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Delusion is a subjective belief, which is based on a mistaken judgment without any grounds. We thought the symptoms from the perspective of cognitive science. In the process of discovering the grounds by which delusions occur in patients, by the setting of goals which are not restricted by others, and by enhancing the presence such that new frame construction with integrity can be continuously possible, we report the case that delusion has disappeared and has been cured. When considering what client‐centered medical care is, it is necessary to reconsider the mechanism of cognition of patients from the perspective of information fields which occur within relationships, and to support patients so that they can select what they want to do from the standpoint of the goals they seek.

A recent large-scale study revealed that glucocorticoid treatment increased fracture risk, which occurred at a far smaller dose and by a shorter duration than previously thought. To study the underlying mechanism for the increased risk of fracture, we studied the early changes in bone mineral density (BMD) and body composition by dual energy X-ray absorptiometry (DXA) after initiating high-dose glucocorticoid treatment. High-dose glucocorticoid treatment was arbitrarily defined as daily doses ofor=40 mg of a predonisolone equivalent. The 33 patients enrolled in this study had not received glucocorticoid treatment before. Only 2 months of treatment resulted in substantial BMD loss, most markedly in the lumbar spine, followed by the femoral neck and total body, which suggests the preferential trabecular bone loss. Body composition was also greatly affected. Thus, 2-month treatment with glucocorticoid significantly reduced bone mineral content (BMC), lean body mass (LBM) and increased fat mass (FAT). Our results are likely to have some clinical relevance. First, BMD loss occurs quite rapidly after starting glucocorticoid treatment, and patients receiving glucocorticoid treatment should be more carefully monitored for their BMD. Second, LBM, which mainly represents muscle volume, decreases rapidly after initiating glucocorticoid treatment. Decreased LBM might be also responsible for the increased risk of fracture, since falling is a well-known risk factor for fracture, and patients receiving glucocorticoid treatment should also be evaluated for their body composition.

Achondroplasia is the most common genetic form of human dwarfism, for which there is presently no effective therapy. C-type natriuretic peptide (CNP) is a newly identified molecule that regulates endochondral bone growth through GC-B, a subtype of particulate guanylyl cyclase. Here we show that targeted overexpression of CNP in chondrocytes counteracts dwarfism in a mouse model of achondroplasia with activated fibroblast growth factor receptor 3 (FGFR-3) in the cartilage. CNP prevented the shortening of achondroplastic bones by correcting the decreased extracellular matrix synthesis in the growth plate through inhibition of the MAPK pathway of FGF signaling. CNP had no effect on the STAT-1 pathway of FGF signaling that mediates the decreased proliferation and the delayed differentiation of achondroplastic chondrocytes. These results demonstrate that activation of the CNP-GC-B system in endochondral bone formation constitutes a new therapeutic strategy for human achondroplasia.

Thyroid hormones enhance osteoclast formation and their excess is an important cause of secondary osteoporosis. 3,5,3' -Triiodo-L-thyronine (T3) induced the mRNA expression of receptor activator of nuclear factor-kappa B ligand (RANKL), which is a key molecule in osteoclast formation, in primary osteoblastic cells (POB). This effect was amplified in the copresence of 1 alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)). Although T3 alone did not induce octeoclasts in coculture of bone marrow cells with POB, T3 enhanced 1,25(OH)(2)D(3)-induced osteoclast formation. Thyroxine (T4) also enhanced 1,25(OH)(2)D(3)-induced osteoclast formation. These data suggested that T4 was locally metabolized to T3 for its action, since T4 is a prohormone with little hormonal activity. The mRNA expression of type-2 iodothyronine deiodinase (D2), which is responsible for maintaining local T3 concentration, was induced by 1,25(OH)(2)D(3) dose- and time-dependently. Our data would facilitate our understanding of the mechanism of osteoclast formation by thyroid hormones and suggest a novel interaction between thyroid hormones and 1,25(OH)(2)D(3).

