Relation between aortic stiffness and coronary flow reserve in patients with coronary artery disease.

OBJECTIVES: To investigate the relation between aortic stiffness and coronary flow reserve (CFR) in patients with coronary artery disease (CAD). DESIGN: Observational study. SETTING: Coronary care unit of a primary care hospital. PATIENTS: 192 consecutive patients who underwent coronary angiography. MAIN OUTCOME MEASURE: Brachial-ankle pulse wave velocity (ba-PWV), CFR, and severity of CAD. RESULTS: According to the angiographic findings, patients were divided into four subgroups: patients without significant stenosis (normal coronary artery (NCA) group, n = 28) and those with one vessel disease (1VD group, n = 92), two vessel disease (2VD group, n = 50), or three vessel disease (3VD group, n = 22). ba-PWV increased with the number of diseased vessels and was significantly correlated with the number of diseased vessels (NCA group v 1VD group v 2VD group v 3VD group: 1481 (252) v 1505 (278) v 1577 (266) v 1727 (347) cm/s, p < 0.001). CFR had a significant negative correlation with ba-PWV (r = -0.45, p < 0.0001). The diastolic to systolic velocity ratio obtained in 45 patients also was significantly correlated with ba-PWV (r = -0.35, p < 0.05). Multiple regression analysis showed that ba-PWV was an independent determinant of CFR (p < 0.01). CONCLUSIONS: Coronary flow is altered with aortic stiffening in patients with CAD. These results suggest one possible mechanism for recent reports that aortic stiffness is a key cardiovascular risk factor.

K-ras mutation in the endometrium of tamoxifen-treated breast cancer patients, with a comparison of tamoxifen and toremifene.

The putative presence of a mutation in codon 12 of the K-ras gene was investigated in the endometrium of tamoxifen (TAM) and toremifene (TOR)-treated breast cancer patients. DNA was extracted from fresh cytologic samples of the endometrium in 86 TAM and 21 TOR-treated breast cancer patients. Mutations were detected by enriched PCR and an enzyme-linked mini-sequence assay (ELMA). K-ras mutation was found in 35 TAM-treated endometrial samples, and in only one TOR-treated endometrium (P<0.003). In 24 premenopausal patients, K-ras mutation was found in seven (43.8%) of 16 patients with less than 47 months of TAM treatment, while none was found in eight patients with more than 48 months of TAM treatment (P<0.03). In 62 postmenopausal-amenorrheic patients, K-ras mutation was found in three (15.8%) of 19 patients with less than 23 months of TAM treatment, while it was found in 16 (61.5%) of 26 patients with 24-47 months of TAM treatment and nine (52.9%) of 17 patients with more than 48 months of TAM treatment (P=0.002). The presence of K-ras mutation is significantly influenced by the duration of TAM treatment and menstrual status of the patients. TOR may have a lower potential genotoxicity than TAM.

Endometrioid adenocarcinomas of the uterine corpus in women younger than 50 years of age can be divided into two distinct clinical and pathologic entities based on anatomic location.

BACKGROUND: This study used the clinicopathologic profiles of Japanese women younger than 50 years of age with endometrial carcinoma to distinguish the clinicopathologic features of carcinomas of the lower uterine segment (LUS) from those of carcinomas of the corpus mucosa proper (CMP). METHODS: Eighty-eight endometrial carcinomas in women younger than 50 years old (25.3%) were selected from our file of 348 Japanese women with endometrial carcinoma. Seventy-two were classified as carcinomas of the CMP and 16 carcinomas of the LUS. A tumor was judged to be a carcinoma of the LUS when it involved a continuous area ranging from the lower corpus to the upper cervix with or without intervention of a portion of uninvolved LUS. RESULTS: The mean ages of women with carcinomas of the CMP and LUS were 41.2 and 39.0 years, respectively. In comparison to carcinomas of the LUS, carcinomas of the CMP were more strongly associated with reproductive risk factors including parity (P = 0.01) and polycystic ovary syndrome (P = 0.02). There was no significant difference in body mass index or the incidence of diabetes mellitus and hypertension between women presenting with carcinomas of the CMP and LUS. Histologically, carcinomas of the LUS more frequently showed a high-grade endometrioid tumor (P = 0.02) with deep myometrial invasion (P < 0.01) and were less associated with endometrial hyperplasia (P < 0.01) than those of the CMP. CONCLUSIONS: Carcinomas of the LUS occurred predominantly in women younger than 50 years of age and had clinicopathologic features distinct from carcinomas of the CMP in women younger than 50 years of age.

