the LTBP-TGF-beta complex may play a pivotal role in ECM accumulation in IgA nephropathy, and that modification of LTBP-ECM interaction might provide a new therapeutic strategy against the progression of glomerulosclerosis.

Glomerular infiltration of macrophages is a characteristic alteration of renal histopathology in hyperlipidemic renal injury. Each macrophage has two key enzymes to synthesize LTB4:5-lipoxygenase and LTA4 hydrolase. In this study we examined the long-term effects of LTB4 antagonist on real function and histopathology of spontaneously hypercholesterolemic (SHC) rat, which is model of hyperlipidemic renal injury, to see if the LTB4 antagonist could reduce the progression of renal damage. Spontaneously hypercholesterolemic rats fed a normal diet (C) developed end-stage renal failure in 26 weeks, while those fed a diet supplemented with LTB4 antagonist (E) showed normal renal function, and mild histopathological alterations (SCr: C, 1.4 +/- 0.3; E, 0.6 +/- 0.1 mg/dl, P0.03) without statistical differences in serum total cholesterol, body weight and blood pressure between two groups. These results suggest that LTB4 plays an important role in progression of hyperlipidemic renal injury.

Cowden’s disease, multiple hamartoma syndrome, is a dominantly inherited disorder characterized by multiple hamartomas of ectodermal, endodermal, and mesodermal origin and also by a high incidence of malignant tumors. Despite many efforts to identify the genetic alterations responsible for the syndrome, the molecular mechanism remains unclear. We report a case of Cowden’s disease in which karyotype analysis revealed a small duplication (about 1 Mb) at 15q11–q13. This part of the genome is a region that is deleted in the Prader-Willi/Angelman syndrome and is a “hot spot” of chromosomal duplication.

The incidence and clinical characteristics of hypoparathyroidism (Hypo) were evaluated in 8188 hemodialysis (HD) and 1207 CAPD patients treated in 65 hospitals or clinics in Japan. Hypo was defined by an intact parathyroid hormone (PTH) level below 160 pg/ml, which corresponded to the low normal limit of intact PTH to maintain a normal osteoblastic surface in 40 bone biopsy specimens of Japanese dialysis patients, and patients were classified into two groups: absolute Hypo (A-Hypo), intact PTH60 pg/ml, and relative Hypo (R-Hypo), 60 pg/mlor = intact PTH160 pg/ml. A total of 2537 (31.0%) and 2736 (33.4%) HD patients were classified into A- and R- Hypo, and 401 (31.3%) and 379 (31.4%) CAPD patients occupied A- and R-Hypo, respectively. A high incidence of Hypo was observed in the HD patients with diabetes mellitus (DM) and old age (or = 70 years old) compared with that of a nationwide epidemiological report for dialysis patients by Japanese Society for Dialysis Therapy. Hypo patients who were treated by CAPD had a background of being younger, having a shorter duration on dialysis, and were less frequently diagnosed with DM than in those Hypo patients on HD. Bone pain and metastatic calcification were observed in approximately 20% and 25% of Hypo patients, respectively. No difference was observed in the background factors and the prevalence of signs and symptoms between the A- and R-Hypo groups, regardless of the mode of treatment (HD or CAPD). These results suggest that a very high incidence and specific backgrounds (DM and aging) of Hypo exist in Japanese dialysis patients.

The effects of Gosha-Jinki-Gan on the urinary bladder contraction in anesthetized dogs were studied to elucidate the mode of action. The bladder contraction was induced by electrical stimulation of the left distal end of the pelvic nerve under the bilateral pelvic nerve and hypogastric nerve transections, or by the infusion of acetylcholine (200 micrograms) in to the abdominal aorta. The bladder contraction induced by pelvic nerve stimulation was significantly inhibited by 10 and 100 mg/kg of intravenous Gosha-Jinki-Gan administration. A similar phenomenon was observed by the administration of atropine sulfate (0.1 mg). The acetylcholine-induced contraction was significantly inhibited by administration of 100 mg/kg of Gosha-Jinki-Gan. These findings suggested that Gosha-Jinki-Gan inhibits the urinary bladder contraction induced by the stimulation of cholinergic nerve.

