Dietary supplementation of the citrus antioxidant auraptene inhibits N,N-diethylnitrosamine-induced rat hepatocarcinogenesis

OBJECTIVES: We have previously reported that an antioxidant, auraptene (AUR), isolated from citrus fruit effectively inhibits chemically induced carcinogenesis in digestive tracts, such as the oral cavity, esophagus and large bowel. In this study, we investigated the modifying effects of dietary supplementation with AUR on N,N-diethylnitrosamine (DEN)-initiated hepatocarcinogenesis in male F344 rats in two different experiments to determine whether the compound exerts a cancer-chemopreventive action in other organs. METHODS: In the first experiment, animals were fed diets containing AUR at dose levels of 100 and 500 ppm for 7 weeks 1 week before, during, and 1 week after the start of liver carcinogenesis induced by DEN (40 ppm in drinking water for 5 weeks) to predict the modulatory effect on hepatocarcinogenesis. After 7 weeks, the numbers of hepatocellular enzyme-altered foci (EAF; cm(2)) which stained positive for the placental form of glutathione S-transferase (GST-P) and transforming growth factor (TGF)-alpha were determined on immunohistochemically stained sections. In the second experiment conducted to confirm the findings, animals subjected to DEN treatment were fed AUR-containing diets (100 and 500 ppm) during either the initiation stage ('initiation' feeding for 7 weeks) or post-initiation phase ('post-initiation' feeding for 25 weeks) of DEN-induced hepatocarcinogenesis. RESULTS: In the first experiment, feeding with AUR at both doses during DEN exposure decreased the mean numbers of GST-P-positive and TGF-alpha-positive EAF/cm(2), and the reduction in the number of TGF-alpha-positive EAF by feeding 500 ppm AUR was statistically significant (p < 0.005). In the second experiment, the 'initiation' feeding with 500 ppm AUR significantly inhibited the incidence (33 vs. 83%, p = 0.000511) and multiplicity (0.67 +/- 1.09 vs. 1.96 +/- 1.85, p < 0.005) of liver cell carcinoma. Also, the 'post-initiation' feeding with AUR at both doses significantly reduced the development of hepatocellular carcinoma (100 ppm: incidence, 15%, p = 0.000006; multiplicity: 0.25 +/- 0.64, p < 0.001; 500 ppm: incidence, 11%, p = 0.000002; multiplicity, 0.26 +/- 0.81, p < 0.001). In addition, AUR feeding reduced cell proliferation and the apoptotic index in liver cell neoplasms. CONCLUSIONS: The results suggest that the citrus antioxidant AUR is a potential chemopreventive agent against DEN-induced hepatocarcinogenesis in rats.     

Genes associated with liver metastasis of colon cancer, identified by genome-wide cDNA microarray

To uncover mechanisms underlying progression of colorectal carcinogenesis and to identify genes associated with liver metastasis, we analyzed expression profiles of 14 primary colorectal cancers (CRCs) with liver metastases, and compared them with profiles of 11 non-metastatic carcinomas and those of 9 adenomas of the colon. A hierarchical cluster analysis using data from a cDNA microarray containing 23,040 genes indicated that the cancers with metastasis had different expression profiles from those without metastasis, although a number of genes were commonly up-regulated in primary cancers of both categories. We documented 54 genes that were frequently up-regulated and 375 that were frequently down-regulated in primary tumors with metastases to liver, but not in tumors without metastasis. Subsequent quantitative PCR experiments confirmed that PRDX4, CKS2, MAGED2, and an EST (GenBank accession number BF696304) were expressed at significantly higher levels in tumors with metastasis. These data should contribute to a better understanding of the progression of colorectal tumors, and facilitate prediction of their metastatic potential.     

Ventilatory and cardiovascular responses to hypercapnia after 20 days of head-down bed rest

INTRODUCTION: Few studies have attempted to investigate the influence of prolonged head-down bed rest (HDBR) on hypercapnic ventilatory chemosensitivity, and there are no data available regarding associated changes in arterial BP and heart rate (HR). The aim of this study was to clarify the influence of prolonged HDBR on ventilatory and cardiovascular responses to hypercapnia. METHODS: There were five healthy men who participated in this study. Resting ventilatory and cardiovascular responses to hypercapnia were measured by means of Read's CO2 rebreathing method 4 d before and on the 19th day of HDBR. Measured variables included systolic and diastolic BP (SBP and DBP, respectively), inspired minute ventilation (VI), and end-tidal partial pressure of CO2 (PETCO2). RESULTS: Ventilatory response to hyperoxic hypercapnia (deltaVI/ deltaPETCO2) decreased significantly on the 19th day of HDBR (1.42 +/- 0.65 to 0.90 +/- 0.41 L x min(-1) x torr(-1), p < 0.05). On the other hand, SBP, DBP, and HR responses (deltaSBP/deltaPETCO2, deltaDBP/deltaPETCO2, and deltaHR/deltaPETCO2) were unchanged. DISCUSSION: The results from this study suggest that prolonged HDBR leads to diminished central hypercapnic ventilatory chemosensitivity.     