Phenotypic changes of adrenomedullin receptor components, RAMP2, and CRLR mRNA expression in cultured rat vascular smooth muscle cells.

Adrenomedullin is known to inhibit cell proliferation in cultured rat vascular smooth muscle cells, through a cAMP-dependent process. The calcitonin receptor-like receptor could function as an adrenomedullin receptor when co-expressed with receptor activity-modifying protein 2. To determine whether vascular adrenomedullin receptor components, the calcitonin receptor-like receptor and the receptor activity-modifying protein 2, phenotypically change during in vitro culture conditions, we examined the expression of adrenomedullin receptor components, adrenomedullin-induced cAMP production, and the inhibition of cell proliferation in culture rat vascular smooth muscle cells during serial passages. The results demonstrated that the receptor activity-modifying protein 2 and calcitonin receptor-like receptor mRNAs increased in a passage-dependent manner in rat vascular smooth muscle cells. Furthermore, the responses of both the elevation of cAMP and the inhibition of cell proliferation became larger in vascular smooth muscle cells with an increasing number of passages. The results suggest that the increase in functional AM receptor during phenotypic change may in part contribute to the development of vascular lesions, such as in atherosclerosis.

Alteration of the adrenomedullin receptor components gene expression associated with the blood pressure in pregnancy-induced hypertension.

Adrenomedullin (AM) is a potent vasodilator. Pregnancy-induced hypertension (PIH) is a common cause of maternal or fetal mortality. We measured the changes of adrenomedullin receptor components gene expression, receptor activity-modifying protein 2 (RAMP2) and calcitonin receptor-like receptor (CRLR), at feto-maternal tissues in human normotensive pregnant women and pregnancy-induced hypertensive women by Northern blot analysis. Samples of the placenta, uterine muscle, umbilical artery, and fetal membranes were obtained from each patient under informed consent. RAMP2 mRNA significantly decreased in the umbilical artery (54%, P < 0.01) and uterus (53%, P < 0.01) of the patients with PIH. CRLR mRNA also significantly decreased in both tissues of the patients with PIH. On the other hand, the RAMP2 mRNA was significantly increased in the fetal membrane of the patients with PIH. In addition, there was a significant negative correlation between the RAMP2 mRNA levels in the umbilical artery (systolic; r = -0.623, P < 0.01, diastolic; r = -0.552, P < 0.01) and uterine muscle (systolic; r = -0.563, P < 0.01, diastolic; r = -0.553, P< 0.01) and blood pressure. However, there was no correlation between the mRNA level and blood pressure in fetal membrane and placenta, suggesting that there is no close relationship to the pathogenesis in PIH. These findings suggested that the reduced expression of adrenomedullin receptor component in umbilical artery and uterus may have some role in PIH.

Efficacy and safety of PTCA using brachial approach and low-dose heparin.

Percutaneous transluminal coronary angioplasty (PTCA) is routinely performed using the femoral approach. However, recent reports suggest the usefulness of the brachial approaches for patients for whom the femoral approach is impossible due to peripheral vessel disease or to shortened postoperative rest times. However, some reports have revealed that the incidence of vascular complications undergoing brachial-approach PTCA may be higher than those with the femoral approach, possibly due to relatively higher dose of heparin. Accordingly, in this study we evaluated the efficacy and safety of PTCA using the brachial approach and low-dose heparin, hypothesizing that lowering the heparin dose might result in reduced vascular complications. The study population of patients admitted for angina pectoris consisted of 217 subjects (221 lesions) who underwent brachial-approach PTCA and 102 subjects (115 lesions) who underwent PTCA via the femoral approach. Both groups were monitored for complications. There were no significant differences in patient or lesion characteristics between the groups. Incidence of vascular complications tended to be lower in the brachial group than in the femoral group (1.8% vs. 3.5%), although the difference did not reach statistical significance. Use of anodynes was also significantly lower in the brachial group (3.6% vs. 33%). PTCA from the brachial approach with low-dose heparin is as safe and effective a strategy as compared with the femoral approach with standard dose of heparin.

