High-resolution CT findings of primary lung cancer with cavitation: a comparison between adenocarcinoma and squamous cell carcinoma.

AIM: To evaluate the high-resolution computed tomography (CT) findings of primary lung cancer with cavitation and compare the findings in adenocarcinoma and squamous cell carcinoma. MATERIALS AND METHODS: The high-resolution CT findings of tumours with cavitation were retrospectively evaluated in 60 patients. Forty-seven of the lesions were diagnosed as adenocarcinomas; 13 were diagnosed as squamous cell carcinomas. The diameters of the tumour and cavity, the maximum thickness of the cavity wall, shape of the cavity wall, the number of cavities, and the presence of ground-glass opacity, bronchial obstruction, intratumoural bronchiectasis, emphysema, and honeycombing were evaluated. The mechanisms of cavity formation were examined according to the pathological features. RESULTS: The maximum thickness of the cavity wall was significantly greater in squamous cell carcinomas than in adenocarcinomas (p=0.002). Ground-glass opacity and intratumoural bronchiectasis were significantly more common in adenocarcinomas than in squamous cell carcinomas (p<0.001 and p=0.040, respectively). Regarding the pathological findings, intratumoural bronchiectasis with or without alveolar wall destruction contributed to a significant difference between adenocarcinoma and squamous cell carcinoma (p<0.001; odds ratio [OR], 20.35; 95% confidence interval [CI], 3.87-107.10). CONCLUSION: The cavity wall tends to be thicker in squamous cell carcinomas than in adenocarcinomas. The presence of ground-glass opacity and intratumoural bronchiectasis is strongly suggestive of adenocarcinoma.

SADS: A new component of Fas-DISC is the accelerator for cell death signaling and is downregulated in patients with colon carcinoma.

Fas is the death receptor, transducing cell death signaling upon stimulation by Fas ligand. During Fas-initiated cell death signaling, the formation of Fas-death inducing signaling complex (Fas-DISC) is the first step. Here we have identified a new component of Fas-DISC which we call 'small-accelerator for death signaling' (SADS). SADS cDNA encodes a 150 amino acid polypeptide (Mr = 16,700). During Fas-mediated cell death, SADS enhances the interaction of Fas-death domain-interactive factors (FADD) and procaspase-8, and deletion mutant analysis has identified FADD- and caspase-8-interactive domains in SADS. Inhibition or removal of SADS delays Fas-mediated cell death. In addition, we demonstrate the deletion or mutation of SADS in patients with colon carcinoma and that exogenous SADS expression in human colon carcinoma SW480 cells that lack SADS leads to re-acquisition of Fas-mediated cell death. Here, we propose that SADS is one of the cell death-associated factors and enhances Fas-DISC formation, especially FADD and procaspase-8 recruitment.

Anaesthesia for a patient with paraneoplastic limbic encephalitis with ovarian teratoma: relationship to anti-N-methyl-D-aspartate receptor antibodies.

Paraneoplastic limbic encephalitis associated with ovarian teratoma has recently been related to the development of antibodies to specific heteromers of the N-methyl-d-aspartate receptor and exhibits various manifestations including psychiatric symptoms, hypoventilation, seizures and derangement of autonomic nervous system function. Although recovery can sometimes occur spontaneously, early tumour resection with immunotherapy facilitates earlier recovery. Herein, we describe anaesthetic management of a 20-year-old woman who developed general convulsions and decreased level of consciousness, whom we suspected of having paraneoplastic limbic encephalitis and was scheduled for left ovarian tumour resection. Anaesthetic management was successful with no complications but the case acts as focus of discussion for the potential interaction of N-methyl-D-aspartate receptors and anaesthetic sensitivity.

Usefulness of an artificial neural network for a beginner to achieve similar interpretations to an expert when examining myocardial perfusion images.

