Effects of perinatal exposure to bisphenol A on the behavior of offspring in F344 rats

The objective of this investigation is to evaluate whether perinatal maternal exposure to bisphenol A (BPA) at 4, 40, and 400 mg/kg per day affects the behavior of offspring in F344 rats. Perinatal BPA exposure inhibited the body weight increases of male and female offspring in a dose-dependent manner, which continued after weaning. Spontaneous activity analyses revealed that BPA elongated immobile time during the dark phase in female offspring. At 4 weeks of age, male offspring exposed to BPA at 40 and 400 mg/kg per day performed avoidance responses significantly higher in the shuttlebox avoidance test. At 8 weeks of age, however, male offspring only at 4 mg/kg per day showed significantly lower responses. In the open-field behavior test at 8 weeks of age, male offspring exposed to BPA only at 4 mg/kg per day showed a higher percent of grooming than the control male offspring. In conclusion, perinatal exposure to BPA caused the behavioral alterations in the offspring.     

Pharmacological profile of AS-9705, a novel benzotriazolecarboxamide derivative,as a gastroprokinetic agent with potent anti-emetic activity

The pharmacological profile of AS-9705 ((R)-N-(1-ethyl-1H-hexahydroazepin-3- yl)-6- methoxy-1H-benzotriazole-5-carboxamide fumarate monohydrate, CAS 219622-61-4), a novel gastroprokinetic agent with potent anti-emetic activity, was investigated in the present study. AS-9705 inhibited [3H]spiperone binding to human dopamine D2.long receptors, and [3H]R(+)-7-OH-DPAT binding to human dopamine D3 receptors (IC50 values of 58.5 +/- 14.0 and 60.8 +/- 7.8 (nmol/l), respectively) and had negligible affinity (IC50 > 10 mumol/l) for other neurotransmitter recognition sites examined. Moreover, in ferrets or dogs, AS-9705 dose-dependently inhibited emesis induced by R(+)-7-OH-DPAT and apomorphine with ID50 values of 0.05 mg/kg p.o. and 0.04 mg/kg p.o., respectively. AS-9705 dose-dependently enhanced normal gastric emptying and potently inhibited the delay in gastric empting induced by apomorphine, morphine, cisplatin, clonidine and cholecystokinin in rats. Furthermore, in conscious fasting dogs, AS-9705 dose-dependently stimulated gastric motility. In conclusion, AS-9705 is a novel gastroprokinetic agent with potent antiemetic activity and minimal CNS adverse effects and is, therefore, worthy of clinical investigation.     

Pharmacokinetic characterization of a human immunodeficiency virus protease inhibitor, saquinavir, during ethanol intake in rats

Throughout therapeutic drug monitoring of human immunodeficiency virus (HIV) protease inhibitors in HIV-infected patients, it was found that plasma concentrations of saquinavir (SQV) were reduced in patients who had a habit of alcohol intake during double protease therapy with SQV and ritonavir (RTV). This study confirmed the pharmacokinetic profiles of SQV during ethanol intake in rats. After oral administration of SQV alone (20 mg/kg) in rats prepared by free access to 15% ethanol solution for 14 days (day 14 rats), the area under the concentration vs time curves (AUC) showed a significant decrease (p<0.01) in comparison with control rats from 0.78+/-0.10 to 0.38+/-0.03 microg h/ml. For intravenous administration of SQV alone (5 mg/kg) to day 14 rats, the total body clearance increased significantly by 1.4-fold (p<0.05), whereas for intracolonic administration of SQV alone, no significant differences in the values of pharmacokinetic parameters were found between control and day 14 rats. With RTV, which has the strongest inhibitory effect on the CYP3A enzyme of the current HIV protease inhibitors, the AUC values of SQV at RTV doses of 2 and 20 mg/kg in day 14 rats also decreased significantly (p<0.01) from 1.30+/-0.06 to 0.57+/-0.05 microg h/ml and from 17.63+/-1.66 to 4.18+/-0.94 microg h/ml, respectively, indicating that the degree of the decrease of AUC values after oral administration with RTV after ethanol intake was larger than the mono-therapy with SQV. This study showed that ethanol-intake decreases the bioavailability of SQV after oral administration alone or with RTV. These observations provide useful information for the treatment of HIV-infected patients when they receive a combination therapy with SQV and RTV, and arouse attention for the effects of alcohol intake.     

