Biomedical subjects

R Kimura

Publications and source records attributed to R Kimura.

At least 19 recordsLinked to original sources

PubMed2006

Plasma protein S activity correlates with protein S genotype but is not sensitive to identify K196E mutant carriers.

BACKGROUND: Protein S (PS) is an anticoagulant protein that functions as a cofactor for activated protein C (APC), and congenital PS deficiency is a well-known risk factor for the development of deep vein thrombosis (DVT). Recently, we and others identified the K196E missense mutation in the second epidermal growth factor-like domain of PS as a genetic risk factor for DVT in the Japanese population. The incidence of this mutation is high in the Japanese population. OBJECTIVES: In the present study, we investigated the relationship between plasma PS activity and the presence of the K196E mutation. PATIENTS AND METHODS: We measured PS activity as a cofactor activity for APC in 1,862 Japanese individuals and determined the PS K196E genotype in this population. RESULTS: Individuals heterozygous for the mutant E-allele had lower plasma PS activity than wildtype subjects (mean +/- SD, 71.9 +/- 17.6%, n = 34 vs. 87.9 +/- 19.8%, n = 1,828, P < 0.0001). However, the PS activity of several heterozygous individuals (n = 8) was greater than the population average. In contrast, multiple wildtype subjects (n = 26) had PS activity less than 2 SD below the population mean, indicating that other genetic or environmental factors affect PS activity. CONCLUSIONS: Plasma PS activity itself is not suitable for identifying PS 196E carriers and other methods are required for carrier detection.

Adult↗

PubMed2005

Vascular endothelial growth factor antagonist reduces brain edema formation and venous infarction.

BACKGROUND AND PURPOSE: Cerebral venous ischemia often induces severe brain edema. Vascular endothelial growth factor (VEGF), which induces angiogenesis, is also known as vascular permeability (VP) factor. The present study was undertaken to investigate whether the inhibition of VEGF could reduce brain edema formation and cerebral venous infarction (CVI) in a rat 2-vein occlusion (2-VO) model. METHODS: We used 2-VO model in which 2 adjacent cortical veins were photochemically occluded. Male Wistar rats (n=25) were divided into 2 groups: one group was treated with a VEGF antagonist (antagonist group, n=10) and the second group was treated with phosphate-buffered solution (PBS) (PBS group, n=15). VEGF antagonist or PBS was injected intraperitoneally immediately after 2-VO. The developing ischemic infarct was evaluated by magnetic resonance imaging (MRI) and histology 24 hours after occlusion. RESULTS: VEGF expression was observed in the cytoplasm of neurons exclusively in the area of vasogenic edema that was shown as a high-intensity area in the apparent diffusion coefficient of water map. Ischemic volumes calculated from each MR images, which are related to infarction and/or vasogenic edema, respectively, were significantly smaller in the antagonist group as compared with the PBS group (P<0.05) CONCLUSIONS: Our study is the first to provide evidence that the inhibition of VEGF attenuates VP and reduces CVI in the acute stage. Although VEGF is a significant angiogenesis factor, we concluded that the inhibition of VEGF might be a new therapy for both brain edema formation and CVI.

Animals↗

PubMed2005

Clinical features of postoperative cerebral venous infarction.

There is a potential risk of sacrificing the cortical vein during neurosurgical operations, particularly in the interhemispheric or subtemporal approach. An impaired cortical vein might cause cerebral venous circulatory disturbances (CVCDs) resulting in venous infarction. In this article, we have reviewed the management and results of eight cases with symptomatic postoperative venous infarction. We have encountered eight cases with symptomatic postoperative venous infarction (0.3%) during the past 5 years. The series is composed of 3 males and 5 females, with ages that ranged from 43 to 76 years (mean age of 58.1 years), and consisted of five brain tumors, one cavernoma, one dural AVF, and one trigeminal neuralgia. Initial symptoms occurred intra-operatively in two, on 0 day after the operation in one, 1 day in three, 3 days in one, and 4 days in one case. The symptoms were intra-operative brain edema in two cases, disorientation in one, cerebellar signs in one, hemiparesis in one, aphasia in two, and headache in one case. Two cases required surgical intervention. The results were a good outcome in 6 and a fair outcome in 2 cases. In conclusion, there are two types of postoperative venous infarction; severe onset (severe type) and gradual onset (mild type). The former needs immediate treatment from the intra-operative period onward, and the prevention of the ongoing venous thrombosis is essential in the latter.

