Biomedical subjects

Kunio Doi

Publications and source records attributed to Kunio Doi.

At least 37 records · Page 2Linked to original sources

PubMed2006

Analysis and minimization of overtraining effect in rule-based classifiers for computer-aided diagnosis.

Computer-aided diagnostic (CAD) schemes have been developed to assist radiologists detect various lesions in medical images. In CAD schemes, classifiers play a key role in achieving a high lesion detection rate and a low false-positive rate. Although many popular classifiers such as linear discriminant analysis and artificial neural networks have been employed in CAD schemes for reduction of false positives, a rule-based classifier has probably been the simplest and most frequently used one since the early days of development of various CAD schemes. However, with existing rule-based classifiers, there are major disadvantages that significantly reduce their practicality and credibility. The disadvantages include manual design, poor reproducibility, poor evaluation methods such as resubstitution, and a large overtraining effect. An automated rule-based classifier with a minimized overtraining effect can overcome or significantly reduce the extent of the above-mentioned disadvantages. In this study, we developed an "optimal" method for the selection of cutoff thresholds and a fully automated rule-based classifier. Experimental results performed with Monte Carlo simulation and a real lung nodule CT data set demonstrated that the automated threshold selection method can completely eliminate overtraining effect in the procedure of cutoff threshold selection, and thus can minimize overall overtraining effect in the constructed rule-based classifier. We believe that this threshold selection method is very useful in the construction of automated rule-based classifiers with minimized overtraining effect.

Diagnosis, Computer-Assisted↗

PubMed2006

Computerized detection of intracranial aneurysms for three-dimensional MR angiography: feature extraction of small protrusions based on a shape-based difference image technique.

We have improved a computerized scheme for the detection of intracranial aneurysms for three-dimensional (3-D) magnetic resonance angiography (MRA) by the use of image features of small protrusions extracted based on a shape-based difference image (SBDI) technique. Initial candidates were identified by use of a multiple gray-level thresholding technique in dot enhanced images, and by finding short branches in skeleton images. Image features related to aneurysms were determined based on candidate regions segmented by use of a region growing technique. For extracting additional features on small protrusions or small aneurysms, we have developed an SBDI technique, which was based on the shape-based difference between an original segmented vessel and a vessel with suppressed local change in thickness. The SBDI technique was useful for obtaining local changes in vessel thickness, i.e., SBD regions, which could be small aneurysms in the case of true positives, but thin or very small regions in the case of false positives. Many false positives were removed by means of rule-based schemes and linear discriminant analysis on various 3-D localized image features, including SBDI features. We tested the computerized scheme on 53 cases with 61 aneurysms and 62 nonaneurysm cases based on a leave-one-out-by-patient test method. As a result, false positives per patient decreased from 5.8 to 3.8, while a high sensitivity of 97% was maintained by use of the SBDI technique, in which SBDI features were effective for removing some false positives. The computer-aided diagnostic (CAD) scheme may be robust and useful in assisting radiologists in the detection of intracranial aneurysms for MRA.

False Positive Reactions↗

PubMed2006

Reduction of bias and variance for evaluation of computer-aided diagnostic schemes.

Computer-aided diagnostic (CAD) schemes have been developed to assist radiologists in detecting various lesions in medical images. In addition to the development, an equally important problem is the reliable evaluation of the performance levels of various CAD schemes. It is good to see that more and more investigators are employing more reliable evaluation methods such as leave-one-out and cross validation, instead of less reliable methods such as resubstitution, for assessing their CAD schemes. However, the common applications of leave-one-out and cross-validation evaluation methods do not necessarily imply that the estimated performance levels are accurate and precise. Pitfalls often occur in the use of leave-one-out and cross-validation evaluation methods, and they lead to unreliable estimation of performance levels. In this study, we first identified a number of typical pitfalls for the evaluation of CAD schemes, and conducted a Monte Carlo simulation experiment for each of the pitfalls to demonstrate quantitatively the extent of bias and/or variance caused by the pitfall. Our experimental results indicate that considerable bias and variance may exist in the estimated performance levels of CAD schemes if one employs various flawed leave-one-out and cross-validation evaluation methods. In addition, for promoting and utilizing a high standard for reliable evaluation of CAD schemes, we attempt to make recommendations, whenever possible, for overcoming these pitfalls. We believe that, with the recommended evaluation methods, we can considerably reduce the bias and variance in the estimated performance levels of CAD schemes.