Ghrelin, an endogenous ligand for the GH secretagogue receptor, was isolated from rat stomach and is involved in a novel system for regulating GH release. Although previous studies in rodents suggest that ghrelin is also involved in energy homeostasis and that ghrelin secretion is influenced by feeding, little is known about plasma ghrelin in humans. To address this issue, we studied plasma ghrelin-like immunoreactivity levels and elucidated the source of circulating ghrelin and the effects of feeding state on plasma ghrelin-like immunoreactivity levels in humans. The plasma ghrelin-like immunoreactivity concentration in normal humans measured by a specific RIA was 166.0 10.1 fmol/ml. Northern blot analysis of various human tissues identified ghrelin mRNA found most abundantly in the stomach and plasma ghrelinlike immunoreactivity levels in totally gastrectomized patients were reduced to 35% of those in normal controls. Plasma ghrelin-like immunoreactivity levels were increased by 31% after 12-h fasting and reduced by 22% immediately after habitual feeding. In patients with anorexia nervosa, plasma ghrelin-like immunoreactivity levels were markedly elevated compared with those in normal controls (401.2 58.4 vs. 192.8 19.4 fmol/ml) and were negatively correlated with body mass indexes. We conclude that the stomach is a major source of circulating ghrelin and that plasma ghrelin-like immunoreactivity levels reflect acute and chronic feeding states in humans. (J Clin Endocrinol Metab 86: 4753– 4758, 2001)

Longitudinal bone growth is determined by endochondral ossification that occurs as chondrocytes in the cartilaginous growth plate undergo proliferation, hypertrophy, cell death, and osteoblastic replacement. The natriuretic peptide family consists of three structurally related endogenous ligands, atrial, brain, and C-type natriuretic peptides (ANP, BNP, and CNP), and is thought to be involved in a variety of homeostatic processes. To investigate the physiological significance of CNP in vivo , we generated mice with targeted disruption of CNP ( Nppc −/− mice). The Nppc −/− mice show severe dwarfism as a result of impaired endochondral ossification. They are all viable perinatally, but less than half can survive during postnatal development. The skeletal phenotypes are histologically similar to those seen in patients with achondroplasia, the most common genetic form of human dwarfism. Targeted expression of CNP in the growth plate chondrocytes can rescue the skeletal defect of Nppc −/− mice and allow their prolonged survival. This study demonstrates that CNP acts locally as a positive regulator of endochondral ossification in vivo and suggests its pathophysiological and therapeutic implication in some forms of skeletal dysplasia.

Brain natriuretic peptide (BNP), a hormone produced primarily by the cardiac ventricle, is thought to be involved in a variety of homeostatic processes through its cognate receptor, guanylyl cyclase A (GC-A). We previously created transgenic mice overexpressing BNP under the control of the liver-specific human serum amyloid P component promoter (BNP-transgenic mice) and demonstrated that they exhibit reduced blood pressure and cardiac weight accompanied by an elevation of plasma cGMP concentrations and marked skeletal overgrowth through the activation of endochondral ossification. To address whether BNP exerts its biological effects solely through GC-A, we produced BNP-transgenic mice lacking GC-A (BNP-Tg/GC-A-/- mice) and examined their cardiovascular and skeletal phenotypes. The GC-A-/- mice are hypertensive with cardiac hypertrophyrelative to wild-type littermates, which is not alleviated by overexpression of BNP in BNP-Tg/GC-A-/- mice. The BNP-Tg/GC-A-/- mice, however, continue to exhibit marked longitudinal growth of vertebrae and long bones comparably to BNP-Tg mice. This study provides genetic evidence that BNP reduces blood pressure and cardiac weight through GC-A, whereas it dramatically alters endochondral ossification in the absence of this receptor. Therefore, the BNP-Tg/GC-A-/- mice provide the first experimental model demonstrating that this natriuretic peptide can signal in a tissue-specific manner through a receptor other than GC-A.

