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Aims To examine the effects of a 24-month treatment with ipragliflozin on carotid intima-media thickness (IMT) in type 2 diabetes patients. Methods and results In this multicenter, prospective, randomized, open-label, and blinded-endpoint investigator-initiated clinical trial, adults with type 2 diabetes and haemoglobin A1C (HbA1c) of 6.0–10.0% (42–86 mmol/mol) were randomized equally to ipragliflozin (50 mg daily) and non-sodium-glucose cotransporter-2 (SGLT2) inhibitor use of standard-care (control group) for type 2 diabetes and were followed-up to 24 months. The primary endpoint was the change in mean common carotid artery IMT (CCA-IMT) from baseline to 24 months. A total of 482 patients were equally allocated to the ipragliflozin (N = 241) and control (N = 241) groups, and 464 patients (median age 68 years, female 31.7%, median type 2 diabetes duration 8 years, median HbA1c 7.3%) were included in the analyses. For the primary endpoint, the changes in the mean CCA-IMT from baseline to 24 months were 0.0013 [95% confidence interval (CI), −0.0155–0.0182] mm and 0.0015 (95% CI, −0.0155–0.0184) mm in the ipragliflozin and control groups, respectively, with an estimated group difference (ipragliflozin-control) of −0.0001 mm (95% CI, −0.0191–0.0189; P = 0.989). A group difference in HbA1c change at 24 months was also non-significant between the treatment groups [−0.1% (95% CI, −0.2–0.1); P = 0.359]. Conclusion Twenty-four months of ipragliflozin treatment did not affect carotid IMT status in patients with type 2 diabetes recruited in the PROTECT study, relative to the non-SGLT2 inhibitor-use standard care for type 2 diabetes.

In Japan, diagnostic criteria of subclinical Cushing’s syndrome (SCS) were formulated in 1996, using cutoff value for serum cortisol of 3.0 μg/dL after an overnight 1-mg dexamethasone suppression test (DST). It has made considerable contributions to the understanding and pathology of SCS. However, it has elicited two main problems: (i) the relatively low reliability of a low range of serum cortisol essential for the diagnosis by DST; (ii) different cutoff values for serum cortisol after a 1-mg DST compared with those of other countries. For the proposal of new diagnostic criteria, we conducted a retrospective cross-sectional study. 530 cases (270 men and 260 women, mean age: 60.1 ± 11.1 years) with an adrenal tumor were assessed. In the present study, the assay kits adopted for measurement of serum cortisol differed among facilities. A calibration formula was previously developed by Kuwa et al. for standardization of different kits. Using this formula, standardization of the serum cortisol values after a 1-mg DST and at night was done. As a result, using current criteria, the diagnosis of 11 out of 92 SCS cases was changed to “non-SCS”, and all of 189 non-SCS cases remained non-SCS after calibration. After all, diagnostic concordance rate before and after calibration was 96.1%, suggesting that the actual diagnosis did not change dramatically, by calibration. The cortisol values after a 1-mg DST were compared based on the presence or absence of complications (hypertension, impaired glucose tolerance or diabetes, and hypercholesterolemia). As a result, when serum cortisol after a 1-mg DST was stratified by increments of 1.0 μg/dL, the coincidental occurrence of hypertension and impaired glucose tolerance was more frequently observed in the 2-2.99 μg/dL group than in the 0-0.99 μg/dL group (39.3% vs. 23.5%, p=0.018), suggesting that the threshold for the onset of complications of adrenal tumors may be serum cortisol of 2-3μg/dL after a 1-mg DST. Under the consideration of international consistency, serum cortisol ≥1.8 μg/dL after a 1-mg DST may be useful for the detection of ‘not completely healthy’ subjects with adrenal tumor. Additionally, in the present study, almost all of the respective criteria, such as basal ACTH

New diagnostic criteria and the treatment policy for adrenal subclinical Cushing's syndrome (SCS) are proposed on behalf of the Japan Endocrine Society. The Japanese version has been published, and the essential contents are presented in this English-language version. The current diagnostic criteria for SCS have elicited two main problems: (i) the relatively low reliability of a low range of serum cortisol essential for the diagnosis by an overnight 1-mg dexamethasone suppression test (DST); (ii) different cutoff values for serum cortisol after a 1-mg DST compared with those of other countries. Thus, new criteria are needed. In the new criteria, three hierarchical cortisol cutoff values, 5.0, 3.0 and 1.8 μg/dL, after a 1-mg DST are presented. Serum cortisol ≥5 μg/dL after a 1-mg DST alone is considered sufficient to judge autonomous cortisol secretion for the diagnosis of SCS, and the current criterion based on serum cortisol ≥3 μg/dL after a 1-mg DST can continue to be used. Clinical evidence suggests that serum cortisol ≥1.8-2.9 μg/dL after a 1-mg DST is not always normal, so cases who meet the cutoff value as well as a basal adrenocorticotropic hormone (ACTH) level

A 32-year-old Chinese woman with rapid weight gain and progressive edema was found to have typical Cushingoid features. Her endocrine data were consistent with a diagnosis of ACTH-dependent Cushing's syndrome. To differentiate ectopic ACTH syndrome (EAS) from Cushing's disease (CD), various dynamic endocrine and imaging tests were performed. Her ACTH response was negative to corticotropin-releasing hormone (CRH) and positive to desmopressin. Magnetic resonance imaging of the pituitary showed no mass lesion. Computed tomography scan of the chest revealed a large mass (21 × 15 mm) in the anterior mediastinum, where positron emission tomography showed accumulation of [(18)F] fluorodeoxyglucose. Selective venous sampling showed marked step-up in ACTH level in the internal thoracic vein but not in the cavernous sinus after CRH stimulation. These data are compatible with the diagnosis of EAS. The resected tumor was pathologically consistent with thymic neuroendocrine tumor (NET) positive for ACTH by immunohistochemistry and abundant V1b receptor gene expression by RT-PCR. Postoperatively, her circulating ACTH/cortisol levels became normalized, and responded to stimulation with CRH but not with desmopressin. Her Cushingoid appearance gradually disappeared, and she was free from recurrence 5 years after surgery. This is a rare case of desmopressin-responsive EAS caused by thymic NET with predominant V1b gene expression, which was successfully localized by imaging modalities combined with selective venous sampling.