Adult↗

PubMed2004

Syringomyelia caused by cervical spondylosis.

Syringomyelia is generally associated with Chiari type malformations, spinal tumors, or spinal trauma. Cervical spondylosis is only rarely involved. We here present a case of a 64-year-old woman with severe radicular pain in the right arm and the syringomyelic syndrome. Lateral radiographs of the cervical spine demonstrated spondylotic change at the C4/5 and C6/7 levels, and instability at C4/5. Dynamic magnetic resonance (MR) imaging revealed the spinal cord to be compressed at C5 and C6 with the body in extension, and the syrinx extended from C2 to the Th3 level on sagittal images. It was reduced remarkably after anterior decompression and stabilization at C4/5 and C6/7, and her symptoms also improved after surgery. We concluded that the syrinx in this case might have developed due to craniospinal pressure dissociation caused by intermittent spinal cord compression.

Cervical Vertebrae↗

PubMed2004

Cis-acting effect of the IL1B C-31T polymorphism on IL-1 beta mRNA expression.

Since the effect of IL1B polymorphisms on IL-1beta production is still controversial, we selected two polymorphisms to test their cis-acting effect on IL-1beta mRNA expression by means of the allele-specific transcript quantification and the haplotype analysis. As for the C-31T polymorphism, we found that expression of the -31T allele was 2.2 times of the -31C allele. This higher transcription efficiency may correspond to the fact that C-31T is located in a TATA box. The other polymorphism, C+3954T, did not alter the levels of transcription. The use of the allele-specific transcript quantification enables us to exclude trans-acting effects of polymorphisms on the gene expression and contributes to understanding the roles of the IL1B polymorphisms in susceptibility to multifactorial diseases.

Cell Line↗

PubMed2003

Vasogenic edema and VEGF expression in a rat two-vein occlusion model.

Vasogenic edema plays an important etiologic role in the pathogenesis of cerebral venous circulation disturbances (CVCDs). Since vascular endothelial growth factor (VEGF) is a major mediator in angiogenesis and vascular permeability, including induction of vasogenic edema, the present study was undertaken to investigate whether it has any relevance to CVCDs. Male Wistar rats (n = 15) were used. Two adjacent cortical veins were occluded photochemically using rose bengal dye and fiberoptic illumination, with evaluation 24 hours thereafter by magnetic resonance imaging (MRI). Each brain was removed from the skull immediately after MRI and processed for hematoxylin-eosin staining (H&E staining) of sections for histopathology and comparison with MRI data. VEGF expression as demonstrated immunohistochemically appeared to coincide with vasogenic edema, diagnosed as high intensity areas on apparent diffusion coefficient of water (ADCw) maps. On the basis of these data, we conclude that VEGF is related to formation of vasogenic edema in the acute stage of CVCD.

Animals↗

PubMed2003

Distribution of OL-protocadherin protein in correlation with specific neural compartments and local circuits in the postnatal mouse brain.

OL-protocadherin (OL-pc) is a cell adhesion molecule that belongs to the cadherin superfamily. A previous study showed that expression of OL-pc mRNA was specific to certain brain nuclei including those of the olfactory and limbic systems, thus suggesting its involvement in neural circuit formation. Here, we examined the distribution of OL-pc protein in the postnatal mouse brain by immunohistochemistry to confirm the possibility of such a role. The results showed that the protein could be mapped to many brain compartments including brain nuclei and higher subdivisions as previously observed for the expression pattern of the mRNA. Sharp boundaries of the distribution were often seen in areas such as the interpedunclar nucleus, cerebellar cortex, and inferior olive. In addition, the protein was detected in some fibers that could not be examined by the previous study using in situ hybridization. For example, prominent staining was noted in the stria medularis, stria terminalis, fasciculus retroflexus, optic tract, and inferior thalamic radiation, structures that seem to connect OL-pc-positive brain regions. These OL-pc-positive brain nuclei and fiber tracts coincide with some local circuits of functional systems such as the olfactory system, nigrostriatal projection, olivo-cerebellar projection, and visual system. These results support the possibility that OL-pc is involved in the formation of specific neural compartments and circuits in the developing brain.