Cardiac fibrosis, defined as a proliferation of interstitial fibroblasts and biosynthesis of extracellular matrix components in the ventricles of the heart, is a consequence of remodeling processes initiated by pathologic events associated with a variety of cardiovascular disorders, which leads to abnormal myocardial stiffness and, ultimately, ventricular dysfunction. Brain natriuretic peptide (BNP) is a cardiac hormone produced primarily by ventricular myocytes, and its plasma concentrations are markedly elevated in patients with congestive heart failure and acute myocardial infarction. However, its precise functional significance has been undefined. In this paper, we report the generation of mice with targeted disruption of BNP ( Nppb −/− mice). We observed multifocal fibrotic lesions in the ventricles from Nppb −/− mice. No signs of systemic hypertension and ventricular hypertrophy are noted in Nppb −/− mice. In response to ventricular pressure overload, focal fibrotic lesions are increased in size and number in Nppb −/− mice, whereas no focal fibrotic changes are found in wild-type littermates ( Nppb +/+ mice). This study establishes BNP as a cardiomyocyte-derived antifibrotic factor in vivo and provides evidence for its role as a local regulator of ventricular remodeling.

Excess of body fat, or obesity, is a major health problem and confers a higher risk of cardiovascular and metabolic disorders such as diabetes, hypertension, and coronary heart disease. Leptin is an adipocyte-derived satiety factor that plays an important role in the regulation of energy homeostasis, and its synthesis and secretion are markedly increased in obese subjects. To explore the metabolic consequences of an increased amount of leptin on a long-term basis in vivo, we generated transgenic skinny mice with elevated plasma leptin concentrations comparable to those in obese subjects. Overexpression of leptin in the liver has resulted in complete disappearance of white and brown adipose tissue for a long period of time in mice. Transgenic skinny mice exhibit increased glucose metabolism accompanied by the activation of insulin signaling in the skeletal muscle and liver. They also show small-sized livers with a marked decrease in glycogen and lipid storage. The phenotypes are in striking contrast to those of recently reported animal models of lipoatrophic diabetes and patients with lipoatrophic diabetes with reduced amount of leptin. The present study provides evidence that leptin is an adipocyte-derived antidiabetic hormone in vivo and suggests its pathophysiologic and therapeutic implications in diabetes.

Prophet of Pit-1 (Prop-1), which is a paired-like homeodomain transcription factor, is capable of binding to sites in an early enhancer of the Pit-1 gene and regulating its expression. According to a previous report, Prop-1 messenger RNA (mRNA) is expressed in the developing pituitary gland before Pit-1 mRNA expression and maximum expression are observed at e 12.0. After e 14.5, Prop-1 mRNA expression rapidly decreases, and only trace amounts of mRNA are detectable in adult mouse pituitary. Human Pit-1 is expressed considerably, not only in normal adult pituitary but also in pituitary adenomas, so we studied human Prop-1 gene expression in adult pituitary and pituitary adenomas. We also cloned human Prop-1 complementary DNA (cDNA) and sequenced the Prop-1 cDNAs in pituitary adenomas. The amino acid sequence of human Prop-1 cDNA that we cloned was identical to that of the previously reported sequence, except Thr substituted at codon 142 instead of Ala. This amino acid substitution is considered to be a pol...

The natriuretic peptide family consists of three structurally related endogenous ligands: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). The biological actions of natriuretic peptides are thought to be mediated through the activation of two guanylyl cyclase (GC)-coupled receptor subtypes (GC-A and GC-B). In this study, we examined the effects of ANP and CNP, which are endogenous ligands for GC-A and GC-B, respectively, on bone growth using an organ culture of fetal mouse tibias, an in vitro model of endochondral ossification. CNP increased the cGMP production much more potently than ANP, thereby resulting in an increase in the total longitudinal bone length. Histological examination revealed an increase in the height of the proliferative and hypertrophic chondrocyte zones in fetal mouse tibias treated with CNP. The natriuretic peptide stimulation of bone growth, which was mimicked by 8-bromo-cGMP, was inhibited by HS-142-1, a non-peptide GC-coupled natriuretic peptide receptor antagonist. The spontaneous increase in the total longitudinal bone growth and cGMP production was also inhibited significantly by HS-142-1. CNP mRNA was expressed abundantly in fetal mouse tibias, where no significant amounts of ANP and BNP mRNAs were detected. A considerable amount of GC-B mRNA was present in fetal mouse tibias. This study suggests the physiologic significance of the CNP/GC-B pathway in the process of endochondral ossification.

