Removing arsenic from groundwater in Cambodia using high performance iron adsorbent.

In Cambodia, groundwater has been contaminated with arsenic, and purification of the water is an urgent issue. From 2010 to 2012, an international collaborative project between Japan and Cambodia for developing arsenic-removing technology from well water was conducted and supported by the foundation of New Energy and Industrial Technology Development Organization, Japan. Quality of well water was surveyed in Kandal, Prey Veng, and Kampong Cham Provinces, and a monitoring trial of the arsenic removal equipment using our patented amorphous iron (hydr)oxide adsorbent was performed. Of the 37 wells surveyed, arsenic concentration of 24 exceeded the Cambodian guideline value (50 µg L(-1)), and those of 27 exceeded the WHO guideline for drinking water (10 µg L(-1)). Levels of arsenic were extremely high in some wells (>1,000-6,000 µg L(-1)), suggesting that arsenic pollution of groundwater is serious in these areas. Based on the survey results, 16 arsenic removal equipments were installed in six schools, three temples, two health centers, four private houses, and one commune office. Over 10 months of monitoring, the average arsenic concentrations of the treated water were between 0 and 10 µg L(-1) at four locations, 10-50 µg L(-1) at eight locations, and >50 µg L(-1) at four locations. The arsenic removal rate ranged in 83.1-99.7%, with an average of 93.8%, indicating that the arsenic removal equipment greatly lower the risk of arsenic exposure to the residents. Results of the field trial showed that As concentration of the treated water could be reduced to <10 µg L(-1) by managing the As removal equipment properly, suggesting that the amorphous iron (hydr)oxide adsorbent has high adsorbing capacity for As not only in the laboratory environment but also in the field condition. This is one of the succeeding As removal techniques that could reduce As concentration of water below the WHO guideline value for As in situ.

Symmetry and broken-symmetry in molecular orbital descriptions of unstable molecules. 3. The nature of chemical bonds of spin frustrated systems.

Symmetry and broken symmetry in the molecular orbital description of spin frustration systems have been investigated in relation to the resonating valence bond (RVB) theory of the spin liquid state and non-BCS superconductivity. Broken symmetry (BS) and resonating BS (RBS) molecular orbital (MO) methods have been employed to obtain resonating valence bond (RVB)-type explanations of spin frustrated systems. RBS MO solutions are expanded using the localized molecular orbitals (LMO) to elucidate a universal MO-VB description. The BS and RBS MO descriptions of triangular spin frustrated systems corresponding to transition structures for exchange-forbidden radical insertions were investigated in comparison with the RVB-type explanations of such systems. The BS and RBS calculations by the use of three different axial (SDW) solutions or three noncollinear GSO (helical SDW) solutions of a triangular hydrogen cluster were performed to obtain potential curves with and without resonance (quantum) effects. The resonating GSO (noncollinear) state responsible for short-range correlation was found to be the most stable for the system. The reliability of the approximate spin projection (AP) procedure to eliminate the high-spin component was also elucidated, comparing with the AP BS and RBS potential curves. The BS GSO (GHF) computations of several triangular systems, N(CH(2))(3), (CH(2))(3), and Mn(II)(3)O(4), were performed to obtain total energies and total spin angular momentums and effective exchange integrals (J) between local spins, which are crucial for construction of effective spin Hamiltonian models. The exact diagonalization of the Heisenberg models was also performed to depict the energy levels and magnetic susceptibility curves for triangular and kagome lattices to elucidate spin frustration effects and related quantum spin behaviors. Implications of the computational results have been discussed in relation to magnetic properties of several triangular and kagome systems synthesized recently and the superconductivity of triangular systems discovered recently.

Diagnostic implications of MR imaging for mucinous adenocarcinoma arising from fistula in ano.

Mucinous adenocarcinoma associated with chronic fistula in ano is rare, and diagnosis is often difficult. Two cases of mucinous adenocarcinoma arising from fistula in ano occur in a patient with longlasting fistulas, persisting for more than 10 years, are presented. In two cases, T2-weighted MR images revealed symptomatic features; that is, the hyperintense heterogeneous content looked like a gathering of various sizes of granules. This is due to the fact that mucinous adenocarcinomas usually consist of the gathering of many small mucous lakes. This finding has the implications in diagnosing mucinous adenocarcinoma arising from carcinoma in ano.