Aging↗

PubMed2003

The SDF1-G801A polymorphism is not associated with SDF1 gene expression in Epstein-Barr virus-transformed lymphoblastoid cells.

The effects of the SDF1-3'A on AIDS progression have been attributed to the altered amount of stromal cell-derived factor 1 (SDF-1). However, the contribution of the SDF1-G801A polymorphism to SDF-1 expression is still unclear. In contrast to fresh peripheral blood mononuclear cells (PBMCs), Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs) express the SDF-1 mRNA. Using EBV-transformed LCLs from 42 individuals with different genotypes, we investigated the SDF-1 mRNA levels and methylation status in the SDF1 gene. Both in PBMCs and in EBV-transformed LCLs, CpG dinucleotides in the 5' region of the SDF1 gene were unmethylated. As for the 3' untranslated region (3'UTR), by contrast, CpG dinucleotides were methylated in PBMCs, whereas site-specific demethylation around the polymorphic site was detected in EBV-transformed LCLs. The levels of the demethylation were correlated with the SDF-1 mRNA levels. However, the genotype for the SDF1-G801A polymorphism did not significantly alter the SDF-1 mRNA levels. The allele preferences in transcription and methylation were also absent in the heterozygous cells. In conclusion, this study suggested a contribution of site-specific demethylation in the 3'UTR to the SDF1 gene expression, but did not show any evidence for the contribution of the SDF1-G801A polymorphism to the amount of the SDF-1 mRNA.

Alleles↗

PubMed2002

The contribution of 2,3,5-trichlorophenyl methyl sulfone, a metabolite of 1,2,4-trichlorobenzene, to the delta-aminolevulinic acid synthetase induction by 1,2,4-trichlorobenzene in rat liver.

In the present study, we investigated the contribution of methylsulfonyl metabolite derived from 1,2,4-trichlorobenzene (1,2,4-TCB) on the delta-aminolevulinic acid (ALA) synthetase induction by the parent compound in rats. The time courses of increasing of hepatic microsomal total cytochrome P450 content after a single i.p. administration of 1,2,4-TCB (1.36 mmol/kg), and 2,3,5- and 2,4,5-trichlorophenyl methyl sulfones (2,3,5- and 2,4,5-TCPSO2Mes) (50 micromol/kg each) were in parallel with those of increasing of the total heme content in liver microsomes. 1,2,4-TCB significantly increased the heme oxygenase activity, but 2,3,5- and 2,4,5-TCPSO2Mes did not. On the other hand, 1,2,4-TCB and 2,3,5-TCPSO2Me markedly enhanced the ALA synthetase activity. No change was observed in this enzyme activity after the administration of 2,4,5-TCPSO2Me. After the administration of 1,2,4-TCB to the rats treated with DL-buthionine-(S,R)-sulfoximine (BSO) and to the non-BSO-treated rats, the concentrations of both 2,3,5- and 2,4,5-TCPSO2Mes were significantly lower in liver of the BSO-treated rats than in liver of the non-BSO-treated rats. Additionally, the 1,2,4-TCB did not elevate the ALA synthetase activity in the BSO-treated rats. On the other hand, the administration of 2,3,5-TCPSO2Me to BSO-treated rats resulted in induction of ALA synthetase. The results strongly suggest that the methyl sulfone derived from 1,2,4-TCB, i.e., 2,3,5-TCPSO2Me, contributes highly to the induction of the ALA synthetase activity by the parent compound.

5-Aminolevulinate Synthetase↗

PubMed2002

Metabolite of 2,2',4',5-tetrabromobiphenyl, 3-methylsulphonyl-2,2',4',5-tetrabromobiphenyl, a potent inducer of CYP2B1/2 in rat.

