Suppression of postoperative intimal hyperplasia of vein grafts with edaravone in rat models - a scanning electron microscope study

PURPOSE

Postoperative intimal hyperplasia, the most common cause of vein graft occlusion, is initiated by endothelial injury. In the present study, the mechanism by which the free radical scavenger edaravone (Radicut, Mitsubishi Tanabe Pharma Co, Japan) protects against endothelial injury in postoperative intimal hyperplasia was investigated.

METHODS

In 18 male Lewis rats, a right epigastric vein graft was interposed into the common femoral artery. Nine rats received a pre-operative intraperitoneal administration of edaravone (3.0 mg/kg, edaravone group) and the other nine rats received an equal volume of saline (saline group). After 1 h, five vein grafts from each group were treated with Verhoeff-van Gieson elastica stain and subjected to a histological examination. The other four vein grafts from each group were examined with an S-800 Hitachi scanning electron microscope (SEM) (Hitachi High-Technologies Co, Japan) at ×1000 magnification, as were three unoperated right epigastric veins (unoperated vein group). The endothelial areas of the vein grafts were measured using computerized planimetry of the SEM images (ImageJ version 1.37, National Institutes of Health, USA). The mean endothelial areas (%) were compared between the two groups.

RESULTS

Verhoeff-van Gieson elastica stain revealed no significant differences between the two groups. SEM showed that endothelial cells in the unoperated epigastric vein had a cobblestone-like appearance. In the saline group, the endothelial cells were comb-shaped and had adherent monocytes. In the edaravone group, however, the cobblestone-like appearance of endothelial cells was well preserved, with little monocyte adhesion. Moreover, the mean (± standard error of the mean) endothelial area was significantly higher in vein grafts from the edaravone group than in those from the saline group (74±1.8% versus 56±4.3%, P<0.05), and was similar to those in the unoperated epigastric veins (72±1.9%).

CONCLUSION

These findings show that endothelial injury is present soon after placement of the interposition graft. The authors believe that edaravone suppresses postoperative intimal hyperplasia by alleviating endothelial injury.     

Mizoribine therapy for patients with lupus nephritis: the association between peak mizoribine concentration and clinical efficacy

The clinical efficacy of mizoribine (MZR; 4-carbamoyl-1-b-d-ribofuranosylimidazolium) in patients with lupus nephritis was investigated. Thirteen Japanese patients with biopsy-proved lupus nephritis were enrolled in this study. A change in global assessments score, total protein (TP) of serum, serum creatinine, creatinine clearance (Ccr), proteinuria, titers of serum anti-ds DNA antibody, C3, C4, and hemolytic complement activity (CH50) were examined. Following MZR treatment, the level of urinary protein decreased (P < 0.05), whereas the level of Ccr increased (P < 0.05). Moreover, the level of TP significantly increased from 5.5 g/dl to 6.3 g/dl (P < 0.01) and the level of C3 increased significantly (P < 0.01). However, there was no change in the levels of both C4 and CH50. The titer of anti-ds DNA antibody significantly decreased (P < 0.05). The dosage of prednisolone could be tapered from 24.8 mg to 14.9 mg daily during the period. The clinical effects associated with MZR concentration in the blood revealed that there was a significant correlation between the peak MZR blood concentration of more than 0.66 μg/ml and clinical improvement (P = 0.021). Our results suggest that an optimal MZR blood concentration was important for the treatment of lupus nephritis. The first two authors contributed equally to this work.     

Methotrexate reduces the levels of pentosidine and 8-hydroxy-deoxy guanosine in patients with rheumatoid arthritis

This study was performed to investigate whether methotrexate (MTX) affects the levels of oxidative stress markers, including pentosidine one of the glycation end products (AGEs) or 8-hydroxy-deoxy guanosine (8-OHdG). These stress markers represent DNA damage; 19 rheumatoid arthritis (RA) patients underwent MTX treatment. The levels of serum total, urinary total, urinary-free pentosidine and also urinary 8-OHdG, as well as clinical parameters, including disease activity scores for 28 joints (DAS28) were measured at baseline and at 3 and 6 months after the initial treatment with MTX. After the initial treatment with MTX, serum total and urinary total pentosidine levels were reduced at 6 months, and urinary-free pentosidine levels were reduced at 3 and 6 months. Urinary 8-OHdG levels also were significantly reduced at 6 months after the initial treatment with MTX. This study demonstrated that MTX plays a role as a regulator against pentosidine formation and oxidative DNA damage in RA patients.     