An incidentally discovered small and asymptomatic para-aortic paraganglioma.

Preoperative diagnosis of asymptomatic paraganglioma is difficult due to the lack of specific symptoms. In this report, we present a rare case of a small and asymptomatic para-aortic paraganglioma. A 34-year-old woman who complained of back pain was admitted for further examination. No abnormal findings were observed on physical or laboratory examinations. An abdominal CT scan and an abdominal MRI incidentally noted a mass about 3 cm in diameter adjacent to the right edge of the inferior vena cava. The following aortic angiography showed the tumor with a feeding artery diverting directly from the aorta. The tumor was completely resected by laparotomy. The resected tumor, 3 x 3 x 3 cm in size, was soft, dark-reddish and encapsulated. Immunohistochemical examinations showed that it was positive for neuron-specific enolase, chromogranin A and adrenocorticotropin. Under these findings, the diagnosis of para-aortic paraganglioma was determined. Seven years after the operation, she remains asymptomatic and free of disease.

High expression of ABCG2 induced by EZH2 disruption has pivotal roles in MDS pathogenesis.

Both proto-oncogenic and tumor-suppressive functions have been reported for enhancer of zeste homolog 2 (EZH2). To investigate the effects of its inactivation, a mutant EZH2 lacking its catalytic domain was prepared (EZH2-dSET). In a mouse bone marrow transplant model, EZH2-dSET expression in bone marrow cells induced a myelodysplastic syndrome (MDS)-like disease in transplanted mice. Analysis of these mice identified Abcg2 as a direct target of EZH2. Intriguingly, Abcg2 expression alone induced the same disease in the transplanted mice, where stemness genes were enriched. Interestingly, ABCG2 expression is specifically high in MDS patients. The present results indicate that ABCG2 de-repression induced by EZH2 mutations have crucial roles in MDS pathogenesis.

Genetic cholesteryl ester transfer protein deficiency caused by two prevalent mutations as a major determinant of increased levels of high density lipoprotein cholesterol.

Genetic determinants of HDL cholesterol (HDL-C) levels in the general population are poorly understood. We previously described plasma cholesteryl ester transfer protein (CETP) deficiency due to an intron 14 G(+1)-to-A mutation(Int14 A) in several families with very high HDL-C levels in Japan. Subjects with HDL-C > or = 100 mg/dl (n = 130) were screened by PCR single strand conformational polymorphism analysis of the CETP gene. Two other mutations were identified by DNA sequencing or primer-mediated restriction map modification of PCR products: a novel intron 14 splice donor site mutation caused by a T insertion at position +3 from the exon14/intron14 boundary (Int14 T) and a missense mutation (Asp442 to Gly) within exon 15 (D442G). The Int14 T mutation was only found in one family. However, the D442G and Int14 A mutations were highly prevalent in subjects with HDL-C > or = 60 mg/dl, with combined allele frequencies of 9%, 12%, 21% and 43% for HDL-C 60-79, 80-99, 100-119, and > or = 120 mg/dl, respectively. Furthermore, prevalences of the D442G and Int14 A mutations were extremely high in a general sample of Japanese men (n = 236), with heterozygote frequencies of 7% and 2%, respectively. These two mutations accounted for about 10% of the total variance of HDL-C in this population. The phenotype in a genetic compound heterozygote (Int14 T and Int14 A) was similar to that of Int14 A homozygotes (no detectable CETP and markedly increased HDL-C), indicating that the Int14 T produces a null allele. In four D442G homozygotes, mean HDL-C levels (86 +/- 26 mg/dl) were lower than in Int14 A homozygotes (158 +/- 35 mg/dl), reflecting residual CETP activity in plasma. In 47 D442G heterozygotes, mean HDL-C levels were 91 +/- 23 mg/dl, similar to the level in D442G homozygotes, and significantly greater than mean HDL-C levels in Int14 A heterozygotes (69 +/- 15 mg/dl). Thus, the D442G mutation acts differently to the null mutations with weaker effects on HDL in the homozygous state and stronger effects in the heterozygotes, suggesting dominant expression of a partially defective allele. CETP deficiency, reflecting two prevalent mutations (D442G and Int14 A), is the first example of a genetic deficiency state which is sufficiently common to explain a significant fraction of the variation in HDL-C in the general population.