1. 3-Methylsulphonyl- and 4-methylsulphonyl-2,2',4',5-tetrabromobiphenyls (3-MeSO(2)- and 4-MeSO(2)-TetraBrBs) were detected in the liver, lung, kidney, adipose tissue and faeces of the 2,2',4',5-tetrabromobiphenyl (TetraBrB)-dosed rat. 2. The administration of 0.05-2.0 micromol kg(-1) doses of 3-MeSO(2)-TetraBrB produced corrresponding increases in the hepatic concentration of the methyl sulphone metabolite, corresponding increases in the content of total cytochrome P450, and corresponding increases in the activities of 7-benzyloxy-, 7-ethoxy- and 7-pentoxyresorufin O-dealkylases. The inducing effects of the 3-MeSO(2)-TetraBrB (0.2 micromol kg(-1)), both on the content of total P450 and on the activities of the three alkoxyresorufin O-dealkylases, were higher than that of the parent TetraBrB (342 micromol kg(-1)). 3. The major phenobarbital (PB)-inducible forms of P450, CYP2B1, CYP2B2, CYP3A2 and CYP2C6, were substantially induced by 3-MeSO(2)-TetraBrB, but CYP1A1 and CYP1A2 were not. On the other hand, the activities of drug-metabolizing enzymes and the four PB-inducible forms of P450 were unchanged by 4-MeSO(2)-TetraBrB treatment. 4. The induction profiles of these enzymes and P450 forms in rat treated with 3-MeSO(2)-TetraBrB were similar to those treated with PB. 5. The inducing ability of 3-MeSO(2)-TetraBrB (0.5 micromol kg(-1)) both on the activities of the three alkoxyresorufin O-dealkylases and on the contents of four PB-inducible forms of P450 was roughly equal to that of PB (431 micromol kg(-1) twice at a 24-h interval) or 3-MeSO(2)-2,2',4',5-tetrachlorobiphenyl (1 micromol kg(-1)). It is noteworthy that the effects of 3-MeSO(2)-TetraBrB on the drug-metabolizing enzymes CYP2B1 and CYP2B2 were several thousand-fold higher than those of parent TetraBrB, while the effect of its isomeric 4-MeSO(2)-TetraBrB were not. 6. The extent of hepatic accumulation of the 3-MeSO(2) metabolite after the administration of TetraBrB (342 micromol kg(-1)) was almost the same as that after the administration of 3-MeSO(2)-TetraBrB (0.1-0.2 micromol kg(-1)). The relationship between the hepatic concentration of the 3-MeSO(2) metabolite and the extent of enzyme induction after the administration of TetraBrB or 3-MeSO(2)-TetraBrB suggests that 3-MeSO(2)-TetraBrB plays an important role in the induction of microsomal drug-metabolizing enzymes by TetraBrB.

Animals↗

PubMed2002

Selective and sustained occupancy of prostatic alpha1-adrenoceptors by oral administration of KMD-3213 and its plasma concentration in rats.

This study examined the ex-vivo occupancy by KMD-3213 of alpha1-adrenoceptors in the prostate and other tissues of rats in terms of tissue selectivity and duration of occupancy in relation to plasma concentration. Oral administration of KMD-3213 (0.2-20.2 micromol kg(-1), 0.5 h) dose-dependently decreased [3H]prazosin binding sites (Bmax) in the prostate (42-74%) and submaxillary gland (54-88%) compared with the control value. In contrast, there was only a slight change in the Bmax values in the spleen and cerebral cortex of KMD-3213-treated rats. The alpha1-adrenoceptor occupancy in the prostate and submaxillary gland was increased, with plasma free concentration of KMD-3213 at 0.5 h after oral administration of KMD-3213 (0.6-20.2 micromol kg(-1)). The receptor occupancy in these tissues was much greater than that in the spleen, heart or cerebral cortex. After oral administration of KMD-3213 (6.1 micromol kg(-1)), the alpha1-adrenoceptor occupancy in the prostate and submaxillary gland occurred rapidly, in parallel with the rise in the plasma concentration of the drug, and it lasted for at least 24 h, despite a remarkable decrease in the plasma concentration. It is concluded that KMD-3213 may produce fairly selective and sustained occupancy of alpha1-adrenoceptors in the prostate, a target organ for treatment of bladder outlet obstruction in patients with benign prostatic hyperplasia.

Administration, Oral↗

PubMed2002

High prevalence of anticardiolipin antibodies in patients with HCV-associated oral lichen planus.

