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Statin therapy has been found to produce substantial reductions in low-density lipoprotein cholesterol (LDL-C) levels, resulting in a reduced risk for cardiovascular events. Recently, research interest has focused on modification of high-density lipoprotein cholesterol (HDL-C) levels for the potential prevention of cardiovascular events. The effects of pitavastatin and atorvastatin on HDL-C have not been directly compared.This study compared the effects of pitavastatin and atorvastatin on HDL-C and other lipids and glucose metabolism in Japanese patients with elevated LDL-C levels and glucose intolerance. The tolerability of the 2 treatments was also compared.This was a multicenter, open-label, parallel-group trial. Patients with LDL-C levelsor=140 mg/dL and glucose intolerance (defined according to Japanese criteria for borderline diabetes and World Health Organization criteria for impaired fasting glucose and impaired glucose tolerance) were randomly assigned to receive either pitavastatin 2 mg/d or atorvastatin 10 mg/d for 52 weeks. Levels of serum lipids and lipoproteins and measures of glucose metabolism (fasting insulin, fasting glucose, glycosylated hemoglobin, and homeostasis model assessment for insulin resistance) were obtained at baseline and at 8, 26, and 52 weeks of treatment. The effect of study drug on glucose metabolism was evaluated as a tolerability outcome. Tolerability was further assessed based on adverse events, either spontaneously reported or elicited by questioning; physical examination findings; and clinical laboratory test results. Study physicians rated the relationship of adverse events to study medication as unrelated, suspected, or probable.Two hundred seven patients were enrolled in the study, and efficacy was evaluated in 173 patients (88 pitavastatin, 85 atorvastatin). Thirty-four patients were excluded for reasons including failure to start medication or lack ofor=6 months of follow-up. Women accounted for 62% (108/173) of the evaluable population, which had a mean age of 63.3 years and a mean weight of 63.0 kg; 89% (154/173) had diabetes mellitus. The percent change in HDL-C levels was significantly greater in the pitavastatin group compared with the atorvastatin group (8.2 vs 2.9, respectively; P=0.031), as was the percent change in apolipoprotein (Apo) A-I (5.1 vs 0.6; P=0.019). The percent change in LDL-C levels was significantly lower with atorvastatin compared with pitavastatin (-40.1 vs -33.0, respectively; P=0.002), as were the percent changes in non-HDL-C (-37.4 vs -31.1; P=0.004), Apo B (-35.1 vs -28.2; P0.001), and Apo E (-28.1 vs -17.8; P0.001). The significant results for these parameters were unchanged when all 189 subjects who receivedor=1 dose of study medication were included in the analysis, using last-value-carried-forward methodology. There were no significant differences between treatments with respect to the measures of glucose metabolism. Both statins appeared to be well tolerated. Adverse events occurred in 9% (9/96) of the pitavastatin group and 14% (13/93) of the atorvastatin group (P=NS). Two patients in the pitavastatin group and none in the atorvastatin group had an alanine aminotransferase value3 times the upper limit of normal (P=NS).In these patients with elevated LDL-C levels and glucose intolerance, 52 weeks of treatment with pitavastatin 2 mg/d was associated with significantly greater increases in HDL-C and Apo A-I levels than atorvastatin 10 mg/d. Both treatments were well tolerated.

穿刺吸引細胞診へのDPPIV活性染色の併用が有用であった副甲状腺過形成の1例を経験したので報告する. 症例は49歳, 男性. 慢性腎不全により昭和59年4月19日に透析導入された. 3年前よりPTHの上昇を認め, ときどき腰痛があるため平成10年9月30日当院内科を受診し, 超音波検査で左甲状腺下極背側に副甲状腺腫瘤を指摘された. また右甲状腺下極に腫瘤を認め精査目的のため穿刺吸引細胞診が行われた. 小型で均一な細胞がシート状から細胞密度の高い集塊として出現し, 特に乳頭状集塊, 核溝, 核内細胞質封入体は認められなかったため, 濾胞性腫瘍ないし腺腫様甲状腺腫を疑った. 一方, DPP IV活性染色が強陽性であったことから, パパニコロウ脱色標本を用いて, 免疫染色を行ったところPTHは陽性であったがTgは陰性であり副甲状腺病変が推定された. 組織学的には主細胞が胞巣状に増殖し, 脂肪組織の混在は認めず他の3腺も同様な組織所見を示し副甲状腺過形成と診断された. また副甲状腺摘出時, 甲状腺とはお互いに被膜なしに連続し, 一部甲状腺内に迷入していた. 本症例のごとく甲状腺腫瘍性病変との鑑別を要する場合, 本酵素の著明な発現が副甲状腺過形成を推察する一つの指標になり得ると思われた.