Algorithms↗

PubMed2006

Computer-aided diagnostic scheme for the detection of lung nodules on chest radiographs: localized search method based on anatomical classification.

We developed an advanced computer-aided diagnostic (CAD) scheme for the detection of various types of lung nodules on chest radiographs intended for implementation in clinical situations. We used 924 digitized chest images (992 noncalcified nodules) which had a 500 x 500 matrix size with a 1024 gray scale. The images were divided randomly into two sets which were used for training and testing of the computerized scheme. In this scheme, the lung field was first segmented by use of a ribcage detection technique, and then a large search area (448 x 448 matrix size) within the chest image was automatically determined by taking into account the locations of a midline and a top edge of the segmented ribcage. In order to detect lung nodule candidates based on a localized search method, we divided the entire search area into 7 x 7 regions of interest (ROIs: 64 x 64 matrix size). In the next step, each ROI was classified anatomically into apical, peripheral, hilar, and diaphragm/heart regions by use of its image features. Identification of lung nodule candidates and extraction of image features were applied for each localized region (128 x 128 matrix size), each having its central part (64 x 64 matrix size) located at a position corresponding to a ROI that was classified anatomically in the previous step. Initial candidates were identified by use of the nodule-enhanced image obtained with the average radial-gradient filtering technique, in which the filter size was varied adaptively depending on the location and the anatomical classification of the ROI. We extracted 57 image features from the original and nodule-enhanced images based on geometric, gray-level, background structure, and edge-gradient features. In addition, 14 image features were obtained from the corresponding locations in the contralateral subtraction image. A total of 71 image features were employed for three sequential artificial neural networks (ANNs) in order to reduce the number of false-positive candidates. All parameters for ANNs, i.e., the number of iterations, slope of sigmoid functions, learning rate, and threshold values for removing the false positives, were determined automatically by use of a bootstrap technique with training cases. We employed four different combinations of training and test image data sets which was selected randomly from the 924 cases. By use of our localized search method based on anatomical classification, the average sensitivity was increased to 92.5% with 59.3 false positives per image at the level of initial detection for four different sets of test cases, whereas our previous technique achieved an 82.8% of sensitivity with 56.8 false positives per image. The computer performance in the final step obtained from four different data sets indicated that the average sensitivity in detecting lung nodules was 70.1% with 5.0 false positives per image for testing cases and 70.4% sensitivity with 4.2 false positives per image for training cases. The advanced CAD scheme involving the localized search method with anatomical classification provided improved detection of pulmonary nodules on chest radiographs for 924 lung nodule cases.

Databases, Factual↗

PubMed2006

Experimental determination of subjective similarity for pairs of clustered microcalcifications on mammograms: observer study results.

Presentation of images of lesions similar to that of an unknown lesion might be useful to radiologists in distinguishing between benign and malignant clustered microcalcifications on mammograms. Investigators have been developing computerized schemes to select similar images from large databases. However, whether selected images are really similar in appearance is not examined for most of the schemes. In order to retrieve images that are useful to radiologists, the selected images must be similar from radiologists' diagnostic points of view. Therefore, in this study, the data of radiologists' subjective similarity for pairs of clustered microcalcification images were obtained from a number of observers, and the intra- and inter-observer variations and the intergroup correlations were determined to investigate whether reliable similarity ratings by human observers can be determined. Nineteen images of clustered microcalcifications, each of which was paired with six other images, were selected for the observer study. Thus, subjective similarity ratings for 114 pairs of clustered microcalcifications were determined by each observer. Thirteen breast, ten general, and ten nonradiologists participated in the observer study; some of them completed the study multiple times. Although the intraobserver variations for the individual readings and the interobserver variations for pairs of observers were not small, the interobserver agreements were improved by taking the average of readings by the same observers. When the similarity ratings by a number of observers were averaged among the groups of breast, general, and nonradiologists, the mean differences of the ratings between the groups decreased, and good concordance correlations (0.846, 0.817, and 0.785) between the groups were obtained. The result indicates that reliable similarity ratings can be determined by use of this method, and the average similarity ratings by breast radiologists can be considered meaningful and useful for the development and evaluation of a computerized scheme for selection of similar images.

Breast Diseases↗

PubMed2006

The activity of matrix metalloproteinases (MMPS) and tissue inhibitors of metalloproteinases (TIMPs) in mammary tumors of dogs and rats.