Late-night salivary cortisol (NSC) has been recognized as a sensitive and easy-to-perform screening test for the diagnosis of overt Cushing's syndrome (CS). However, there have been few reports on the diagnostic utility of salivary cortisol (SC) measurement in the diagnosis of subclinical Cushing's syndrome (SCS). Therefore, the present study was designed to evaluate the usefulness of SC measurements at late-night and after overnight 1 mg dexamethasone suppression test (DST) for the diagnosis of SCS in 42 patients with adrenal incidentaloma. We evaluated 16 patients with SCS, 12 with nonfunctioning adenoma (NFA), 8 with primary aldosteronism (PA), and 6 with pheochromocytoma (Pheo). NSC levels in SCS patients (0.238 ± 0.106 µg/dL) were significantly (P < 0.05) higher than those in NFA patients (0.154 ± 0.104 µg/dL); the cutoff value (0.11 µg/dL) by ROC analysis gave high sensitivity (100%) with low specificity (50%). Post DST SC levels in SCS patients (0.238 ± 0.116 µg/dL) were significantly (P = 0.0081) higher than those in NFA patients (0.136 ± 0.110 µg/dL); the cutoff value (0.12 µg/dL) by ROC analysis gave high sensitivity (93.8%) with somewhat improved specificity (58.3%). Both NSC and post DST SC levels were comparable between NFA, PA, and Pheo patients. In conclusion, our study revealed that measurements of NSC and/or post DST SC among patients with adrenal incidentaloma prove to have high sensitivities, but low specificities for the diagnosis of SCS from NFA, suggesting its possible alternative option before the screening tests for SCS currently employed in Japan.

Subclinical Cushing's syndrome (SCS), a subtle cortisol hypersecretion from an adrenal tumor, may be a common adrenal disease. However, the cardiovascular prognosis and the optimal surgical and conservative treatment in SCS remain elusive. The present study was undertaken to evaluate the prevalence of cardiovascular risk factors in 16 SCS cases, their relationships to cortisol secretory activities, and the clinical outcome after surgical and medical treatment. The prevalence of hypertension, impaired glucose tolerance (IGT), diabetes mellitus (DM), dyslipidemia and obesity in our SCS cases were 56%, 50%, 50%, and 19%, respectively, and 75% of cases were associated with two or more cardiovascular risk factors. In our series, 24-h urinary free-cortisol excretion showed a significant positive correlation with HbA1c and a negative correlation with high-density lipoprotein-cholesterol, but no correlation with age, body mass index, blood pressure or glycemic and lipid profile was found. Eight cases underwent unilateral adrenalectomy (operated (OP) group); the remaining eight cases were a conservative-treatment group (non-OP group). The number of cardiovascular risk factors decreased significantly in the OP group, but not in the non-OP group. In terms of differential changes in risk factors between the groups, more significant improvements of hypertension, dyslipidemia and IGT/DM were observed in the OP group than in the non-OP group. In conclusion, the present study showed the increased prevalence of cardiovascular risk factors in SCS patients with mild hypercortisolism related to impaired glucose/lipid metabolism. Adrenalectomy decreased accumulated cardiovascular risk factors in certain SCS patients, suggesting the possible involvement of mild hypercortisolism in the development of cardiovascular risk factors in SCS.

In a previous paper, new sets of parameters to replace the Michel parameters were proposed to analyze data for the muon decay $\mu^{+} \to e^{+}\nu_{e}\bar{\nu_{\mu}}$. Both $(V-A)$ and $(V+A)$ charged currents with finite neutrino mass have been used to study this decay. In the present paper, this parameterization is extended to a more general form, and a method for data analysis (least squares) is discussed for the propose of determining the rate of contribution from the $(V+A)$ current. We find that there is a simple form in which the set of parameters is related primitively to the physical quantities. It is shown that the Michel parameters are one of the other sets that are obtained from this simple form by rearranging one term. We derive the condition to obtain the same information regarding unknown physical quantities in the case that the data are analyzed using these simple and rearranged forms separately. We find that there is some possibility to get different results from these analyses, because the equivalent condition is very delicate and the QED radiative corrections should be treated carefully. We propose a consistent formula for data analysis. It is useful to compare the value obtained in the least squares fit using the simple form with that obtained using the prediction of the standard model, because a large difference is not expected, especially in the case of the Majorana neutrino. Finally, we point out that the method we proposed to determine the type of neutrino in the previous paper is incorrect., Comment: 21 pages

ObjectiveDifferential expression of several genes between ACTH-secreting pituitary tumors causing Cushing' disease (CD), silent corticotroph adenoma (SCA), and non-functioning pituitary tumors (NFT) was investigated.Design and methodsWe used tissue specimens from 35 pituitary tumors (12 CD, 8 SCA, and 15 NFT). Steady-state mRNA levels of the genes related to proopiomelanocortin (POMC) transcription, synthesis, processing, and secretion, such as neurogenic differentiation 1 (NeuroD1), T-box 19 (Tpit), corticotropin releasing hormone receptor (CRHR), vasopressin receptor 1b (V1bR), prohormone convertase (PC) 1/3 and PC2, 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 and type 2, glucocorticoid receptor α (GRα), annexin A1, histone deacetylase 2 (HDAC2), and BRM/SWI2-related gene 1, were determined by real-time RT-PCR.Results and conclusionPOMC and Tpit mRNA levels were greater in CD and SCA than those in NFT. NeuroD1 mRNA levels were less in CD than those in NFT, but almost comparable between SCA and NFT. PC1/3 mRNA levels were greater in CD, but less in SCA than those in NFT. PC2 mRNA levels in CD and SCA were less than those in NFT. CRHR, V1bR, and 11β-HSD2 mRNA levels in CD were greater than those in SCA and NFT. HDAC2 mRNA levels in CD and SCA were lower than those in NFT. In conclusion, our study demonstrated that the genes related to transcription, synthesis, processing, and secretion of POMC are differentially regulated in ACTH-secreting pituitary tumors causing CD and SCA compared with those in NFT. This may partly explain the development of clinically active and inactive CD.

We report the case of a 38-year-old man with secondary adrenal insufficiency due to pituitary stalk transection that may have been caused by birth injury. He was admitted to our hospital with epigastalgia and severe hyponatremia (120 mEq/L). His past history showed fetal distress due to an abnormal delivery, and he received growth hormone replacement therapy for growth hormone-deficient short stature. Magnetic resonance imaging of the brain revealed an atrophic anterior lobe, a pseudo-posterior lobe of the pituitary gland, and a transection of the pituitary stalk. Endocrinological examination revealed secondary adrenal insufficiency due to a suprapituitary lesion, with concomitant impaired secretion of growth hormone, gonadotropins, and thyroid-stimulating hormone. Hyponatremia was improved immediately after administration of hydrocortisone. This is a case of adult development of pituitary stalk transection syndrome, involving the sequential impairment of the secretion of several pituitary hormones, and finally presenting severe hyponatremia caused by secondary adrenal insufficiency.