症例は47歳女性. 喉の圧迫感と呼吸困難を訴えて受診した. 入院時検査での血清CEAは1.5ng/m1, カルシトニン値は32pg/ml と異常は認めなかった. 胸部X線写真にて気管の狭窄を, 超音波検査とCT検査で大きな甲状腺腫を指摘された. 穿刺吸引細胞診では壊死性背景は認めず, 紡錘形ないし多稜形の細胞は疎結合性から孤立散在性に出現し, 一部に濾胞状集塊を認めた. また, 細胞質に乏しい裸核状の細胞も散見され, 核は類円形で偏在性を示し, クロマチンは細穎粒状で大きな核小体を認めた. 個々の細胞異型は目立つものの単調な細胞出現であることから, 乳頭癌ないし髄様癌を疑ったが, DAPIV活性染色が陰性であることより髄様癌と推定した. 組織学的に腫瘍細胞は充実性ないし濾胞状に増生し, 免疫組織学的に充実部, 濾胞構造領域ともに, サイログロブリンは陰性, カルシトニン, クロモグラニンAは陽性であり濾胞型髄様癌と診断された.

A 61-year-old woman was admitted to the hospital because of general fatigue. Laboratory examinations showed hyponatremia, plasma hypo-osmolarity, and inappropriate increased concentration of the plasma antidiuretic hormone (ADH) in the presence of concentrated urine. Magnetic resonance imaging revealed a mass lesion in the anterior mediastinum. An extended thymectomy was performed under the diagnosis of thymoma with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Histologically the tumor was located in the thymic tissue and was diagnosed as ganglioneuroblastoma. Immunohistochemical studies showed the existence of ADH in the tumor cells. To the knowledge of the authors, this is the first case of ganglioneuroblastoma of the thymus with SIADH.

1990年～1995年までに限局性肝疾患に対しエコーガイド下に肝穿刺吸引細胞診を施行した81症例について検討を行った. 対象は病理診断の確定した肝細胞癌48例, 胆管細胞癌4例, 転移性肝癌11例, 肝細胞腺腫1例, その他の良性病変17例である. 穿刺吸引細胞診において, 肝細胞癌48例中44例が陽性, 4例が疑陽性であった. 陽性44例中43例は肝細胞癌と診断が可能で, 1例は肝細胞癌と確定できなかった.疑陽性と判定した4例は細胞異型が弱く悪性にできなかったもの3例, 残り1例は細胞異型は認めたものの細胞量不十分であることから疑陽性と判定した. 胆管細胞癌4例ではすべて細胞診陽性で, 3例を腺癌と診断したが, 1例は確定できなかった. 転移性肝癌11例では腺癌9例, カルチノイド2例が診断できた. その内訳は大腸癌9例 (腺癌7例, カルチノイド2例), および膵癌1例, 胃癌1例. 肝細胞腺腫1例は細胞異型を認めず陰性と判定した. その他良性病変は17例中5例を疑陽性と判定した. これらはいずれも大小不同, 核小体を過大評価にしたことが原因であった. 肝細胞癌, 特に高分化型肝細胞癌の細胞像について, N/C比の増大, クロマチン分布の不均一性, しかも単一細胞出現が重要と思われた.

Tumor cytology has proven to be inadequate for precise diagnosis of thyroid follicular adenoma. This suggests the need for a molecular approach for its diagnosis. Expression of CD26/DPPIV (dipeptidyl peptidas IV), p53, and PTEN was analyzed in smears or sections obtained from 19 patients with histologically proven thyroid follicular adenoma. Papanicolaou staining, CD26/DPPIV activity staining, and HE staining were performed and the specimens were observed morphologically. Immunohistochemical analysis using antibodies against p53 and PTEN was performed. Genetic mutation of PTEN exons was performed using the laser capture microdissection method. The nuclear area of the CD26/DPPIV-positive cells was significantly larger than that of the CD26/DPPIV-negative cells. p53 expression was not observed any specimen. PTEN expression was observed in 18 of 19 cases. DNA sequence analysis did not reveal mutations in exons 5-9 of PTEN in the immunohistochemically PTEN-negative case. In accordance with our previous reports, we found that observation of concomitant CD26-positive and PTEN-negative status in cases of follicular adenoma suggests a state close to follicular carcinoma or progression to cancer, thus warranting careful follow-up.