This study examined whether using an artificial neural network (ANN) helps beginners in diagnostic cardiac imaging to achieve similar results to experts when interpreting stress myocardial perfusion imaging (MPI). One hundred and thirty-eight patients underwent stress MPI with Tc-labeled agents. An expert and a beginner interpreted stress/rest MPI with or without the ANN and the results were compared. The myocardium was divided into 5 regions (the apex; septum; anterior; lateral, and inferior regions), and the defect score of myocardial blood flow was evaluated from 0 to 4, and SSS, SRS, and SDS were calculated. The ANN effect, defined as the difference in each of these scores between with and without the ANN, was calculated to investigate the influence of ANN on the interpreters' performance. We classified 2 groups (insignificant perfusion group and significant perfusion group) and compared them. In the same way, classified 2 groups (insignificant ischemia group and significant ischemia group) and compared them. Besides, we classified 2 groups (normal vessels group and multi-vessels group) and compared them. The ANN effect was smaller for the expert than for the beginner. Besides, the ANN effect for insignificant perfusion group, insignificant ischemia group and multi-vessels group were smaller for the expert than for the beginner. On the other hand, the ANN effect for significant perfusion group, significant ischemia group and normal vessels group were no significant. When interpreting MPI, beginners may achieve similar results to experts by using an ANN. Thus, interpreting MPI with ANN may be useful for beginners. Furthermore, when beginners interpret insignificant perfusion group, insignificant ischemia group and multi-vessel group, beginners may achieve similar results to experts by using an ANN.

Chronic expanding hematoma in combination with a pseudoaneurysm: a case report.

After bleeding from trauma or surgery, most of the hematomas undergo spontaneous reabsorption. But, in some rare cases, hematomas persist for long periods as slowly expanding masses for months or years. These hematomas were termed as chronic expanding hematomas. In this report, we describe a case of chronic expanding hematoma with a pseudoaneurysm that underwent surgical biopsy, which led to an increase in its expansion speed.

Galanin inhibits neural activity in the subfornical organ in rat slice preparation.

The activation of the subfornical organ (SFO), a circumventricular organ, induces water intake and vasopressin release. Since central administrations of galanin (GAL) suppress water intake and vasopressin release, GAL may inhibit the neural activity of SFO neurons. In the present study, we investigated effects of GAL on the SFO using molecular biological, electrophysiological and anatomical techniques. Reverse transcription-polymerase chain reaction analysis demonstrated the presence in the SFO of rats of the mRNAs for each of the three known GAL receptor subtypes (GalR1, GalR2 and GalR3). In extracellular recordings in SFO slice preparations, GAL dose-dependently inhibited the neural activity of cells from a number of recording sites. Many GAL-sensitive SFO neurons showed excitatory responses to angiotensin II (ANGII). The GalR1 agonist M617 inhibited the activity of SFO neurons, whereas the GalR2 and GalR3 agonist GAL(2-11) had almost no effect. In patch-clamp recordings, GAL induced an outward current in SFO neurons without influencing synaptic currents. An immunoelectron microscopic study revealed the existence of GAL-containing synaptic vesicles in the SFO. These results suggest that the SFO has neural inputs involving GAL. The response to GAL is inhibitory, mediated at least in part by GalR1 and provides a plausible explanation for the opposite effects of ANGII and GAL seen in vivo on water intake and vasopressin release.

High incidence of amplification of the epidermal growth factor receptor gene in human squamous carcinoma cell lines.

Southern blot-hybridization analysis of DNAs from human tumors demonstrated amplification of the epidermal growth factor (EGF) receptor gene in 10 of 12 squamous cell carcinoma cell lines tested and in none of 18 tumor cell lines of nonsquamous cell carcinomas. The degree of amplification in the squamous cells varied from 2- to 50-fold relative to the epidermal keratinocyte. Hybridization analysis of the RNA showed that the amplification of the EGF receptor gene is accompanied with an increase of the 5.6 kilobases of EGF receptor mRNA. Scatchard plot analysis and sodium dodecyl sulfate-polyacrylamide gel analysis of the EGF receptor revealed that the synthesis of the EGF receptor is also greater in the cells with amplified EGF receptor gene. In contrast, Southern blot analysis of DNAs of primary tumors showed that incidence of amplification of the EGF receptor gene in squamous cells (1 of 6) was almost as frequent as in nonsquamous cells (1 of 4). These results show that amplification of the EGF receptor gene is commonly found in various tumors. In addition, our data suggest that primary squamous cell carcinomas with amplified EGF receptor gene may readily adapt to growth in tissue culture.