Breakdown of the blood-brain barrier, which consists of endothelial cells, is implicated essential in the pathogenesis of multiple sclerosis (MS). To examine the endothelial cell damage, we determined the von Willebrand factor and thrombomodulin, markers for endothelial cell activation and/or injury, in the peripheral blood of patients with MS. The subjects were 26 patients with relapsing-remitting MS and 35 control subjects (mean age +/- standard deviation, 44.8 +/- 9.6 years). Patients with systemic vasculitis were excluded. The plasma activity of von Willebrand factor was significantly higher in patients with MS in the active phase (n = 23; 44.6 +/- 9.6 years) than in the age-matched controls. This suggests that von Willebrand factor could be a useful marker for evaluating the breakdown of blood-brain barrier resulting from endothelial damage in MS. In contrast, the serum level of thrombomodulin was not significantly different between patients with active MS and the controls. In MS patients (n = 15; 44.2 +/- 2.2 years), the plasma activity of von Willebrand factor was significantly lowered after immunosuppressive treatment. This suggests that von Willebrand factor could be used as a parameter for assessing the effect of treatment in MS.

Conventional and double-barreled microelectrodes were used to examine the anion selectivity of Cl- conductance in the basolateral membrane of rabbit renal proximal tubule S3 segment. The permeability sequence determined by anion replacements in the presence of K+ channel blocker quinine was SCN- > I- > Br- > Cl- > gluconate in both nonperfused and luminally perfused tubules. The anion-selective microelectrodes with higher sensitivity to I- enabled us to measure intracellular I- activities. With these electrodes, we could compare the conductive movements of Cl- and I- in response to the increase in bath K+ concentrations and confirmed that the conductance sequence was also I- > Cl-. Although the basolateral potential changes generated by Cl- and Br- currents were stimulated by adenosine 3',5'-cyclic monophosphate (cAMP), the potential changes by SCN- and I- currents were somewhat inhibited by cAMP. In addition, the conductive uptake of I- was, in contrast to that of Cl-, inhibited by cAMP These results are consistent with the existence of at least two distinct anion conductances in this membrane, which are differently regulated by cAMP.

Thromboxane A2 (TXA2) is a potent vasoconstrictor which is known to be involved in the pathogenesis of experimental glomerulonephritis, although its exact pathogenic significance is not clear in human glomerulonephritis. We have investigated the expression of thromboxane synthase (TXS) in kidney tissues from patients with IgA nephropathy (IgAN), using RT-PCR and immunohistochemical methods. Biopsied renal tissues from thirty-four patients with IgAN (24 whole tissues and 10 isolated glomeruli) and normal renal tissues from 11 nephrectomized kidneys (control, eight whole tissues and three isolated glomeruli) were included in this study. TXS mRNA expression was observed in 10 out of 24 (42%) whole tissue specimens from IgAN, but no such message was disclosed in the control tissue. There was no detectable TXS mRNA expression in the isolated glomeruli either from IgAN patients or controls, although constant mRNA expressions for GAPDH and VPF/VEGF were observed. IgAN patients with positive TXS mRNA had significantly reduced GFR with elevated serum creatinine and serum beta 2-microglobulin levels. Immunostaining, using a monoclonal anti-TXS antibody, identified the localization of the TXS protein in the interstitial areas where monocyte/macrophage infiltration was abundant, as well as in the arterioles of the kidney tissues with advanced tissue damage. It was concluded that TXA2 produced by the interstitial infiltrating cells during the inflammatory process might be involved in the progression of IgA nephropathy.

Endothelin (ET) is well known to be a potent vasoconstrictor peptide with autocrine and paracrine function. It has been documented that ET is also present in non-muscle tissues. The distribution of ET and ET-A receptor (ET-AR) in the monkey lacrimal gland was investigated by immunohistochemistry. Three adult male monkeys (Macaca fuscata) were perfused with a fixative. The lacrimal glands were then dissected and sectioned. Using rabbit anti-ET and anti-ET-AR antibodies, the immunohistochemical procedure was performed following an ABC technique. Some sections were treated with rhodamine-phalloidin, which selectively binds to actin filaments. ET immunoreactivity was present in stellate-shaped cells located around the alveoli. In sections double-stained with anti-ET antibody and rhodamine-phalloidin, ET immunoreactivity and abundant filamentous actin were identified in the same stellate cells. Immunostaining for ET-AR was also found in the stellate shape cells. The configuration of, and the abundance of actin filaments in the stellate-shaped ET- and ET-AR immunoreactive cells suggest that they are myoepithelial cells, which are contractile and may contribute to the process of lacrimal gland secretion or maintenance of the contour of the glandular endpieces. Our results indicate that endothelin is present in myoepithelial cells of the monkey lacrimal gland.