Graves' disease was found in a 41-year-old, married male patient with Klinefelter's syndrome. The patient began having finger tremor 5 years previously, and developed palpitation and weight loss 3 months prior to examination. He had a diffuse goiter, exophthalmos, and atrial fibrillation. Plasma levels of T3, T4 and free T4 were 2.8 ng/ml, 16.6 micrograms/dl and 4.5 ng/dl respectively. [123I] uptake was 53%, and TSH receptor antibody was 75%. Although he had no gynecomastia, his general physical appearance was that of typical eunuchoism. Chromosome studies showed a karyotype of 47,XXY. A diagnosis of Graves' disease associated with Klinefelter's syndrome was made.

The aim of this study was to search for diagnostic markers that could correctly identify thyroid nodular lesions requiring urgent surgical treatment. We investigated whether galectin-3 and dipeptidyl peptidase IV (CD26/DPPIV) could be potential markers for improving the diagnostic accuracy of conventional cytology. Seventy-nine patients with histologically proven thyroid diseases were analyzed. The immunocytochemical staining results showed galectin-3 expression in neoplastic cells of all 37 papillary carcinomas, five of six follicular carcinomas, all three anaplastic carcinomas, one of three medullary carcinomas, and two of 14 follicular adenomas. All 16 adenomatous goiters were negative for galectin-3 immunostaining. On the other hand, all 37 papillary carcinomas, all six follicular carcinomas, and one of three anaplastic carcinomas revealed CD26/DPPIV expression, whereas all three medullary carcinomas were negative. Among benign thyroid lesions, four of 14 follicular adenomas and two of 16 adenomatous goiters exhibited varying degrees of immunoreactivity for CD26/DPPIV. RT-PCR analysis demonstrated overexpression of galectin-3 and CD26/DPPIV mRNAs in all six papillary and all three follicular carcinomas analyzed, whereas the mRNA expressions of these molecules were barely or not detectable in benign thyroid lesions and normal thyroid tissues, except for one case of follicular adenoma. In conclusion, we demonstrate that galectin-3 and CD26/DPPIV were consistently coexpressed at protein and mRNA levels in differentiated thyroid carcinomas. We propose that combined immunostaining for galectin-3 and CD26/DPPIV in the preoperative evaluation of thyroid nodules may play a role in accurate cytodiagnosis. Diagn. Cytopathol. 2002;26:366–372. © 2002 Wiley-Liss, Inc.

A 21-year-old man was referred to our hospital because of a liver mass lesion detected by abdominal ultrasonography. He had received no hormonal treatment. Physical examinations revealed no abnormalities, and laboratory data, including hepatic function test results, were within normal ranges, with the exception of elevated levels of serum protein induced by vitamin K absence or antagonist (PIVKA)-II (2.2 AU/ml). Abdominal ultrasonography revealed a hyperechoic mass lesion measuring 10 x 10 cm, with hypoechoic areas located in the right posterior segment of the liver. A low-density area and a hypervascular area were detected in the right posterior segment of the liver by computed tomography and celiac angiography, respectively. As hepatocellular carcinoma could not be completely excluded, the tumor was resected. The tissue consisted of sheets of tumor cells with eosinophilic cytoplasm and round nuclei showing a thin trabecular pattern, and these histological findings indicated liver cell adenoma. After resection of the tumor, serum PIVKA-II returned to the normal level.

Twenty pancreata of non-diabetic patients and 17 pancreata of diabetic patients, including two patients with insulin-dependent diabetes mellitus, were immunohistochemically studied using antiserum against human islet amyloid polypeptide (IAPP). The islet beta cells in non-diabetic patients were immunoreactive for both IAPP and insulin. Amyloid deposition immunoreactive for IAPP was detected in six of 20 pancreata of non-diabetic patients. The plasma glucose level of three of these six patients was elevated to more than 200 mg/dl, and that of the other three ranged from 143 to 162 mg/dl; all six were receiving intravenous hyper-alimentation and had no history of diabetes prior to treatment. Amyloid deposition was present in all patients with non-insulin-dependent diabetes mellitus (NIDDM). The deposition was absent in the pancreata of two secondary diabetic patients, one of whom had received steroid hormone for bronchial asthma and the other of whom had liver cirrhosis with hepatocellular carcinoma; deposition was also absent in the pancreas of a patient with impaired glucose tolerance diagnosed on a 75-g oral glucose load. Heterogeneous expression of immunoreactivities of beta cells for insulin and for IAPP was present, suggesting independently regulated production and secretion of the peptides. Immunoreactivity of beta cells was more sensitively decreased for IAPP than for insulin in the islets of NIDDM patients. The decreased immunoreactivity for IAPP suggested an initial stage of disturbed beta-cell function, even if the immunoreactivity for insulin was apparently intact or the amyloid deposition in the islets was insignificant. The degree of amyloid deposition immunoreactivity for IAPP did not necessarily reflect the severity of diabetes mellitus. Amyloid deposits were seen at the narrow spaces beneath the insular capsule of connective tissues and the perivascular region or, in some cases, occupying the whole of the islet. The diabetogenic role of IAPP is unclear, but the deposition might be an accelerating factor which disturbs beta-cell function.