C-type natriuretic peptide (CNP) is a local regulator in the brain and vascular wall. We present data to demonstrate the production and action of CNP in the osteoblast. CNP increased cGMP production, far more potently than atrial natriuretic peptide (ANP) in an osteoblastic cell line, MC3T3-E1. Since ANP and CNP are the ligands for two particulate guanylate cyclases, guanylate cyclase-A (GC-A) and guanylate cyclase-B (GC-B), respectively, these results reveal the expression of GC-B in MC3T3-E1. In addition, CNP mRNA and CNP-like immunoreactivity were detected in cell extracts from MC3T3-E1 and its culture medium, respectively. Both CNP and 8-bromo cGMP dose-dependently decreased [ 3 H]thymidine uptake, without affecting alkaline phosphatase activity. These results indicate that CNP is a novel autocrine/paracrine regulator of osteoblast and suggest the presence of “bone natriuretic peptide system.”

The effect of glucose infusion on renal handling of purine bases and oxypurinol was examined in 6 normal subjects. Five hundred milliliters of 1.1 M glucose solution were administered intravenously in 1 h. Fractional clearances of uric acid, xanthine and oxypurinol were significantly increased during glucose infusion, but that of hypoxanthine was not changed, while a 1-hour infusion of 500 ml of 1.1 M mannitol had no effect on the fractional clearances of purine bases and oxypurinol. These data indicate that the effect of glucose infusion on the renal clearances of uric acid, xanthine and oxypurinol was not related to osmotic diuresis but induced by glycosuria and/or hyperglycemia. Accordingly, the glycosuria- and/or hyperglycemia-induced decrease in the biological half-life of oxypurinol must be considered in the administration of allopurinol to gouty patients with uncontrolled diabetes mellitus.

To investigate whether the concentration of uridine in plasma is related to the urinary excretion of urea, 45 healthy male subjects with normouricemia and normal blood pressure were studied after providing informed consent. Immediately after collection of 24-hour urine, blood samples were drawn after an overnight fast except for water. The contents of ingested foods during the 24-hour urine collection period were described by the subjects and analyzed by a dietician. Simple regression analysis showed that plasma uridine was correlated with the urinary excretions of urea (R = 0.41, P < .01), uric acid (R = 0.36, P < .05), and uridine (R = 0.30, P < .05), as well as uric acid clearance (R = 0.35, P < .05) and purine intake (R = 0.30, P < .05). In contrast, multiple regression analysis showed a positive relationship only between plasma uridine and urinary excretion of urea. These results suggest that an increase in de novo pyrimidine synthesis leads to an increased concentration of uridine in plasma via nitrogen catabolism in healthy subjects with normouricemia and normal blood pressure.

Natriuretic peptides constitute a family of three structurally related peptides: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). Particulate guanylate cyclases, GC-A, and GC-B, are the receptors for these peptides to mediate their action. ANP and BNP possess high affinities for GC-A, and CNP is the preferred ligand for GC-B. In this article, we report our study of the expression and possible role(s) of natriuretic peptides in ATDC5 cells, which represent a chondrogenic cell line. ATDC5 cells produced cyclic guanosine monophosphate (cGMP) in response to natriuretic peptides. CNP was far more potent than ANP in terms of cGMP production. The messages for GC-A and GC-B were demonstrated by means of Northern blot analysis, and the presence of CNP was shown by Southern blotting coupled with reverse transcription-polymerase chain reaction (RT-PCR). These results suggest that the CNP/GC-B system is preferentially expressed in ATDC5 cells. GC-B mRNA expression was higher at 14 days after confluency than that at confluency. CNP or 8-bromo cGMP reduced [3H] thymidine uptake and slightly increased the message for collagen type X, which is a marker of hypertrophic chondrocytes. These data suggest that the CNP/GC-B system is likely to be an autocrine/paracrine regulator of ATDC5 cells, thus affecting both their growth and differentiation.