Effects of ML-236b (compactin) on sterol synthesis and low density lipoprotein receptor activities in fibroblasts of patients with homozygous familial hypercholesterolemia.

We studied biochemical genetics of low density lipoprotein (LDL) receptor mutations in fibroblasts from six homozygous and five heterozygous patients with familial hypercholesterolemia (FH). Three of six homozygotes are receptor-negative type and the other three homozygotes are receptor-defective type. In the cells from three receptor-negative homozygotes, the receptor binding, internalization, and degradation of (125)I-LDL were 0.5+/-0.3 ng/mg protein (mean+/-SEM), 14+/-8 and 8+/-6 ng/mg protein per 6 h (four normal cells; 44+/-3, 386+/-32, and 1,335+/-214 ng/mg protein per 6 h), respectively. In the cells from three receptor-defective homozygotes, the receptor binding, internalization, and degradation of (125)I-LDL were 6+/-2, 29+/-8, and 90+/-32 ng/mg protein per 6 h, respectively. In these six homozygotes, two pairs of siblings are included. Two siblings in the same family were classified as receptor-negative and two siblings in another family were classified as receptor-defective. The receptor-negative phenotypes and the receptor-defective phenotypes bred true in individual families. The cells from five heterozygotes showed approximately 46% of the normal activities of receptor.ML-236B, competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), completely inhibited the incorporation of [(14)C]acetate into digitonin-precipitable sterols in fibroblasts from normal subjects and heterozygous and homozygous patients with FH with the concentration of 0.5 mug/ml. However, at 0.05 mug/ml of ML-236B sterol synthesis in fibroblasts from homozygotes was not completely suppressed in contrast to normal and heterozygous cells. Moreover, after preincubation with 0.05 mug/ml of ML-236B for 24 h in medium containing lipoproteins, sterol synthesis in the cells from receptor-negative homozygote showed 75% of the initial activity compared with that of 25% without preincubation. In the cells from a normal subject and a heterozygote, sterol synthesis was inhibited even after preincubation. These results suggest that (a) the inhibitory effect of ML-236B is overcome in homozygote cells by their high intracellular levels of HMG-CoA reductase and (b) that a higher dose of ML-236B may be required to lower serum cholesterol levels in FH homozygotes than in heterozygotes.

Methylenetetrahydrofolate reductase C677T is not associated with expression of pyrimidine metabolic enzyme genes in colorectal cancer.

Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism may influence the chemosensitivity of colorectal cancers to fluorouracil (5-FU) by increasing intracellular 5,10-methylenetetrahydrofolate. The effect of this polymorphism on the expression of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT) and thymidine phosphorylase (TP) in colorectal cancer was investigated. The MTHFR C677T polymorphism was analysed and TS, DPD, OPRT and TP mRNA expression was measured in tumour and adjacent normal mucosal tissue. In all patients, the genotypes of the tumour and normal tissues were identical. No differences were found in the expression of TS, DPD or TP mRNA by genotype in either tumour or normal tissue. Although the OPRT mRNA level in tumour tissue was not associated with the genotype, normal mucosa with the TT genotype showed a significantly higher OPRT mRNA level than mucosa with other genotypes. The MTHFR C667T polymorphism is not associated with intratumoural expression of TS, DPD, OPRT or TP.

Induction of tumoricidal activity of polymorphonuclear leukocytes by a linear beta-1,3-D-glucan and other immunomodulators in murine cells.