To assess the anterior mediastinal mass in recurrent testicular cancer, with relation to thymic hyperplasia after treatment.The anterior mediastinal regions were fully evaluated by chest computed tomography (CT) at the initial staging and after treatment in 24 of 44 patients with testicular cancer.One patient with stage IIB tumor had thymic hyperplasia before treatment, and one with stage III had benign thymic hyperplasia after chemotherapy with salvage surgery. Three of 4 patients who had recurrence had an anterior mediastinal mass. One had benign thymic hyperplasia confirmed by histology and 2 had metastatic tumor confirmed by histology and clinical course, in which the mass became so enlarged that it obstructed major vessels.Although the relationship of the CT finding to the response to treatment in the anterior mediastinal mass and other metastatic lesions provide some clues helpful in differentiating benign from malignant masses, surgical exploration is recommended for the patient with an indication for salvage surgery.

Gosha-Jinki-Gan is clinically used for the treatment of pollakiuria in patients with benign prostatic hyperplasia. The effect of Gosha-Jinki-Gan on the function of the urinary bladder in anesthetized dogs was examined. Gosha-Jinki-Gan (100 mg/kg) inhibited the rhythmic bladder contractions (RBC). However, the frequency of RBC increased resembling the effect of atropine (0.1 mg/body), and the amplitude decreased. On the cystometrogram, Gosha-Jinki-Gan caused an increase in maximum vesical volume (not significant). These findings indicated that Gosha-Jinki-Gan is a useful drug for the treatment of pollakiuria.

We performed transurethral balloon laser hyperthermia of the prostate (TUBAL-H) in 6 mongrel dogs. To evaluate the changes in proximal urethral function after TUBAL-H, the urethral cross sectional area (CSA, cm2) and urethral pressure (Pu, cmH2O) were measured using a balloon probe that allows their simultaneous measurement, and the urethral compliance (Comp, cm3/cmH2O) was calculated from these parameters and serially evaluated. In addition, the changes in Pu, CSA and Comp after administration of an alpha-adrenoceptor antagonist were evaluated before and 16 weeks after TUBAL-H. Before TUBAL-H, the mean Comp was 0.013, and the mean maximum CSA (MCSA) was 0.66. Eight weeks after TUBAL-H, the mean Comp was 0.038, and the mean MCSA was 1.39, showing a significant increase (p0.01). Sixteen weeks, after TUBAL-H, the mean Comp was 0.026, and the mean MCSA was 1.21, being lower than those at 8 weeks after TUBAL-H, but significantly higher than those before TUBAL-H (p0.05). After administration of the alpha-adrenoceptor antagonist, phentolamine (1 mg/kg), before TUBAL-H, the mean Comp significantly increased to 0.046 (p0.05), and the mean MCSA to 1.40 (p0.01). The mean Comp was significantly increased to 0.033 (p0.05), by phentolamine administration 16 weeks after TUBAL-H, but no other changes were observed. After TUBAL-H, urethral elasticity increased, and this increase persisted for 4 months. The responses of Comp and MCSA to alpha-adrenoceptor antagonist administration before and 16 weeks after TUBAL-H suggested that part of the effects of TUBAL-H is due to damage to alpha-adrenoceptors.

CD79b is an invariant component of antigen receptors on B lymphocytes. Previous data have suggested that monoclonal antibody (mAb) to CD79b would introduce negative signals into B lymphocytes and suppress humoral immunity. We tested this hypothesis in this study using in vitro assay systems, and revealed that anti-CD79b mAb effectively suppressed the antibody response to a T-cell dependent antigen. The speculated mechanisms for this immunosuppression were: (i) down-modulation of antigen receptors, (ii) inhibition of B lymphocyte differentiation, and (iii) induction of B lymphocyte unresponsiveness. Of these three, we confirmed that the first two were actually induced by anti-CD79b mAb treatment, whereas the in vitro system could not induce the unresponsiveness of B lymphocytes.