Thyroid hormones (THs), 3,3′,5-triiodo-L-thyronine (T3) and L-thyroxine (T4), are important for the normal development of the growth plate (GP); congenital TH deficiency leads to severe dwarfism. In mouse chondrogenic cell line, ATDC5, T3 enhanced differentiation and increased Alizarin red staining, but did not affect Alcian blue staining. In organ-cultured mouse tibias, THs stimulated the cartilage growth, especially in the hypertrophic zone. Interestingly, T4 was as equally potent as T3 in organ-cultured tibias, which suggests that T4 is metabolized locally to T3, because T4 is a prohormone and must be converted to T3 for its activity. Two enzymes catalyze the conversion; type I deiodinase (D1) and type II deiodinase (D2). D1 has a ubiquitous distribution and D2, with a high affinity for T4, is present where the maintenance of intracellular T3 concentration is critical. Messenger RNAs (mRNAs) for D1 and D2 were detected in neonatal mouse tibias and ATDC5 cells. The enzyme activity was unaffected by the D1 inhibitor 6-propyl-2-thiouracil, suggesting that D2 mainly catalyzes the reaction. D2 mRNA was detected in differentiated ATDC5 cells. In organ-cultured mouse tibias, D2 activity was greater at later stages. In contrast, thyroid hormone receptors (TRs) were expressed in neonatal mouse tibias and ATDC5 cells, but their expression levels in ATDC5 cells were stable throughout the culture periods. Therefore, increased T3 production at later stages by D2 is likely to contribute to the preferential effects of THs in the terminal differentiation of GP. This article is the first to show that T4 is activated locally in GP and enhances the understanding of TH effects in GP.

In a previous study we showed that the involvement of EP4 subtype of the prostaglandin E (PGE) receptor is crucial for lipopolysaccharide (LPS)-induced osteoclast formation in vitro. The present study was undertaken to test whether EP4 is actually associated with LPS-induced bone resorption in vivo. In wild-type (WT) mice, osteoclast formation in vertebrae and tibiae increased 5 days after systemic LPS injection, and urinary excretion of deoxypyridinoline, a sensitive marker for bone resorption, statistically increased 10 days after injection. In EP4 knockout (KO) mice, however, LPS injection caused no significant changes in these parameters throughout the experiment. LPS exposure for 4 h strongly induced osteoclast differentiation factor (ODF) mRNA expression in primary osteoblastic cells (POB) both from WT and EP4 KO mice, and this expression was not inhibited by indomethacin, suggesting prostaglandin (PG) independence. LPS exposure for 24 h further induced ODF expression in WT POB, but not in EP4 KO POB. Indomethacin partially inhibited ODF expression in WT POB, but not in EP4 KO POB. These data suggest that ODF is induced both PG dependently and PG independently. LPS exposure for 24 h induced slightly greater osteoclastgenesis inhibitory factor (OCIF) mRNA expression in EP4 KO than in WT POB. These findings suggest that the reduced ODF expression and apparently increased OCIF expression also are responsible for the markedly reduced LPS-induced osteoclast formation in EP4 KO mice. Our results show that the EP4 subtype of the PGE receptor is involved in LPS-induced bone resorption in vivo also. Since LPS is considered to be largely involved in bacterially induced bone loss, such as in periodontitis and osteomyelitis, our study is expected to help broaden our understanding of the pathophysiology of these conditions.