The cytotoxic activity of polymorphonuclear leukocytes (PMN) against tumor cells induced in vitro by antitumor immunomodulators was examined by a 51Cr release cytotoxicity assay. Among 28 immunomodulators and other agents thus far tested, only beta-1,3-glucan from Alcaligenes faecalis var. myxogenes IFO 13140, Bacillus Calmette-Guérin, Propionibacterium acnes, zymosan A, and Nocardia cell wall skeleton were found to cause induction. The cytotoxic activity of PMN with the beta-1,3-glucan was very high, almost 100% cytolysis being observed at an effector:target ratio as low as 3. The other four potent immunomodulators had effects very similar to that of the beta-1,3-glucan. All five tumor cell lines tested, MM46, MM48, MH134, EL-4, and YAC-1, were lysed, whereas normal spleen and thymus cells and PMN were not. Of four types of effector cells tested, PMN and casein-induced macrophages were effective, whereas resident macrophages and J774 cells were not effective. The cytotoxic activity of PMN was greater than that of induced macrophages, although both were induced by casein. From results on the polysaccharides tested, a linear beta-1,3-glucan structure and a minimum number average degree of polymerization of 125 of the beta-1,3-glucan seemed to be required for induction of cytotoxicity of PMN. The cytotoxic features of PMN and possible chemical structures of antitumor polysaccharides for induction of cytotoxicity are discussed.

Induction of renal pelvic carcinoma by phenacetin in hydronephrosis-bearing rats of the SD/cShi strain.

Carcinogenicity of phenacetin (PH) to the urinary tract was tested with the use of spontaneously hydronephrosis-bearing rats. In Experiment 1, 55 SD/cShi male rats were fed with 2% PH-containing diet for 85 weeks, and 32 SD/cShi male rats fed basal diet for 85 weeks served as controls. Forty-three of 53 rats fed with PH had renal pelvic carcinoma with lung metastases in three. The mean induction time was 78 weeks. Ureteral carcinoma and urinary bladder carcinoma were observed in 2 and 6 of 53 rats given PH, respectively. No urinary tract carcinoma was found in control animals. In Experiment 2, early lesions of the kidney affected by PH were also evaluated with the use of SD/cShi and Sprague-Dawley (SD) rats. Two groups of animals containing 6 SD/cShi or 6 SD male rats per group were fed 2% PH-containing diet for 8 weeks. Control animals containing 6 SD/cShi rats or 6 SD rats were fed basal diet for 8 weeks. Simple hyperplasia was found in 5 of 6 SD/cShi rats given PH and 2 of 6 SD/cShi control rats. Papillary necrosis was seen in 4 of 6 SD/cShi and 2 of 6 SD rats given PH. SD/cShi rats, especially those treated with PH, showed higher but not significant 5-bromo-2'-deoxyuridine labeling indices in the covering epithelium of the renal pelvis and papillae. In this short term experiment PH and its metabolites, N-hydroxyphenacetin and N-acetyl-p-aminophenol, were measured in urine and plasma by using high performance liquid chromatography. Significantly higher PH and slightly higher metabolites were detected in urine and plasma of SD/cShi rats compared to SD rats. These results indicated that the renal pelvis of SD/cShi rats had more sensitivity to PH carcinogenicity. This paper provides experimental proof of PH carcinogenicity toward the renal pelvis in an animal model.

alphaPIX nucleotide exchange factor is activated by interaction with phosphatidylinositol 3-kinase.

p21-activated kinase (PAK) is a common effector protein of the small GTPases Cdc42 and Rac, leading to the activation of downstream mitogen activated protein kinases. PAK also mediates polarized cytoskeletal changes induced by these GTPases. The recently identified PAK-interacting exchange factor (PIX) acts as a guanine nucleotide exchange factor on Rac, and colocalizes with PAK in a focal complex, but little is known about the associated signaling cascades, including upstream activators of PIX. In this study, we show that one of the isoforms of PIX, alphaPIX, is activated by signaling cascades from the platelet-derived growth factor (PDGF) receptor and EphB2 receptor, and from integrin-induced signaling through phosphatidylinositol 3-kinase (PI3-kinase). alphaPIX is activated by forming a complex with these receptors either via association with PAK and Nck, or direct association with the p85 regulatory subunit of PI3-kinase. Synthetic phosphoinositide and membrane targeted PI3-kinase augmented the alphaPIX activity in vivo. In Xenopus, aggregates of mesodermal cells derived from embryos microinjected with alphaPIX significantly increased the peripheral spreading on fibronectin substrate in response to PDGF through PI3-kinase. These results indicate that alphaPIX is activated by PI3-kinase, and is involved in the receptor mediated signaling leading to the activation of the kinase activity of PAK, and the migration of mesodermal cells on extracellular matrix.