We conducted zymography for detecting the activity of matrix metalloproteinases (MMPs) and reverse zymography for the activity of tissue inhibitors of metalloproteinases (TIMPs) in canine spontaneous and rat 7, 12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumor tissues. The activities of MMPs of canine mammary tumors were quite higher than those of the rat chemically induced tumors. The activities of MMPs were significantly higher in malignant tissues than in benign ones of canine tumors, whereas the activity of only MMP-2 was higher in both benign and malignant rat tumors compared to normal tissues. There were no differences of MMPs activities between benign and malignant rat tumors. The results of reverse zymography indicated that the activities of TIMP-1, -2 and -3 were strikingly higher in rat tumors than in canine tumors. The activities were higher in malignant tissues than in benign ones of dogs, and higher in tumor tissues than in normal mammary tissues of rats. The results of film in situ zymography for tissue localization of gelatinolytic activity showed that the digested area was more extended in malignant tumors than in benign ones of dogs. However, the area was similarly extended in both benign and malignant rat tumors. These results may indicate that the canine spontaneous malignant mammary tumors possess more aggressive nature than the rat chemically induced counterpart, resulting from the high level of MMPs and low level of TIMPs activities of the tumor tissues.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2006

Histopathological characteristics of Ito cells and Kupffer cells in the feline liver.

The histopathological characteristics of Ito cells and Kupffer cells were investigated in the liver of 21 cats (age range: 6 months -18 years) autopsied in our laboratory during 2003. Immunohistochemical examinations were performed using antibodies against lysozyme, desmin and alpha-smooth muscle actin. No Kupffer cells reacted with the antibody against lysozyme. However, macrophages in the lung and spleen showed a positive reaction with the antibody. This finding suggests a possibility that the amount of lysozyme in the Kupffer cells of feline liver is comparatively small. On the other hand, large vacuole-laden cells were observed in the hepatic perisinusoid of some feline cases, and these cells showed a positive reaction with antibodies against desmin and alpha-smooth muscle actin. These cells could be Ito cells with large lipid vacuoles. This conclusion was supported by electron microscopic observation and oil red O staining. However, no such large vacuole-laden perisinusoidal cells were detected in the liver of young cats less than 2 years old. The present study revealed the histopathological features of Kupffer cells and Ito cells in the feline liver.

Actins↗

PubMed2006

Changes in submaxillary gland gene expression in F344 rats by multiple dosing of theophylline.

Multiple exposure to theophylline, a phosphodiesterase (PDE) inhibitor, induces acinar hypertrophy in the salivary gland. This study examined the effect of theophylline on the gene expression of secretory proteins and phosphodiesterases in the submaxillary gland. Male F344 rats received saline or theophylline (50 mg/kg) intraperitoneally for 4 days. The gene expressions for the secretory protein, cystatin S (CysS), and PDE subfamilies 3A and 4D in the submaxillary gland were quantified using RT-PCR. Theophylline exposure resulted in a sustained increase in mRNA expression for CysS and PDE3A, but PDE4D gene expression was unchanged. Our results suggest that submaxillary hypertrophy is primarily caused by the enhanced transcription of CysS, and that the transcription of each PDE subfamily gene is regulated differently.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2006

Effect of temporal subtraction technique on interpretation time and diagnostic accuracy of chest radiography.

OBJECTIVE: Our purpose was to compare reviewing time and diagnostic accuracy in the interpretation of radiographs without and with subtraction images and to examine whether this temporal subtraction technique can contribute to improving radiologists' performance. MATERIALS AND METHODS: Thirty cases with newly developed chest abnormalities on chest radiographs and 90 negative cases were selected. All chest radiographs were obtained with a computed radiography system. For the 90 negative cases, subtraction images were classified into two groups: 33 clean images without misregistration artifacts and 57 images with some misregistration artifacts. Eight radiologists (four board-certified radiologists and four radiology residents) participated in observer tests and interpreted the original radiographs without and with subtraction images using an independent test method. The reviewing time for each radiologist was recorded in each case. The observers' performance was evaluated by use of receiver operating characteristic (ROC) analysis. RESULTS: When subtraction images were available, the mean reviewing time per case was reduced significantly from 13.6 to 10.8 seconds for the cases with newly developed abnormalities (p < 0.001) and from 29.8 to 14.1 seconds for negative cases (p < 0.001). The reduction in the mean reviewing time with subtraction images was greater for clean images than for images with artifacts (17.7 vs 14.5 seconds, p < 0.001). The average mean area under the ROC curve value increased significantly from 0.942 without subtraction images to 0.988 with subtraction images (p = 0.025). There were significant differences in the sensitivity (0.963 with and 0.888 without the subtraction images) and the specificity (0.976 with and 0.899 without the subtraction images) (p < 0.001). CONCLUSION: The temporal subtraction technique can reduce reviewing time and also improve diagnostic accuracy in the interpretation of chest radiographs.