Effects of mild aerobic physical exercise on membrane fluidity of erythrocytes in essential hypertension

1. The present study was undertaken to investigate the effects of aerobic physical exercise on membrane function in mild essential hypertension. 2. Hypertensive patients were divided into an exercise group (n = 8) and a non-exercise (control) group (n = 8). Physical exercise within the intensity of the anaerobic threshold level was performed twice a week for 6 months. Membrane fluidity of erythrocytes was examined by means of electron paramagnetic resonance (EPR) and spin-labelling methods before and after the trial period in both groups. 3. After physical exercise, blood pressure decreased significantly. 4. Compared with the non-exercise group, in the exercise group both the order parameter (S) and the peak height ratio (ho/h-1) in the EPR spectra of erythrocytes were significantly reduced (S, 0.717 +/- 0.004 vs 0.691 +/- 0.008, respectively (n = 8), P < 0.05; ho/h-1, 5.38 +/- 0.06 vs 4.89 +/- 0.06, respectively (n = 8), P < 0.05). These findings indicated that exercise increased membrane fluidity and improved the membrane microviscosity of erythrocytes. 5. There was no direct correlation between blood pressure reduction and the exercise-induced increase in membrane fluidity of erythrocytes. 6. In the non-exercise (control) group, blood pressure and membrane fluidity were not changed after a 6 month follow-up period. 7. The results show that aerobic physical exercise increased erythrocyte membrane fluidity and improved the rigidity of cell membranes in hypertensive patients. The improvement of rheological properties of erythrocytes may explain, in part, the cellular mechanisms for the beneficial effects of physical exercise in hypertension.     

Increased plasma concentrations of the mature form of adrenomedullin during cardiac surgery and hepatosplanchnic hypoperfusion

Adrenomedullin is a potent vasodilatory peptide. Plasma adrenomedullin (AM) concentrations increase during and after cardiopulmonary bypass (CPB). However, the cause of this increase and its site of production have not been identified. We investigated the role of the hepatosplanchnic and cerebral circulations in the increase of plasma AM and investigated whether tissue hypoxygenation is a cause of the AM increase seen during CPB. We measured plasma total AM (AM-T) and the biologically active form of AM, mature AM (AM-m), in seven patients undergoing CPB. Both plasma AM-T and AM-m concentrations increased significantly 60 min after weaning from CPB. At this time point, arterial AM-T and AM-m concentrations were 18-fold and 10-fold larger, respectively, than baseline values measured after the induction of anesthesia. The plasma AM-m concentration and the ratio of AM-m/AM-T in blood from the hepatic vein were significantly larger than those from the radial artery or jugular bulb. The AM-m/AM-T ratio decreased during CPB, suggesting that production of the intermediate form of AM, AM-glycine, is more than that of AM-m. The oxygen tension of the hepatic venous blood (PhvO2) was significantly less during CPB. Plasma AM-m concentrations sampled from the hepatic vein showed a significant negative correlation with PhvO2 at 10 min (r = 0.824; P < 0.02) and 60 min (r = 0.828; P < 0.02) after the onset of CPB. These data suggest that the hepatosplanchnic circulation is an important source of AM-m during CPB. Furthermore, hypoxygenation of the hepatosplanchnic region may be an important cause of this AM-m increase.     

Liberal use of tricuspid valve detachment for transatrial ventricular septal defect closure

BACKGROUND: Although temporary tricuspid valve detachment is useful for improved visualization of ventricular septal defect through right atriotomy, liberal use of this adjunct is not widely supported, mainly because of concerns about iatrogenic complications such as heart blocks and tricuspid valve dysfunction. The objective of this study was to determine whether liberal use of this adjunct can improve operative outcome. METHODS: Between January 1997 and March 2002, trans-atrial closure of isolated ventricular septal defect (conoventricular or canal type) was performed in 87 consecutive patients. Tricuspid valve detachment was used in 4 out of 44 patients (prudent-use group) and 19 out of 43 patients (liberal-use group) in the first and second half of this period, respectively (p = 0.0002). Patient demographics and use of other surgical and cardiopulmonary bypass techniques remained virtually unchanged during this period. RESULTS: In the prudent-use group, there was one operative death with prolonged bypass time and one residual defect that required reoperation; neither of these patients underwent tricuspid valve detachment. All other patients (both groups) were free from mortality and clinically significant complications, including heart block, tricuspid regurgitation, and residual defect. The liberal-use group had shorter cardiopulmonary bypass time than the prudent-use group (59 +/- 14 vs 67 +/- 22 minutes, p = 0.037). CONCLUSIONS: Tricuspid valve detachment should be used liberally for moderate- or even low-difficulty exposure of ventricular septal defect, regardless of patient background, because it is a safe and effective adjunct that can improve speed, programmability, reproducibility, and reliability.     

Thromboembolic events associated with Guglielmi detachable coil embolization with use of diffusion-weighted MR imaging. Part II. Detection of the microemboli proximal to cerebral aneurysm

BACKGROUND AND PURPOSE: The purpose of this study was to document the incidence and radiologic appearance of thromboembolic events during Guglielmi detachable coil (GDC) embolization for asymptomatic basilar artery (BA) bifurcation and BA-superior cerebellar artery (SCA) aneurysms by using diffusion-weighted (DW) MR imaging, with special emphasis on the evidence of thromboembolic events in vascular territories proximal from the treated aneurysm, which cause cerebellar infarction, and to discuss which step of the procedure (aneurysm or catheter manipulation) may play a role for most thromboembolic events. METHODS: Since 1999, 38 asymptomatic BA bifurcation and BA-SCA aneurysms were treated with GDCs at the National Cardiovascular Center. DW studies were performed for 26 patients between 2 and 5 days after GDC embolizations. All DW images were reviewed by two radiologists for depiction of abnormalities. These findings were retrospectively evaluated with clinical and technical factors of thromboembolic events. RESULTS: DW images showed new hyperintense lesions in 18 patients (69%), with seven (27%) incurring neurologic deteriorations. All symptomatic patients fully recovered by discharge. Fourteen (78%) of 18 patients showed new lesions proximal to the treated aneurysm; that is, in the cerebellar hemispheres. In three cases treated with the balloon-assisted technique, new hyperintense lesions were seen. CONCLUSION: In our experience, most thromboembolic events related to the use of the GDC embolization may be caused by catheter manipulation, especially in the case of the balloon-assisted technique. Caution should be exercised in the handling of catheters. Furthermore, a softer and smaller caliber catheter and simple GDC technique should be considered.     