Hampered expression of isoaspartyl protein carboxyl methyltransferase gene in the human cataractous lens.

Isoaspartyl protein carboxyl methyltransferase (PIMT) is implicated in the repair of age-damaged proteins by converting altered aspartic acid residues to normal L-aspartic acid residues. Northern blot and reverse transcription (RT)-PCR analyses have revealed that PIMT gene expression in the human lens is detected exclusively in epithelial cells, and that the mRNA levels in cataractous lens epithelia are significantly lower than those in normal age-matched lens tissue. These results suggest that PIMT may play a vital role in maintaining the clarity of the lens and preventing cataract formation.

Left ventricular functional reserve in patients with syndrome X: evaluation by continuous ventricular function monitoring.

OBJECTIVES: The objective of this study was to evaluate cardiac functional reserve in patients with syndrome X. BACKGROUND: Syndrome X is characterized by stress-induced anginal pain and ST segment depression, normal findings on coronary angiography and normal left ventricular function at rest. Reduced coronary vasodilative reserve and abnormal myocardial lactate metabolism have been described in such patients. METHODS: To assess left ventricular functional reserve in patients with syndrome X, continuous radionuclide monitoring of left ventricular end-diastolic volume, end-systolic volume and ejection fraction was performed in 12 patients and 13 normal control subjects during supine bicycle ergometer exercise. RESULTS: In control subjects, end-diastolic volume increased at peak exercise from 100% to 106.5% (p < 0.01), end-systolic volume decreased from 39.1% to 22.6% (p < 0.01) and ejection fraction increased from 60.9% to 78.6% (p < 0.01). In patients with syndrome X, end-diastolic volume increased at peak exercise from 100% to 106% (p < 0.01), and end-systolic volume decreased at ST segment depression < or = 0.5 mm (the ST point) from 37% to 28.8% (p < 0.01) but increased at peak exercise to 44.7% (p < 0.01 vs. the ST point). Thus, ejection fraction increased at the ST point from 63% to 72.7% (p < 0.01) but decreased at peak exercise to 57.7% (p < 0.01 vs. the ST point and control subjects) in proportion to the degree of ST segment depression. In nine patients (75%), ejection fraction at peak exercise was lower than baseline values. All patients and control subjects showed a rapid ejection fraction increase just after exercise during the recovery period. The degree of ejection fraction "overshoot" in patients was similar to that in control subjects, but the interval from the end of exercise to the overshoot in patients was significantly longer than that in control subjects (118 vs. 65 s, p < 0.01). CONCLUSIONS: In patients with syndrome X subjected to exercise stress, left ventricular function remained normal before the onset of ST segment depression. Once ST segment depression appeared, left ventricular function deteriorated in proportion to the degree of depression, and reduced left ventricular function persisted into the recovery period. Continuous ventricular function monitoring is thus a useful predictor of reduced left ventricular functional reserve in patients with syndrome X.

Effects of short-term aminophylline administration on cardiac functional reserve in patients with syndrome X.

