Left lobe living donor liver transplantation in adults.

Adult left lobe (LL) living donor liver transplantation (LDLT) has not generally been recognized as a feasible procedure because of the problem of graft size. The objectives of this study were to assess the feasibility and short- and long-term results of adult LL LDLT in comparison with right lobe (RL) LDLT. Data on 200 consecutive LL LDLTs, including five retransplants, were retrospectively compared with those of 112 RL LDLTs, in terms of survival, complications and donor morbidity. The mean graft weight to standard volume ratio of LL grafts was 38.7% whereas that of RL grafts was 47.6% (p < 0.0001). The 1-, 5- and 10-year patient survival rates of LL LDLT were 85.6%, 77.9% and 69.5%, respectively, which were comparable to those of RL LDLT (89.8%, 71.3% and 70.7%, respectively). The incidence of small-for-size syndrome was higher in LL LDLT (19.5%) than in RL LDLT (7.1%) (p < 0.01). The overall donor morbidity rates were comparable between LL (36.0%) and RL (34.8%), whereas postoperative liver function tests and hospital stay were significantly better (p < 0.0001) in LL donors. In conclusion, adult LL LDLT has comparable outcomes to that of RL LDLT. LL LDLT is viable and is the first choice in adult LDLT.

Inhibition of renin-angiotensin system affects prognosis of advanced pancreatic cancer receiving gemcitabine.

BACKGROUND: The renin-angiotensin system (RAS) is thought to have a role in carcinogenesis, and RAS inhibition may prevent tumour growth. METHODS: We retrospectively investigated the impact of angiotensin I-converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs) in 155 patients with pancreatic cancer receiving gemcitabine monotherapy. Patients were divided into three groups: the ACEI/ARB group (27 patients receiving an ACEI or ARB for hypertension (HT)), the non-ACEI/ARB with HT group (25 patients receiving antihypertensive drugs other than ACEIs or ARBs), and the non-HT group (103 patients receiving no antihypertensive drugs). RESULTS: Patient characteristics were not different, except for age and HT medications. Progression-free survival (PFS) was 8.7 months in the ACEI/ARB group, 4.5 months in the non-ACEI/ARB with HT group, and 3.6 months in the non-HT group. Overall survival (OS) was 15.1 months in the ACEI/ARB group, 8.9 months in the non-ACEI/ARB with HT group, and 9.5 months in the non-HT group. The use of ACEIs/ARBs was a significant prognostic factor for both PFS (P=0.032) and OS (P=0.014) in the multivariate analysis. CONCLUSIONS: The ACEIs/ARBs in combination with gemcitabine might improve clinical outcomes in patients with advanced pancreatic cancer. Prospective trials are needed to test this hypothesis.

Deceleration of regenerative response improves the outcome of rat with massive hepatectomy.

Small residual liver volume after massive hepatectomy or partial liver transplantation is a major cause of subsequent liver dysfunction. We hypothesize that the abrupt regenerative response of small remnant liver is responsible for subsequent deleterious outcome. To slow down the regenerative speed, NS-398 (ERK1/2 inhibitor) or PD98059 (selective MEK inhibitor) was administered after 70% or 90% partial hepatectomy (PH). The effects of regenerative speed on liver morphology, portal pressure and survival were assessed. In the 70% PH model, NS-398 treatment suppressed the abrupt replicative response of hepatocytes during the early phase of regeneration, although liver volume on day 7 was not significantly different from that of the control group. Immunohistochemical analysis for CD31 (for sinusoids) and AGp110 (for bile canaliculi) revealed that lobular architectural disturbance was alleviated by NS-398 treatment. In the 90% PH model, administration of NS-398 or PD98059, but not hepatocyte growth factor, significantly enhanced survival. The abrupt regenerative response of small remnant liver is suggested to be responsible for intensive lobular derangement and subsequent liver dysfunction. The suppression of MEK/ERK signaling pathway during the early phase after hepatectomy makes the regenerative response linear, and improves the prognosis for animals bearing a small remnant liver.

