The ameliorating effects of 5,7-dihydroxy-6-methoxy-2(4-phenoxyphenyl)-4H-chromene-4-one, an oroxylin A derivative, against memory impairment and sensorimotor gating deficit in mice

We previously reported that oroxylin A, a γ-aminobutyric acid A (GABA_A) receptor antagonist, ameliorates drugs-induced memory impairments. We synthesized several oroxylin A derivatives in efforts to find a substance that has pro-cognitive effects as well as improves sensorimotor gating. The aim of the present study is to investigate the effect of a novel oroxylin A derivative, 5,7-dihydroxy-6-methoxy-2(4-phenoxyphenyl)-4H-chromene-4-one (DMPC), on pharmacological models of schizophrenia, which exhibit memory impairment and sensorimotor gating deficit. Memory impairment was induced by scopolamine, a muscarinic receptor antagonist, or MK-801, an N-methyl-d-aspartate receptor antagonist. Sensorimotor gating deficits were induced by MK-801 and measured by prepulse inhibition (PPI) of the acoustic startle response task. DMPC treatment (20 mg/kg) significantly attenuated scopolamine- or MK-801-induced memory impairment and it even enhanced cognitive performance of normal animals. Furthermore, DMPC significantly ameliorated MK-801-induced PPI deficits in the acoustic startle response task. In an in vitro study, DMPC (20 μM) inhibited intracellular Cl^? influx induced by muscimol, a selective GABA_A receptor agonist. These results suggest that DMPC would be a potential candidate for alleviating cognitive dysfunction and sensorimotor gating deficits in schizophrenia, and that its effects may be mediated, in part, via blockade of the GABAergic neurotransmitter system.     

Repaglinide,but Not Nateglinide Administered Supraspinally and Spinally Exerts an Anti-Diabetic Action in D-Glucose Fed and Streptozotocin-Treated Mouse Models

We have recently demonstrated that some anti-diabetic drugs such as biguanide and thizolidinediones administered centrally modulate the blood glucose level, suggesting that orally administered anti-diabetic drugs may modulate the blood glucose level by acting on central nervous system. The present study was designed to explore the possible action of another class of anti-diabetic drugs, glinidies, administered centrally on the blood glucose level in ICR mice. Mice were administered intracerebroventricularly (i.c.v.) or intrathecally (i.t.) with 5 to 30 µg of repaglinide or nateglinide in D-glucose-fed and streptozotocin (STZ)-treated models. We found that i.c.v. or i.t. injection with repaglinide dose-dependently attenuated the blood glucose level in D-glucose-fed model, whereas i.c.v. or i.t. injection with nateglinide showed no modulatory action on the blood glucose level in D-glucose-fed model. Furthermore, the effect of repaglinide administered i.c.v. or i.t. on the blood glucose level in STZ-treated model was studied. We found that repaglinide administered i.c.v. slightly enhanced the blood glucose level in STZ-treated model. On the other hand, i.t. injection with repaglinide attenuated the blood glucose level in STZ-treated model. The plasma insulin level was enhanced by repaglinide in D-glucose-fed model, but repaglinide did not affect the plasma insulin level in STZ-treated model. In addition, nateglinide did not alter the plasma insulin level in both D-glucose-fed and STZ-treated models. These results suggest that the anti-diabetic action of repaglinide appears to be, at least, mediated via the brain and the spinal cord as revealed in both D-glucose fed and STZ-treated models.     

Decreasing Effect of Lidocaine·HCl on the Thickness of the Neuronal and Model Membrane

This study examined the mechanism of action of a local anesthetic, lidocaine·HCl. Energy transfer between the surface fluorescent probe, 1-anilinonaphthalene-8-sulfonic acid, and the hydrophobic fluorescent probe, 1,3-di(1-pyrenyl) propane, was used to determine the effect of lidocaine·HCl on the thickness (D) of the synaptosomal plasma membrane vesicles (SPMV) isolated from the bovine cerebral cortex, and liposomes of the total lipids (SPMVTL) and phospholipids (SPMVPL) extracted from the SPMV. The thickness (D) of the intact SPMV, SPMVTL and SPMVPL were 1.044±0.008, 0.914±0.005 and 0.890±0.003 (arbitrary units, n=5) at 37℃ (pH 7.4), respectively. Lidocaine·HCl decreased the thickness of the neuronal and model membrane lipid bilayers in a dose-dependent manner with a significant decrease in the thickness, even at 0.1 mM. The decreasing effect of lidocaine·HCl on the membrane thickness might be responsible for some, but not all of its anesthetic action.     

