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Kazuo Chihara

Publications and source records attributed to Kazuo Chihara.

At least 73 records · Page 4Linked to original sources
PubMed2003

Parathyroid hormone-Smad3 axis exerts anti-apoptotic action and augments anabolic action of transforming growth factor beta in osteoblasts.

Although several studies indicated that parathyroid hormone (PTH) exerted anabolic action on bone, its precise mechanisms have been unknown. On the other hand, transforming growth factor beta (TGF-beta), abundantly stored in bone matrix, stimulates bone formation with a local injection in rodents. Although our previous study suggested that Smad3 is an important molecule for the stimulation of bone formation, no reports have been available about the effects of PTH on Smad3. In this present study, we examined the effects of PTH on Smad3 and the physiological significance in mouse osteoblastic cells. PTH promoted the expression of Smad3 mRNA within 10 min and the protein level in a dose-dependent manner in MC3T3-E1 and rat osteoblastic UMR-106 cells. Protein kinase A (PKA) activator as well as protein kinase C (PKC) activators increased Smad3 protein level, and both PKA and PKC inhibitors antagonized PTH-induced Smad3, indicating that PTH promotes the production of Smad3 through both PKA and PKC pathways. Next, we examined anti-apoptotic effects of PTH and Smad3 in these cells, employing trypan blue, transferase-mediated nick end labeling, and Hoechst staining. Pretreatment with PTH or overexpression of Smad3 decreased the number of apoptotic cells induced by dexamethasone and etoposide. Moreover, a dominant negative mutant, Smad3DeltaC, abrogated PTH-induced anti-apoptotic effects. On the other hand, PTH augmented TGF-beta-induced transcriptional activity. Furthermore, PTH enhanced TGF-beta-induced production of type I collagen, whereas it did not affect TGF-beta-reduced proliferation in MC3T3-E1 cells. These observations indicated that PTH amplified the anabolic effects of TGF-beta by accelerating the transcriptional activity of Smad3. In conclusion, we first demonstrated that PTH-Smad3 axis exerts anti-apoptotic effects in osteoblasts and reinforces the anabolic action by TGF-beta in osteoblasts. Hence, PTH-Smad3 axis might be involved in the bone anabolic action of PTH.

Animals↗
PubMed2003

Cortical motor areas in plantar response: an event-related functional magnetic resonance imaging study in normal subjects.

The role of the cerebral cortices in normal plantar response was investigated with event-related functional magnetic resonance imaging (fMRI) at 3 Tesla in 12 right-handed normal subjects. During fMRI acquisition, the lateral (LS) and medial (MS) side of the left sole was mechanically stimulated every 16 s to evoke the plantar response under monitoring of the surface electromyogram. LS activated the contralateral supplementary motor area (SMA) more intensively than MS. In contrast, no difference was found in the commonly activated areas including the contralateral primary sensorimotor area, bilateral secondary sensory areas and the thalamus. The results support the hypothesis that the normal plantar response is influenced by the cerebral cortices, and that the SMA likely participates in the regulation of the plantar reflex arc at the spinal level.

Adult↗
PubMed2003

Cloning and characterization of the 5(')-flanking region of the human ghrelin gene.

Ghrelin, a novel growth hormone releasing peptide, was recently isolated from stomach. We have cloned and characterized the 5(')-flanking region, containing from -2000 to -1 upstream from the translation start site of the human ghrelin gene. There was neither typical GC nor CAAT box but there were a TATATAA element and putative binding sites for several transcription factors. Ghrelin promoter was activated only in human stomach derived ECC10 cells among several cell lines examined. Functional analysis showed that promoter activity was increased by deletion of nucleotides from -2000 to -605 whereas it was decreased by further deletion and that the TATATAA element is not functioning. Glucagon and its second messenger cAMP enhanced the promoter activity, suggesting that stimulated transcription of ghrelin gene by glucagon might be responsible for increased ghrelin production during fasting at least in part. These initial characterizations will facilitate further studies of the regulatory mechanisms for ghrelin gene expression.

5' Flanking Region↗
PubMed2003

The role of circulating ghrelin in growth hormone (GH) secretion in freely moving male rats.