Estimation of standard liver volume for Japanese adults.

INTRODUCTION: Accurate pretransplant estimation of the recipient's standard liver volume (SLV) is important. The purpose of this study was to compare reported formulas for clinical estimation of liver volume among Japanese adults. METHODS: We reviewed data on 70 healthy adults (46 men, 24 women, ages 20 to 65 years old) evaluated for living donor liver transplantation. Liver volume (LV) was measured using two- or three-dimensional computed tomography volumetry (CTV). The formulas of DeLand (LV = 1020 x body surface area [BSA] - 220), Urata (LV = 706.2 x BSA + 2.4), Noda (LV = 50.12 x BW(0.78)), Heinemann (LV = 1072.8 x BSA - 345.7), Vauthey (LV = 18.51 x BW + 191.8) and Yoshizumi (LV = 772 x BSA) were applied to estimate LV. We calculated the differences for individual donors betwen CTV and LV estimated by each formula. RESULTS: Mean LVs as estimated by the formulae of DeLand and Heinemann et al were significantly greater (P < .01) than the mean CTV, while LV estimated by the formula of Urata was significantly less (P < .05) than the CTV. The formulas of DeLand and Heinemann overestimated LV, while the formula of Urata underestimated it. The formulae of Noda et al and Yoshizumi et al tended to underestimate the LV when the CTV was greater than 1600 cm(3). When the Yoshizumi formula was applied, the number of donors with an acceptable difference (+/-15%) between CTV and estimated LV was 55 (78.6%). CONCLUSIONS: The Yoshizumi formula was applicable, especially for patients with a BSA < 2.0, whereas the well-known Urata formula made LV underestimates.

The hepatitis B virus X protein enhances AP-1 activation through interaction with Jab1.

Hepatitis B virus X protein (HBx) has many cellular functions and is a major factor in hepatitis and hepatocellular carcinoma caused by HBV infection. A proteomic approach was used to search for HBx-interacting proteins in order to elucidate the molecular mechanism of hepatocarcinogenesis. HBx was attached to myc and flag tags (MEF tags) and expressed in 293T cells; the protein complex formed within the cells was purified and characterized by mass spectrometry. COP9 signalosome (CSN) subunits 3 and 4 were subsequently identified as HBx-interacting proteins. In addition, CSN subunit 5, Jun activation domain-binding protein 1 (Jab1), was shown to be a novel cellular target of HBx. In vivo and in vitro interactions between HBx and Jab1 were confirmed by standard immunoprecipitation and GST pull-down assays. An analysis of HBx deletion constructs showed that amino acids 30-125 of HBx were responsible for binding to Jab1. Confocal laser microscopy demonstrated that HBx was mainly localized in the cytoplasm, while Jab1 was found mainly in the nucleus and partially in the cytoplasm, and that the two proteins colocalized in the cytoplasm. The cotransfection of HBx and Jab1 resulted in substantial activator protein 1 (AP-1) activation and knockdown of endogenous Jab1 attenuated AP-1 activation caused by HBx. In addition, the coexpression of HBx and Jab1 potentiated phosphorylation of JNK, leading to the subsequent phosphorylation of c-Jun, whereas the level of c-Jun and JNK phosphorylation induced by HBx was decreased in Jab1 knockdown cells. These results suggest that the interaction between HBx and Jab1 enhances HBx-mediated AP-1 activation.

Impact of histone demethylase KDM3A-dependent AP-1 transactivity on hepatotumorigenesis induced by PI3K activation.