Prognostic significance of preoperative metabolic tumour volume and total lesion glycolysis measured by 18F-FDG PET/CT in squamous cell carcinoma of the oral cavity

Purpose

Metabolic tumour volume (MTV) and total lesion glycolysis (TLG) from ¹⁸F-FDG PET/CT are emerging prognostic biomarkers in human solid cancers; yet few studies have investigated their clinical and prognostic significance in oral cavity squamous cell carcinoma (OSCC). The present retrospective study evaluated the utility of pretreatment MTV and TLG measured by ¹⁸F-FDG PET/CT to predict survival and occult metastasis (OM) in OSCC.

Methods

Of 162 patients with OSCC evaluated preoperatively by ¹⁸F-FDG PET/CT, 105 who underwent definitive surgery with or without adjuvant therapy were eligible. Maximum standardized uptake value (SUV_max), MTV and TLG were measured. For calculation of MTV, 3-D regions of interest were drawn and a SUV threshold of 2.5 was used for defining regions. Univariate and multivariate analyses identified clinicopathological and imaging variables associated with OM, disease-free survival (DFS) and overall survival (OS).

Results

The median (range) SUV_max, MTV and TLG were 7.3 (0.7–41.9), 4.5 ml (0.7–115.1 ml) and 18.3 g (2.4–224.1 g), respectively. Of 53 patients with clinically negative lymph nodes, OM was detected in 19 (36 %). By univariate and multivariate analyses, MTV (P?=?0.018) and TLG (P?=?0.011) were both independent predictive factors for OM, although they were not independent of each other. The 4-year DFS and OS rates were 53.0 % and 62.0 %, respectively. Univariate and multivariate analyses revealed that MTV (P?=?0.001) and TLG (P?=?0.006), with different cut-off levels, were both independent predictive factors for DFS, although they were not independent of each other, and MTV (P?=?0.001), TLG (P?=?0.002) and the involved resection margin (P?=?0.007) were independent predictive factors for OS.

Conclusion

Pretreatment MTV and TLG may be useful in stratifying the likelihood of survival and predicting OM in OSCC.     

Clinicopathologic Characteristics of Breast Cancer Stem Cells Identified on the Basis of Aldehyde Dehydrogenase 1 Expression

Purpose

Breast cancer displays varying molecular and clinical features. The ability to form breast tumors has been shown by several studies with aldehyde dehydrogenase 1 (ALDH1) positive cells. The aim of this study is to investigate the association between ALDH1 expression and clinicopathologic characteristics of invasive ductal carcinoma.

Methods

We investigated breast cancer tissues for the prevalence of ALDH1⁺ tumor cells and their prognostic value. The present study included paraffin-embedded tissues of 70 patients with or without recurrences. We applied immunohistochemical staining for the detection of ALDH1⁺ cells. Analysis of the association of clinical outcomes and molecular subtype with marker status was conducted.

Results

ALDH1⁺ and ALDH1^- tumors were more frequent in triple-negative breast cancers and in luminal A breast cancers, respectively (p<0.01). ALDH1 expression was found to exert significant impact on disease free survival (DFS) (ALDH1⁺ vs. ALDH1^-, 53.1±6.7 months vs. 79.2±4.7 months; p=0.03) and overall survival (OS) (ALDH1⁺ vs. ALDH1^-, 68.5±4.7 months vs. 95.3±1.1 months; p<0.01). In triple-negative breast cancer (TNBC) patients, DFS and OS showed no statistical differences according to ALDH1 expression (ALDH1⁺ vs. ALDH1^-, 45.3±9.4 months vs. 81.3±7.4 months, p=0.52; 69.0±7.5 months vs. 91.3±6.3 months, p=0.67). However, non-TNBC patients showed significant OS difference between ALDH1⁺ and ALDH1^- tumors (ALDH1⁺ vs. ALDH1^-, 77.6±3.6 months vs. 98.0±1.0 months; p=0.04) with no statistical difference of DFS (ALDH1⁺ vs. ALDH1^-, 60.5±8.0 months vs. 81.8±4.6 months; p=0.27).

Conclusion

Our findings suggest that the expression of ALDH1 in breast cancer may be associated with TNBC and poor clinical outcomes. On the basis of our findings, we propose that ALDH1 expression in breast cancer could be correlated with poor prognosis, and may contribute to a more aggressive cancer phenotype.     