Prostaglandin E2 (PGE2) exerts its effects through the PGE receptor that consists of four subtypes (EP1, EP2, EP3, and EP4). Osteoclast formation in the coculture of primary osteoblastic cells (POB) and bone marrow cells was enhanced more by 11-deoxy-PGE1 (an EP4 and EP2 agonist) than by butaprost (an EP2 agonist) and other agonists, which suggests that EP4 is the main factor in PGE2-induced osteoclast formation. PGE2-induced osteoclast formation was not observed in the coculture of POB from EP4-deficient (EP4 k/o) mice and spleen cells from wild-type (w/t) mice, whereas osteoclasts were formed in the coculture of POB from w/t mice and spleen cells from EP4-k/o mice. In situ hybridization (ISH) showed that EP4 messenger RNA (mRNA) was expressed on osteoblastic cells but not on multinucleated cells (MNCs) in w/t mice. These results indicate that PGE2 enhances osteoclast formation through its EP4 subtype on osteoblasts. Osteoclast formation by interleukin 1alpha (IL-1alpha), tumor necrosis factor alpha (TNF-alpha), basic fibroblast growth factor (bFGF), and lipopolysaccharide (LPS) was hardly observed in the coculture of POB and bone marrow cells, both from EP4-k/o mice, which shows the crucial involvement of PG and the EP4 subtype in osteoclast formation by these molecules. In contrast, osteoclast formation by 1,25-hydroxyvitamin D3 (1,25(OH)2D3) was not impaired and that by parathyroid hormone (PTH) was only partially impaired in EP4-k/o mice, which may be related to the fact that EP4-k/o mice revealed no gross skeletal abnormalities. Because it has been suggested that IL-1alpha, TNF-alpha, bFGF, and LPS are involved in inflammatory bone loss, our work can be expected to contribute to an understanding of the pathophysiology of these conditions.

There is recent evidence that natriuretic peptides are important regulators of bone and cartilage, although they were originally identified as the cardiac hormones causing natriuresis and hypotension. Three members of natriuretic peptide family are known: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). The biologically active receptors for these peptides are particulate guanylate cyclases; the two known types are GC-A and GC-B. ANP and BNP have high affinities for GC-A, and CNP is the preferred ligand for GC-B. In this paper we report the results of our study of the expression and possible role(s) of natriuretic peptides in the ROB-C26 cell, which is an osteogenic cell line with multiple potentials for differentiating into myoblast, osteoblast, and adipocyte. ROB-C26 cells produced cGMP in response to natriuretic peptides at both their basal state and after enhanced differentiation into osteoblast which was induced by bone morphogenetic protein [(BMP)-2]. CNP was far more potent than ANP in cGMP production. In contrast, enhanced differentiation into adipocyte by dexamethasone resulted in the marked decrease in their responsiveness to natriuretic peptides. Although the messages for GC-A and GC-B were demonstrated by Northern blot analysis at both the basal stage and after BMP treatment, they were down-regulated after dexamethasone treatment. The presence of CNP was shown by RT-PCR and immunohistochemistry in ROB-C26 cells. C3H10T1/2, which is another and more primitive mesenchymal cell line, also produced cGMP in response to CNP, and less potently to ANP. Culturing ROB-C26 cells with CNP or 8-bromo cGMP decreased [(3)H]thymidine uptake and slightly increased the message for alkaline phosphatase, which is a marker for osteoblast differentiation. These results suggest that the CNP/GC-B system is preferentially expressed in the cells of osteogenic lineage and their expression is down-regulated with differentiation into adipocyte lineage. The CNP/GC-B system is likely to be an autocrine/paracrine regulator of osteoblast growth and differentiation.

Longitudinal bone growth is determined by the process of endochondral ossification in the cartilaginous growth plate, which is located at both ends of vertebrae and long bones and involves many systemic hormones and local regulators. Natriuretic peptides organize a family of three structurally related peptides: atrial natriuretic peptide, brain natriuretic peptide (BNP), and C-type natriuretic peptide. Atrial natriuretic peptide and BNP are cardiac hormones that are produced predominantly by the atrium and ventricle, respectively. C-type natriuretic peptide occurs in a wide variety of tissues, where it acts as a local regulator. These peptides can influence body fluid homeostasis and blood pressure control through the activation of two guanylyl cyclase (GC)-coupled natriuretic peptide receptor subtypes—GC-A and GC-B. We report here marked skeletal overgrowth in transgenic mice that overexpress BNP. Transgenic mice with elevated plasma BNP concentrations exhibited deformed bony skeletons characterized by kyphosis, elongated limbs and paws, and crooked tails. Bone abnormalities resulted from a high turnover of endochondral ossification accompanied by overgrowth of the growth plate. Studies using an in vitro organ culture of embryonic mouse tibias revealed that BNP increases the height of cartilaginous primordium directly, thereby stimulating the total longitudinal bone growth. The present study demonstrates that natriuretic peptides can affect the process of endochondral ossification.