Staining for dipeptidyl aminopeptidase IV (DAP IV [EC: 3.4.14.5]) activity was applied to aspiration biopsy specimens or imprint preparations of surgical biopsy specimens from thyroid tumors. Material was obtained from 55 patients with histologically proven thyroid diseases: 9 with papillary carcinoma, 5 with follicular carcinoma, 11 with follicular adenoma, 13 with adenomatous goiter, 8 with Hashimoto's thyroiditis, and 9 with other benign conditions. Most tumor cells, follicular lumina in cell clusters, and intranuclear inclusions were strongly positive for DAP IV in all examples of papillary or follicular carcinoma. In contrast, only a few epithelial cells were labeled for DAP IV in follicular adenoma and adenomatous goiter. Some Hurthle cells in Hashimoto's thyroiditis also were positive for DAP IV. When a DAP IV scoring system based on the percentage of positive cells and staining intensity was used, all benign tissues except one (from a follicular adenoma) were found to have extremely low scores. These results indicate that staining for DAP IV activity is a simple but useful tool to aid in distinguishing benign from malignant thyroid neoplasms.

We report a case of a 14 year-old girl with Wegener's granulomatosis (WG) complicated by its direct brain invasion and insulin dependent diabetes mellitus (IDDM). This case was diagnosed as WG early in its onset and successfully treated. As for IDDM of this case, the presence of HLA-DR4 and the islet cell surface antibody (ICSA) was demonstrated. To our knowledge, this is the first case report on IDDM associated with WG. We consider that WG may precipitate the development of IDDM in a genetically predisposed subject.

Foeto-placental function and hormone levels in the maternal, foetal and amniotic compartments have been investigated in an acromegalic woman who was treated with 20 mg bromocriptine/day throughout gestation. Bromocriptine therapy during pregnancy had no effect on urinary oestriol excretion and plasma levels of unconjugated oestriol, progesterone, human placental lactogen, cystine aminopeptidase and heat-stable alkaline phosphatase. The maternal and foetal (cord) blood and amniotic fluid showed prolactin levels of 3.8, 6.5 and 1700 ng/ml, respectively, in the 39th week of pregnancy during bromocriptine therapy. Compared with data from normal pregnancies, these values demonstrated that bromocriptine or an active metabolite crossed the term placenta to suppress prolactin secretion from the foetal pituitary gland and that the prolactin level in amniotic fluid was scarcely affected by the drug. Maternal, foetal and amniotic fluid growth hormone levels were 27.0, 33.0 and 3.8 ng/ml, respectively, thus indicating that dopamine agonists suppress growth hormone only in acromegalic patients, and not in normal babies. Bromocriptine had no effect on thyroid-stimulating hormone concentrations in the maternal, foetal and amniotic compartments.

A case of a 68-year-old female patient with hypokalemic myopathy is presented. Her persistent diarrhea due to radiation enteropathy with a total dose of 8,400 rad for the treatment of cervical cancer caused potassium loss in the stool. It finally induced generalized muscle weakness with hypokalemia as low as 1.6 mEq/l with elevated CK 3,845 IU/l. The muscle biopsy of the left vastus lateralis demonstrated typical findings of hypokalemic myopathy. Radiation to the pelvic space can cause damage of the terminal ileum. Hypokalemic myopathy associated with radiation enteropathy is very rare in the literature.