Survivin initiates cell cycle entry by the competitive interaction with Cdk4/p16(INK4a) and Cdk2/cyclin E complex activation.

Survivin is observed uniquely in tumor cells and developmental cells, which undergo either inappropriate or programmed cell growth. In the current study, we investigated the influence of Survivin on cell cycle. Overexpression of Survivin resulted in accelerated S phase shift, resistance to G1 arrest, and activated Cdk2/Cyclin E complex leading Rb phosphorylation. In addition, nuclear translocation of Survivin followed by an interaction with Cdk4 was detected. Interestingly, Survivin nuclear translocation coincided with S phase shift, and prevention of nuclear transport suppressed Survivin nuclear translocation and S phase shift. Further, we also observed that Survivin competitively interacted with the Cdk4/p16(INK4a) complex in a cell free system and in vivo. These results suggest that Survivin initiates the cell cycle entry as a result of nuclear translocation followed by an interaction with Cdk4.

Survivin initiates procaspase 3/p21 complex formation as a result of interaction with Cdk4 to resist Fas-mediated cell death.

Caspase 3 is an essential death factor for the Fas-mediated cell death, and its inactivation in cells is initiated by an interaction with p21 on mitochondria or with IAP family member ILP. Survivin is also a member of IAP family and is specifically expressed during embryogenesis and in tumor cells and suppresses cell death signaling. In our current study, we demonstrated that Survivin translocation into the nucleus is dependent on Fas stimulation and cell proliferation. Survivin also interacts with the cell cycle regulator Cdk4, leading to Cdk2/Cyclin E activation and Rb phosphorylation. As a result of Survivin/Cdk4 complex formation, p21 is released from its complex with Cdk4 and interacts with mitochondrial procaspase 3 to suppress Fas-mediated cell death. Here, we propose that Survivin supports procaspase 3/p21 complex formation as a result of interaction with Cdk4 resulting in suppression of cell death signaling.

Galectin-1 regulates initial axonal growth in peripheral nerves after axotomy.

The signals that prompt the axons to send out processes in peripheral nerves after axotomy are not well understood. Here, we report that galectin-1 can play an important role in this initial stage. We developed an in vitro nerve regeneration model that allows us to monitor the initial axon and support cell outgrowth from the proximal nerve stump, which is comparable to the initial stages of nerve repair. We isolated a factor secreted from COS1 cells that enhanced axonal regeneration, and we identified the factor as galectin-1. Recombinant human galectin-1 (rhGAL-1) showed the same activity at low concentrations (50 pg/ml) that are two orders of magnitude lower than those of lectin activity. A similarly low concentration was also effective in in vivo experiments of axonal regeneration with migrating reactive Schwann cells to a grafted silicone tube after transection of adult rat peripheral nerve. Moreover, the application of functional anti-rhGAL-1 antibody strongly inhibited the regeneration in vivo as well as in vitro. The same effect of rhGAL-1 was confirmed in crush/freeze experiments of the adult mouse sciatic nerve. Because galectin-1 is expressed in the regenerating sciatic nerves as well as in both sensory neurons and motor neurons, we suggest that galectin-1 may regulate initial repair after axotomy. This high activity of the factor applied under nonreducing conditions suggests that galectin-1 may work as a cytokine, not as a lectin.

Effects of combination of ACE inhibitor and angiotensin receptor blocker on cardiac remodeling, cardiac function, and survival in rat heart failure.