Hepatitis C virus (HCV) has been linked to extrahepatic manifestations such as oral lichen planus (OLP). In addition, anticardiolipin antibodies (aCL) and cryoglobulin have been demonstrated in chronic hepatitis C. The aim of this study was to investigate these prevalences in patients with HCV-associated OLP. The prospective study investigated the role of these factors in 133 subjects: 28 with OLP-HCV(+) (group 1), 22 with OLP-HCV(-) (group 2), 33 without OLP-HCV(+) (group 3), and 50 healthy volunteers matched for age and sex served as control group (group 4). Levels of immunoglobulin G (IgG) and IgM aCL antibodies, and cryoglobulin in serum were evaluated by enzyme-linked immunosorbent assay. The prevalence of aCL in groups 1, 2, 3, and 4 were 32.1, 18, 36.3, and 8%, respectively. The positive rate of aCL was significantly higher in groups 1 and 3 than that in the control group (group 1; p=0.02 vs. the control group, group 3; p<0.01 vs. the control group). There were no significant differences in cryoglobulin among the groups. The findings of the present study showed a high prevalence of IgG and IgM aCL in the serum of patients with HCV infectious diseases. A positive factor for aCL was determined by age, sex, the presence of OLP, and HCV infection.

Adult↗

PubMed2001

Brain receptor binding characteristics and pharmacokinetic-pharmacodynamic analysis of thyrotropin-releasing hormone analogues.

Thyrotropin-releasing hormone (TRH) receptor binding in the rat brain after intravenous (i.v.) injections of novel TRH analogues, taltirelin and montirelin, was examined and the data were analyzed in relation to their plasma concentrations which were simultaneously determined. Taltirelin and montirelin inhibited specific [3H]-Me-TRH binding in the rat brain and their Ki values were 311 and 35.2 nM, respectively. The i.v. injection of taltirelin and montirelin (0.1-3 mg/kg) produced a significant reduction in [3H]-Me-TRH binding sites (Bmax values) in the rat brain. The reduction by both agents tended to reach a maximum after 60 min and lasted up to at least 120 min. On the other hand, the i.v. injection of both agents had little significant effect on the apparent dissociation constant (Kd) for [3H]-Me-TRH in the rat brain. Plasma concentrations of taltirelin and montirelin in rats peaked immediately after i.v. injection, and thereafter they decreased with t 1/2 of 23.0 and 14.1 min, respectively. Counter-clockwise hysteresis between the plasma concentration and receptor occupancy of these agents was observed after the i.v. injection of taltirelin and montirelin, and the temporal delay between plasma concentration and brain receptor occupancy was successfully minimized using the "effect compartment" model in combination with the "linear-effect" model. We concluded that taltirelin and montirelin exert a fairly potent effect following sustained occupation of brain TRH receptors under in vivo condition. Thus, both agents could be clinically useful for the treatment of CNS disorders.

Animals↗

PubMed2001

Further comments on fibrosing colonpathy study.

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Animals↗

PubMed2001

Sequential-replenishment mechanism of exocytosis in pancreatic acini.

Here we report exocytosis of zymogen granules, as examined by multiphoton excitation imaging in intact pancreatic acini. Cholecystokinin induces Ca 2+ oscillations that trigger exocytosis when the cytosolic Ca 2+ concentration exceeds 1 microM. Zymogen granules fused with the plasma membrane maintain their Omega-shaped profile for an average of 220 s and serve as targets for sequential fusion of granules that are located within deeper layers of the cell. This secondary exocytosis occurs as rapidly as the primary exocytosis and accounts for most exocytotic events. Granule-granule fusion does not seem to precede primary exocytosis, indicating that secondary fusion events may require a plasma-membrane factor. This sequential-replenishment mechanism of exocytosis allows the cell to take advantage of a large supply of fusion-ready granules without needing to transport them to the plasma membrane.

Animals↗

PubMed2001

A mutation of the Wilson disease protein, ATP7B, is degraded in the proteasomes and forms protein aggregates.

BACKGROUND & AIMS: Wilson disease is a genetic disorder characterized by the accumulation of copper in the body as a result of a defect of copper excretion from hepatocytes. The intracellular localization of the Wilson disease gene product, ATP7B, was recently identified as the late endosomes. Various mutations have been documented in patients with Wilson disease. The clinical manifestations vary greatly among the patients; however, there is little information on the genotype-phenotype correlation. METHODS: We investigated the distribution of a common ATP7B mutant His1069Gln and a mutant Asp1270Ser by expressing the mutants tagged with green fluorescent protein in Huh7 and HEK293 cells. Intracellular organelles were visualized by fluorescence microscopy. RESULTS: Although the wild-type ATP7B and Asp1270Ser mutant localized in the late endosomes, His1069Gln mutant did not locate in the late endosomes and was degraded by the proteasomes in the cytoplasm. Furthermore, His1069Gln formed aggresomes composed of the degradates and intermediate filaments at the microtubule-organizing center. These aggresomes were similar to Mallory bodies on electron microscopy. CONCLUSIONS: The different protein properties of ATP7B mutants may explain the variety of clinical spectrums in patients with Wilson disease.