To examine the physiological significance of plasma ghrelin in generating pulsatile growth hormone (GH) secretion in rats, plasma GH and ghrelin levels were determined in freely moving male rats. Plasma GH was pulsatilely secreted as reported previously. Plasma ghrelin levels were measured by both N-RIA recognizing the active form of ghrelin and C-RIA determining total amount of ghrelin. Mean +/- SE plasma ghrelin levels determined by N-RIA and C-RIA were 21.6 +/- 8.5 and 315.5 +/- 67.5 pM, respectively, during peak periods when plasma GH levels were greater than 100 ng / ml. During trough periods when plasma GH levels were less than 10 ng / ml, they were 16.5 +/- 4.5 and 342.1 +/- 29.8 pM, respectively. There were no significant differences in plasma ghrelin levels between two periods. Next, effect of a GH secretagogue antagonist, [D-Lys-3]-GHRP-6, on plasma GH profiles was examined. There were no significant differences in both peak GH levels and area under the curves of GH (AUCs) between [D-Lys-3]-GHRP-6-treated and control rats. These findings suggest circulating ghrelin in peripheral blood does not play a role in generating pulsatile GH secretion in freely moving male rats.

Animals↗
PubMed2003

Inactivation of menin, the product of the multiple endocrine neoplasia type 1 gene, inhibits the commitment of multipotential mesenchymal stem cells into the osteoblast lineage.

The physiological roles of menin, the product of the multiple endocrine neoplasia type 1 gene, are not known. Homozygous menin knockout mice exhibit cranial and facial hypoplasia. We, therefore, investigated the role of menin in the regulation of osteoblastic differentiation. Menin antisense oligonucleotides (AS-oligo) reduced endogenous menin expression in the C3H10T1/2 (10T1/2) mouse mesenchymal stem cells and antagonized alkaline phosphatase (ALP) activity and the expression of type I collagen, Runx2/cbfa1 (Runx2), and osteocalcin (OCN) induced by bone morphogenetic protein 2 (BMP-2). AS-oligo did not affect adipogenic markers (Oil red staining and PPARgamma expression) and chondrogenic markers (Alcian blue staining and type IX collagen) induced by BMP-2 in 10T1/2 cells. Menin co-immunoprecipitated with Smad1 and Smad5, and inactivation of menin antagonized BMP-2-induced transcriptional activity of Smad1/5. In osteoblastic MC3T3-E1 cells, AS-oligo affected neither BMP-2-stimulated ALP activity nor the expression of Runx2 and OCN. Stable inactivation of menin in MC3T3-E1 cells increased ALP activity, mineralization, and the expression of type I collagen and OCN. In 21-day cultures of MC3T3-E1 cells and BMP-2-treated 10T1/2 cells, endogenous menin expression increased up to day 14 and declined thereafter. These data indicate that menin inactivation specifically inhibits the commitment of pluripotent mesenchymal stem cells to the osteoblast lineage, mediated by menin and Smad1/5 interactions. Menin is important for both early differentiation of osteoblasts and inhibition of their later differentiation, and it might be crucial for intramembranous ossification.

3T3 Cells↗
PubMed2003

Effect of high phosphate concentration on osteoclast differentiation as well as bone-resorbing activity.

Although high inorganic phosphate (Pi) concentration in culture media directly inhibits generation of new osteoclasts and also inhibits bone resorption by mature osteoclasts, its precise mechanism and the physiological role have not been elucidated. The present study was performed to investigate these issues. Increase in extracellular Pi concentration ([Pi](e)) (2.5-4 mM) concentration dependently inhibited 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] or parathyroid hormone (PTH)-(1-34)-induced osteoclast-like cell formation from unfractionated bone cells in the presence of stromal cells. Increase in [Pi](e) (2.5-4 mM) concentration dependently inhibited 1,25(OH)(2)D(3)-, PTH-(1-34)-, or receptor activator of NF-kappaB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF)-induced osteoclast-like cell formation from hemopoietic blast cells in the absence of stromal cells. Increase in [Pi](e) (2.5-4 mM) dose dependently stimulated the expression of osteoprotegerin (OPG) mRNA and increased the expression of OPG mRNA suppressed by PTH-(1-34) or 1,25(OH)(2)D(3) in unfractionated bone cells, while it did not affect RANKL mRNA. Increase in [Pi](e) (2.5-4 mM) concentration dependently inhibited the bone-resorbing activity of isolated rabbit osteoclasts. Increase in [Pi](e) (4 mM) induced the apoptosis of isolated rabbit osteoclasts while it did not affect the apoptosis of osteoclast precursor cells and mouse macrophage-like cell line C7 cells that can differentiate into osteoclasts in the presence of RANKL and M-CSF. These results indicate that increase in [Pi](e) inhibits osteoclast differentiation both by up-regulating OPG expression and by direct action on osteoclast precursor cells. It is also indicated that increase in [Pi](e) inhibits osteoclastic activity at least in part by the direct induction of apoptosis of osteoclasts.