BACKGROUND: The mechanism and treatment of diastolic heart failure are poorly understood. We compared the effects of an ACE inhibitor, an angiotensin receptor blocker (ARB), and their combination on diastolic heart failure in Dahl salt-sensitive (DS) rats. METHODS AND RESULTS: DS rats fed an 8% NaCl diet from 7 weeks of age were treated with benazepril 10 mg/kg alone, valsartan 30 mg/kg alone, or combined benazepril and valsartan at 5 and 15 mg/kg, respectively, or at 1 and 3 mg/kg, respectively. At 16 weeks of age, DS rats exhibited prominent concentric left ventricular (LV) hypertrophy and diastolic dysfunction with preserved systolic function, as estimated by echocardiography. Despite comparable hypotensive effects among all drug treatments, the combination of benazepril 5 mg/kg and valsartan 15 mg/kg improved diastolic dysfunction and survival in DS rats more effectively than ACE inhibitor or ARB alone. Furthermore, the increase in LV endothelin-1 levels and hydroxyproline contents in DS rats was significantly suppressed only by combined benazepril and valsartan, and LV atrial natriuretic peptide mRNA upregulation in DS rats was suppressed to a greater extent by the combination therapy than monotherapy. CONCLUSIONS: The combination of ACE inhibitor and ARB, independently of the hypotensive effect, improved LV phenotypic change and increased LV endothelin-1 production and collagen accumulation, diastolic dysfunction, and survival in a rat heart failure model more effectively than either agent alone, thereby providing solid experimental evidence that the combination of these 2 agents is more beneficial than monotherapy for treatment of heart failure.

Angiotensin II has multiple profibrotic effects in human cardiac fibroblasts.

BACKGROUND: Angiotensin II (Ang II) is implicated in cardiac remodeling and is increasingly recognized for its profibrotic activity. METHODS AND RESULTS: Because little is known about the direct cellular effects of Ang II on human cardiac fibroblasts, we isolated fibroblasts from ventricles of explanted human hearts and added Ang II (100 nmol/L) to determine its role in growth, extracellular matrix accumulation, and adhesion. To assess which Ang II receptor is involved, Ang II was added in the presence of irbesartan (10 micromol/L), a specific AT(1) receptor antagonist; PD 123319 (10 micromol/L), a specific AT(2) receptor antagonist, or divalinil (100 nmol/L), an AT(4) receptor inhibitor. In human ventricles (n=13), message levels of atrial natriuretic peptide and AT(1) receptor were inversely correlated, which suggests a decrease in AT(1) receptor expression with progressive heart failure. Northern analysis and fluorescence-activated cell sorting demonstrated AT(1) receptor in cultured human cardiac fibroblasts. Ang II increased mitogen-activated protein kinase activity and in DNA synthesis (5-fold, P<0.01) stimulated a 2-fold increase in transforming growth factor-beta(1) (P<0.05) mRNA levels at 2 hours and a 2-fold increase in laminin (P<0.05) and fibronectin (P<0.05) mRNA levels at 24 hours. Ang II also enhanced plasminogen activator inhibitor-1 expression, which inhibits metalloproteinases that degrade the extracellular matrix. All of these effects were inhibited by irbesartan but not PD 123319 or divalinil. In addition, Ang II increased cardiac fibroblast attachment to collagens I and III, which was associated with an increase in focal adhesion kinase activity. CONCLUSIONS: Activation of the AT(1) receptor in human heart promotes fibrosis. Ang II plays a novel role in stimulation of plasminogen activator inhibitor-1 expression and adhesion of cardiac fibroblasts to collagen.

Circulating levels of secretory type II phospholipase A(2) predict coronary events in patients with coronary artery disease.