Etidronic Acid↗

PubMed2006

The critical roles of serum/glucocorticoid-regulated kinase 3 (SGK3) in the hair follicle morphogenesis and homeostasis: the allelic difference provides novel insights into hair follicle biology.

Mutation in the serum/glucocorticoid regulated kinase 3 (Sgk3, also known as Sgkl or Cisk) gene causes both defective hair follicle development and altered hair cycle in mice. We examined Sgk3-mutant YPC mice (YPC-Sgk3(ypc)/Sgk3(ypc)) and found expression of SGK3 protein with altered function. In the hair follicles of YPC mice, the aberrant differentiation and poor proliferation of hair matrix keratinocytes during the period of postnatal hair follicle development resulted in a complete lack of hair medulla and weak hair. Surprisingly, the length of postnatal hair follicle development and anagen term was shown to be dramatically shortened. Also, phosphorylation of GSK3beta at Ser9 and the nuclear accumulation of beta-catenin were reduced in the developing YPC hair follicle, suggesting that phosphorylation of GSK3beta and WNT-beta-catenin pathway takes part in the SGK3-dependent regulation of hair follicle development. Moreover, the above-mentioned features, especially the hair-cycling pattern, differ from those in other Sgk3-null mutant strains, suggesting that the various patterns of dysfunction in the SGK3 protein may result in phenotypic variation. Our results indicate that SGK3 is a very important and characteristic molecule that plays a critical role in both hair follicle morphogenesis and hair cycling.

Alleles↗

PubMed2006

Integrating PET and CT information to improve diagnostic accuracy for lung nodules: A semiautomatic computer-aided method.

UNLABELLED: Our objective was to develop and evaluate 3 semiautomatic computer-aided diagnostic (CAD) schemes for distinguishing between benign and malignant pulmonary nodules by use of features extracted from CT, 18F-FDG PET, and both CT and 18F-FDG PET. METHODS: We retrospectively collected 92 consecutive cases of pulmonary nodules (<3 cm) in patients who underwent both thoracic CT and whole-body PET/CT. Forty-two of the nodules were malignant and 50 benign, as confirmed by pathologic examination and clinical follow-up. The interval between CT and PET was less than 1 mo. Four clinical parameters, including patient age, sex, smoking status, and history of previous malignancy, were used for the CAD schemes. Sixteen CT features based on size, shape, margin, and internal structure of nodules were independently rated subjectively by 2 chest radiologists. Four PET features were viewed on a PET/CT workstation. CAD schemes based on clinical parameters together with CT features, PET features, and both CT and PET features were then used to differentiate benign from malignant nodules. Finally, the output from the CAD schemes was evaluated by use of receiver-operating-characteristic analysis. RESULTS: When we used clinical parameters and CT features as input units (CAD scheme 1), the area under the receiver-operating-characteristic curve (A(z) value) of the CAD scheme was 0.83. When we used clinical parameters and PET features as input units (CAD scheme 2), the A(z) value for the computer output was 0.91. However, when we used all data as input units (CAD scheme 3), the A(z) value for the computer output was 0.95. The performance of CAD scheme 3 was better than that of CAD scheme 1 or 2. A statistically significant difference existed between the A(z) values of CAD schemes 3 and 2 (P = 0.037) and between those of CAD schemes 3 and 1 (P = 0.015). CONCLUSION: Our CAD scheme based on both PET and CT was better able to differentiate benign from malignant pulmonary nodules than were the CAD schemes based on PET alone and CT alone.

Aged↗

PubMed2005

Changes in cytochrome P450 isozymes (CYPs) protein levels during lactation in rat liver.