A hypothesis is proposed that the aberrant response of the tubuloglomerular feedback to salt load is the abnormality in the kidney in the genesis of essential hypertension. This thesis is based upon the following facts on the kidney, salt and hypertension. To effectively achieve the primary function of the kidney, that is, to maintain the milieu interieur or the extracellular fluids, the kidney must maintain a high glomerular filtration rate (GFR) and almost a complete tubular reabsorption in the face of limited salt intake or low ECF volume and in the face of changes in systemic blood pressure. Autoregulation of renal blood flow and GFR is therefore critical. In addition to myogenic responses in the resistant afferent artery, the juxtaglomerular apparatus (JGA) plays a crucial role in the autoregulation of renal plasma flow and GFR through tubuloglomerular feedback (TGF). That the JGA and TGF have appeared first in amphibian species in evolution suggests that the transition from aquatic sea life, where salt is always in excess to terrestrial life, required this particular structure and function of the kidney. Salt intake in the natural environments on land is very limited, and chronic excess salt intake is a habit peculiar to humans in recent culture or civilization. Thus, it is hypothesized that through evolution the TGF is primarily set to maintain high GFR in the face of low salt intake. We propose that aberrant TGF responses to salt loading may underlie the genesis of essential hypertension in humans. Indeed, hypertension is not seen in human cultures that ingest a very low salt intake.

Recently we clarified the mechanism in which arginine-vasopressin (AVP) applied from the luminal side inhibits the basolateral Cl- conductance, which is stimulated by basolateral AVP. However, to prove that these vasopressin phenomena are expressed via receptor mediated actions, we examined the effect of specific V1 and V2 receptor antagonists, OPC-21268 and OPC-31260, respectively, on the electrical response to vasopressin in the rabbit CCD perfused in vitro. In the presence of the V2-antagonist, basolateral AVP caused only the activation of luminal Na+ conductance, indicating a V1 action. In the presence of the V1 antagonist, basolateral AVP caused the same biphasic responses in electrical parameters as cyclic AMP, representing a pure V2 action. On the other hand, a rise in cell Ca2+ in response to AVP was completely abolished in the presence of the V1-antagonist, but not by the V2-antagonist in the bath. These data confirm our earlier findings that rabbit CCD possesses both V1 and V2 receptors in the basolateral membrane. We conclude that electrical responses to AVP in the rabbit CCD are a complex of V1 and V2 receptor-mediated actions.

The effects of extracellular ATP on cytosolic Ca2+ concentrations ([Ca2+]i) and cell membrane potentials (Vb) of rabbit renal proximal tubules were investigated using fura 2 and microelectrodes. ATP transiently increased [Ca2+]i without an apparent sustained phase, and the maximum effect was obtained at 10 microM. ADP, adenosine 5'-O-(3-thiotriphosphate), and 2-methylthioadenosine 5'-triphosphate were equally effective as ATP, whereas UTP, adenosine, and alpha beta-methyleneadenosine 5'-triphosphate were far less effective. The [Ca2+]i responses to ATP were strongly inhibited by reactive blue 2, a P2-purinergic receptor antagonist. The removal of extracellular Ca2+ as well as the addition of thapsigargin also markedly attenuated the responses to ATP. In addition, ATP had virtually no effect on Vb, except for the occasional small depolarization by 300 microM ATP. These results indicate that extracellular ATP increases [Ca2+]i through a P2-purinergic receptor and that this effect of ATP is dependent on both extracellular and intracellular Ca2+.

1. The kidney maintains the milieu intérieur of the body. To effectively achieve this function, the kidney must maintain a high glomerular filtration rate and high reabsorption in the face of limited salt intake or low extracellular volume and in the face of changes in systemic blood pressure. 2. Autoregulation of the renal blood flow and glomerular filtration rate is therefore critical. In addition to myogenic responses as seen in the resistant artery of other organs, the juxtaglomerular apparatus (JGA) plays a critical role in the autoregulation of the renal plasma flow and glomerular filtration rate through tubuloglomerular feedback (TGF). 3. The fact that the JGA and TGF appear first in amphibian species in evolution suggests that the transition from aquatic life to terrestrial life required this particular structure and function of the kidney. 4. Salt intake in natural environments is often very limited and chronic excess salt intake is a habit peculiar to humans in recent culture. Thus, it is hypothesized that TGF is primarily set to maintain high GFR in the face of low salt intake. 5. Resetting of TGF to salt-loading may exist in hypertension animal models which retards salt excretion. Renal cross-transplantation studies also indicate the principal role of the kidney as the primary organ responsible for the genesis of hypertension. 6. It is suggested that abnormalities as abnormal response of TGF in response to salt-loading may underlie the genesis of essential hypertension in humans. Indeed, hypertension is not seen in human cultures with very low salt intake.