Background-The circulating levels of secretory nonpancreatic type II phospholipase A(2) (sPLA(2)) are increased in various chronic inflammatory diseases and the increase in the levels correlates with the disease severity. sPLA(2) may possibly play a role in atherogenesis and is highly expressed in atherosclerotic arterial walls that are known to have inflammatory features. Thus, this study prospectively examined whether circulating levels of sPLA(2) may have a significant risk and prognostic values in patients with coronary artery disease (CAD). Methods and Results-Plasma levels of sPLA(2) were measured in 142 patients with CAD and in 93 control subjects by a radioimmunoassay. The sPLA(2) levels had a significant and positive relations with serum levels of C-reactive protein, a marker of systemic inflammation, and with the number of the traditional coronary risk factors associated with individuals. Multivariate logistic regression analysis showed that higher levels of sPLA(2) (>246 ng/dL; 75th percentile of sPLA(2) distribution in controls) were a significant and independent risk factor for the presence of CAD. In multivariate Cox hazard analysis, the higher levels of sPLA(2) were a significant predictor of developing coronary events (ie, coronary revascularization, myocardial infarction, coronary death) during a 2-year follow-up period in patients with CAD independent of other risk factors, including CRP levels, an established inflammatory predictor. Conclusions-The increase in circulating levels of sPLA(2) is a significant risk factor for the presence of CAD and predicts clinical coronary events independent of other risk factors in patients with CAD; these results may reflect possible relation of sPLA(2) levels with inflammatory activity in atherosclerotic arteries.

Remnant lipoprotein levels in fasting serum predict coronary events in patients with coronary artery disease.

BACKGROUND: Remnant lipoproteins are atherogenic, but assays of remnants have not been available in routine clinical laboratories because of the lack of practical and validated methods. A simple and reliable method for such an assay, using an immunochemical approach, has recently been developed. This study prospectively examined whether remnant lipoprotein levels in fasting serum, measured by our method, may have prognostic value in patients with coronary artery disease (CAD). METHODS AND RESULTS: Remnant lipoprotein levels in fasting serum were measured in 135 patients with CAD by an immunoaffinity mixed gel containing anti-apolipoprotein (apo) A-1 and anti-apoB-100 monoclonal antibodies. Patients were followed up for 5.1 mg cholesterol/dL; 75th percentile of distribution of remnant levels) than in those with the lowest tertile of remnant levels (

Procaspase 3/p21 complex formation to resist fas-mediated cell death is initiated as a result of the phosphorylation of p21 by protein kinase A.

Caspase 3 is an essential factor for Fas-mediated cell death and exists endogenously in cells where its activation is suppressed by p21 and ILP. Inside the cell, procaspase 3 interacts with p21 on mitochondria. In the present study, we investigated the molecular basis for procaspase 3/p21 complex formation. During Fas-mediated cell death, mitochondria are damaged, accompanied by decreased mitochondrial membrane-potential and decreased intracellular ATP levels. This mitochondrial damage occurs before an estrangement of the procaspase 3/p21 complex, and we demonstrate that intracellular ATP-deprivation also initiates an estrangement of procaspase 3/p21 complex formation and accelerates Fas-mediated cell death. In addition, our current results revealed that the phosphorylated p21 by PKA interacts with procaspase 3. Here, we report that the mitochondrial role, especially for ATP synthesis, and PKA are necessary for the procaspase 3/p21 complex formation to resist Fas-mediated cell death.

Estradiol supplementation suppresses hyperventilation-induced attacks in postmenopausal women with variant angina.

OBJECTIVES: We sought to examine whether estradiol (E2) supplementation suppresses anginal attacks in women with variant angina. BACKGROUND: Estrogen is known to improve endothelial function. Coronary spasm plays an important role in the pathogenesis of not only variant angina but also ischemic heart disease in general, and endothelial dysfunction seems to be involved in the pathogenesis of coronary spasm. METHODS: Fifteen postmenopausal women with variant angina (mean age 54.2 years) were given a hyperventilation (HV) test, a provocation test for coronary spasm, in the early morning of day 1 (baseline), day 3 (after 2-day transdermal E2 supplementation, 4 mg) and day 5 (after 2-day placebo administration). We measured the flow-mediated (endothelium-dependent) dilation (FMD) of the brachial artery with the ultrasound technique before each HV test. RESULTS: The anginal attacks with ST segment elevation were induced by HV in all patients on days 1 and 5. However, no attacks were induced on day 3. Supplementation with E2 augmented FMD (3.5 +/- 0.6*, 8.9 +/- 0.7 and 4.0 +/- 0.5* on days 1, 3 and 5, respectively; *p < 0.01 vs. day 3). The serum E2 levels on days 1, 3 and 5 were 22.7 +/- 2.8*, 96.2 +/- 9.2 and 30.7 +/- 7.1* pg/ml, respectively (*p < 0.01 vs. day 3). CONCLUSIONS: The present results demonstrated for the first time, to our knowledge, that E2 supplementation suppresses the HV-induced attacks in women with variant angina, in part because of the improvement of endothelial function.

