Multisensory perception of the six basic emotions is modulated by attentional instruction and unattended modality.

Previous studies have shown that the perception of facial and vocal affective expressions interacts with each other. Facial expressions usually dominate vocal expressions when we perceive the emotions of face-voice stimuli. In most of these studies, participants were instructed to pay attention to the face or voice. Few studies compared the perceived emotions with and without specific instructions regarding the modality to which attention should be directed. Also, these studies used combinations of the face and voice which expresses two opposing emotions, which limits the generalizability of the findings. The purpose of this study is to examine whether the emotion perception is modulated by instructions to pay attention to the face or voice using the six basic emotions. Also we examine the modality dominance between the face and voice for each emotion category. Before the experiment, we recorded faces and voices which expresses the six basic emotions and orthogonally combined these faces and voices. Consequently, the emotional valence of visual and auditory information was either congruent or incongruent. In the experiment, there were unisensory and multisensory sessions. The multisensory session was divided into three blocks according to whether an instruction was given to pay attention to a given modality (face attention, voice attention, and no instruction). Participants judged whether the speaker expressed happiness, sadness, anger, fear, disgust, or surprise. Our results revealed that instructions to pay attention to one modality and congruency of the emotions between modalities modulated the modality dominance, and the modality dominance is differed for each emotion category. In particular, the modality dominance for anger changed according to each instruction. Analyses also revealed that the modality dominance suggested by the congruency effect can be explained in terms of the facilitation effect and the interference effect.

Efficacy of low-dose rosuvastatin in patients with type 2 diabetes and hypo high-density lipoprotein cholesterolaemia.

OBJECTIVE: To analyse the efficacy of low-dose rosuvastatin for treating hypo high-density lipoprotein (HDL) cholesterolaemia in patients with type 2 diabetes and dyslipidaemia. METHODS: Patients with HDL-cholesterol (C) < 40 mg/dl and triglycerides (TG) < 400 mg/dl who were receiving treatment with lipid-lowering drugs other than rosuvastatin (or previously untreated with lipid-lowering drugs) and with low-density lipoprotein [LDL]-C ≥ 120 mg/dl were included. Patients were treated with 2.5 or 5 mg rosuvastatin orally, once daily, to achieve the target LDL-C level specified in Japanese guidelines. Changes in total cholesterol, HDL-C, TG, LDL-C, LDL-C/HDL-C and non-HDL-C at 3 and 6 months were prospectively analysed. Safety was evaluated by examining changes in hepatorenal function, glucose metabolism and creatine kinase. RESULTS: Out of 49 patients, all lipid parameters other than TG were significantly improved at 3 and 6 months. At 3 months, 83.3% of patients had achieved the target LDL-C level. Among nonlipid parameters, no changes were observed except for estimated glomerular filtration rate, which was improved by + 5.2% and + 9.6% at 3 and 6 months, respectively. CONCLUSIONS: Low-dose rosuvastatin was effective in improving hypo-HDL cholesterolaemia and may have renoprotective effects.

Increased expression of drug-metabolizing enzymes in human hepatocarcinoma FLC-4 cells cultured on micro-space cell culture plates.

Human hepatocellular carcinoma cell lines cultured in a monolayer show negligible activities of drug-metabolizing enzymes such as cytochrome P450s (CYPs) and UDP-glucuronosyltransferases (UGTs). Here, we show that culture of human hepatocellular carcinoma FLC-4 cells on 24-well plates arrayed with uniform micro-sized compartments on the bottom of the plates (micro-space cell culture plates) resulted in increased expression of drug-metabolizing enzymes (CYP1A2, CYP2C9, CYP3A4, UGT1A1, etc.) and nuclear receptors (pregnane X receptor, constitutive androstane receptor, etc.). When cells were treated with a typical CYP3A substrate (triazolam), CYP2C9 substrate (diclofenac) or UGT1A1 substrate (SN-38), large amounts of their metabolites were detected in the medium of cells cultured on micro-space cell culture plates. The formation of metabolites from triazolam, diclofenac and SN-38 was strongly inhibited by co-treatment with a CYP3A inhibitor (ketoconazole), CYP2C9 inhibitor (sulfaphenazole) and UGT1A1 inhibitor (ketoconazole), respectively. On the other hand, formation of metabolites was not observed in the medium of cells cultured in a monolayer. Finally, the cytotoxic effect of aflatoxin B1 was more potent in cells cultured on micro-space cell culture plates than in cells cultured in a monolayer. The results suggest that FLC-4 cells cultured on micro-space cell culture plates are useful for studying drug metabolism and drug-induced hepatotoxicity.