Carboplatin (CBDCA), a derivative of cis-diamminedichloroplatinum, has low renal and neural toxicity. The dose-limiting factor of this agent is myelosuppression. We experienced various degrees of myelosuppression, when the dose of CBDCA was determined by the body surface area (BSA) in CBDCA-based combination chemotherapy for testicular cancer. Calvert demonstrated that the dose of CBDCA administered should be adjusted by renal function, because CBDCA was excreted through the glomerulus. We report the relationship among 3 factors; the administration dose of CBDCA, renal function and the degree of myelosuppression. We treated 6 patients with testicular cancer. A total of 22 courses of CBDCA-based combination chemotherapy was performed. The area under the curve (AUC) was calculated by the following formula, which was demonstrated in Calvert's study. CBDCA dose = AUC x (GFR + 25), GFR; glomerular filtration rate. The degree of myelosuppression was examined. All chemotherapy courses were divided into 2 and 3 groups according to BSA and AUC, respectively. WBC and Plt reduction rates and nadir counts were significantly correlated with AUC, and showed no significant relationship to the dose determined by BSA. This study revealed that the degree of myelosuppression was closely related with AUC, which reflects the renal function.

Effects of long-term omeprazole treatment on the process of epithelial cell proliferation and differentiation in the adult rat gastric mucosa were investigated. Animals were treated with omeprazole (25 mg/kg body weight/day) for 28 days to induce anacidity in the stomach. The treatment induced a marked decrease in the number of chief cells in the gastric mucosa and at the same time an increase in that of immature pepsinogen-producing cells expressing class III mucin. This was accompanied by a decrease to 60% and 10% of the control values in the mucosal levels of pepsinogen and its mRNA, respectively. Moreover, the expression of cathepsin E in surface mucous cells was reduced. Cell proliferation studies revealed that the rate of bromodeoxyuridine-labeled cells was increased by omeprazole. The above-described changes were reversed by cessation of the treatment and they were not caused by the omeprazole-treatment at a dose which does not induce anacidity in the stomach. These results suggest that long-term omeprazole treatment reversibly increases the epithelial cell proliferation and suppresses its differentiation in the adult rat gastric mucosa probably by altering the acidic environment specific for the stomach.

A 54-year-old man was admitted as an emergency following an episode of syncope and severe dyspnea. The clinical presentation and laboratory data strongly suggested pulmonary embolism, so intravenous thrombolytic therapy was performed. Immediately following the initiation of thrombolytic therapy, the patient experienced cardiopulmonary arrest, but he was successfully resuscitated. Ascending venography of the left lower limb demonstrated a large intraluminal thrombus which was apparently floating between the femoral vein and inferior vena cava. In addition to the anticoagulation therapy, a Greenfield filter was implaced intravenously to prevent recurrent embolization.

A 52-year-old man has slowly developed a non-flapping tremor during 30 years. He also had suffered from poor concentration for two years. He had, however, no history of episodic disturbance of consciousness. He had no other neurological symptoms except for tremor and hyperreflexia. The tremor was postural and intentional, and extremely increased at the end point. The factor of intentional tremor and hyperkinesia volitionnelle seems to be present in the tremor. Laboratory examination disclosed a hyperammonemia, reduction in Fisher ratio, and poor excretion of ICG. Selective abdominal angiography visualized a large shunt vessel between the left gastric vein and the left renal vein. The normal liver scintigram with 99mTc excluded the dysfunction of liver, and we conclude that the shunt vessel might be congenital. Tremor markedly improved after normalizing blood ammonia level by resection of the shunt vessel. The present case suggests that tremor, even without episodic disturbance of consciousness, could be based on the portal-systemic encephalopathy.