Epigenetic gene regulation linked to oncogenic pathways is an important focus of cancer research. KDM3A, a histone H3 lysine 9 (H3K9) demethylase, is known to have a pro-tumorigenic function. Here, we showed that KDM3A contributes to liver tumor formation through the phosphatidylinositol 3-kinase (PI3K) pathway, which is often activated in hepatocellular carcinoma. Loss of Kdm3a attenuated tumor formation in Pik3ca transgenic (Tg) mouse livers. Transcriptome analysis of pre-cancerous liver tissues revealed that the expression of activator protein 1 (AP-1) target genes was induced by PI3K activation, but blunted upon Kdm3a ablation. Particularly, the expression of Cd44, a liver cancer stem marker, was regulated by AP-1 in a Kdm3a-dependent manner. We identified Cd44-positive hepatocytes with epithelial-mesenchymal transition-related expression profiles in the Pik3ca Tg liver and confirmed their in vivo tumorigenic capacity. Notably, the number and tumor-initiating capacity of Cd44-positive hepatocytes were governed by Kdm3a. As a mechanism in Kdm3a-dependent AP-1 transcription, Kdm3a recruited c-Jun to the AP-1 binding sites of Cd44, Mmp7 and Pdgfrb without affecting c-Jun expression. Moreover, Brg1, a component of the SWI/SNF chromatin remodeling complex, interacted with c-Jun in a Kdm3a-dependent manner and was bound to the AP-1 binding site of these genes. Finally, KDM3A and c-JUN were co-expressed in 33% of human premalignant lesions with PI3K activation. Our data suggest a critical role for KDM3A in the PI3K/AP-1 oncogenic axis and propose a novel strategy for inhibition of KDM3A against liver tumor development under PI3K pathway activation.

Sharpin promotes hepatocellular carcinoma progression via transactivation of Versican expression.

Sharpin (Shank-associated RH domain-interacting protein, also known as SIPL1) is a multifunctional molecule that participates in various biological settings, including nuclear factor-κB signaling activation and tumor suppressor gene inhibition. Sharpin is upregulated in various types of cancers, including hepatocellular carcinoma (HCC), and is implicated in tumor progression. However, the exact roles of Sharpin in tumorigenesis and tumor progression remain largely unknown. Here we report novel mechanisms of HCC progression through Sharpin overexpression. In our study, Sharpin was upregulated in human HCC tissues. Increased Sharpin expression enhanced hepatoma cell invasion, whereas decrease in Sharpin expression by RNA interference inhibited invasion. Microarray analysis identified that Versican, a chondroitin sulfate proteoglycan that plays crucial roles in tumor progression and invasion, was also upregulated in Sharpin-expressing stable cells. Versican expression increased in the majority of HCC tissues and knocking down of Versican greatly attenuated hepatoma cell invasion. Sharpin expression resulted in a significant induction of Versican transcription synergistically with Wnt/ß-catenin pathway activation. Furthermore, Sharpin-overexpressing cells had high tumorigenic properties in vivo. These results demonstrate that Sharpin promotes Versican expression synergistically with the Wnt/ß-catenin pathway, potentially contributing to HCC development. A Sharpin/Versican axis could be an attractive therapeutic target for this currently untreatable cancer.

Modulation of prostacyclin generation in cultured human vascular endothelial cells and the effects of human alpha-natriuretic polypeptide.

Vascular endothelial cells have been known to possess not only a barrier function but also other biologically important functions maintaining vascular homeostasis. Among these, the generation of prostacyclin is one of the most conspicuous functions, and the modulation of its synthesis and liberation has been of interest with reference to the interaction with several vasoactive substances, including human atrial alpha-natriuretic polypeptide. This paper investigates the regulatory mechanism of prostacyclin generation using cultured human vascular endothelial cells as far as Ca2+ flux, (Na+ + K+)-ATPase activity, and Na+-Ca2+ exchange systems are concerned. Through these experimental studies the following results were obtained. Prostacyclin generation was triggered by an increase of Ca2+ influx, and an increase in intracellular Na+ also enhanced it, and this was accompanied by a decreased Ca2+ efflux arising from suppression of Na+-Ca2+ exchange systems. (Na+ + K+)-ATPase activity as well as prostacyclin generation was also enhanced by the increase of intracellular Na+. These results indicate a possible link between the mechanism which generates prostacyclin in the human vascular endothelial cells and the mobilization of electrolytes; however, in this aspect human atrial alpha-natriuretic polypeptide had no effect on the endothelial cells.