Ligand-dependent assembly of pregnane X receptor, constitutive androstane receptor and liver X receptor is applicable to identify ligands.

Pregnane X receptor (PXR), constitutive androstane receptor (CAR) and liver X receptor (LXR) are intracellular sensors for foreign chemicals and/or endogenous compounds. Docking of a ligand into the ligand-binding domain (LBD) of a nuclear receptor induces conformational changes and switches the nuclear receptor into an active conformation. In this study, we examined whether assembly assays to exploit the ligand-dependent interaction of N- and C-terminal regions of the LBD could be used for detection of ligands for PXR, CAR and LXR. Rifampicin, CITCO and T1317 significantly enhanced interactions for human PXR, human CAR and human LXR, respectively. The effects of ligands on the interaction of LBDs in PXR and CAR reflected the species differences in ligand response of PXR and CAR. In conclusion, it appears that the present assay, which exploits the interaction between N- and C-terminal regions of LBDs, is applicable to identify ligands.

Hypokalemia, diabetes mellitus, and hypercortisolemia are the major contributing factors to cardiac dysfunction in adrenal Cushing's syndrome.

Although cardiovascular complications are the major determinant of the prognosis of Cushing's syndrome (CS), factors contributing to the cardiovascular lesions are still unclear. We investigated clinical factors determining cardiac function in patients with adrenal CS. Fifty patients with adrenal CS were studied. Patients were divided into 3 groups based on their NYHA classification and electrocardiographic (ECG) findings: group A with NYHA grade 0 and normal ECG, group B with NYHA grade I and abnormal ECG, and group C with NYHA grade II or higher. Clinical and echocardiographic findings were compared between the groups. Heart failure of grade I or higher was seen in 40% and grade II or higher was seen in 8% of the patients. Age, HbA1c, and prevalence of diabetes mellitus were positively correlated and serum potassium levels were negatively correlated with the severity of cardiac dysfunction. Decreased ejection fraction (EF) and the ratio of the peak to late transmittal filling velocities (E/A), and increased left ventricular mass index (LVMI) were frequently observed. Multivariate analysis demonstrated that serum potassium and HbA1c levels were independent factors contributing to EF, while serum potassium and cortisol levels were independent factors contributing to LVMI. These results clearly demonstrated that hypokalemia, diabetes mellitus, and hypercortisolemia are the major contributing factors to cardiac dysfunction in adrenal CS. Strict control of these conditions is warranted for the prevention of cardiac dysfunction in adrenal CS.

Cardiovascular risks and their long-term clinical outcome in patients with subclinical Cushing's syndrome.

Although subclinical Cushing's syndrome has been commonly experienced, details of the clinical outcome and its indication for adrenalectomy have yet to be established. In the present study, we investigated the prevalence of cardiovascular risks, their clinical outcome during long-term follow up before and after adrenalectomy in 20 patients with subclinical Cushing's syndrome. We also correlated the hypercortisolism and age with the cardiovascular risks and the clinical outcome. The prevalence of hypertension, impaired glucose metabolism, dyslipidemia, and obesity was 45%, 65%, 65%, and 25%, respectively. In the non-operated group (n = 12), six patients (50%) showed deterioration of at least one of the cardiovascular risks. Four patients showed an increase of at least one risk, while none of the patients showed a decrease in the number of risks. One patient developed overt Cushing's syndrome. In the operated group (n = 10) including two operated patients of the non-operated group, eight patients (80%) showed an improvement of at least one of the cardiovascular risks after surgery and five patients (50%) showed a decrease of at least one risk. The prognosis in terms of the changes of the cardiovascular risks was significantly better in the operated group than in the non-operated group (p<0.001). Neither the hypercortisolism nor age correlated to the presence and the clinical outcome of the cardiovascular risks. The present study clearly demonstrated probability of deterioration during the clinical course and improvement after adrenal surgery in patients with subclinical Cushing's syndrome. Careful follow-up of the cardiovascular risks is therefore warranted. Adrenalectomy could be a treatment of choice despite the hypercortisolism and age of the patients, especially when the cardiovascular risks show signs of deterioration.