Animals↗
PubMed2003

Oncogenic ras induces gastrin/CCKB receptor gene expression in human colon cancer cell lines LoVo and Colo320HSR.

Gastrin has the ability to stimulate cell growth in some colorectal cancer cells and some of these cells also express gastrin/CCKB receptors, suggesting that gastrin and its autocrine loop are involved in their proliferation. We previously reported that oncogenic ras induced gastrin gene expression in colon cancer cells. The aim of this study was to investigate whether oncogenic ras also induces gastrin/CCKB receptor gene expression. A transiently transfected activated ras vector stimulated gastrin/CCKB receptor transcriptional activities in both Colo320HSR and LoVo cells, but these ras-increased activities were inhibited by a specific MEK inhibitor, PD98059. An RPA demonstrated that activated ras increased endogenous gastrin/CCKB receptor mRNA levels and PD98059 decreased them in LoVo cells. These findings suggest that oncogenic ras induces gastrin/CCKB receptor gene expression through some intracellular signaling pathways, including MEK, in colon cancer cell lines.

Base Sequence↗
PubMed2003

Effective anti-viral therapy for hemophagocytic syndrome associated with B-cell lymphoma.

A rheumatoid arthritis (RA) patient treated with low-dose methotrexate (MTX) therapy suffered from hemophagocytic syndrome (HPS) associated with B-cell lymphoma (B-LAHS). Administration of acyclovir and intravenous immunoglobulin promptly resolved laboratory test abnormalities accompanied with HPS. Moreover, hemophagocytic histiocytes and lymphoma cells in the bone marrow disappeared without anti-cancer therapy. Two months after reintroduction of MTX for RA flare, lymphoma re-grew rapidly without bone marrow involvement and HPS. Two cycles of combination chemotherapy induced the lymphoma to a complete remission/unconfirmed (CRu), but then the chemotherapy was discontinued due to severe side effects. In this case, on the basis of RA and MTX induced immunosuppressive state, Epstein-Barr virus (EBV) infection was associated with the development of HPS and lymphoma. Anti-viral therapy alone was effective against HPS and lymphoma at initial presentation and improved her general condition. This case indicates that anti-cancer therapy should be preceded by anti-viral therapy and withdrawal of immunosuppressive therapy in patients under immunosuppressive therapy, as long as the clinical situation permits.

Acyclovir↗
PubMed2003

Effects of an excess and a deficiency of endogenous parathyroid hormone on volumetric bone mineral density and bone geometry determined by peripheral quantitative computed tomography in female subjects.

Peripheral quantitative computed tomography (pQCT) is useful for evaluating volumetric bone mineral density (vBMD) as well as bone mineral density (BMD) of cortical and trabecular bones separately. Although PTH affects cortical and trabecular bones differently, the effects of endogenous PTH on vBMD and bone geometry have not previously been examined with pQCT. We, therefore, investigated the effects of an excess and a deficiency of endogenous PTH on bone by employing dual-energy x-ray absorptiometry and pQCT in 36 female patients with primary hyperparathyroidism (hyper), nine female patients with idiopathic or postoperative hypoparathyroidism (hypo), and 100 normal controls matched to age, gender, and body size (cont). Lumbar BMD by dual-energy x-ray absorptiometry was higher in the order: hypo > cont = hyper, and radius-1/3 BMD was significantly higher in the order: hypo > cont > hyper. The area of radius-1/3 was significantly higher in hyper than in cont. As for pQCT, trabecular vBMD was significantly higher in the order: hypo > cont > hyper at the 4% site (hypo, 157.5 +/- 36.7 mg/cm(3); cont, 123.4 +/- 47.5 mg/cm(3); hyper, 98.4 +/- 41.7 mg/cm(3)). Cortical vBMD was higher in the order: hypo > cont > hyper at the 20% site (hypo, 1141.1 +/- 53.1 mg/cm(3); cont, 1090.2 +/- 72.9 mg/cm(3); hyper, 1038.6 +/- 89.1 mg/cm(3)). Total bone area and endosteal and periosteal circumferences were significantly higher in hyper than in cont and hypo. Cortical area and thickness were higher in the order: hypo > cont > hyper. Bone strength indices were not significantly different among the three groups. In conclusion, vBMD evaluation revealed that an excess of endogenous PTH was catabolic for both cortical and trabecular bones, and that bone mass (especially trabecular bone mass) was preserved under a condition of deficient endogenous PTH. An excess of endogenous PTH stimulated periosteal bone formation, which might partly compensate for a decrease in bone strength induced by low BMD.