Clinical usefulness of ECG-gated18F-FDG PET combined with99mTc-MIBI gated SPECT for evaluating myocardial viability and function

OBJECTIVES: This study sought to evaluate an imaging approach using gated 99mTc-MIBI (MIBI) SPECT and gated 18F-FDG (FDG) PET for assessment of myocardial viability and cardiac function. METHODS: Forty-eight patients (38 men, mean age 68.1 +/- 9.6 years) underwent ECG-gated FDG PET and MIBI SPECT within a week. The baseline diagnoses were coronary artery disease (31), mitral regurgitation (1), paroxysmal arrhythmia (10), and dilated cardiomyopathy (6). The gated FDG PET data were analyzed using pFAST software, and the gated MIBI SPECT data were analyzed using QGS software. Fifteen patients were diagnosed with myocardial infarction, and follow-up study was performed to assess the functional outcome four months later. An improvement in LVEF of >5% was defined as significant. The LV myocardium was divided into 17 segments, and regional defect scores were visually assessed using a 4-point scale for each segment (0 = normal, 1 = mildly reduced, 2 = moderately reduced, 3 = absent). A segment with a greater defect score on MIBI SPECT than on FDG PET was defined as a mismatch. The patients were divided into two groups: those with at least two mismatched segments (MM-group), and those with none or one (M-group). RESULTS: LVEF, EDV and ESV measured by gated FDG PET were highly correlated with those obtained by gated MIBI SPECT (r = 0.848, 0.855 and 0.911, p < 0.0001, respectively). The mean values of LVEF did not differ significantly, but EDV and ESV obtained by gated FDG PET were significantly grater than those obtained by gated MIBI SPECT (p < 0.0001). In 15 patients diagnosed with myocardial infarction, a significant association (p < 0.05) was found between the relative uptake of FDG PET and MIBI SPECT and the functional outcome 4 months later. Global LV function improved in 6 of the 8 patients showing mismatch but in only 1 of the 7 patients with matched defects, resulting in a sensitivity of 86% and specificity of 75%. The overall accuracy to predict global functional outcome was high (80%). CONCLUSION: This imaging approach allows accurate evaluation of myocardial viability. Furthermore, the high correlations of gated FDG PET and gated MIBI SPECT measurements hold promise for the assessment of left ventricular function using gated FDG PET.     

Transaortic Mitral Valve Repair Combined with a Modified Bentall Procedure in a Patient with Marfan’s Syndrome: Report of a Case

We report a case of transaortic mitral valve repair combined with aortic root and arch replacement in a patient with Marfans syndrome. Preoperative computed tomography and echocardiography showed acute aortic dissection (DeBakey type 1), severe aortic regurgitation, annuloaortic ectasia, and mild mitral regurgitation (MR). We performed artificial chordae implantation to the anterior mitral leaflet (AML) through the aortic root, followed by insertion of an aortic composite graft and replacement of the aortic arch. The patient is well 55 months after the operation, with minimal MR. We think that the transaortic approach is a good alternative for exposure and correction of the AML and its apparatus in special circumstances.     

Optical Coherence Tomography Before and After Vitrectomy with Internal Limiting Membrane Removal in a Child with Optic Disc Pit Maculopathy

Background

The pathogenesis of optic disc pit maculopathy is still unknown, although recent optical coherence tomographic (OCT) analyses have made a great contribution to clarifying its morphological appearance. The best treatment for this disease is also controversial.

Case

We report on a 7-year-old girl with optic disc pit maculopathy associated with a separation of the internal limiting membrane (ILM) near the optic disc.

Observations

The OCT images before treatment showed a conduit from the perineural space to the schisislike separation of the sensory retina with a dome-shaped separation of the ILM. A serous detachment (SD) in the macula, centered on the fovea, was also present. In OCT images after laser photocoagulation, the conduit appeared to be closed, but the SD was still present. Vitrectomy with ILM removal and gas tamponade resulted in a marked reduction of the SD in the macular area. Focal macular electroretinograms and visual acuity demonstrated a recovery of macular function.