Living donor liver transplantation for hepatocellular carcinoma: a special reference to a preoperative des-gamma-carboxy prothrombin value.

BACKGROUND: Des-gamma-carboxy prothrombin (DCP) is a sensitive marker related to vascular invasion of hepatocellular carcinoma (HCC). The aim of this study was to clarify the risk factors of HCC recurrence in living donor liver transplantation (LDLT) with special reference to preoperative DCP values. METHODS: Forty consecutive adult HCC patients who underwent LDLT were examined for a correlation between the DCP value and vascular invasion. Risk factors for recurrence were also investigated using clinicopathological variables including preoperative DCP levels. RESULTS: The incidence of positive histological vascular invasion in patients with DCP values above 300 mAU/mL was higher than that with those with DCP value below 300 mAU/mL. Other significant risk factors for recurrence were over 5 cm tumor diameter, not meeting the Milan criteria, AFP value >400 ng/mL, histological vascular invasion, poorly differentiated histology, and male gender. Among the patients who did not meet the Milan criteria, those with both no more than 5 cm of tumor diameter and no more than 300 mAU/mL DCP exhibited a good prognosis. CONCLUSIONS: A high DCP value, namely >300 mAU/mL correlated with histological vascular invasion and was one of the strongest prognostic variables. Therefore, special attention should be paid to HCC patients with high DCP values. No correlation between the number of tumor nodules and recurrence was found; therefore, the Milan criteria may require revision regarding the number of tumor nodules.

Effect of prostaglandin E1 on fractional distribution of cardiac output and organ blood flow in man: a simultaneous and non-invasive determination using double dose thallium-201 scintigraphy.

Taking advantage of the fact that the distribution of Thallium-201 in an organ almost parallels the blood flow to the organ, we devised a non-invasive method of simultaneously determining blood flow and its distribution in human organs. With this method, we investigated the effect of exogenous prostaglandin E1 (PGE1) on the central and peripheral circulation. Scintigraphy was performed after two injections of 201Tl chloride, one at rest and one after the administration of PGE1 or saline. In eight subjects given PGE1 (0.2 microgram X kg-1 X min-1, iv), blood pressure fell, whereas both heart rate and cardiac output rose. The fractional distribution was increased in the heart (+13.3 +/- 2.98%, mean +/- SD), but decreased in the liver (-10.2 +/- 1.95%) and gastro-intestinal tract (-7.09 +/- 2.65%). No significant change was observed in the kidneys or leg. The blood flow in all these organs was increased. In the six control subjects given saline, there was no change in these central and peripheral haemodynamics. Thus, the intravenous infusion of PGE1 in man causes uneven blood flow distribution in heart, liver, kidney, gastro-intestinal organs and leg muscles, despite increased blood flow to all these organs. The method used in this study is relatively non-invasive and useful in evaluating organ blood flow in man, and seems to be widely applicable to physiological and pharmacologic research.

Centrally induced vasopressor responses to ouabain in DOCA-salt hypertensive rats.

To investigate the effect of inhibition of cerebral Na+, K+-ATPase on cardiovascular regulation ouabain was injected into the lateral ventricle or the posterior hypothalamus in either conscious or urethane anaesthetised, deoxycorticosterone-salt hypertensive (DOCA) and sham operated (sham) rats. Ouabain injected intracerebroventricularly produced dose dependent vasopressor responses and tachycardia in the conscious rat; the magnitude of the pressor response was consistently larger in DOCA than in sham rats. In anaesthetised rats the pressor responses were accompanied by corresponding increases in abdominal sympathetic nerve activity. Thus the magnitude of the pressor responses, tachycardia, and the increases in nerve activity was again significantly greater in DOCA than in sham rats. Intrahypothalamic injections of ouabain produced pressor responses that were accompanied by consistent increases in both heart rate and abdominal sympathetic nerve activity in anaesthetised rats. In contrast to the intracerebroventricular injections the percentage increases from baseline blood pressure were significantly greater in sham than in DOCA rats at 5 min after injection. These results indicate that the centrally induced vasopressor response to ouabain, via the periventricular or bulbospinal system or both, is increased in DOCA-salt hypertensive rats whereas the pressor mechanism via the posterior hypothalamus is suppressed in DOCA rats.