Useful detection of CD147 （EMMPRIN） for pathological diagnosis of early hepatocellular carcinoma in needle biopsy samples

AIM To make clear whether CD147 (EMMPRIN)expression in pathological tumor samples with a fineneedle aspiration biopsy is useful for pathological diagnosis of early hepatocellular carcinoma (HCC).METHODS Twenty-two patients (15 men and 7 women;median age 68 years, range 56-81 years) underwent a liver tissue biopsy in order to make a diagnosis of HCC.Paraffin-embedded liver biopsy tissue samples from 22 patients were stained with anti-CD147 antibody,murine monoclonal antibody 12C3 (MAb12C3) for immunohistochemical analysis. An immunohistochemical analysis of CD147 was performed and the degree of staining compared between tumor and non-tumor tissue. In addition, the degree of staining within tumor tissue was compared according to a number of clinicopathological variables.RESULTS The degree of staining of CD147 was significantly higher in tumor tissues than non-tumor tissues, even in tumors less than 15 mm in diameter.The expression of this protein was significantly elevated in HCC tissue specimens from patients with a low value of serum AST and γ-GTP.CONCLUSION CD147 serves potentially as a pathological target for cancer detection of early HCC.     

The hepatic sinusoidal endothelial lining and colorectal liver metastases

Colorectal cancer （CRC） is a common malignant disease and the severe nature of cases in men and women who develop colorectal cancer makes this an important socio-economic health issue. Major challenges such as understanding and modeling colorectal cancer pathways rely on our understanding of simple models such as outlined in this paper. We discuss that the development of novel standardized approaches of multidimensional （correlative） biomolecular microscopy methods facilitates the collection of （sub） cellular tissue information in the early onset of colorectal liver metastasis and that this approach will be crucial in designing new effective strategies for CRC treatment. The application of X-ray micro-computed tomography and its potential in correlative imaging of the liver vasculature will be discussed.     

Dobutamine stress test unmasks cardiac sympathetic denervation in Parkinson's disease

OBJECTIVE: Cardiac uptake of [(123)I]metaiodobenzyl guanidine (MIBG) is reduced in patients with Parkinson's disease (PD). However, the cardiac sympathetic abnormality associated with this reduction is unclear. To unmask this abnormality in PD patients we examined the functional consequences of cardiac beta-receptor activation. METHODS: Cardiovascular responses to stepwise administration of the beta1-receptor agonist, dobutamine (DOB), were assessed in 25 PD patients and 12 age-matched controls. Changes in blood pressure were compared to determine the optimal dose at which to detect denervation supersensitivity, and cardiac contractility was measured by DOB echocardiography, based on peak aortic flow velocity. The relations of these cardiovascular responses to the ratio of MIBG uptake into the heart vs. that into the mediastinum (H/M ratio) were analyzed. RESULTS: At 4 microg/kg/min DOB, systolic blood pressure increased more in PD patients than in controls (PD, 17.5+/-12.3 mm Hg; control, 7.2+/-6.2 mm Hg, p<0.01), suggesting the presence of denervation supersensitivity. At this DOB dose cardiac contractility also increased more in PD than in controls (PD, 39.0+/-15.7%; control, 23.5+/-5.2%, p<0.005) and this hyperdynamic response was significantly correlated with reduced H/M ratios (early: r=-0.63, p<0.01, delayed: r=-0.66, p<0.01). CONCLUSION: Low-dose DOB unmasks cardiac sympathetic denervation in PD patients, and decreased MIBG uptake indicates the presence of denervation supersensitivity within the heart, resulting in hyperdynamic cardiac contractility in response to a beta 1-stress condition.     

Evaluation of brain perfusion SPECT using an easy Z-score imaging system (eZIS) as an adjunct to early-diagnosis of neurodegenerative diseases

The eZIS allows computer-assisted statistical analysis of brain perfusion SPECT images. We evaluated the diagnostic value of brain perfusion SPECT using eZIS in patients with various neurodegenerative diseases at a very early stage, within one year from onset.