Improvement of endothelial function and insulin sensitivity with vitamin C in patients with coronary spastic angina: possible role of reactive oxygen species.

OBJECTIVES: This study was designed to examine the effect of antioxidant supplementation on the endothelial function and insulin sensitivity in patients with coronary spastic angina (CSA). BACKGROUND: Insulin resistance may play a key role in coronary heart disease, and there is a possible link between acetylcholine-induced coronary vasoconstriction and hyperinsulinemia in patients with CSA. Endothelial dysfunction is present in the systemic arteries in CSA patients, and reactive oxygen species may cause inactivation of nitric oxide in these patients. METHODS: We measured flow-mediated dilation of the brachial artery using ultrasound technique in 22 patients with CSA and 20 control subjects. We also evaluated glucose tolerance using a 75-g oral glucose tolerance test and insulin sensitivity using steady-state plasma glucose (SSPG) methods in the same patients. RESULTS: The incidence of impaired glucose tolerance was higher in the CSA group than in the control group. Vitamin C infusion augmented flow-mediated dilation and decreased SSPG levels in the CSA group (from 3.27 +/- 0.77% to 7.00 +/- 0.59% [p < 0.001 by analysis of variance (ANOVA)] and from 177.3 +/- 13.3 to 143.1 +/- 14.9 mg/dl [p = 0.047 by ANOVA], respectively) but not in the control group (from 6.47 +/- 0.66% to 6.80 +/- 0.60% and from 119.8 +/- 11.7 mg/dl to 118.1 +/- 11.3 mg/dl, respectively). The steady-state plasma insulin levels were not affected by vitamin C infusion in either group. CONCLUSIONS: Vitamin C improves both endothelial function and insulin sensitivity in patients with CSA. Thus, reactive oxygen species and/or decreased nitric oxide bioactivity may play an important role in the genesis of both endothelial dysfunction and insulin resistance in patients with CSA.

Deficiency in nitric oxide bioactivity in epicardial coronary arteries of cigarette smokers.

OBJECTIVES: This study sought to examine nitric oxide-mediated regulation of epicardial coronary arterial tone in cigarette smokers. BACKGROUND: Cigarette smoking is a major risk factor for coronary artery disease and is highly prevalent in patients with coronary spastic angina. Long-term exposure to cigarette smoking has been recently reported to suppress endothelium-dependent arterial relaxation in vivo humans. METHODS: Responses of epicardial coronary artery diameter to single or combined infusion of acetylcholine and NG-monomethyl-L-arginine (L-NMMA) into the left main coronary artery were examined in 11 current smokers and 17 nonsmokers using quantitative coronary angiography. RESULTS: Acetylcholine dilated one-third of the proximal segments and most of the distal segments of coronary arteries in nonsmokers, whereas it constricted most of the proximal and distal segments in smokers. L-NMMA decreased the basal diameter of coronary arteries in nonsmokers but had minimal effect on the basal diameter in smokers. L-NMMA abolished the dilator response to acetylcholine in the coronary arteries of nonsmokers but had minimal effect on the constrictor response to acetylcholine in the arteries of smokers. The dilator response to nitroglycerin was significantly increased in the coronary arteries of smokers compared with in those of nonsmokers. The constrictor response to L-NMMA at rest was significantly correlated with the dilator response to nitroglycerin and with the diameter changes to acetylcholine in both smokers and nonsmokers. CONCLUSIONS: Nitric oxide bioactivity at rest and at acetylcholine-stimulated conditions in smokers was decreased, leading to the supersensitivity of the artery to the dilator effect of nitroglycerin as well as the constrictor effect of acetylcholine in smokers. Cigarette smoking affects nitric oxide-mediated regulation of coronary artery tone.