A 25-year-old man was found to have a large right adrenal mass detected by abdominal echography and computed tomography, and presented with a mild gynecomastia. Endocrine study showed increased serum concentrations and urinary excretion of estrogens and dehydroepiandorosterone sulfate (DHEA-S). The patient had no Cushingoid features but autonomous cortisol secretion, compatible with the diagnosis of subclinical Cushing's syndrome. Surgical removal of the adrenal tumor led to normalization of serum and urinary excretion of estrogens and DHEA-S. Histopathological examination revealed a high-grade adrenocortical carcinoma (ACC). The disorganized expression of all the steroidogenic enzymes in individual tumor cells was demonstrated by immunohistochemical analysis, and the abundant expression of both aromatase mRNA and insulin-like growth factor (IGF)-II mRNA was shown by RT-PCR. These data suggest the excessive secretion of estrogen as well as the ineffective steroidogenesis by the adrenal tumor. This is a very rare case of estrogen-secreting ACC associated with subclinical Cushing's syndrome.

A 54-year-old man with type 2 diabetes was referred to our hospital for endocrine evaluation of acromegaly. Physical examination showed typical acromegalic features without Cushingoid features. Magnetic resonance imaging of the brain revealed the presence of a pituitary macroadenoma. Basal plasma levels of GH and insulin-like growth factor-I under fasting hyperglycemia (202 mg/dl) were markedly elevated. Plasma GH levels paradoxically increased after stimulation with TRH and LH-RH, and decreased after bromocriptine and octreotide administration. Endocrine examination of the hypothalamo-pituitary-adrenal (HPA) axis showed a lack of circadian rhythm of ACTH and cortisol, non-suppressibility to low-dose (1 mg), but suppressibility to high-dose (8 mg) dexamethasone, and normal response to CRH stimulation. The tumor resected by transsphenoidal surgery was histopathologically consistent with the diagnosis of eosinophilic adenoma: positive immunoreactivities of GH, PRL and ACTH were demonstrated, but negative immunoreactivities of prohormone convertase (PC) 1/3 by immunohistochemical method. After surgery, plasma GH and IGF-I levels decreased along with normalization of HPA axis. Metabolic co-morbidities such as diabetes and hypertension disappeared after removal of the pituitary tumor. This is a very rare case of GH-producing pituitary adenoma causing typical acromegaly with concomitant production of ACTH causing subclinical Cushing's disease.

Insulinoma is the most common cause of fasting hypoglycemia resulting from autonomous insulin hypersecretion. We describe herein a unique case with paradoxical hypoglycemic episodes induced by hyperglycemia. A 55-year-old female had repeated hypoglycemic episodes after meal or during increased physical activity. Although fasting (10 hr) failed to provoke hypoglycemia, oral glucose tolerance test (GTT) caused an exaggerated insulin response (885 microU/ml) at 30 min, followed by hypoglycemia (36 mg/dl) after 90 min. Moreover, intravenous GTT also induced an exaggerated insulin response (2900 microU/ml) at 10 min, followed by hypoglycemia (34 mg/dl) after 40 min. Although MRI and CT scan of the abdomen failed to detect any mass lesions in the pancreas, Octreoscan revealed increased radioactive uptake around the pancreatic head region. Treatment with a daily injection of octreotide (100 microg) alleviated her hypoglycemic episodes. At surgery, two islet cell adenomas were identified in the pancreas and resected. Postoperatively, she was free from hypoglycemic episodes after meal. Postoperative oral and intravenous GTT did not induce hypoglycemia. Thus, this is a very rare case of glucose-responsive and octreotide-sensitive insulinoma in whom GTT and octreotide proved to be a useful provocation and treatment for hypoglycemic episodes.

A 70-year-old man with abdominal aortic aneurysm underwent surgical repair with Hemashield vascular graft. Postoperatively, he was found to have very low plasma cortisol levels, which failed to increase after stimulation with ACTH. A tentative diagnosis of adrenal insufficiency was made despite the lack of its clinical manifestations and a replacement therapy with hydrocortisone was started. He had also elevated plasma levels of TSH, thyroid hormones and estrogen without any clinical manifestations. Such abnormal hormone levels were spontaneously normalized three months after operation, which was later proven to be factitious by different immunometric assays (IMA). Since the vascular graft coated with bovine type I collagen has been reported to induce a transient immune response in some patients after surgery, we speculated that certain antibodies generated against heterologous collagen and/or yet-unknown components derived from the graft may have caused such factitious data; exogenous addition of bovine type I collagen and albumin to patient's serum, however, failed to affect the assay results. Whatever the cause, caution must be paid that some patients with surgical repair using heterologous materials may have such factitious hormone data by IMAs.

We report a 21-year-old woman with ectopic ACTH syndrome due to islet cell carcinoma with multiple liver metastases. On admission, she showed Cushingoid appearance (moon face, central obesity etc.) and had acute respiratory distress syndrome due to pneumocystis carinii pneumonia. Laboratory examination revealed marked elevations of plasma ACTH (735 pg/ml) and cortisol (145 microg/dl) with a profound hypokalemia (2.0 mEq/l). She was found to have multiple masses in the liver and a solid mass in the tail of pancreas by abdominal computerized tomography scanning. Treatment with octreotide successfully reduced elevated plasma ACTH and cortisol levels, and she received frequent transhepatic arterial embolization and chemotherapy. The primary pancreatic tumor was surgically removed, revealing islet cell carcinoma which contained high content of ACTH (100 microg/g wet weight) and abundantly expressed proopiomelanocortin and somatostatin receptor subtype-2 mRNAs as determined by Northern blot analysis. Postoperatively, she was free from symptoms for almost one year. However, progressive enlargement of multiple liver metastases refractory to chemotherapy led her to decide on total hepatectomy and liver transplantation from her father. After liver transplantation, she remained almost free from symptoms for almost one year. However, metastases developed to the mediastinal and paraaortic lymph nodes as detected by 111[In] pentetreotide scintigraphy. Eleven months after liver transplantation, she was again treated with octreotide and, 16 months after, with metyrapone, both of which were effective in reducing ACTH and cortisol levels, respectively, until she died of acute respiratory failure. This case of a young female patient with ectopic ACTH-producing islet cell carcinoma of the pancreas was quite unique in that she survived for 5 years despite the acute onset and rapid progression of the multiple liver metastases at least in part due to the long-lasting favorable response to octreotide and living-related liver transplantation.