OBJECTIVES: This study sought to evaluate the effect of adenosine receptor blockade by aminophylline on cardiac functional reserve in patients with syndrome X. BACKGROUND: Aminophylline may have a potentially antiischemic effect through the inhibition of adenosine and, thus, the coronary steal phenomenon in patients with syndrome X. METHODS: A single-blind, placebo-controlled study of an intravenous infusion of aminophylline (6 mg/kg body weight over 15 min) or placebo (20 ml of saline solution over 15 min) was performed during continuous radionuclide monitoring of left ventricular ejection fraction in 12 patients performing supine bicycle ergometric exercise. RESULTS: Aminophylline increased exercise time (aminophylline 400 s vs. placebo 355 s, p < 0.01), decreased degree of ST segment depression (aminophylline 1.6 mm vs. placebo 2.4 mm, p < 0.01) and either abolished (seven patients) or diminished (five patients) chest pain during exercise. Aminophylline also increased left ventricular ejection fraction at rest (aminophylline 66.5% vs. placebo 62.3%, p < 0.05) but did not improve its deterioration at peak exercise (aminophylline 60.1% vs. placebo 56.6%, p = NS) or shorten the abnormally prolonged interval between the end of exercise and the overshoot (aminophylline 115 s vs. placebo 130 s, p = NS). CONCLUSIONS: Aminophylline infusion increases ischemic threshold and prolongs exercise duration in patients with syndrome X. It is hypothesized that aminophylline acts by inhibiting the coronary steal phenomenon through adenosine receptor blockade. It does not improve the deterioration in left ventricular function at peak exercise or the delayed response in ejection fraction in the recovery period, presumably because the beneficial effects of aminophylline that result from the redistribution of coronary blood flow are limited.

Neuropharmacology of control of respiratory rhythm and pattern in mature mammals.

This review summarizes the current understanding of the neurotransmitters and neuromodulators that are involved, firstly, in respiratory rhythm and pattern generation, where glutamate plays an essential role in the excitatory mechanisms and glycine and gamma-aminobutyric acid mediate inhibitory postsynaptic effects, and secondly, in the transmission of input signals from the central and peripheral chemoreceptors and of motor outputs to respiratory motor neurons. Finally, neuronal mechanisms underlying respiratory modulations caused by respiratory depressants and excitants, such as general anesthetics, benzodiazepines, opioids, and cholinergic agents, are described.

Marked improvement of diabetic diarrhea with the somatostatin analogue octreotide.

Somatostatin and its long-acting analogue octreotide have been used in various diarrheal disorders, including neoplastic and nonneoplastic diseases of the gastrointestinal tract. In two insulin-dependent diabetic patients with autonomic neuropathy and chronic steatorrheic diarrhea refractory to conventional medications, subcutaneous administration of octreotide markedly improved the volume and frequency of stools in both patients. This change was accompanied by a clear improvement in their rapid gastrointestinal tract transit times. The treatment also greatly improved their orthostatic hypotension. No adverse effects of octreotide were observed after treatment for 7 months in one patient and 2 months in the other.

Increased plasma levels of immunoreactive endothelin and von Willebrand factor in NIDDM patients.

OBJECTIVES: To elucidate the significance of plasma levels of endothelin (ET) and von Willebrand factor (vWF) as possible markers for endothelial dysfunction in non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: Plasma levels of ET and vWF were determined in 22 NIDDM patients with or without retinopathy and 10 normal control subjects. RESULTS: The plasma levels of immunoreactive endothelin (irET) and vWF in NIDDM patients were 0.78 +/- 0.06 pmol/l and 218.3 +/- 18.4%, respectively, which represented significant (P < 0.05, P < 0.01, respectively) differences from the values in the control group (0.50 +/- 0.06 pmol/l and 139.1 +/- 11.1%, respectively, n = 10). However, when the diabetic patients were divided into two groups according to the presence or absence of diabetic retinopathy, the plasma levels of irET and vWF in the NIDDM patients with retinopathy were significantly higher (1.01 +/- 0.07 pmol/l and 283.0 +/- 21.4%, respectively, n = 12) compared with the control group and NIDDM patients without retinopathy (0.59 +/- 0.06 pmol/l and 164.3 +/- 17.0%, respectively). Plasma levels of irET showed a significant (P < 0.01) positive correlation with the levels of vWF. CONCLUSIONS: These data strongly suggest that increased plasma irET reflects the endothelial cell damage in NIDDM.

Suppressed plasma renin activity in adrenal regeneration hypertension.