Suspected non-small cell lung cancer: incidence of occult brain and skeletal metastases and effectiveness of imaging for detection--pilot study

PURPOSE: To estimate the incidence of occult metastases to the brain and skeleton in patients suspected of having non-small cell lung cancer (NSCLC) (stage higher than T1Nomo) with surgically resectable disease, to assess the accuracy of screening magnetic resonance (MR) imaging and radionuclide bone scanning for help in identifying occult metastases, and to determine the effectiveness of a high dose of MR contrast material. MATERIALS AND METHODS: Twenty-nine patients suspected of having NSCLC localized to the lung or to the lung and regional nodes underwent preoperative MR imaging with contrast material enhancement and radionuclide bone scanning for detection of brain or skeletal metastases. Patients were followed up for 12 months to determine the incidence of clinical metastatic disease. RESULTS: Eight (28%) patients had occult metastatic disease to the brain or skeleton. Brain metastases were identified on MR images in five of six patients. Bone metastases were identified on MR images in four of five patients and on bone scans in three of five patients. MR imaging was no more accurate than bone scanning for skeletal evaluation. A high dose of MR contrast material allowed detection of more metastases and of small lesions. CONCLUSION: Contrast-enhanced MR imaging of the brain is indicated for the exclusion of brain metastases in patients with clinically operable known or possible NSCLC and a large (> 3-cm) lung mass. Skeletal imaging may be indicated if an isolated brain metastasis is detected.     

A 10-s rest improves chest compression quality during hands-only cardiopulmonary resuscitation: A prospective,randomized crossover study using a manikin model

Objectives

This study was designed to assess changes in cardiopulmonary resuscitation (CPR) quality and rescuer fatigue when rescuers are provided with a break during continuous chest compression CPR (CCC-CPR).

Methods

The present prospective, randomized crossover study involved 63 emergency medical technician trainees. The subjects performed three different CCC-CPR methods on a manikin model. The first method was general CCC-CPR without a break (CCC), the second included a 10-s break after 200 chest compressions (10/200), and the third included a 10-s break after 100 chest compressions (10/100). All methods were performed for 10 min. We counted the total number of compressions and those with appropriate depth every 1 min during the 10 min and measured mean compression depth from the start of chest compressions to 10 min.

Results

The 10/100 method showed the deepest compression depth, followed by the 10/200 and CCC methods. The mean compression depth showed a significant difference after 5 min had elapsed. The percentage of adequate compressions per min was calculated as the proportion of compressions with appropriate depth among total chest compressions. The percentage of adequate compressions declined over time for all methods. The 10/100 method showed the highest percentage of adequate compressions, followed by the 10/200 and CCC methods.

Conclusion

When rescuers were provided a rest at a particular time during CCC-CPR, chest compression quality increased compared with CCC without rest. Therefore, we propose that a rescuer should be provided a rest during CCC-CPR, and specifically, we recommend a 10-s rest after 100 chest compressions.     

Hospitalizations and Emergency Department Use in Mayo Clinic Biobank Participants Within the Employee and Community Health Medical Home

ObjectiveTo evaluate the participants in the Mayo Clinic Biobank for their representativeness to the entire Employee and Community Health program (ECH) primary care population with regard to hospital utilization.Patients and MethodsParticipants enrolled in the Mayo Clinic Biobank from April 1, 2009, to December 31, 2010, were linked to the ECH population. These individuals were categorized into risk tiers (0-4) on the basis of the number of health conditions present as of December 31, 2010. Outcomes were ascertained through December 31, 2011. Hazard ratios (HRs) and 95% CIs for risk of hospitalization, emergency department (ED) visits, and for risk of hospitalization and emergency department (ED) visits were estimated.ResultsThe 8927 Biobank participants were part of ECH (N=84,872). Compared with the entire ECH population, the Biobank-ECH participants were more likely to be female (64.3% vs 54.6%), older (median age, 58 years vs 47 years), and categorized to tier 0 (6.4% vs 24.0%). There were strong positive associations between tier (tier 4 vs combined tiers 0 and 1) and risk of hospitalization (HR, 5.8; 95% CI, 4.6-7.5) and ED visits (HR, 5.4; 95% CI, 4.2-6.8) among Biobank-ECH participants. Similar associations for risk of hospitalization (HR, 8.5; 95% CI, 7.8-9.3) and ED visits (HR, 6.9; 95% CI, 6.4-7.5) were observed for the entire ECH population.ConclusionAlthough the Biobank-ECH participants were older and had more chronic conditions compared with the overall ECH population, the associations of risk tier with utilization outcomes were similar, supporting the use of the Biobank participants to assess biomarkers for health care outcomes in the primary care setting.