Ampulla cardiomyopathy after hypoglycemia in three young female patients with anorexia nervosa.

Ampulla cardiomyopathy is named after the echocardiographic abnormalities occurring in this condition, characterized by extensive akinesis (ballooning ) of the apical region with hypercontraction of the basal segment of the ventricle. We describe 3 young female anorexia nervosa patients showing evidence of this cardiac complication after hypoglycemia. One case was complicated by echocardiographically confirmed ampulla cardiomyopathy while the other 2 patients showed increases in myocardial enzymes and transient electrocardiographic abnormalities consistent with this complication. The precipitating event for all three patients was hypoglycemic coma, and this is the first case report in which this factor lead to the complication of ampulla cardiomyopathy in anorexia nervosa patients.

[Aldosterone].

Aldosterone is one the representative cardiovascular hormones involved in the blood pressure and body-fluid homeostasis. Elevation of aldosterone leads to systemic hypertension through its action on the mineralocorticoid receptor (MR) in the kidney. More recent studies demonstrated that aldosterone may produce target organ damage through its direct actions on the non-epithelial MR of the heart in addition to its systemic effects. Clinical experience in primary aldosteronism supports the concept that aldosterone is a risk factor of cardiovascular complications, since concentric type of cardiac hypertrophy is most common in primary aldosteronism among various types of endocrine hypertension. Clinical mega-trial in congestive heart failure (RALES study, EPHESUS study) demonstrated blocking angiotensin II action is not sufficient for cardioprotection unless aldosterone action is equally blocked. An important phenomenon related to this issue is the aldosterone breakthrough which implies a reelevation of plasma aldosterone during chronic administration of ACE inhibitors and Angiotensin receptor antagonists. Normal level of aldosterone could still be a risk factor. Combination of ACE inhibitor or ARB with aldosterone antagonist could result in a better cardioprotection in cardiovascular diseases. Although spironolactone has been the only one aldosterone antagonist, a new antagonist eplerenone has been developed. Eplerenone is specific to MR and is practically devoid of the major side effect gynecomastia of spironolactone. Another topic of aldosterone is its very quick cardiovascular effect presumably via a non-genomic action. All these recent findings support that this adrenocortical steroid hormone is as important as angiotensin II. Determining aldosterone levels is therefore much morel important than before in the diagnosis and treatment of cardiovascular diseases.

The diagnostic standard of preclinical Cushing's syndrome: evaluation of the dexamethasone suppression test using various cortisol kits.

Incidental discovery of an adrenal mass, the so-called adrenal incidentaloma, has been increasing due to the advances in non-invasive diagnostic imaging tools. The criteria of diagnosis for preclinical Cushing's syndrome (preCS) in Japan were made by Nawata et al. supported by the Ministry of Health and Welfare in 1995. The results of suppression of cortisol by dexamethasone (DEX) (plasma cortisol above 3 microg/dl after 1 mg of DEX and above 1 microg/dl after 8 mg of DEX) are essential for the diagnosis of preCS due to an adrenal adenoma. However, plasma cortisol levels after the two doses of DEX suppression tests were found to be discrepant and repeated DEX suppression tests sometimes yielded different results. Therefore, we examined the cortisol values of DEX suppression tests in patients with preCS using four different cortisol assay kits: Amerlex cortisol kit (AMA), SPAC-S cortisol kit (SPA), ADVIA-Centaur cortisol assay (ADV) and ECLusys 2010 cortisol assay (ECL). The diagnosis for preCS was done using the AMA kit. Correlation between the kits was good. However, cortisol levels measured by SPA, ADV and ECL were lower than those measured by AMA. In the 1 mg DEX test, the cortisol levels measured with the SPA, ADV and ECL kits were suppressed in 2 patients with preCS. With 8 mg of DEX, cortisol levels measured with the SPA and ADV kits were suppressed in 2 patients with preCS. The diagnosis of preCS is decided by the cortisol kit used, but the cortisol levels differ among the kits. It is suggested that the lack of the standardization of cortisol measurement is one of the causes of confusion in the diagnosis of preCS.

Two young female patients with anorexia nervosa complicated by Mycobacterium tuberculosis infection.