Methods

SPECT using eZIS was performed for patients with Alzheimer disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD,), idiopathic Parkinson disease (PD) and vascular Parkinsonism (VP), multiple systemic atrophy of the cerebellar type (MSA-C), cortical cerebellar atrophy (CCA) and amyotrophic lateral sclerosis (ALS).

Results

Decreased rCBF was observed in the posterior cingulate cortex, precuneus and parietal cortex in AD; in the frontal gyrus and insula in FTD; in the occipital lobe, precuneus gyrus and posterior cingulate cortex in DLB; in the striatum and the thalamus in VP; in the cerebellum in CCA; in the cerebellum and pons in MSA-C and in the frontal cortex including the central sulcus in ALS. Increased rCBF in the striatum, thalamus and cerebellar dentate nuclei were observed in PD.

Conclusions

A specific rCBF pattern was observed for each disease using eZIS analysis, consistent with previous reports. Our results showed eZIS can be easily used as an adjunct to early-diagnosis of neurodegenerative diseases in any hospital.     

Brain ECF antioxidant interactions in hamsters during arousal from hibernation

Warming from hibernation to cenothermia involves intense metabolic activity and large fluxes in regional blood flow and volume. During this transition, levels of the antioxidants, ascorbate (AA), urate and glutathione (GSH) in brain tissue, extracellular fluid (ECF) and plasma change substantially. Striatal ECF was sampled and manipulated using very slow perfusion microdialysis to examine the mechanisms that influence the changing profile of striatal ECF AA, urate and GSH levels during arousal from hibernation to cenothermia in Syrian hamsters (Mesocricetus auratus). Omission of glucose from the perfusate had no effect upon the respective decrease, increase and transient increase in striatal ECF levels of AA, GSH and urate observed during arousal from hibernation to cenothermia. In contrast, inhibition of xanthine dehydrogenase/oxidase (XOR) activity by reverse dialysis with oxypurinol, itself a free radical scavenger, decreased ECF urate and preserved ECF AA levels. This suggests that some ECF AA is oxidized by free radical products of XOR flux and/or by other free radical producing processes activated during the transition from hibernation to cenothermia. Local supplementation of ECF AA, GSH and cystiene had no effect upon the profile of transient increase of ECF urate observed during arousal from hibernation. The production of free radicals by XOR and the disappearance of AA from the ECF continues for at least 2h immediately after the hamster has attained cenothermia. The hamster, immediately after arousal from hibernation, can be utilized as a natural model to study free radical production and effective scavenging at cenothermia.     

Relationship between serum leptin and fatty liver in Japanese male adolescent university students

OBJECTIVE: The aim of this study was to elucidate the relationship between serum leptin levels and fatty liver in male adolescents. METHODS: We investigated the relationship between the concentration of circulating leptin and fatty liver by measuring the serum concentration of leptin in 284 male students who received the matriculation health examination in Okayama University in 1996 (n = 197; age, 18-20 yr) or 1997 (n = 87; age, 18-20 yr). RESULTS: Serum leptin levels correlated positively with body mass index (BMI), percent body fat (%FAT), thickness of skin fold (TSF), and serum concentration of ALT in 197 subjects. Examination of serum leptin in 67 subjects with BMI > or = 24.2 but < 28.6 kg/m2 showed a progressively higher levels in subjects with high serum ALT. Serum leptin levels in subjects with abnormally high serum ALT (> or = 37 IU/L) were significantly higher (p < 0.05) than in subjects with normal serum ALT, independent of BMI, %FAT, and TSF. Serum leptin levels were also significantly higher in subjects with fatty liver (detected by abdominal ultrasonography), independent of BMI and %FAT, compared with subjects without fatty liver. Stepwise multiple regression analysis showed that serum leptin level was an independent risk factor for fatty liver. In addition, serum leptin levels correlated with serum ALT (r = 0.518; p < 0.0005) and cholinesterase (r = 0.511; p < 0.0005) levels in 48 subjects with fatty liver. CONCLUSIONS: Our results demonstrated that serum leptin concentrations are high in male adolescents with simple obesity and are associated with high serum ALT or fatty liver, independent of BMI and %FAT, suggesting that the concentration of circulating leptin correlates with fatty liver caused by accumulation of visceral fat.