The effects of pregnancy on CYPs protein level in the liver have been investigated in our previous study. Since pregnancy was associated with a decrease in CYPs protein level, the objective of this study was to investigate whether CYPs protein can revert to the virgin control level after delivery. Western blot analysis was performed to investigate the changes of total nine CYPs protein (CYP1A1, CYP2B1/CYP2B2, CYP2C6, CYP2C12, CYP2D1, CYP2D4, CYP2E1, CYP3A1 and CYP4A1) at three distinct phases: delivery (postpartum day 0, PPD 0), peak lactation (PPD 14) and on weaning (PPD 28). By PPD 0, CYP1A1, 2B1, 2B2, 2C6, 2E1 and CYP4A1 were markedly down-regulated when compared with virgin controls. By PPD 14, however, CYP1A1, 2B1, 2B2 and CYP2C6 returned to the virgin control level. All the decreased CYPs during lactation were at the virgin control level at PPD 28. The expression of CYP2C12, CYP2D1 and CYP 3A1 did not differ between lactating, post-lactation and virgin control rats. CYP2D4 was not detectable in microsomal proteins obtained from virgin control rats at a protein loading of 20 mug total protein per lane.

Animals↗

PubMed2005

Microarray analysis on Phase II drug metabolizing enzymes expression in pregnant rats after treatment with pregnenolone-16alpha-carbonitrile or phenobarbital.

We previously reported the expression profiles of 9 cytochrome P450 isozymes (CYPs) proteins and those of 40 CYPs genes in pregnant rat's liver, placenta and fetal liver after treatment with pregnenolone-16alpha-carbonitrile (PCN) or phenobarbital (PB). This study was carried out focusing on the gene expression profiles of Phase II drug metabolizing enzymes, Glutathione S-transferase isozymes (GSTs) and UDP-glycosyltransferase isozymes (UDPGTs). Fischer 344 (F344) pregnant rats were daily treated intraperitoneally with 50 mg/kg of PCN or 80 mg/kg of PB from 13 to 16 days of gestation (DG). They were sacrificed on 17 DG, and microarray analysis using Affymetrix Rat Expression Array 230 A was performed. Among 16 GSTs genes examined in this study, 7 genes were significantly induced in dam's liver and 3 genes in fetal liver, respectively, in the PCN-group, while 8 genes were significantly induced in dam's liver and 1 gene in fetal liver, respectively, in the PB-group. On the other hand, among 11 UDPGTs genes examined, 5 genes were significantly induced in dam's liver and 3 genes in fetal liver, respectively, in the PCN-group, while 5 genes were significantly induced in dam's liver and 1 gene in fetal liver, respectively, in the PB-group. There were no significant changes in the placenta of all groups. This is the first report of the gene expression profiles of Phase II drug metabolizing enzymes in pregnant rat and fetal livers and placenta after treatment with typical inducers of drug metabolizing enzymes.

Animals↗

PubMed2005

Intracranial aneurysms at MR angiography: effect of computer-aided diagnosis on radiologists' detection performance.

PURPOSE: To retrospectively evaluate the effect of computer-aided detection (CAD) on radiologists' performance in detection of intracranial aneurysms with magnetic resonance (MR) angiography. MATERIALS AND METHODS: The institutional review board approved this study and did not require patient informed consent. Fifty maximum intensity projection MR angiograms in 50 patients were used for observer performance study. The group included 22 patients (age range, 43-86 years; mean, 60.2 years; 6 men and 16 women) with intracranial aneurysms and 28 patients (age range, 32-80 years; mean, 58.8 years; 10 men and 18 women) without aneurysms. The MR angiograms were obtained with three-dimensional time-of-flight 1.5-T MR imaging. Fifteen radiologists, including eight neuroradiologists and seven general radiologists, participated in the observer performance test. They interpreted the angiograms first without and then with the aid of the computer output by using an automated computerized scheme. The observers' performance without and with the computer output was evaluated with receiver operating characteristic analysis. RESULTS: For all 15 observers, average area under the receiver operating characteristic curve (A(z)) value for detection of aneurysms was increased significantly from 0.931 to 0.983 (P = .001) when they used the computer output. A(z) values for general radiologists and neuroradiologists increased from 0.894 to 0.983 (P = .022) and from 0.963 to 0.984 (P = .014), respectively. Improvement in the performance of general radiologists in terms of the A(z) value was much greater than that of neuroradiologists. Performance of general radiologists with CAD (A(z) = 0.983) slightly exceeded that of neuroradiologists without CAD (A(z) = 0.963) (P = .048). CONCLUSION: CAD improved neuroradiologists' and general radiologists' performance for detection of intracranial aneurysms with MR angiography; improvement was greater for general radiologists than it was for neuroradiologists.

Adult↗

PubMed2005

Hair cycle induction by hair plucking in Mini rats.