Inflammatory cytokines, such as interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha, activate nuclear factor-kappa B (NF-kappaB) which transactivates inducible nitric oxide synthase (iNOS) gene in vascular smooth muscle cells (VSMCs). However, it remains obscure whether cytokine-mediated iNOS expression in VSMCs requires signaling pathway(s) other than NF-kappaB activation. The present study was designed to elucidate whether protein tyrosine kinases (PTKs) are involved in the cytokine-induced NF-kappaB activation and iNOS expression in cultured rat VSMCs. Both IL-1beta and TNF-alpha stimulated NF-kappaB activity, iNOS mRNA and protein expression with massive nitrite/nitrate (NOx) production in rat VSMCs. PTK inhibitors (genistein, herbimycin A) dose-dependently inhibited the cytokine-stimulated NOx production and iNOS mRNA expression. However, neither genistein nor herbimycin A affected the cytokine-stimulated phosphorylation and degradation of IkappaB-alpha, or NF-kappaB activation, whereas they completely blocked the cytokine-stimulated iNOS transcriptional activity. Tyrphostin B42 (AG490), a Jak-2 tyrosine kinase inhibitor, similarly blocked the cytokine-induced NOx production, iNOS expression and its promoter activity without affecting NF-kappaB-dependent transcription. Transfection of a dominant-negative Jak-2 mutant antagonized the cytokine-induced NOx production and iNOS expression, while wild-type Jak-2 expressing construct was without effect. These data indicate that the cytokine-induced iNOS expression involves activation of Jak-2 signaling pathway independent from NF-kappaB activation in rat VSMCs.

Primary aldosteronism (PA), an autonomous aldosterone hypersecretion from adrenal adenoma and/or hyperplasia, and subclinical Cushing syndrome (SCS), a mild but autonomous cortisol hypersecretion from adrenal adenoma without signs or symptoms of Cuhing's syndrome, are now well-recognized clinical entities of adrenal incidentaloma. However, the clinicopathological features of PA associated with SCS (PA/SCS) remain unknown. The present study was undertaken to study the prevalence of PA/SCS among PA patients diagnosed at our institute, and characterize their clinicopathlogical features. The prevalence of PA/SCS was 8 of 38 PA patients (21%) studied. These 8 PA/SCS patients were significantly older and had larger tumor, higher serum potassium levels, lower basal plasma levels of aldosterone, ACTH and DHEA-S as well as lower response of aldosterone after ACTH stimulation than those in 12 patients with aldosterone-producing adenoma without hypercortisolism. All 8 PA/SCS patients showed unilateral uptake by adrenal scintigraphy at the ipsilateral side, whereas the laterality of aldosterone hypersecretion as determined by adrenal venous sampling varied from ipsilateral (3), contralateral (2), and bilateral side (2). 6 PA/SCS patinets who underwent adrenalectomy required hydrocortisone replacement postoperatively. Histopathological analysis of the resected adrenal tumors from 5 PA/SCS patients revealed a single adenoma in 3, and double adenomas in 2, with varying degrees of positive immunoreactivities for steroidgenic enzymes (3β-HSD, P450(C17)) by immunohistochemical study as well as CYP11B2 mRNA expression as measured by real-time RT-PCR. In conclusion, PA/SCS consists of a variety of adrenal pathologies so that therapeutic approach differs depending on the disease subtype.

Telmisartan, a selective antagonist for angiotensin type1 receptor and a partial agonist for peroxisome proliferator-activated receptor-gamma, decreases blood pressure and has been shown to improve glucose and lipid metabolism, suggesting potential cardiovascular protective effects. In this study, we investigated whether long-term treatment with telmisartan improved endothelial function in 35 hypertensive patients with type 2 diabetes mellitus (T2DM). Office and home early morning blood pressure levels and flow-mediated vasodilation (FMD) were evaluated before and after 12 months of treatment with telmisartan. Blood samples were also obtained for measurement of several biochemical parameters and of adiponectin (AN) and highly sensitive C-reactive protein (hs-CRP) before and after treatment. After 12 months of treatment, office and morning blood pressure levels had significantly decreased, and levels of plasma glucose, glycosylated hemoglobin, total cholesterol, triglyceride and low-density lipoprotein cholesterol had also significantly decreased. Plasma AN and high-density lipoprotein cholesterol levels increased, but hs-CRP levels decreased. Furthermore, FMD significantly increased; changes in percent FMD showed a significant negative correlation with changes in systolic and diastolic blood pressure and a significant positive correlation with changes in AN. Stepwise multivariate regression analysis revealed that changes in plasma AN and office systolic blood pressure were both independent determinants for endothelial function after telmisartan treatment. In conclusion, this study shows that long-term treatment with telmisartan improves not only blood pressure and glucose and lipid metabolism but also endothelial function in hypertensive patients with T2DM, possibly by increased circulating AN and decreased blood pressure.

Primary aldosteronism (PA) has been recognized as a relatively benign form of hypertension associated with a low incidence of vascular complications. Recent reports, however, indicate that cerebrovascular accidents are common in PA. We report a case of multiple aneurysms with PA in a middle-aged woman who presented with subarachnoid hemorrhage. A 47-year-old woman with a history of untreated hypertension was referred to our hospital for subarachnoid hemorrhage. Cerebral angiography showed multiple small aneurysms. The initial intervention was aneurysm clipping for a ruptured aneurysm at the bifurcation of the right middle cerebral artery. Despite medication, she continued to suffer from uncontrolled hypertension and hypokalemia. She was diagnosed with PA on the basis of elevated plasma aldosterone, suppressed plasma rennin, and a right adrenal tumor detected by abdominal CT scanning. She underwent several more neck clippings for the remaining aneurysms (unruptured), followed by a total right adrenectomy. Histological examination revealed an adrenal adenoma. After the operation, her blood pressure returned to normal without any vasodepressors. Recent studies have demonstrated that hyperaldosteronism might have direct vasculo-toxic actions, including remodeling, fibrosis, and proliferation. Cerebrovascular accidents caused by PA are reported to have high rates of mortality and recurrence when the PA is overlooked or untreated. Physicians must be alert to the possibility of PA in patients with hypertension and persistent hypokalemia, especially in those who are young or middle-aged. We also recommend screening for intracranial aneurysms by low-invasive magnetic resonance angiography.