To clarify the role of the enucleated adrenal in the suppression of plasma renin activity (PRA) in adrenal regeneration hypertension (ARH), PRA response to furosemide administration was compared at the 9th experimental week in three groups of rats, which had been subjected to (a) sham operation (control), (b) unilateral nephrectomy, (c) unilateral nephrectomy plus contralateral adrenal enucleation, and given on tap water or high sodium intakes. Urine volume and sodium, and changes in body weight and hematocrit, determined 90 min after administration of furosemide, did not show any significant differences among any of the experimental groups. The basal PRA was significantly decreased in rats of the other groups as compared to the control rats drinking tap water. A decrease in basal PRA was much more pronounced in the unilaterally nephrectomized rats with or without an enucleated adrenal, drinking saline. After furosemide administration, PRA significantly increased in the control rats drinking saline as well as in the unilaterally nephrectomized rats drinking tap water, with or without an enucleated adrenal, but the PRA values in these three groups were only half those of the control rats drinking tap water. An insignificant increase in PRA was found in unilaterally nephrectomized (plus or minus enucleation) rats drinking saline. These findings suggest that the lack of a PRA response in ARH may be due to the pronounced suppression of the juxtaglomerular cells caused by a high sodium intake and the reduction of the renal mass, independently of the corticosteroid(s) secreted by the enucleated adrenal.

Influence of adrenal enucleation of plasma renin substrate concentration in saline loaded and unilaterally nephroadrenalectomized rats.

The influence of adrenal enucleation on plasma renin substate (PRS) concentration was investigated by comparison with sham operation (control) or adrenalectomy in unilaterally nephroadrenalectomized rats given 1% saline for drinking. Two days after adrenal enculeation or adrenalectomy, a significant increase in plasma renin activity (PRA), with a concomitant decrease in PRS, was observed. Those changes were less pronounced in adrenal enucleated rats than in adrenalectomized ones. Ten days later PRA markedly decreased to the control level in both groups. PRS rose to the control level at 10 days after adrenal enucleation without increasing further, while that in the adrenalectomized rats remained low as before. These results suggest that the fall in PRS occuring immediately after adrenal enucleation may be due both to enhanced PRS consumption resulting from increased PRA and to diminished PRS production caused by corticosteroid deficiency, and that restoration of corticosterone secretion by the enucleated adrenal gland may account for recovery of PRS.

Mineralocorticoid and renal receptor binding activity of 21-deoxyaldosterone.

Since several aldosterone metabolites are known to be active, we have assessed the mineralocorticoid biological and renal receptor binding activities of the aldosterone metabolites, 21-deoxyaldosterone (21-deoxy-Aldo), 21-deoxytetrahydroaldosterone (21-deoxy-THAldo), and 3 alpha, 5 beta-tetrahydroaldosterone (THAldo). We synthesized these steroids by bioreduction of aldosterone with intestinal bacteria. Mineralocorticoid agonist activity of 21-deoxy-Aldo, 21-deoxy-THAldo and THAldo, determined by bioassay using adrenalectomized rats, was 1-5%, less than 0.01%, and 0.1-0.5% that of aldosterone, respectively. 21-Deoxy-Aldo showed no antagonist activity. The relative affinity in competing with [3H]aldosterone for binding to mineralocorticoid receptors in adrenalectomized rat kidney cytosols was 94%, less than 0.01%, and less than 0.01% that of aldosterone. The relative binding affinity for rat renal glucocorticoid receptors was 23%, less than 0.01%, and less than 0.01% that of dexamethasone, and for corticosteroid-binding globulin 17%, less than 0.01%, and less than 0.01% that of cortisol. These results show that the naturally occurring steroid, 21-deoxy-Aldo, possesses mineralocorticoid agonist activity which is equivalent to that of 11-deoxycorticosterone, and has substantial affinity for rat renal mineralocorticoid and glucocorticoid receptors. The results also implicate the pathophysiological role of 21-deoxy-Aldo as a potential mineralocorticoid in 21-hydroxylase deficiency, where urinary excretion of this steroid is invariably elevated.