Local immune response in squamous cell carcinoma of the uterine cervix.

The role of Langerhans cells as antigen-presenting cells was examined in cervical carcinomas. Frozen samples were obtained from 34 women with stage Ib and II cervical carcinomas. Langerhans cells (CD1), T lymphocytes (CD4 and CD8), B lymphocytes (CD22), and natural killer (CD57, NK) cells were all quantitatively assessed in cervical carcinomas using immunohistochemical methods. These results were related to the MHC class I and II expression on the tumor cells. The majority of Langerhans cells were distributed among cancer cells and they were positively correlated with CD4+, NK and B cells in cervical carcinomas. This is suggestive of the presence of local immune response. The numbers of Langerhans, CD4+, CD8+ and NK cells did not significantly correlate with age at operation, lymph node metastases or depth of cervical wall invasion. The downregulation of MHC class I expression found in 8 (24%) carcinomas was not associated with the decrease in the number of immunologic cells. The upregulation of MHC class II expression found in 26 (76%) carcinomas was significantly associated with the increase in the number of Langerhans cells (p < 0.007). However, the association between the upregulation of MHC-II expression and CD4+ cells did not reach statistical significance (p < 0.07). This is probably due to a small case in this study. MHC-II-restricted immunity may partly contribute to the local immune response in stages Ib and II squamous cell carcinoma of the uterine cervix.

APP processing and synaptic plasticity in presenilin-1 conditional knockout mice.

We have developed a presenilin-1 (PS1) conditional knockout mouse (cKO), in which PS1 inactivation is restricted to the postnatal forebrain. The PS1 cKO mouse is viable and exhibits no gross abnormalities. The carboxy-terminal fragments of the amyloid precursor protein differentially accumulate in the cerebral cortex of cKO mice, while generation of beta-amyloid peptides is reduced. Expression of Notch downstream effector genes, Hes1, Hes5, and Dll1, is unaffected in the cKO cortex. Although basal synaptic transmission, long-term potentiation, and long-term depression at hippocampal area CA1 synapses are normal, the PS1 cKO mice exhibit subtle but significant deficits in long-term spatial memory. These results demonstrate that inactivation of PS1 function in the adult cerebral cortex leads to reduced Abeta generation and subtle cognitive deficits without affecting expression of Notch downstream genes.

Subsequent endometrial carcinoma with adjuvant tamoxifen treatment in Japanese breast cancer patients.

This study aimed to detail the clinicopathologic features of endometrial carcinomas that developed in Japanese patients receiving adjuvant tamoxifen treatment for breast cancer patients. Ten endometrial carcinomas in tamoxifen-treated breast cancer patients were collected from two medical centers. The endometrial carcinomas included two stage Ia, four stage Ib, two stage Ic and two stage IIIc. Three tumors were Grade 1, six were Grade 2, and one was Grade 3. The tumor was limited to the endometrium in two cases. Myometrial invasion was limited to the inner half of the myometrium in five cases and involved the outer half in three. A mild degree of lymphovascular space invasion was identified in five cases. Deep cervical invasion was recognized in one case. The cell types comprised nine endometrioid adenocarcinomas and one serous carcinoma. Five of eight postmenopausal endometrial carcinomas were associated with polypoid endometrial lesions composed of cystically dilated atrophic and proliferative glands widely separated by fibrotic stroma. Two patients with retroperitoneal lymph node metastases died of endometrial cancer. One patient developed a contralateral breast cancer during tamoxifen treatment. No patient died of breast cancer. We did not demonstrate a higher frequency of either high-grade tumors or unfavorable histologic subtypes in tamoxifen-treated Japanese breast cancer patients.

Brain Abeta amyloidosis in APPsw mice induces accumulation of presenilin-1 and tau.