For the diagnosis of Cushing' s syndrome (CS), the overnight 1 mg dexamethasone suppression test (DST) has been widely used as a standard low-dose DST. However, it is evident that 1 mg DST may not be sensitive enough to detect CS when the cortisol cut-off concentration is 5 microg/dL. Therefore, we developed and validated 0.5 mg DST as a new screening method for diagnosis of ACTH-dependent CS. To compare 0.5 mg DST with 1 mg DST, 110 patients with ACTH-dependent CS were enrolled, including 88 with Cushing' s disease (CD), 8 with subclinical CD and 14 with ectopic ACTH syndrome, as well as 134 control subjects. Subjects were given either 0.5 mg or 1 mg dexamethasone orally at 23:00 on different days, with blood samples collected the following morning between 8:00 and 9:00 to determine plasma cortisol concentration. The area under the receiver operator characteristics curve observing the 0.5 mg DST was higher than that of the 1 mg DST. The most sensitive and specific cut-off value of plasma cortisol concentration using 0.5 mg DST was found to be 3.05 microg/dL with 99.1% sensitivity and 98.4% specificity, identical to the 3 microg/dL cut-off currently used in the Japanese guideline for diagnosis of subclinical CD. In conclusion, 0.5 mg DST is a sensitive and specific screening test for diagnosis of ACTH-dependent CS. We recommend 0.5 mg DST with a cortisol cut-off concentration of 3 microg/dL to be used as the initial step in diagnosing ACTH-dependent CS.

A 59-year-old man was admitted because of congestive heart failure. He was suspected to have acromegaly, and magnetic resonance imaging revealed a pituitary macroadenoma. Endocrine examination revealed elevated plasma levels of growth hormone (GH) and insulin-like growth factor (IGF)-1, and an oral glucose tolerance test failed to suppress plasma GH levels, consistent with the diagnosis of GH-producing pituitary tumor. Treatment with octreotide, followed by transsphenoidal surgery resulted in normalization of plasma GH/IGF-1 levels, accompanied by the improvement of cardiac function. Thus, it is suggested that excess GH/IGF-1 axis is involved in the development of acromegaly-related cardiomyopathy in the present case.

A 75-year-old man was admitted to our hospital because of unconsciousness. His plasma glucose was very low, but his serum levels of insulin and IGF-I were also low. He was found to have a giant solitary pleural tumor, which was completely resected, after which his hypoglycemia ameliorated postoperatively. Histologically, the tumor was consistent with the pathological diagnosis of a solitary fibrous tumor derived from the pleura. Immunohistochemical study revealed positive immunostaining for IGF-II in tumor cells. The presence of high molecular weight (HMW) form of IGF-II in the tumor tissue and patient's serum was confirmed by Western blot analysis. Steady-state mRNA levels of IGF-II and prohormone convertases (PC) 4, a potential protease responsible for IGF-II processing, as determined by RT-PCR were about 14-fold greater and 5-fold less in the tumor tissue than those in normal placental tissue, respectively. Therefore, it is suggested that biologically active, unprocessed HMW form of IGF-II generated from the impaired processing of IGF-II precursor by the defective PC4 expression in the tumor was responsible for the non-islet cell tumor hypoglycemia (NICTH) in the present case.

Flow-mediated vasodilatation (FMD) is a vascular functional test to detect endothelial dysfunction at the early stage of cardiovascular diseases. Patients with active acromegaly have higher morbidity and mortality due to cardiovascular events. To determine whether active acromegaly is associated with endothelial dysfunction, we studied 17 patients with active acromegaly for measurements of FMD, carotid intima-media thickness (IMT) and brachial-ankle pulse wave velocity (baPWV), and other biochemical parameters before and 3 months after transsphenoidal surgery (TSS). Baseline %FMD in patients with active acromegaly was significantly lower than that in age- and sex-matched control subjects. After TSS, the mean %FMD in acromegaly significantly increased from 5.3% to 7.4%; 12 patients had increased %FMD (responders), whereas 5 patients had decreased or unchanged %FMD (non-responders). However, neither carotid IMT nor baPWV changed after TSS. Serum levels of GH, insulin-like growth factor (IGF)-1, total cholesterol, low-density lipoprotein cholesterol (LDL-C), hemoglobin HA(1C), fasting plasma glucose and insulin levels, and homeostasis model assessment (HOMA)-R significantly decreased, whereas high-density lipoprotein cholesterol significantly increased. Responders had significantly lower baseline %FMD than did non-responders and both insulin levels and HOMA-R significantly decreased in responders, but not in non-responders after TSS. Simple regression analysis revealed that the change of %FMD showed a significant negative correlation with that of LDL-C, but not of IGF-1 or GH, in responders. In conclusion, it is suggested that endothelial dysfunction associated with active acromegaly improves soon after TSS, which is related to LDL-C and/or insulin resistance, but not to excess GH and/or IGF-1 itself.

This retrospective study was aimed 1) to compare the difference of the findings between adrenal CT scan and adrenal venous sampling (AVS) in 35 cases with definite primary aldosteronism (PA) for assessment of the diagnostic efficacy of PA subgroup (unilateral and bilateral adrenal hypersecretion: UAH and BAH), and 2) to determine the clinical and biochemical parameters as potential predictors for PA subgroup. There were significant discordant results based on AVS and CT scan in subgrouping PA; 9 of 17 BAH patients (53%) had unilateral lesion on CT scan, while 4 of 18 UAH patients (22%) had no apparent or bilateral lesions on CT scan. Among three diagnostic criteria, absolute values of plasma aldosterone concentration (PAC) in both adrenal veins, lateralized and contralateral ratios of aldosterone/cortisol after ACTH stimulation during AVS to determine the laterality, none of them showed 100% diagnostic accuracy if applied alone. Among several clinical and biochemical parameters, hypokalemia (