Jcl:WistarTGN(ARGHGEN)1Nts rat (Mini rat) is a transgenic rat in which the growth hormone (GH) expression is suppressed by the presence of an antisense transgene for the rat GH gene, and the hair cycle of male Mini rats enters a long-lasting telogen phase after 8 weeks old. In the present study, effects of hair plucking on the hair cycle in the dorsal skin of 11-week-old male Mini rats were examined up to 54 days after the hair plucking. As a result, hair plucking brought about an anagen phase, and hair cycle arrest in telogen phase occurred again. Male Mini rats, having follicles in anagen-inducible long-lasting telogen phase, will offer a powerful tool for investigating the molecular nature and organization of the so-called hair cycle clock.

Animals↗

PubMed2005

Encepalomyocarditis virus-induced apoptosis and ultrastructural changes in the lacrimal and parotid glands of mice.

Development of acinar cell apoptosis and ultrastructural changes in the exorbital lacrimal and parotid glands was examined in DBA/2 mice infected with 10(2) PFU/mouse of EMC-D virus. Pyknotic acinar cells, most of which were positive for TUNEL and cleaved caspase-3 and had ultrastructural characteristics of apoptotic cells, developed earlier and were more frequently observed in the parotid gland than in the exorbital lacrimal gland, while the total damage of acinar cells and interstitial infiltration of macrophages were more prominent in the latter than in the former. These findings indicate that EMC-D virus induces acinar cell apoptosis in these glands. In addition, corresponding to the results of the detection of viral RNA signals by in situ hybridization, small aggregates of virus-like particles having typical size and structure of EMC virus were frequently observed in both the cytoplasm and the nucleus of acinar cells in the exorbital lacrimal gland, while they were found only in the cytoplasm of a few acinar cells in the parotid gland. In conclusion, between the exorbital lacrimal and parotid glands, there was a reverse relationship observed between the development of acinar cell apoptosis and that of total damage of acinar cells.

Animals↗

PubMed2005

Hydroxyurea (HU)-induced apoptosis in the mouse fetal lung.

In this study, the cytotoxicologic effects of HU on the fetal lung were assessed by exposing pregnant mice to HU on day 13 of gestation. The number of TUNEL-positive cells, i.e., apoptotic cells, in the fetal lung began to increase at 3 h after treatment (h), peaked at 6 h, and decreased thereafter, and the sequence of the number of cleaved caspase 3-positive cells corresponded to that of TUNEL-positive cells. Such positive reactivity for TUNEL and cleaved caspase 3 was mainly seen in pulmonary mesenchymal cells. Prior to the induction of apoptosis, the number of p53-positive cells in the fetal lung prominently increased at 1 and 3 h, and decreased thereafter. Among p53 transcriptional target genes (p21, fas, bax, apaf1, cyclin G, mdm2, and gad 45) examined, the expression levels of p21, bax, and cyclin G mRNAs were significantly elevated. In addition, the expression of fas mRNA tended to show higher levels compared with controls until 24 h. In addition, the results of flow cytometric analysis suggested that cell cycle arrest might be induced in S phase at 3 h. The present results suggest that HU-induced apoptosis in the mouse fetal lung may be closely related with the induction of p53.

Animals↗

PubMed2005

Impaired proliferation of non-parenchymal cells participates in an impairment of liver regeneration in db/db mice.

In this study, we examined the possibility that impaired proliferation of non-parenchymal cells affects in an impairment of liver regeneration in db/db mice, which are congenitally deficient in receptors for leptin. Liver regeneration after a two thirds partial hepatectomy (2/3 PH) was impaired in 10-week-old female db/db mice. The proliferation of both hepatocytes and non-parenchymal cells estimated from a bromodeoxyuridine (BrdU) labeling index was suppressed, and the protein expression of vascular endothelial growth factor was blocked in db/db mice. Although the extent of fatty change and the level of epidermal growth factor receptor protein expression in the liver were improved in 5-week-old db/db mice, the regeneration of liver was impaired after 2/3 PH in both 5- and 10-week-old db/db mice. These results suggested that suppressed proliferation of non-parenchymal cells contributes to the impairment of liver regeneration in db/db mice. As leptin has also the angiogenic effect, the angiogenic inhibitor FR-118487 was administered to ICR mice to examine liver regeneration after 2/3 PH, and the rate of regeneration was affected. In conclusion, it is suggested that the suppressed proliferation of non-parenchymal cells contributes to the impairment of liver regeneration probably through a disrupted angiogenesis in db/db mice.

Angiogenesis Inhibitors↗