APPsw transgenic mice (Tg2576) overproducing mutant amyloid beta protein precursor (betaAPP) show substantial brain Abeta amyloidosis and behavioural abnormalities. To clarify the subsequent abnormalities, the disappearance of neurons and synapses and dystrophic neurite formation with accumulated proteins including hyperphosphorylated tau were examined. Tg2576 demonstrated substantial giant core plaques and diffuse plaques. The number of neurons was significantly decreased in the areas containing the amyloid cores compared with all other areas and corresponding areas in non-transgenic littermates in sections visualized by Nissl plus Congo red double staining (p<0.001). The presynaptic protein alpha-synuclein and postsynaptic protein drebrin were also absent in the amyloid cores. betaAPP and presenilin-1 were accumulated in dystrophic neurites in and around the core plaques. Tau phosphorylated at five independent sites was detected in the dystrophic neurites in the amyloid cores. Thus, the giant core plaques replaced normal brain tissues and were associated with subsequent pathological features such as dystrophic neurites and the appearance of hyperphosphorylated tau. These findings suggest a potential role for brain Abeta amyloidosis in the induction of secondary pathological steps leading to mental disturbance in Alzheimer's disease.

The effect of nulliparity on survival in endometrial cancer at different ages.

OBJECTIVE: Nulliparity is a major independent risk factor for endometrial cancer in Japan. We examined the effect of nulliparity on survival in endometrial cancer at different ages. METHODS: A retrospective study of 328 Japanese women with endometrial cancer was performed. The subjects were divided into two groups: a younger age group (women < 50 years) and an older age group (women >/= 50 years). Parity was analyzed for its influence on survival. RESULTS: No effect of nulliparity was observed on survival in the younger group. In the older women, nulliparity did not affect survival in 189 subjects with surgical stage I and II tumors (P < 0.27). In contrast, the cumulative 10-year survival rates associated with nulliparity, a parity of 1 or 2, and a parity of 3 or more were 7.7, 48.0, and 56.2% in 54 subjects with surgical stage III and IV tumors, respectively (P < 0.03). In these 54 subjects, the cumulative 10-year survival rates associated with < 6-month and > 7-month delays in diagnosis were 57.1 and 16.6%, respectively (P < 0.02). The prognostic impact of parity disappeared after adjustment for delay in diagnosis. Multivariate analysis including histopathological variables, parity, and delay in diagnosis showed no independent prognostic variable in the older subjects with surgical stage III and IV tumors. CONCLUSIONS: The negative effect of nulliparity on survival was observed in the older subjects with advanced-surgical-stage tumors. Delay in diagnosis contributed to the prognostic impact of nulliparity.

Pharmacological characterization of KUR-1246, a selective uterine relaxant.

The aim of the present study was to evaluate the efficacy and beta 2-adrenoceptor (AR) selectivity of KUR-1246, a new uterine relaxant. Inhibition of spontaneous or drug-induced uterine contractions by KUR-1246 was evaluated in pregnant rats and rabbits by an organ bath method or by a balloon method. The selectivity of KUR-1246 was assessed simultaneously in organs isolated from late-pregnant rats. The affinity of KUR-1246 for human beta 1-, beta 2-, and beta 3-ARs was determined using two radioligands. KUR-1246 suppressed both spontaneous and drug-induced contractions in isolated uteri, the rank order of potency being isoproterenol > KUR-1246 > terbutaline > ritodrine. ICI-118551 (selective beta 2-AR antagonist) competitively antagonized the KUR-1246-induced inhibition of spontaneous uterine contractions, but CGP-20712A (selective beta 1-AR antagonist) and SR-58894A (selective beta 3-AR antagonist) did not. All beta-AR agonists tested produced significant inhibition of spontaneous uterine contractions in vivo: ED(30) value for KUR-1246 was 0.13 microg/kg/min, a potency about 6 times and 400 times greater than that of terbutaline and ritodrine, respectively. In contrast, the positive chronotropic effect was minimal in KUR-1246-treated rats. KUR-1246 displaced radioligand binding to beta 1-, beta 2-, and beta 3-ARs, the pK(i) values being 5.75 +/- 0.03, 7.59 +/- 0.08, and 4.75 +/- 0.03 for beta 1-, beta 2-, and beta 3-ARs, respectively. For the selectivity of KUR-1246 for human beta 2-AR, we obtained values of 39.2 ([IC(50) for beta 1-AR]/[IC(50) for beta 2-AR]) and 198.2 ([IC(50) for beta 3-AR]/[IC(50) for beta 2-AR]), indicating an apparently higher affinity for human beta 2-AR than for other beta-AR subtypes. The present study clearly demonstrated that KUR-1246 is a more selective beta 2-AR agonist than the drugs presently used for relaxing uterine muscle.