Preliminary evaluation of image reconstruction by ordered-subset expectation maximization in thallium-201 lung scintigraphy

OBJECTIVES: We observed whether clearer tumor delineation and greater tumor to non-tumor (T/N) count ratios could be obtained using an iterative ordered-subsets expectation maximization (OSEM) algorithm than conventional filtered-back projection algorithm (FBP) in the image reconstruction of thallium-201 (201Tl) lung scintigraphy. METHODS: In 29 patients with lung cancer and phantom studies, tomograms were reconstructed using FBP and OSEM algorithms, with and without a prefilter (Butterworth filter: BW), whose cut-off frequencies were 0.10 cycles/pixel for FBP and 0.10 and 0.17 cycles/pixel for OSEM. Visual interpretation and tumor to non-tumor (T/N) count ratios were obtained and compared. RESULTS: Without a prefilter, T/N ratios from OSEM and FBP were 1.89 +/- 0.31 (early) and 2.00 +/- 0.54 (late) for OSEM, 1.90 +/- 0.33 (early) and 2.05 +/- 0.59 (late) for FBP, respectively. The OSEM reconstruction without prefiltering showed clearer tumor contours than FBP without a prefilter. Incorporation of BW showed visually low-noised images but decreased T/N ratios in both reconstructions with BW (0.10 cycles/pixel). No greater T/N ratios were obtained by OSEM than FBP, with or without prefiltering. With BW with a cut-off frequency of 0.17 cycles/pixel, the same T/N ratios as those without BW were obtained. The tumor model sized 0.9 cm in the phantom study was invisible in both OSEM and FBP reconstructions without a prefilter, but visible with a prefilter. The influence of prefiltering on T/N ratios was also observed in phantom studies. CONCLUSIONS: Visually improved tumor delineation could be obtained in OSEM reconstruction without a prefilter as compared to FBP reconstruction without a prefilter for tumors greater than 2 cm. Prefiltering should be incorporated into OSEM reconstruction in diagnosing small tumors. However, the influence of prefilter (BW) setting on semi-quantitative interpretation needs further discussion.     

High-dose-rate brachytherapy with local injection of bleomycin for N0 oral tongue cancer--possibilities of the control of tumor implant by inserting applicators and the decrease in tumor dose

Twenty-eight patients with N0 oral tongue cancer were treated with high-dose-rate (HDR) interstitial brachytherapy combined with local injection of bleomycin between December 1997 and June 2001 at the Department of Radiology, National Kyushu Medical Center Hospital. A median dose of 5 mg of bleomycin was injected locally, and 16-20 Gy was delivered to the area surrounding applicators for control of the tumor implant during the initial two days. The two-year local recurrence-free survival rate was 96% [T1, 2: 100% (8/8, 15/15), T3: 80% (4/5)]. The two-year secondary neck node metastasis rate was 7.1% [T1: 12.5% (1/8), T2: 6.7% (1/15), T3:0% (0/5)]. There were no tumor implants in any patients. We tried to decrease the minimal tumor dose step by step. The groups with median minimal tumor doses of 60 Gy, 50 Gy, and 40 Gy had local recurrence rates of 12.5% (1/8), 0% (0/14), and 0% (0/6), respectively. Local recurrence rates were not increased by decreasing the minimal tumor dose. Two patients (7%) had secondary neck node metastasis. Late adverse effects were tongue ulcer: 11% (3/28), oral floor ulcer: 4% (1/28), and osteonecrosis: 4% (1/28). These results suggest that control of the tumor implant and the decrease in minimal tumor dose below 60 Gy may be possible with the local injection of bleomycin and delivery of doses to the area surrounding the applicators when NO tongue cancer is treated using 192Ir-HDR brachytherapy.     

Simple visualization of the corticospinal pathway using tractography: one-ROI and two-ROI methods

Diffusion tensor imaging (DTI), a magnetic resonance (MR) technique to analyze diffusion anisotropy of the brain, is able to demonstrate subtle white matter anatomy. Tractography is expected to be a unique, non-invasive tool to provide more pertinent insights into brain structure and orientation not accessible by conventional MRI. In this report, preliminary experiences of visualization of the corticospinal tract using tractography are described. DTI of the brain was performed in 5 normal volunteers using single-shot echo-planar imaging, then tractography was generated by our original software. We determined that the two-region-of-interest (ROI) method is superior to the one-ROI method.