Measurement of late-night and/or midnight salivary cortisol currently used in US and European countries is a simple and convenient screening test for the initial diagnosis of Cushing's syndrome (CS). Unfortunately, this test has not been widely used in Japan. The purpose of this study was to evaluate the usefulness of the measurement of late-night salivary cortisol as a screening test for the diagnosis of CS in Japan. We studied 27 patients with various causes of CS, consisting of ACTH-dependent Cushing's disease [5] and ectopic ACTH syndrome [4] and ACTH-independent adrenal CS [11] and subclinical CS [7]. Eleven patients with type 2 diabetes and obesity and 16 normal subjects served as control group. Saliva samples were collected at late-night (23:00) in a commercially available device and assayed for cortisol by radioimmunoassay. There were highly significant correlations (P0.0001) between late-night serum and salivary cortisol levels in normal subjects (r = 0.861) and in patients with CS (r = 0.788). Late-night salivary cortisol levels in CS patients (0.975 +/- 1.56 microg/dl) were significantly higher than those in normal subjects (0.124 +/- 0.031 microg/dl) and in obese diabetic patients (0.146 +/- 0.043 microg/dl), respectively. Twenty-five out of 27 CS patients had late-night salivary cortisol concentrations greater than 0.21 microg/dl, whereas those in control group were less than 0.2 microg/dl. Receiver operating characteristic curve (ROC) analysis showed that the cut-off point of 0.21 microg/dl provides a sensitivity of 93% and a specificity of 100%. Therefore, it is concluded that the measurement of late-night salivary cortisol is an easy and reliable noninvasive screening test for the initial diagnosis of CS, especially useful for large high-risk populations, such as diabetes and obesity.

Aim: Endothelial dysfunction is considered an early event in the development of atherosclerosis. The present study was undertaken to determine whether the accumulation of cardiovascular risk factors and insulin resistance are associated with endothelial function in diabetic patients.Methods: 101 patients with type 2 diabetes without macroangiopathy stratified by the number of cardiovascular risk factors (dyslipidemia, hypertension, obesity) and 9 normal control subjects were studied for vascular endothelial functions by measuring flow-mediated vasodilation (FMD) using a high-resolution ultrasound method, brachial-ankle pulse wave velocity (baPWV), carotid intima-media thickness (IMT), and the ankle-brachial index (ABI).Results: FMD negatively correlated with baPWV and carotid IMT, and positively correlated with ABI. FMD was significantly lower in diabetic patients associated with 3 other risk factors than in those with diabetes alone. In subjects with fasting plasma glucose ≤ 140mg/dL, FMD showed significant negative correlations with fasting insulin levels and homeostasis model assessment (HOMA)-R. Multivariate analysis revealed that insulin resistance as represented by HOMA-R and systolic blood pressure showed a significant association with impaired FMD.Conclusion: The present results suggest that the accumulation of cardiovascular risk factors is associated with endothelial dysfunction in diabetic patients, and that insulin resistance as well as high blood pressure could play a pathogenic role in the development of endothelial dysfunction.

Silent corticotroph adenoma (SCA) is defined as an ACTH-producing pituitary tumor not associated with clinical and endocrine feartures of Cushing's syndrome, but its underlying molecular mechanism(s) remains unknown thus far. We tested the hypothesis that reduced expression of prohormone convertase (PC) 1/3 responsible for proteolytic processing of proopiomelanocortin (POMC) in SCA may lead to production of unprocessed, biologically inactive POMC and/or precursor of ACTH. Among 30 non-functioning pituitary macroadenomas (NFA) examined, we found 6 SCAs by immunohistochemical study using anti-ACTH antibody. Preoperative endocrine and diagnostic image tests did not reveal any differences between SCA and the remaining NFA except for the higher recurrence rate of SCA. While steady-state PC1/3 mRNA levels determined by RT-PCR were almost comparable between SCAs and NFAs, immunohistochemical study showed negative immunostaining for PC1/3 in all 6 SCAs. Our data suggest that defective PC1/3 expression may lead to preferential production of unprocessed, biologically inactive ACTH variants in SCA.

Cortisol assay is used for the diagnosis of hypothalamo-pituitary adrenal disorders. The Incidence of adrenal incidentaloma has been increasing with advances in imaging tools. The criteria for the diagnosis of preclinical Cushing's syndrome in Japan was made by the Nawata group supported by the Ministry of Health and Welfare in 1995. The presence of adrenal adenoma, a lack of overt signs of Cushing's syndrome and autonomic cortisol secretion are essential for the diagnosis of preclinical Cushing's syndrome. For the diagnosis of autonomy of cortisol secretion, cortisol should not be suppressed by either low dose dexamethasone (DEX) of 1 mg (cortisolor =3 microg/dl) or high dose DEX of 8 mg (cortisolor =1 microg/dl). We have reported that two doses of DEX suppression tests revealed a discrepancy in several cases of adrenal incidentaloma; therefore, we studied the cortisol values of DEX suppression tests in 47 cases with adrenal incidentaloma using four different cortisol kits (TFB, SPAC, TDX and TOSOH). Correlation between the kits was good; however, correlation coefficient in the low range (or =5 microg/dl) among kits declined. In the inter assay, discrepant results of the cortisol level were seen in six cases after 1 mg of DEX and 18 cases after 8 mg of DEX. In the intra assay, discrepant results of cortisol after 1 mg of DEX and 8 mg of DEX were seen in 31 in TFB, 23 in SPAC, 24 in TDX and 25 in TOSOH. These results revealed that the clinical diagnosis varies according to the cortisol kit used. It is suggested that standardization of the cortisol assay is necessary for the accurate diagnosis of adrenal incidentaloma.

A 49-year-old woman with hypertension, obesity and impaired glucose tolerance (IGT) was admitted for evaluation of pituitary incidentaloma. Although she presented no Cushingoid feature, endocrine examination of hypothalamo-pituitary-adrenal (HPA) axis showed elevated basal plasma ACTH and cortisol levels, their lack of circadian rhythm, non-suppressibility to low-dose (1 mg) dexamethasone, and responsiveness to CRH, suggesting autonomous ACTH secretion from a pituitary tumor. She underwent transsphenoidal surgery, and was diagnosed as chromophobe adenoma with positive ACTH immunoreactivity. Postoperatively, her abnormal HPA axis was resolved, along with improvement of hypertension, obesity and IGT. Thus, her metabolic comorbidities are likely due to subclinical Cushings disease.

Discrepancy of plasma ACTH levels measured by different immunoradiometric assays (IRMA) in a case with malignant gastric carcinoid causing ectopic ACTH syndrome was examined by gel chromatography and immunohistochemical analysis. A 49-year-old male was found to have a large gastric tumor, with muscle wasting, hypertension, diabetes and hypokalemia caused by hypercortisolemia. His plasma ACTH levels, although initially elevated, were found to be almost in normal ranges. The discrepancy of plasma ACTH levels was proven to be due to different IRMA kits used; the initial assay was performed by a kit that could recognize high-molecular weight (HMW) form as well as ACTH(1-39), but the later assay by another kit that could recognize only ACTH(1-39). Pathological examination of the gastric tumor was consistent with the diagnosis of malignant carcinoid. Immunohistochemical study revealed that immunoreactivity of proopiomelanocortin (POMC) was positive within the tumor cells, whereas those of ACTH and prohormone convertase 1/3 were negative. Molecular sieving analysis of patient's plasma by gel chromatography coupled with ACTH radioimmunoassay which could recognize HMW form and ACTH(1-39) and two different IRMAs revealed that the predominant form of ACTH was HMW form with a minor peak of ACTH(1-39). This is a rare case of ectopic ACTH syndrome caused by malignant gastric carcinoid with preferential production of HMW form of ACTH, possibly due to unprocessed POMC.