Centrally-induced vasopressor responses to carbachol are augmented in DOCA-salt hypertensive rats.

Increased sympathetic nervous system activity and vasopressin release has been demonstrated in established DOCA-salt hypertension in the rat. To determine the importance of these mechanisms in centrally-mediated pressor responses in this model of hypertension, both awake rats and rats anaesthetised with urethane were given intracerebroventricular injections of carbachol. The systolic blood pressure after implanting a silicon rubber mould containing DOCA, and with subsequent substitution of 1% saline in tap water, increased from 112 +/- 3 mmHg to a stable 188 +/- 7 mmHg by the end of 4 weeks, measured using a tail-cuff method. The blood pressure consistently became elevated when carbachol was injected into the cerebral ventricles of awake rats. Of the three groups of normotensive rats (NTR), sham-operated rats (SHAM) and DOCA-salt hypertensive rats (DOCA), the magnitude of the pressor phase was largest in the DOCA rats. The heart rate in all three groups of rats decreased similarly. When the rats were later anaesthetised with urethane to allow recording of abdominal sympathetic nerve activity, the carbachol injections caused biphasic blood pressure responses and sympathetic nerve discharge consisting of initial vasodepression and sympathetic nerve inhibition of short duration. This was followed by a sustained pressor phase accompanied by a corresponding increase in sympathetic nerve activity. The magnitude of the pressor response was again larger in the DOCA than in the SHAM rats. Spinal section abolished the initial depressor phase but did not much affect the sustained pressor phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular and sympathetic responses to ouabain injected into the hypothalamus in rats.

To investigate the effects of sodium-potassium activated adenosine triphosphatase inhibition on central cardiovascular regulation a microinjection of ouabain was given into the hypothalamus of urethane anaesthetised rats. Doses of 0.01-1.0 micrograms per rat injected into the posterior hypothalamus produced a rise in blood pressure within 1 min, the maximum rise occurring 15-20 min later in a dose dependent manner. Both heart rate and abdominal sympathetic nerve activity increased with the rise in blood pressure. Ouabain injected into either the anterior preoptic hypothalamus or the ventromedial hypothalamus produced no notable cardiovascular responses. These results suggest that an endogenous digitalis like substance produced in the hypothalamus as a result of sodium loading may participate in central cardiovascular regulation by increasing sympathetic outflow in the discrete area of the brain, as does ouabain.

Centrally induced cardiovascular and sympathetic responses to adrenocorticotrophic hormone.

To investigate the effects of adrenocorticotrophic hormone on central cardiovascular regulation, an intracerebroventricular injection of the drug was given to male Wistar rats. With doses of 1 microgram and 10 micrograms per rat, blood pressure began to rise within 1 min, attaining a maximum value 5-10 min later. Both heart rate and abdominal sympathetic nerve activity increased simultaneously with the rise in blood pressure. Injection into the fourth ventricle or intravenous administration of the drug elicited no appreciable cardiovascular responses. These results suggest that endogenous adrenocorticotrophic hormone produced locally in the hypothalamus may participate in central cardiovascular regulation by increasing sympathetic outflow.

Central attenuation of aortic baroreceptor reflex in prehypertensive DOCA-salt-loaded rats.