Patients with anorexia nervosa (AN) seldom present with infectious illness, despite malnutrition-induced immunodeficiency. We described two young women who had a long-standing history of severe emaciation and pulmonary or lymph node tuberculosis discovered during the treatment of AN. Both patients reported a positive history of BCG vaccination. Contact tracing failed to reveal sources of infection, although the tuberculosis was considered transferred. Since the decline of notification rates for tuberculosis have been stagnant and outbreaks in schools or hospitals have been increasing in Japan, special attention must be given to the possibility of opportunistic infections in AN patients.

Effects of AT1 receptor antagonist and spironolactone on cardiac expression of ET-1 mRNA in SHR-SP/Izm.

Angiotensin II stimulates and angiotensin-converting enzyme inhibitor decreases endothelin-1 expression. Effects of the angiotensin-type 1 antagonist (angiotensin receptor blocker) on tissue expression of endothelin-1 in hypertension remained unknown. We investigated the effects of angiotensin-type 1 antagonist with and without co-administration of the aldosterone receptor antagonist spironolactone on cardiac expression of endothelin-1 mRNA. Angiotensin receptor blocker (candesartan, 1.0 mg/kg per day) was orally administered to male spontaneously hypertensive stroke-prone rats/Izm from 4 weeks of age for 4 weeks, 12 weeks and 28 weeks (angiotensin receptor blocker group). Lowdose spironolactone (10 mg/kg per day, s.c.), which does not affect blood pressure, was co-administered with angiotensin-type 1 antagonist for 28 weeks (angiotensin-type 1 antagonist + spironolactone group). Cardiac expression of endothelin-1 mRNA was determined. In the angiotensin receptor blocker group, although cardiac expression of endothelin-1 mRNA was significantly decreased after 4 weeks of treatment, it was significantly increased after 12 weeks and 28 weeks of treatment. In the angiotensin receptor blocker + spironolactone group, while systolic blood pressure did not show a further decrease from that in the angiotensin receptor blocker group, cardiac expression of endothelin-1 mRNA was decreased to the level in the untreated group. These results suggest that effects on endothelin-1 expression could modify the cardioprotective effects of angiotensin receptor blocker. Coadministration of angiotensin receptor blocker with low-dose spironolactone is recommended for further cardioprotection via suppression of endothelin-1 expression.

Variability in the renin/aldosterone profile under random and standardized sampling conditions in primary aldosteronism.

An increased plasma aldosterone concentration (PAC) with decreased plasma renin activity (PRA) is the abnormal endocrine finding in primary aldosteronism (PA). However, it remains unknown whether this profile is universal when blood samples are obtained in a random manner. We retrospectively evaluated the renin/aldosterone profile in 71 patients with PA due to unilateral adrenal adenoma. Blood samples were obtained randomly at an out-patient clinic and under standardized conditions during hospitalization before surgery. The frequency of PAC above 15 ng/dl, PRA below 0.5 ng angiotensin I/ml x h, and a PAC/PRA ratio greater than 35 was determined. These three variables showed a large intra- and interpatient variation. At least one measurement of PAC, PRA, and PAC/PRA ratio was in the normal range in 39%, 48%, and 31% of patients, respectively. Only 37% of patients always had the characteristic profile associated with PA. The mean values of PAC at the out-patient clinic were slightly, but significantly, lower than those in the hospital. These results clearly demonstrated that the renin/aldosterone profile in PA is not always abnormal due in part to conditions for blood sampling. We conclude that a single normal PAC, PRA, or PAC/PRA ratio does not excluded the diagnosis of PA in a hypertensive patient, but repeated measurements yields one or more abnormal parameters in the vast majority of patients. The PAC/PRA ratio is recommended to use as a screening, but other testing is required to arrive at the correct diagnosis.

GABAergic input contributes to activity-dependent change in cell volume in the hippocampal CA1 region.