A 55-year-old man who was diagnosed as having type 1 diabetes mellitus (DM) at the age of 50 years was started on insulin therapy. At 54 years old of age, he suddenly developed complex partial seizures, which frequently occurred despite intensive anti-epileptic drug therapy. Neurological examination on admission revealed hyporeflexia in bilateral upper and lower extremities without any muscle rigidity, painful spasm or cerebellar ataxia. Laboratory examination showed poor glycemic control with increased glycated hemoglobin levels. Positive anti-thyroglobulin antibodies and anti-thyroid peroxidase (TPO) antibodies and slight elevation of TSH levels are consistent with subclinical hypothyroidism due to Hashimoto’s thyroiditis. A high titer of anti-glutamic acid decarboxylase (GAD) antibodies was detected in the patient’s serum and cerebrospinal fluid (CSF). Electroencephalography showed temporal spikes, consistent with complex partial seizure. This is a very rare case presenting with concomitant type 1 diabetes and drug-resistant epilepsy associated with high titers of circulating and CSF anti-GAD antibodies.

A 46-year-old male with long-term treatment-resistant hypertension and past history of cerebral hemorrhage was found to have suppressed plasma renin activity (PRA) and normal plasma aldosterone concentration (PAC) with aldosterone/renin ratio of 25.3. Furosemide plus upright test did not stimulate PRA, but computed tomography scan of the abdomen revealed no abnormal lesions in either adrenal gland. Selective adrenal venous sampling (SAVS) showed that PAC in the left and the right adrenal vein were 1000 ng/dl and 230 ng/dl, respectively, which increased to 1500 ng/dl and 620 ng/dl, respectively, after ACTH stimulation. Diagnosis of primary aldosteronism due to hypersecretion of aldosterone from the left adrenal gland was made, and laparoscopic left adrenalectomy was performed. Pathological examination of the 'apparently normal' adrenal tissue resected revealed the presence of poorly encapsulated multiple adrenocortical micronodules which showed positive immunoreactivity for 3beta-hydroxysteroid dehydrogenase by immunohistochemical study, but negative immunoreactivity in the hyperplastic zona glomerulosa consistent with paradoxical hyperplasia associated with primary aldosteronism. Postoperatively, PRA was normalized and his high blood pressure was well controlled with lower doses of antihypertensive drugs than those used before surgery. The clinicopathological features of our case are consistent with the diagnosis of unilateral multiple adrenocortical micronodules (UMN), a new subset of primary aldosteronism, in which SAVS proved to be a useful diagnostic tool for its localization.

Three Japanese patients (a man and his two sons) in a family with clinical diagnosis of familial multiple endocrine neoplasia type 1 (MEN1) suffered from insulinoma(s), primary hyperparathyroidism and pituitary microadenoma. Genomic DNA of the patients was analyzed by sequencing for the MEN1 gene and an insertion of six nucleotides, CTGCAG, in exon 4, resulting in insertion of two amino acids, Leu-Gln, after the 256th amino acid of the menin (256insLQ), was identified. CTGCAG is a palindromic sequence and repeated twice in the wild-type allele (nucleotides 879-890). It is speculated that mutations involving only exon 4 of the MEN1 gene might induce development of insulinoma(s).

Both integrins and endothelins (ETs) are known to play important roles in vascular remodeling via proliferation, apoptosis, and migration of vascular smooth muscle cells (VSMCs), whose dysfunctions have been implicated in the pathogenesis of end-organ damage associated with hypertension and arteriosclerosis. However, whether there is any interaction between endothelin-1 (ET-1) and integrins remains unknown. Therefore, the aim of the present study was to elucidate whether ET-1 regulates the expression of integrin alpha(v) in rat VSMCs. ET-1 dose- and time-dependently suppressed the integrin alpha(v) messenger RNA (mRNA) transcripts, as quantified by a real-time quantitative polymerase chain reaction (PCR) method, and decreased the transcriptional activity of integrin alpha(v) gene, as demonstrated by integrin alpha(v)-luciferase assay. The inhibitory effect of ET-1 on integrin alpha(v) gene expression was abrogated by an ETA receptor antagonist (BQ123) but not by an ET(B) receptor antagonist (BQ788). ET-1 also suppressed the cell surface expression of integrin alpha(v)beta5 and the adhesion to vitronectin, but not to fibronectin. These results demonstrate that the adhesion of vitronectin to rat VSMCs is inhibited by ET-1 via the ET(A) receptors by suppressing integrin alpha(v) gene transcription, suggesting that ET-1 is involved in regulation of vascular integrin alpha(v) gene expression.

Recent evidence suggests the possible involvement of inducible nitric oxide synthase (iNOS) in the development and maintenance of hypertension in certain animal models. Inflammatory cytokines activate nuclear factor (NF)-kappaB, which plays a major role in transactivation of the inducible nitric oxide synthase (iNOS) gene. However, it remains unknown whether cytokine-mediated iNOS expression in vascular smooth muscle cells (VSMCs) requires signaling pathway(s) other than NF-kappaB activation. The purpose of this study was to determine whether the p42/p44 MAP kinase pathway is involved in cytokine-induced NF-kappaB activation and/or iNOS expression in cultured rat VSMCs. Nitrite/nitrate (NOx) production stimulated by interleukin (IL)-1beta or tumor necrosis factor (TNF)-alpha in VSMCs was markedly suppressed by inhibiting MAP kinase by pretreatment with a p42/p44 MAP kinase kinase (MAPKK)-1 inhibitor (PD98059) or by transfecting the dominant-interfering form of the nonphosphorylated MAPKK-1 expressing construct (MAPKK S222A). Inhibition of p42/p44 MAP kinase also antagonized the upregulation of iNOS mRNA and protein, as demonstrated by the quantitative RT-PCR method and Western blot analysis, respectively. Furthermore, rat iNOS promoter activity using an iNOS-luciferase construct stimulated by cytokines was inhibited by MAPKK-1 inhibition. However, kappaB-dependent transcription analysis revealed that cytokine-stimulated NF-kappaB activity was unaffected by MAP kinase inhibition. Western blot analysis using anti-IkappaB-alpha and anti-phospho-IkappaB-alpha antibodies showed that PD98059 had no effect on transient phosphorylation or degradation of IkappaB-alpha by cytokines. An electrophoretic mobility shift assay using synthetic oligonucleotide corresponding to the downstream NF-kappaB site of rat iNOS promoter as a probe showed that MAP kinase inhibition did not block cytokine-stimulated activation of NF-kappaB. These data suggest that the MAP kinase pathway is in part involved in cytokine-induced iNOS expression independent from NF-kappaB activation in rat VSMCs.