A 59-year-old man visited Kyoto University Hospital because of general malaise, polyuria, and polydipsia. The diagnosis of primary hyperparathyroidism was made based on hypercalcemia and an elevated circulating PTH level. A nodule was palpable in the left anterior neck. Two weeks later, the serum calcium level was normalized and his symptoms subsided. A temporary expansion, followed by reduction of the tumor size was observed by serial ultrasonography. Histology of the resected tumor showed central necrotic tissue, with some peripherally remaining glandular tissue. We report here a rare case of primary hyperparathyroidism with spontaneous remission due to hemorrhagic infarction in the adenoma.

A rare case of functioning oxyphil parathyroid adenoma associated with primary hyperparathyroidism and marked hungry bone syndrome was revealed in a 29-year-old man with hypercalcemia and elevated circulating parathyroid hormone (PTH) level. A large parathyroid tumor weighing 8.4 g was resected and proved to be an oxyphil adenoma. Hypocalcemia was sustained after the operation, despite intensive calcium supplementation. During the postoperative 8 months, bone mineral density at the lumbar spine increased dramatically from 0.892 g/cm2 to 1.244 g/cm2, and whole body bone mineral content increased from 1, 913.4 g to 2, 419.2 g. This case gives insight to the reversibility of bone loss in this disorder.(Internal Medicine 35: 545-549, 1996)

PGE2 is one of the key molecules in the osteoblast. It is the major prostanoid in the bone, and its production is under the control of both systemic and local factors. PGE2 has been reported to have multiple actions in the osteoblast, such as growth promotion and cell differentiation. To better understand the action of PGE2 in the osteoblast, we determined the PGE receptor subtypes in MC3T3-E1, an osteoblastic cell line derived from the normal mouse calvaria. Northern blot analysis revealed that EP1 and EP4 subtypes are expressed in MC3T3-E1. In contrast, EP3 subtype was not detected by either Northern blot analysis or RT-PCR. The contribution of each subtype was evaluated by studying the effects of subtype-specific analogs on osteoblastic function at confluency and 5 days after confluency. An EP1 agonist, 17-phenyl-omega-trinor PGE2, increased DNA synthesis and decreased alkaline phosphatase activity. 11-Deoxy-PGE1, and EP2 and EP4 agonist, decreased DNA synthesis and increased alkaline phosphatase activity at both stages. Butaprost, an EP2-selective agonist, showed effects similar to those of 11-deoxy-PGE1 only at confluency. Another and more differentiated osteoblastic marker, osteocalcin production, was detectable and was stimulated by 11-deoxy-PGE1 only 5 days after confluency. The exposure of these cells to EP1 agonist changed the cell shape to a more fibroblastic appearance. These results indicate that EP1, EP4, and probably EP2 are present in MC3T3-E1 cells; EP1 promotes cell growth, and EP2 and EP4 mediate differentiation of the osteoblast. Furthermore, the decreased response to EP2-specific agonist 5 days after confluency suggests that the expression of PGE receptor subtype is dependent on the stage of osteoblastic differentiation. This is the first report to determine PGE receptor subtypes in the bone.