The relation of the TRH test to the T3 suppression test was investigated in 43 patients with hyperthyroidism receiving antithyroid drugs for 6 to 27 months (average 14 months). TRH tests were performed by measuring serum TSH levels before and 15, 30, 45, 60, 90 and 120 minutes after intravenous injection of 500 mug of synthetic TRH. Serum TSH was measured by a double antibody radioimmunoassay. Two weeks later, the T3 suppression test was performed by measuring the 24-hr thyroidal uptake of radioiodine after daily administrations of 75 mug of triiodothyronine for 8 days. All patients under study were in euthyroid state, estimated by serum T3-RSU, T4, T3 and FT4I. The value for 24-h uptake after T3 administration was less than 20% in 18 cases, out of which the response to TRH was normal or exaggerated in 15 cases and was absent or impaired in 3 cases. On the other hand, out of 25 cases with the value of 24-h uptake more than 20%, the response to TRH was absent or impaired in 18 cases and was normal or exaggerated in 7 cases. The results of the TRH test and the T3 suppression test were correlated in 33 out of 43 cases. The responsiveness to TRH and the suppressibility with T3 was dissociated in 10 cases, suggesting the TRH test could not replace the T3 suppression test.

Association of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) with multiple sclerosis (MG) is very rare, although many other disorder of the nervous system have been reported to be associated with this syndrome; there is only one case report in the literature. We describe here a patient with the syndrome associated with MS. A 62-year-old women had a variety of neurologic symptoms, where clinical course was typical of MS. Transient episodes of hyponatremia and disturbance of consciousness occurred repeatedly with deterioration of MS. The concentration of antidiuretic hormone (ADH) was high whereas the plasma osmolality was low in the presence of concentrated urine, during the episodes of hyponatremia. Urinary Na excretions exceeded 20 mEq/day. Computed tomography and magnetic resonance imaging revealed lesions in the brain, especially in the periventricular region. The hypothalamus and pituitary appeared normal by these imaging methods. Since the periventricular region surrounds and may be functionally connected to the hypothalamus which plays the central role in the regulation of ADH secretion, it was concluded that association of SIADH and MS in this patient was not coincidental, and that demyelinating processes in the periventricular region exerted an abnormal influence on ADH secretion resulting in SIADH. Contribution of other mechanisms as increased intrathoracic pressure, however, could not be excluded completely.

A subpopulation of lymphocytes forming rosettes with autologous erythrocytes was studied on peripheral blood and thyroid tissues obtained from the patients with various thyroid diseases. The mean (+/-S.D.) percentage of autorosette-forming cells (ARFC) was 10.1(+/-5.5)% in the peripheral blood from patients with hyperthyroid Graves' disease, which was higher than that in normal subjects (5.6 +/- 2.8%), while the levels of ARFC in the peripheral blood from euthyroid patients with Graves' disease under treatment and Hashimoto's thyroiditis did not significantly differ from the normal level. The mean percentages of ARFC in the thyroid tissues from patients with Graves' disease and Hashimoto's thyroiditis were 14.7(+/-8.5) and 13.3(+/-7.8)%, respectively, which were higher than those in the peripheral blood from the same patients. Most of these cases with abnormally high levels of ARFC were accompanied with the abnormally low T cell to B cell ratios. The microscopic examination of the cytological materials from these patients showed an increased number of large stimulated lymphoid cells or lymphoblasts as compared with those who had few ARFC. These results suggest an increase in an activated T cell subset in the circulation and/or in the thyroid tissue, which is probably caused by active immune response to some stimuli.

症例は25才,女性.昭和61年1月より全身倦怠感,耐寒性の低下,便秘が出現.同年8月当科受診し, TSHの高値, T4の低値,マイクロゾームテスト,サイクロイドテスト陽性を認め,橋本病による甲状腺機能低下症と診断. L-thyroxine投与開始後, T3の異常高値が出現.甲状腺中毒症の症状はみられなかった. T3高値の原因として,検査の検果, L鎖がλ型の抗T3IgG抗体を証明した. L-thyroxine投与後,抗T3抗体が出現したまれな1症例を報告した.

We studied a patient with hypokalemic myopathy associated with 17 alpha-hydroxylase deficiency. An 18-year-old high school student, who appeared to be a girl with poorly developed secondary sex characteristics, had generalized muscle weakness. The cause of muscle weakness proved to be hypokalemic myopathy confirmed by clinical findings and muscle biopsy. Endocrinologic study demonstrated 17 alpha-hydroxylase deficiency with male pseudohermaphroditism. The metabolic abnormality of this patient was corrected by the administration of glucocorticoid. The possibility of this rare disease has to be considered when we examine a patient who has hypokalemic myopathy associated with hypogonadism.