Adrenomedullin is a novel vasodilatory peptide originally isolated from pheochromocytoma. Recently, we found that adrenomedullin acts as an autocrine/paracrine apoptosis survival factor for rat endothelial cells. In the present study, we show that adrenomedullin induces the expression of Max, a heterodimeric partner of c-Myc, which may contribute to its ability to rescue endothelial cells from apoptosis. Max is a basic-helix-loop-helix-leucine zipper protein that forms heterodimers with its alternative partners, Mad and Mxi-1, to behave as an antagonist for Myc-Max heterodimer through competition for common DNA targets. The expression of Max is reported to be constitutive and more stable than c-Myc, and serum induces immediate c-Myc stimulation followed by modest Max up-regulation. In quiescent rat endothelial cells, adrenomedullin stimulated the expression of Max without affecting c-Myc. Quantitation with real-time quantitative PCR detected on the ABI Prism 7700 Sequence Detection System revealed that adrenomedullin and calcitonin gene-related peptide (CGRP), as well as serum, up-regulated Max mRNA levels and that down-regulation of Max mRNA after serum deprivation was prevented by adrenomedullin. Neither adrenomedullin nor CGRP affected c-Myc expression. Transfection of a Max-expressing plasmid into endothelial cells rescued the apoptosis induced by serum deprivation. Neutralization with anti-adrenomedullin antiserum or blockade with a CGRP receptor antagonist, CGRP(8-37), reduced Max mRNA levels in growing endothelial cells and enhanced apoptosis after serum starvation. Introduction of an antisense oligodeoxynucleotide against Max mRNA using transferrin receptor-operated transfer led to inhibition of both adrenomedullin-induced up-regulation of Max transcripts and its cell survival effect, whereas random, sense, or missense oligonucleotides were without effect. The negative regulation of E-box-driven transcription by adrenomedullin was demonstrated by using preproendothelin-1 promoter containing c-Myc-Max binding consensus sequence; the promoter activity of preproendothelin-1 was reduced by cotransfecting Max- and Mad-expressing plasmids as well as addition of adrenomedullin and CGRP. The present results demonstrate that adrenomedullin antagonizes serum deprivation-induced endothelial apoptosis by up-regulation of the max gene in an autocrine/ paracrine manner.

A unitary model for the particle production is presented on the basis of the eikonal for­ malism and the Regge theory. The elastic and production processes are treated in a unified way and the diffraction in the former is described explicitly as a shadow of the latter. In our model, the exchange of the Regge cut is important in the particle production and the self-consistency is retained between the input and output forward two-body amplitudes. Our model reproduces rising cross sections and the shrinkage effect in the forward slope parameter. As for the production processes, the increasing average multiplicity, the sharp cutoff of the transverse momentum and the wide rapidity plateau with a bump structure in inclusive spectra are reproduced. High energy experiments at FNALn and at CERN-ISR2J have revealed several regularities in hadronic processes. In proton-proton collisions in the range 300

The double β decay is investigated by the use of the relativistic Coulomb wave function including the finite nuclear size effect. A general form of the V±A interactions is considered. It is shown that the decay rate is enhanced considerably in comparison with the case of the plane wave multiplied by the non-relativistic Fermi factor.

In order to shed light on the important question whether neutrinos are Dirac of Majorana particles, the double β decay is investigated within a general form of weak interaction Hamiltonian. The systematic study is made on the 0^+ →J^+ nuclear transitions for the tow-neutrino and neutrinoless modes both in the two-nucleon- and N^*-mechanism. It is shown that for the neutrinoless mode, only the 0^+ →0^+ transition in the two-nucleon mechanism is allowed if there is no right-handed interaction. When the right-handed interaction gives a sizable contribution, the role of the 0^+ →2^+ transition becomes as important as the 0^+ →0^+ transition. The comparison of our results with the previous ones is also presented.

There is a growing interest in the neutrino masses. Theoretically, there is much freedom in neutrino mass patterns in contrast to quarks and charged leptons because neutrinos are in general considered Majorana particles. Experimentally, the v-oscillation!) and the /3/3 decay2),3) give serious constraints to neutrino masses and their mixing scheme. A special case where there are degeneracies of Majorana neutrino masses has recently been interesting. If the degeneracy happens as a consequence of the special symmetry in the mass matrix, a pair of degenerate Majorana neutrinos may form a Dirac neutrino. This Dirac neutrino is called the pseudo Dirac (PD) neutrino,4)-6) if the symmetry of the mass matrix is not the symmetry of the weak interaction. That is, the lepton number assigned to this Dirac neutrino is not conserved in the weak interaction and thus the mass degeneracy is removed by the higher order perturbation of the weak interaction. A PD neutrino has recently drawn special attention due to the tight neutrino mass bound obtained from the analysis of the /3/3 decay,2),3)

The real part of the forward amplitude for high energy hadron-hadron elastic scattering is estimated from quantum field theory by means of a functional derivative method. If the generalized crossed ladder diagrams are taken into account, it is shown that the relativistic scattering amplitude can be treated in a way similar to the eikomU approximation of the non­ relativistic potential scattering. A massive vector meson is assumed to be exchanged between two colliding particles. Comparison with the p-p scattering data is discussed. § I. Introduction At high energies, the scattering amplitudes of hadrons exhibit remarkable features of exponential dependence on the momtmtum transfer squared, and have little dependence on the energy of incident particles. Roughly speaking, there seems to be two schools of thought to interpret these features. One is the Regge pole model based on i:he analytic properties of scattering amplitudes and the other is the absorption model related to geometrical properties of particles considered. As one of the latter models, Chou and Y ang1> proposed the droplet model in which the elastic scattering amplitude is expressed in an impact parameter representation