Lesion characteristics of acute myocardial infarction: an investigation with intravascular ultrasound.

OBJECTIVE: To use intravascular ultrasound (IVUS) to compare plaque morphology in acute myocardial infarction and stable angina pectoris. DESIGN: Retrospective study. SETTING: Primary care hospital. PATIENTS: 59 consecutive cases of acute myocardial infarction and 50 consecutive cases of stable angina pectoris. METHODS: IVUS was used before coronary intervention. MAIN OUTCOME MEASURES: Plaque morphology (incidence of eccentric plaque, subtle dissections, low echoic thrombus, calcification, echolucent areas, and bright speckled echo material), assessed visually using IVUS. RESULTS: There were no significant differences in plaque eccentricity or calcification between the two groups, but low echoic thrombus (acute myocardial infarction 15% v stable angina pectoris 0%), subtle dissections (37% v 4%), echolucent areas (31% v 0%), and bright speckled echo material (90% v 0%) were more common in the infarction group than in the stable angina group (p < 0.001 for all). There was a longer time between the onset of symptoms and the IVUS examination in patients with low echoic thrombus than in those without (p < 0.03). CONCLUSIONS: Low echoic thrombus, subtle dissections, echolucent areas, and bright speckled echo material are morphological characteristics associated with plaque at the time of acute myocardial infarction. These findings correspond pathologically to ruptured plaque.

Abeta amyloidosis induces the initial stage of tau accumulation in APP(Sw) mice.

To clarify how Abeta deposits induce secondary tauopathy, the presence of phosphorylated tau, glycogen synthase kinase 3alpha (GSK3alpha), GSK3beta, cyclin-dependent kinase 5 (CDK5), mitogen-activated protein kinase (MAPK) and fyn were examined in the Tg2576 brain showing substantial brain Abeta amyloidosis and behavioral abnormalities. Phosphorylated tau at Ser199, Thr231/Ser235, Ser396 and Ser413 accumulated in the dystrophic neurites of senile plaques. The major kinase for tau phosphorylation was GSK3beta. Smaller contributions of GSK3alpha, CDK5 and MAPK were suggested. Thus, brain Abeta amyloidosis has a potential role in the induction of tauopathy leading to the mental disturbances of Alzheimer's disease.

Age-dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer's disease.

The accumulation of amyloid beta protein (Abeta) in the Tg2576 mouse model of Alzheimer's disease (AD) was evaluated by ELISA, immunoblotting, and immunocytochemistry. Changes in Abeta begin at 6-7 months as SDS-insoluble forms of Abeta42 and Abeta40 that require formic acid for solubilization appear. From 6 to 10 months, these insoluble forms increase exponentially. As insoluble Abeta appears, SDS-soluble Abeta decreases slightly, suggesting that it may be converting to an insoluble form. Our data indicate that it is full-length unmodified Abeta that accumulates initially in Tg2576 brain. SDS-resistant Abeta oligomers and most Abeta species that are N-terminally truncated or modified develop only in older Tg2576 mice, in which they are present at levels far lower than in human AD brain. Between 6 and 10 months, when SDS-insoluble Abeta42 and Abeta40 are easily detected in every animal, histopathology is minimal because only isolated Abeta cores can be identified. By 12 months, diffuse plaques are evident. From 12 to 23 months, diffuse plaques, neuritic plaques with amyloid cores, and biochemically extracted Abeta42 and Abeta40 increase to levels like those observed in AD brains. Coincident with the marked deposition of Abeta in brain, there is a decrease in CSF Abeta and a substantial, highly significant decrease in plasma Abeta. If a similar decline occurs in human plasma, it is possible that measurement of plasma Abeta may be useful as a premorbid biomarker for AD.