Absorptiometry, Photon↗
PubMed2003

Optimizing control of acromegaly: integrating a growth hormone receptor antagonist into the treatment algorithm.

Acromegaly is associated with significant morbidities and a 2- to 3-fold increase in mortality because of the excessive metabolic action of GH and IGF-I, a marker of GH output. Reductions in morbidity correspond with decreases in IGF-I, and mortality is lowered following normalization of IGF-I or GH levels. Therefore, this has become an important end point. Current guidelines for the treatment of acromegaly have not considered recent advances in medical therapy, in particular, the place of pegvisomant, a GH receptor antagonist. Treatment goals include normalizing biochemical markers, controlling tumor mass, preserving pituitary function, and relieving signs and symptoms. Surgery reduces tumor volume and is considered first-line therapy. Radiation reduces tumor volume and GH and IGF-I levels, but the onset of action is slow and hypopituitarism typically develops. Therefore, pharmacotherapy is often used following surgery or as first-line therapy for nonresectable tumors. Dopamine agonists can be considered in patients exhibiting minimal disease or those with GH-prolactin-cosecreting tumors but will not achieve hormone normalization in most patients. Somatostatin analogs effectively suppress GH and IGF-I in most patients, but intolerance (e.g. diarrhea, cramping, gallstones) can occur. Pegvisomant, the newest therapeutic option, blocks GH action at peripheral receptors, normalizes IGF-I levels, reduces signs and symptoms, and corrects metabolic defects. Pegvisomant does not appear to affect tumor size and has few adverse effects. Pegvisomant is the most effective drug treatment for acromegaly in normalizing IGF-I and producing a clinical response; it is the preferred agent in patients resistant to or intolerant of somatostatin analogs.

Acromegaly↗
PubMed2003

Factors affecting bone mineral density in hemodialysis patients with diabetic nephropathy.

BACKGROUND: It remains undetermined whether bone mineral density (BMD) of hemodialysis (HD) patients with diabetes mellitus (DM) is reduced or not. The present study was performed to compare BMD between HD patients with DM and chronic glomerulonephritis (CGN). We analyzed the factors which affected BMD of 139 patients with chronic HD enrolled in this cross-sectional study. METHODS: BMD of forearm [1/3-radius (R) and ultradistal (UD)-R] were measured by dual-energy x-ray absorptiometry. RESULTS: 1/3R-BMD and UDR-BMD of DM patients were comparable to those of CGN patients. In DM patients, body mass index (BMI) was positively correlated with UDR-BMD, serum levels of PTH and creatinine were negatively correlated with 1/3R-BMD, and serum level of beta2-microglobulin (betaMG) was positively correlated with UDR-BMD. In CGN patients, duration of HD and height were negatively correlated with 1/3R- and UDR-BMD, serum levels of uric acid and triglyceride were positively correlated with 1/3R- and UDR-BMD, and serum level of total cholesterol was positively correlated with UDR-BMD. In stepwise regression analysis, BMI and serum levels of creatinine and betaMG were selected for UDR-BMD in DM patients, although serum PTH level was selected for 1/3R-BMD. CONCLUSION: BMD at forearm was comparable between DM and CGN in HD patients. The factors affecting BMD seemed to be different between DM and CGN.

Absorptiometry, Photon↗
PubMed2003

Functional giant parathyroid cyst with high concentration of CA19-9 in cystic fluid.