In the present study, we investigated whether ethanol inhibits the activity of xanthine dehydrogenase. Ethanol and/or inosine were administered to normal subjects, and plasma concentration and urinary excretion of purine bases were measured together with blood concentrations of lactic acid and pyruvic acid. In addition, ethanol and pyrazinamide were administered to these subjects, and plasma concentration and urinary excretion of pyrazinamide and its major metabolites were measured. Increases in plasma concentration and urinary excretion of xanthine induced by a combination of ethanol and inosine were greater than the sums of increases induced separately by ethanol and inosine, although increases in plasma concentration and urinary excretion of uric acid induced by the combination of ethanol and inosine were not different from the sums of increases induced separately by ethanol and inosine. Ethanol increased the ratio of blood lactic acid to blood pyruvic acid and decreased plasma concentration and urinary excretion of 5-hydroxypyrazinamide and 5-hydroxypyrazinoic acid. These results suggest that ethanol inhibits xanthine dehydrogenase presumably by an ethanol-induced increase in the cytosolic concentration of NADH in the liver.

The specific lipid alterations in plasma and four different tissues, as well as the activities of plasma lecithin-cholesterol acyltransferase (LCAT) and tissue lipolytic enzymes were determined in experimental nephrotic and control rats. In nephrotic rats, the cholesterol level in the heart was significantly increased, while the kidney level was decreased. When expressed per unit protein, the cholesterol level in the adrenal was also increased. The respective triglyceride and phospholipid levels were similar in both groups, except for the significant increase in the adrenal triglyceride of nephrotic rats when expressed per unit protein. The tissue lipolytic activities were significantly reduced in the heart and adrenals of the nephrotic rats. The plasma LCAT was increased, and electron-microscopically heterogenous lipoproteins (very-low density and high-density lipoproteins) were demonstrated in the nephrotic rats. These results suggest that an excess of abnormal lipoproteins in the circulation may contribute to an increased uptake of cholesterol by circulatory organs like the heart and that an accumulation of cholesterol in the circulatory organs may accelerate atherosclerosis in nephrotic syndrome.

The 2 subjects were a diabetic male with renal hypouricemia and a healthy male with normouricemia. In these subjects, 200 mg of benzbromarone increased fractional uric acid clearance (FUa) and 3.0 g of pyrazinamide decreased FUa. However, pyrazinamide did not inhibit the uricosuric action of benzbromarone at all on the administration of 3.0 g of pyrazinamide together with 200 mg of benzbromarone. These results indicated that in these cases, the relative role of each component could not be determined on the basis of the hypothetical four-component model.

A 74-year-old female was diagnosed as having xanthinuria by measurement of the uric acid level in plasma, purine bases in urine and activity of xanthine oxidase in the duodenal mucosa. The determination of the urinary excretion of purine bases in her family demonstrated a slightly increased urinary excretion of oxypurines in her younger brother, suggesting that he was a heterozygote. The pyrazinamide-loading test and allopurinol-loading test demonstrated that she could neither metabolize pyrazinoic acid into 5-hydroxypyrazinoic acid nor allopurinol into oxypurinol, although there was a slight metabolizing of prazinamide into 5-hydroxypyrazinamide. This suggested that she belonged to the subgroup which can neither metabolize pyrazinamide into 5-hydroxypyrazinamide, pyrazinoic acid into 5-hydroxypyrazinoic acid nor allopurinol into oxypurinol.

Four components are said to be involved in the uric acid transport system of the human kidney, but the definite mechanism of uric acid transport has not yet been clarified. We conducted both the benzbromarone (BZB) loading test and the combined pyrazinamide (PZA) and BZB test 1) to quantify the contribution of the four components involved in the renal handling of uric acid, 2) to determine whether BZB selectively inhibits postsecretory reabsorption of uric acid.

It has been reported that a raised serum uric acid is related to the development of atherosclerosis, but the direct association between hyperuricemia and atherosclerosis remains uncertain1). Therefore, in gout it seems important to investigate serum lipids which are among the known risk factors for atherosclerosis. In previous studies, some investigators suggested that hyperlipidemia in primary gout was secondary to excessive alcohol intake2) and/or obesity3), while others suggested that hyperlipidemia was a consequence of essential factors in primary gout4).