Swelling of brain cells is one of the physiological responses associated with neuronal activation. To investigate underlying mechanisms, we analyzed interactions between changes in cell volume and synaptic responses in the hippocampal slices from rodents. Swelling within the CA1 area was detected as increases in transmittance of near-infrared light (IR), and field excitatory postsynaptic potentials (fEPSPs) were recorded simultaneously. High frequency stimulation (HFS) of afferent fibers induced a transient increase in IR transmittance in both somatic and dendritic regions, which was temporally associated with fEPSPs. Stimulus-induced increases in transmittance were strongly reduced in the presence of DL-2-amino-5-phosphonovaleric acid and 6-cyano-7-nitroquinoxaline-2,3-dione, indicating involvement of glutamate receptors. Application of a GABA-A receptor antagonist, bicuculline, increased the amplitude and time course of the fEPSPs but rather decreased HFS-induced optical signals. When the extracellular Cl(-) was reduced to 10.5 mM, HFS induced a decrease in transmittance, which was also blocked by bicuculline. In hippocampal slices obtained from mice deficient in the 65 kDa isoform of glutamic acid decarboxylase, HFS-induced signals were significantly smaller than in the wild-type mice, although fEPSP profiles did not differ. These results suggest that Cl(-) influx through GABA-A receptors contributes to synaptically evoked swelling in the hippocampal CA1 region.

[Significance of combining spironolactone during long-term administration of ARB].

Blocking aldosterone action has been of clinical interest in the treatment of hypertension and related target organ damage. Although we have previously demonstrated aldosterone escape during long term administration of AT1 antagonist, pathological significance of aldosterone remains unknown. We investigated the effects of co-administration of spironolactone(SPRL) on the cardioprotective effects of AT1A in SHR-SP. Administration of AT1A alone resulted in a significant decrease in cardiac weight, cardiac transverse section area, cardiac fibrosis, and mRNA expression of BNP, type I and type III collagen, while cardiac ET-1 mRNA showed a significant increase. Co-administration of AT1A with SPRL resulted in a significant decrease in all the parameters including ET-1 mRNA expression. These results provide theoretical rationale for combination therapy of AT1A and SPRL in hypertension.

Aldosterone breakthrough during angiotensin II receptor antagonist therapy in stroke-prone spontaneously hypertensive rats.

Aldosterone breakthrough during ACE inhibitor therapy has been reported. This study investigates changes in plasma aldosterone concentration (PAC) and its mechanism and effects on target organ damage during long-term angiotensin II type 1 (AT1) receptor antagonist (AT1A) therapy in hypertensive rats. An AT1A (candesartan, 1 mg/kg per day PO) was administered in stroke-prone spontaneously hypertensive rats from 4 weeks of age for 34 weeks. PAC was significantly decreased during the first 4 weeks but showed aldosterone breakthrough after 8 weeks of AT1A administration. Plasma angiotensin II concentration was significantly elevated, whereas no change was seen in plasma ACTH or serum potassium. The mechanism(s) of aldosterone breakthrough were investigated by giving high doses of candesartan (3 mg/kg per day PO), dexamethasone (200 microg/kg per day IP), or the AT2 antagonist (PD123319, 10 mg/kg per day SC) during the last week of the 24-week AT1A treatment period. Dexamethasone and AT2 antagonist but not high-dose AT1A produced a significant decrease in PAC, with a larger decrease produced by the AT2 antagonist. To clarify the effects of the residual aldosterone, effects of coadministration of low-dose spironolactone (10 mg/kg per day SC), an aldosterone antagonist, on left ventricular hypertrophy and expression of brain natriuretic peptide mRNA were determined. Low-dose spironolactone further improved left ventricular hypertrophy and brain natriuretic peptide mRNA expression despite no additional depressor effect. These results suggest that aldosterone breakthrough occurs during long-term AT1A therapy, mainly by an AT2-dependent mechanism. Residual aldosterone may attenuate the cardioprotective effects of AT1A.

Propylthiouracil-induced lupus-like syndrome developing in a Graves' patient with a sibling with systemic lupus erythematosus.

A 13-year-old girl with Graves' disease, whose younger sister had systemic lupus erythematosus, developed polyarthralgia, fever, neutropenia, hypergammaglobulinemia, and microscopic hematuria after treatment with propylthiouracil (PTU) for 2 years. Myeloperoxidase-anti-neutrophil cytoplasmic antibodies were strongly positive. Anti-single- and anti-double-stranded DNA antibodies were positive, whereas LE cells and anti-Sm antibodies were negative. PTU was discontinued and all symptoms subsided gradually. Two years later, the microscopic hematuria had disappeared completely. Both patients had the identical HLA-DR alleles (HLA-DR9). These present two cases in siblings suggest that both sisters had lupus diathesis, and that the elder sister developed a PTU-induced lupus-like syndrome.