A 63-year-old man was admitted to our hospital for the evaluation of hypercalcemia and anterior neck mass. Laboratory findings revealed hypercalcemia, hypophosphatemia, and hypercalciuria, as well as elevated serum levels of parathyroid hormone (PTH) and alkaline phosphatase. Computerized tomography and magnetic resonance images showed that the mass contained a cystic area. Parathyroid scintigraphy using either 99mTc-sestamibi alone or 201Tl-chloride in conjunction with 99mTc-pertechnetate for thyroid image subtraction showed uptake of the radioactivity into the cyst wall, suggesting that the mass originated from the parathyroid. Fine needle aspiration biopsy revealed that the cyst fluid was serous and bloody with extremely high concentrations of both PTH and CA19-9. The patient was diagnosed as primary hyperparathyroidism caused by parathyroid cyst and cervical exploration was performed. The cyst was dissected away along with the right lobe of the thyroid gland. After tumor removal, serum calcium and PTH levels were normalized. Histological study showed that the tumor possessed malignant potential with capsular invasion as well as moderate cellular atypia with trabecular pattern in arrangement. Parathyroid cells in the wall of the cystic tumor were immunostained positively for CA19-9, suggesting that CA19-9 in the cyst fluid was produced from the cells.

CA-19-9 Antigen↗
PubMed2003

Trial to predict malignancy of affected parathyroid glands in primary hyperparathyroidism.

Parathyroid cancer is rare but relatively frequent in Japan compared to Western countries. Surgical parathyroidectomy is the primary choice for radical treatment of primary hyperparathyroidism (pHPT), hence it is important to distinguish malignant from benign tumor in the determination of surgical indication as well as method of operation. However, it is not easy to diagnose parathyroid cancer prior to operation. In the present study, we analyzed the background data, biochemical data and bone mineral density (BMD) of 131 patients with pHPT (111 benign and 20 malignant). BMD of the lumbar spine and mid-radius was measured by dual-energy X-ray absorptiometry. Serum levels of calcium, alkaline phosphatase (ALP), and parathyroid hormone (PTH) were significantly higher in malignant group compared to benign one. The extent of elevation of mid PTH seemed to be higher than that of intact PTH in malignant group. Age-, gender-, and race-adjusted BMD of distal one-third of radius was significantly decreased in malignant group compared to benign one, although that of lumbar spine was not significantly different between the two groups, indicating that osteopenia was marked in the region which was rich in cortical bone in malignant group. On the other hand, serum levels of calcium, ALP, and mid PTH as well as age were selected as predictors of malignancy in univariate logistic regression analysis, while serum level of intact PTH was not selected. In conclusion, radial BMD was lower in malignant group compared to benign one in pHPT. Serum levels of calcium, ALP and mid PTH were useful to predict malignancy of affected parathyroid glands in pHPT patients.

Alkaline Phosphatase↗
PubMed2003

A study of carotid intima-media thickness in GH-deficient Japanese adults during onset among adults and children.

OBJECTIVES: Increased carotid intima-media thickness (IMT) has been reported among Caucasian adult GH-deficient (AGHD) patients, but not Japanese. Also, it is known that the clinical and biochemical characteristics of AGHD patients are somewhat different based on the onset of the disease in either childhood or adult life. Nevertheless, there has been no study comparing the magnitude of the deviation of their IMT from normal subjects between child-onset (CO) and adult-onset (AO) patients in terms of Z score. The aim of this study, therefore, was first to examine whether Japanese AGHD patients have a risk of early development of atherosclerosis similar to Caucasian patients and secondly to assess the difference in the onset and in progression of atherosclerosis. DESIGN AND SUBJECTS: Thirty-four patients (17 CO-AGHD, age 29+/-7 Years, body mass index (BMI) 24+/-3.8 kg/m(2) and 17 AO-AGHD, age 48+/-12 Years, BMI 23+/-3.6 kg/m(2)) and 34 age- and sex-matched healthy controls (17 CO controls and 17 AO controls) were enrolled in the present study. Blood samples were taken for measurements of lipids, lipoproteins and IGF-I. Subsequently, patients underwent IMT assessment. RESULTS: CO patients were significantly younger than AO patients. The duration of GH-deficiency in CO patients was significantly longer than that in AO patients. Serum triglyceride (TG) was significantly higher in CO patients than in CO controls (P<0.05). Serum total cholesterol and TG were significantly higher in AO patients than in AO controls (P<0.01). The IMT was significantly greater in CO and AO patients (0.82+/-0.08 and 0.79+/-0.03 mm) than in CO and AO controls (0.59+/-0.02 and 0.68+/-0.03 mm, P<0.01 and P<0.01 respectively). There was no significant difference in raw values of IMT between CO and AO patients. However, the Z score of IMT calculated using normal Japanese IMT values was significantly higher in CO than in AO patients (2.07+/-0.68 vs 0.35+/-0.48, P<0.05). CONCLUSIONS: These findings suggest that GH deficiency appears to increase an atherosclerotic risk in Japanese AGHD patients, as with Caucasians, and to cause more extensive IMT thickening in CO-AGHD than AO-AGHD patients.