Conclusion

The dome-shaped separation of the ILM suggested that the vitreous might be exerting a tractional force on the optic disc pit, and vitrectomy with ILM peeling released the traction on the optic disc pit. Jpn J Ophthalmol 2005;49:411–413 © Japanese Ophthalmological Society 2005     

Changes in foveal thickness and macular function after transpupillary thermotherapy for age-related macular degeneration

PURPOSE: To evaluate the effect of transpupillary thermotherapy (TTT) on foveal thickness and macular function in eyes with choroidal neovascularization (CNV) associated with age-related macular degeneration. METHODS: Sixteen eyes with occult CNV and 6 eyes with classic CNV were treated with TTT. Optical coherence tomography and focal macular electroretinograms (FMERGs) elicited by a 15-degree stimulus were performed before, 3 months after TTT in 22 eyes and 6 months after TTT in 18 eyes. RESULTS: Before TTT, the fovea in 20 of the 22 eyes with CNV was significantly thicker than that of normal subjects. The foveal thickness was reduced after TTT in 11 of 14 eyes with occult CNV and remained unchanged in 2 eyes. One eye with occult CNV before TTT developed a classic CNV with significant macular edema and increased foveal thickness 3 months after TTT. The amplitudes of the FMERGs were reduced in all eyes before TTT. In eyes with occult CNV, the mean b-wave amplitude increased significantly after TTT (p = 0.0260 at 3 months, p = 0.0142 at 6 months). When the change of foveal thickness was less than 20% after TTT, all eyes with occult CNV had a 30% or more increase in the b-wave amplitude. In eyes with classic CNV, the mean amplitude of the a- and b-waves did not change significantly after TTT. CONCLUSIONS: TTT improves macular function in eyes with occult CNV associated with age-related macular degeneration more when the change of foveal thickness is slight.     

Surgical significance of superficial cancer spread in early gallbladder cancer

Background: A considerable percentage of gallbladder cancersare accompanied by superficial cancer spread adjacent to themain tumor, therefore cholecystectomy for early gallbladdercancer must be performed carefully to avoid leaving cancer cellsat the surgical margins. Methods: Thirty-two patients with gallbladder cancer invadingno more than perimuscular connective tissue underwent surgicalresection at our medical center. After the operation, resectedspecimens were investigated macroscopically and microscopicallyto clarify the clinicopathological features and the risk factorsof superficial cancer spread. Results: Sixty-six percent of all cases (21 cases) had superficialcancer spread. Comparison between the cases having superficialcancer spread and the cases without it revealed that the macroscopicmorphology of the primary tumor and the depth of cancer invasionin the gallbladder wall were significantly different betweenthe two groups. Furthermore, multivariate analysis indicatedthat ‘superficial raised type’ in macroscopic morphologywas an independent predictive factor for having superficialcancer spread. Superficial cancer spread from the main tumorlocated in the neck of the gallbladder grows predominantly inthe direction of the fundus. More advanced gallbladder caseswere accompanied by more extensive superficial spread. Conclusions: Superficial cancer spread is frequently observedadjacent to the gallbladder cancer, especially in the superficialraised type. A negative margin should be confirmed by intraoperativefrozen section histology while performing cholecystectomy.     

Protective effect of donepezil against Abeta(1-40) neurotoxicity in rat septal neurons

Donepezil, a potent acetylcholinesterase (AChE) inhibitor used for the treatment of Alzheimer's disease (AD), is thought to have a neuroprotective effect in AD patients. Because a deficit in cholinergic neurotransmission is a major feature in AD, and amyloid-beta (Abeta) accumulation has been proposed as a possible causative phenomenon, we were interested to examine the effect of donepezil on Abeta(1-40) induced neurotoxicity in primary cultures of rat septal neurons. Using immunohistochemical staining, almost all the neurons were found to be positive for vesicular acetylcholine transporter (VAChT) in these septal cultures. Septal neuronal cells were cultured for 7 days and then 15 micromol/L of Abeta(1-40) was added to the cell medium for 48 h. The cultured septal neurons were highly susceptible to Abeta toxicity, as shown by morphological examination and lactate dehydrogenase (LDH) assay. Donepezil concentration-dependently reduced the LDH efflux induced by Abeta(1-40), and the effect was significant at 100 nmol/L and above. Donepezil decreased both the negative peak at around 215 nm in the circular dichroism (CD) spectrum and the fluorescence intensity of thioflavin T in the presence of Abeta(1-40). These results suggest that donepezil exerts a neuroprotective effect by reducing the amount of the toxic form of Abeta fibrils in septal neuron cultures. These findings support the idea that the clinical efficacy of donepezil in AD is due to not only activation of cholinergic transmission, but also attenuation of neuronal damage.