Effect of diltiazem on cardiac function assessed by echocardiography and neurohumoral factors after reperfused myocardial infarction without congestive heart failure.

The purpose of this study was to examine the effect of diltiazem on cardiac function and neurohumoral factors (BNP, epinephrine, norepinephrine) after reperfused myocardial infarction without congestive heart failure (Killip class I). On the first day after myocardial infarction following reperfusion therapy patients were randomly assigned to diltiazem treatment (group 1, n=33) or no treatment (group 2, n=39). We then performed echocardiographic examinations on the patients and measured heart rate, mean blood pressure and neurohormones (BNP, epinephrine and norepinephrine). Follow-up evaluations of echocardiography were performed at 4 and 12 weeks and of neurohormones at 1 and 4 weeks after acute myocardial infarction. The highest peaks of plasma BNP, epinephrine, and norepinephrine levels were observed before treatment and decreased with time in both groups. After 4 weeks the level of plasma BNP in the diltiazem treatment group was lower than in the no treatment group [55+/-3 pg/mL vs 85+/-5 pg/mL (P < 0.05)]. Other neurohormones did not differ between groups. Fractional shortening (FS) and ejection fraction (EF)improved after myocardial infarction in both groups, but significantly more in the diltiazem group (P < 0.05) after 12 weeks of treatment. Changes in BNP correlated significantly with changes in left ventricular end systolic volumes, FS and EF. In this study, diltiazem significantly improved systolic function and reduced the level of plasma BNP after myocardial infarction, which suggest that diltiazem may have a beneficial effect on myocardial infarction without congestive heart failure.

Sacrococcygeal teratoma with hydrops fetalis and bilateral hydronephrosis.

A 29-year-old Japanese primipara with fetal sacrococcygeal teratoma and hydronephrosis was referred to our department at 22 weeks of gestation. The preload index of the inferior vena cava (PLI) was 0.75 and fetal cardiac failure was suspected at 28 weeks of gestation. The sodium and chloride concentrations and osmolarity of the fetal urine were 96 mEq/L, 81 mEq/L and 204 mOsm/L, respectively, and we predicted a good renal function. Then, a vesico-amniotic shunting operation was performed at 28 weeks of gestation to keep the renal function and PLI decreased 0.41 after this operation. At 30 weeks of gestation, the fetus was delivered by a cesarean section owing to preterm PROM and a huge growing sacrococcygeal teratoma. The baby was female, weighing 2,020 g, and the 1 minute Apgar score was 1. She died almost 7 hours after birth due to respiratory insufficiency. An autopsy confirmed bilateral hydronephrosis, urethral stenosis, sacrococcygeal immature teratoma, and pulmonary hypoplasia. The size of this tumor revealed 80 x 70 x 45 mm in intrapelvic cavity and 130 x 90 x 50 mm out of body, and this tumor was classified as Type II according to the American Academy of Pediatrics Surgery Section classification.

Topology dependent quantities at the anderson transition

The boundary condition dependence of the critical behavior for the three dimensional Anderson transition is investigated. A strong dependence of the scaling function and the critical conductance distribution on the boundary conditions is found, while the critical disorder and critical exponent are found to be independent of the boundary conditions.

Impaired neurotransmitter systems by Abeta amyloidosis in APPsw transgenic mice overexpressing amyloid beta protein precursor.

APPsw transgenic mice showing substantial features of brain Abeta amyloidosis such as senile plaques and behavioral abnormalities were examined by immunostaining to determine whether Abeta deposits could induce the subsequent disturbance of neurotransmitter systems including somatostatin, substance P and choline acetyltransferase (ChAT), which are prominent in the Alzheimer's disease brain. Somatostatin, substance P and ChAT disappeared in the areas of senile plaque and were accumulated in dystrophic neurites around the amyloid cores. These findings suggest a potential role of brain Abeta amyloidosis in disturbance of the neurotransmitter systems leading to memory disturbance of Alzheimer's disease.