We investigated the effect of aging on nerve conduction parameters in 184 subjects (aged 10-75 years) without any history or signs of peripheral neuropathy, in order to clarify the diagnostic parameters of demyelinating neuropathies in the aged. The CMAP amplitude ratio (proximal CMAP/distal CMAP), duration ratio and area ratio remained unchanged throughout the second to eighth decades. The lower limits of normal CMAP amplitude ratio (mean -3SD) were 0.79 (median nerve), 0.74 (ulnar nerve), 0.59 (peroneal nerve), and 0.48 (tibial nerve). The upper limits of normal CMAP duration ratio (mean 11+ 3SD) were 1.22 (median nerve), 1.19 (ulnar nerve), 1.35 (peroneal nerve), and 1.32 (tibial nerve). The lower limits of normal CMAP area ratio (mean -3SD) were 0.84 (median nerve), 0.78 (ulnar nerve), 0.61 (peroneal nerve), and 0.62 (tibial nerve). There were no age-related changes in amplitude ratio or duration ratio of SNAP, although the standard deviations increased with age. Since the amplitude ratio, duration ratio and area ratio are simple and age-independent, they can provide useful and reliable information for routine nerve conduction studies for aged patients with demyelinating neuropathies.

The present study investigated the effect of long-term treatment with omeprazole on pepsinogen-producing cells and examined whether the selective CCK-B/gastrin receptor antagonist was able to prevent the omeprazole-induced changes, if occurred, in rat stomach. Rats were treated with omeprazole and/or the CCK-B/gastrin receptor antagonist for 28 days. As a result, omeprazole markedly reduced mucosal pepsinogen activity and its mRNA concentration in rat stomach. Morphologically, in fundic glands omeprazole drastically decreased the proportion of mature chief cells and reciprocally increased that of immature chief cells which were positive for class III mucin. These effects of omeprazole were attenuated by an addition of the CCK-B/gastrin receptor antagonist. Our results suggest that omeprazole retards the differentiation of chief cells in fundic mucosa probably through hypergastrinemia in adult rat.

Six cases of ureteral injuries were analyzed. Two cases were male and 4 cases were female. The right side was affected in 1 case and the left in 5 cases. The affected portion was the uretero-pelvic junction in 1 case and lower iliac vessels in the other cases. Five cases were iatrogenic injuries in surgical or gynecological pelvic operation, and the other was due to blunt trauma. Intraoperative diagnosis was made in 4 cases. Drain leakage led to diagnosis in one case and pyelonephritis in another. Ureteroureterostomy was performed in 2 cases, pyeloureterostomy in 1 case, ureteroneocystostomy with psoas hitch in 1 case, Boari bladder flap in 1 case and simple suture in 1 case. 4-0 or 5-0 Dexon with an atraumatic needle was used for all anastomoses. Except for case 1, who died of the recurrence of carcinosarcoma, renal functions were preserved in all patients during the follow-up period ranging from 5 months to 7 years 8 months.

Seventy eight patients with testicular tumor were treated in our hospital between 1982 and 1992. Of 78 patients, 74 had germinal cell tumor (seminoma in 47 patients and non-seminoma in 27), and the other 4 had 3 malignant lymphoma and 1 rhabdomyosarcoma. Ages ranged from 1 to 67 years with the average of 36.1. The age of the patients with seminoma was significantly higher than that of patients with non-seminoma. Most patients complained of painless swelling of the scrotal content, but some patients complained of testicular pain, fever, and so on. Those who complained of such symptoms had significantly worse prognosis than those who had only painless scrotal swelling. Patients with non-seminoma visited us about 4.9 months after the onset of their symptoms and 12.1 months in seminoma. Clinical stages were more progressive in non-seminoma than in seminoma. Inguinal orchiectomy was performed followed by irradiation, chemotherapy, retroperitoneal lymph node dissection or thoracotomy. Recurrence developed in 6 patients and the other 7 patients died of progressive disease within 2 years from the first attendance. The 2-year survival rate calculated by the Kaplan-Meier method was 81 and 70% in seminoma and non-seminoma, respectively, and 100, 88, 63, 75, and 22% in stage I, IIA, IIB, IIIO and IIIA, B, C, respectively.

The Japanese Society of Nephrology is established in 1958 by Drs Oshima, Yoshitoshi and Ueda and since then has grown to the current membership over 6,000. The Society has recently been incorporated and is expected to play a more leadership role in clinical practice, research, education and training of professionals in nephrology and in dissemination of new knowledge to the public domain. The strength and growth of the Society have been clearly seen in the quality and the number of publications by its membership to such prestigious journals as Kidney International and American Journal of Physiology, and submission of abstracts to the annual meeting of the American Society of Nephrology. Proposals for the future of the Society are briefly outlined.