Acetylcysteine↗

PubMed2001

Involvement of p21(WAF1/Cip1), p27(Kip1), and p18(INK4c) in troglitazone-induced cell-cycle arrest in human hepatoma cell lines.

Peroxisome proliferator-activated receptor gamma (PPARgamma) regulates cell growth and differentiation. Recent evidence has suggested that PPARgamma ligands had anti-tumor effects through inhibiting cell growth and inducing cell differentiation in several types of malignant neoplasm. In the present study, we investigated: 1) the expression of PPARgamma in both human hepatoma cell lines and 5 resected human hepatocellular carcinoma (HCC) tissues; 2) the growth-inhibitory effect of troglitazone, a PPARgamma ligand, on those hepatoma cells; and 3) the molecular mechanisms of troglitazone-induced cell-cycle arrest. Five hepatoma cell lines, HLF, HuH-7, HAK-1A, HAK-1B, and HAK-5, were used. The mRNA expression levels of PPARgamma, p21(WAF1/Cip1), and p27(Kip1) were determined by real-time quantitative reverse transcription-polymerase chain reaction. The expression of cell cycle-regulating proteins, such as p21, p27, p18(INK4c), cyclin E, and pRb, was examined using Western blotting. PPARgamma was constitutively expressed in all the cell lines and the HCC tissues used in this study. A cytostatic effect of troglitazone was found in those cell lines, and this inhibition of cell growth was dosage-dependent. G0/G1 arrest was apparently demonstrated in flow cytometric analysis in HLF, HAK-1A, HAK-1B, and HAK-5, all of which showed an increased expression of p21 protein. However, HuH-7, lacking p21 protein expression, did not demonstrate clear arrest in the cell-cycle analysis. HLF, which was deficient in the protein product of the retinoblastoma tumor-suppressor gene (pRb), responded most profoundly to troglitazone, showing an increased expression in not only p21, but also in p27 and in p18. These findings suggested that p21, p27, and p18 might be involved in troglitazone-induced cell-cycle arrest in human hepatoma cells.

CDC2-CDC28 Kinases↗

PubMed2001

Alterations in tight junctions differ between primary biliary cirrhosis and primary sclerosing cholangitis.

Tight junctions (TJ) of biliary epithelial cells (BEC) and hepatocytes prevent bile regurgitation from the biliary tract. Alterations in these TJs may participate in chronic cholestatic liver diseases such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). We examined the localization of 2 TJ proteins, ZO-1 and 7H6, in these diseases. Frozen sections from livers of PBC, PSC, extrahepatic cholestasis (Ex-C), and hepatitis C-associated cirrhosis (LC-C), as well as histologically normal livers, were processed for double-fluorescence immunohistochemistry. In controls and cirrhosis, 7H6 and ZO-1 colocalized surrounding the luminal space of the bile ducts and outlined the bile canalicular spaces between hepatocytes. In untreated PBC, immunostaining for ZO-1 in BEC of bile ducts 40 to 80 microm in diameter was preserved, but that for 7H6 was diminished to absent. In PBC treated with ursodeoxycholic acid (UDCA), immunostaining for 7H6 was well preserved. In PSC as well as in Ex-C, immunostaining for both 7H6 and ZO-1 was well preserved in bile ducts. In hepatocytes, ZO-1 showed preserved immunoreactivity, but immunostaining for 7H6 frequently disappeared. The percentage of bile ducts with immunostaining for 7H6 in all bile ducts with immunostaining for ZO-1 was significantly reduced in PBC compared with that in control, LC-C, Ex-C, and PSC (all P <.0001). Substantial alteration in the TJ protein occurs predominantly in bile ducts in PBC and in hepatocytes in PSC, suggesting increased paracellular permeability along different paracellular routes for bile regurgitation in these chronic cholestatic liver diseases.

Adolescent↗