Adult↗
PubMed2003

Decrease in vitamin D receptor and calcium-sensing receptor in highly proliferative parathyroid adenomas.

OBJECTIVE: A significant decrease in vitamin D receptor (VDR) and calcium-sensing receptor (CaSR) protein expression has been demonstrated recently in parathyroid (PT) adenomas. In this study, we investigated the relationships between the proliferative activity of parathyroid glands (PTGs) and the expression of VDR as well as CaSR, and compared it with the clinical severity in patients with primary hyperparathyroidism (1 degrees HPT). DESIGN: Seven patients with 1 degrees HPT were included in this study. Four patients with thyroid carcinoma served as controls. METHODS: Immunohistochemical staining was performed on serial sections of PTGs with specific antibodies against CaSR, VDR, and Ki67. Areas examined in each section were selected at random in relation to the gland size. The number of Ki67-positive cells was expressed as a labeling index (LI; positive cells per 1000 PT cells). The expression of CaSR and VDR was semi-quantitatively analyzed based on the intensity of staining. After averages of the scores from all areas were calculated, CaSR and VDR scores, and Ki67 LI were assigned to each gland for use in statistical analyses. RESULTS: In PT adenomas, scores of VDR and CaSR were markedly lower than in normal PTGs (P<0.01), while the proportion of Ki67-positive cells in PT adenomas was significantly higher than in normal PTGs (P<0.01). Single regression analyses revealed that Ki67 LI was positively correlated with serum levels of intact parathyroid hormone and Ca, and PTG weight (R=0.70, P<0.05, R=0.78, P<0.01 and R=0.84, P<0.05 respectively). Ki67 LI was negatively correlated with CaSR and VDR scores (R=-0.78, P<0.01 and R=-0.72, P<0.05 respectively). Moreover, there was a strong positive relationship between CaSR and VDR expression (R=0.95, P<0.001). CONCLUSIONS: Marked decreases in VDR and CaSR expression could, at least in part, be responsible for the high proliferation of PT cells and the pathological progression of 1 degree HPT.

Adenoma↗
PubMed2003

The R271W mutant form of Pit-1 does not act as a dominant inhibitor of Pit-1 action to activate the promoters of GH and prolactin genes.

OBJECTIVE: Genetic abnormalities of the pituitary specific transcription factor, Pit-1, have been reported in several patients with GH, prolactin (PRL) and TSH deficiencies. The most common is a mutation altering an arginine to a tryptophan in codon 271 (R271W) in one allele of the Pit-1 gene. According to the previous in vitro expression study, R271W acted as a dominant negative inhibitor of the wild type to activate the GH promoter. However, healthy carriers with this mutation, who should be affected by the dominant negative effect of R271W, have also been reported. The aim of this study was to clarify in more detail the function of this mutant form of Pit-1. METHODS: Transcriptional activity of R271W for the expression of Pit-1-associated genes was investigated in COS7 cells with the aid of transient transfection assays. The 1.8 kb rat GH, 0.6 kb rat PRL or 1.9 kb rat PRL 5'-flanking regions were inserted upstream of the luciferase reporter gene and were used for functional analysis of R271W. Another reporter gene containing seven Pit-1 responsive elements was also used. The same experiments were also performed using JEG3 and CHO cells. RESULTS: We could not confirm the dominant negative effect of R271W on wild type Pit-1. Furthermore, our expression study revealed that R271W could activate the promoters of GH and PRL genes to levels similar to the wild type. CONCLUSION: Taken together with the evidence that phenotypically normal cases have been reported with this mutation, our results deny the relationship between R271W and combined pituitary hormone deficiency.

Animals↗