To determine whether the arterial baroreceptor reflex can act to oppose the development of hypertension, deoxycorticosterone acetate (DOCA)-salt hypertension was produced in sinoaortic-denervated and sham-operated rats. Systolic blood pressure measured by tail cuff started to increase in both sinoaortic-denervated and sham-operated rats 7 days after DOCA treatment, and the hypertension developed identically in both denervated and sham-operated rats. These findings suggest that the baroreceptor reflex cannot act against the development of hypertension. To determine whether the baroreceptor reflex is attenuated before the development of hypertension, bradycardiac and sympathoinhibitory responses to i.v. injections of norepinephrine were examined. Bradycardic and sympathoinhibitory responses were significantly smaller in DOCA-salt-treated rats in both prehypertensive (5th day after DOCA-salt treatment) and hypertensive stages (21st day after treatment). In urethane-anesthetized DOCA-loaded and control rats on the 5th day after treatment, aortic depressor nerve stimulation elicited frequency-dependent depressor and bradycardic responses accompanied by inhibition of sympathetic nerve activity in both DOCA-loaded and control rats. However, those responses were significantly smaller in DOCA-loaded rats than in control rats. These results suggest that the central component of the baroreceptor reflex mediated by the aortic depressor nerve is impaired before hypertension develops and that this impairment may contribute to the development of hypertension in DOCA-salt-treated rats.

Molecular cloning and characterization of a human homologue of TBPIP, a BRCA1 locus-related gene.

Here we clone the human homologue of TBPIP [Tat binding protein 1(TBP-1)-interacting protein]. TBPIP is a molecule that has been cloned from mouse as a cofactor of TBP-1. Eighty-eight per cent of the deduced amino acid sequence of human TBPIP coincides with that of mouse TBPIP. CAT assay reveals that human TBPIP could interact with human TBP-1, then enhance the function of TBP-1 on HIV (human immunodeficiency virus)-Tat-mediated transactivation. Our radiation hybrid mapping indicates that TBPIP is located on chromosome 17q12-21. A DNA database search uncovers that an apparent part of TBPIP has been obtained as a BRCA1 locus-related gene (OV-4) and mapped onto chromosome 17q12-21. Interestingly, the nucleotide structure of human TBPIP is very similar to that of the GT198 gene, which has been cloned from a human breast cancer cell line and also mapped onto the BRCA1 locus. Since a very high rate of gene mutation is observed in the BRCA1-related region in breast cancers and expression of authentic GT198 mRNA could not be confirmed in either BT-474 (other kind of human breast cancer cell line) or normal human testis (where the strong expression of GT198 mRNA is reported), it is likely that GT198 is a mutated form of human TBPIP.

Centrally-induced vasodepressor responses to diltiazem, a calcium channel blocker, in rats.

The effects of a calcium channel blocker, diltiazem, on central cardiovascular regulation were investigated by injecting it intracerebroventricularly (i.c.v.) in urethane-anaesthetized rats. The blood pressure decreased immediately after the injection returning to baseline level 20-30 min later. Both heart rate and abdominal sympathetic nerve activity decreased correspondingly. Diltiazem injected intravenously (i.v.) decreased both blood pressure and heart rate without affecting sympathetic nerve firing. Although the central pressor responses to carbachol and prostaglandin E2 were not affected by i.c.v. pretreatment with diltiazem, diltiazem attenuated the pressor responses to angiotensin II. Furthermore, electrical lesioning of the anteroventral third ventricle (AV3V) area significantly attenuated the depressor responses to diltiazem injected i.c.v. These results suggest that diltiazem injected i.c.v. affects the central nervous system to decrease sympathetic outflow, and thereby to attenuate the central vasopressor effects of angiotensin II in the brain AV3V area.

Visualization of right atrial appendix by thallium-201 myocardial scintigraphy: concise communication.

The atrial myocardium has been barely visible with thallium-201 myocardial scintigraphy. This is probably related to the difference in size, distance from anterior chest wall, and small coronary blood flow of the atrium, compared with the ventricle. We have encountered eight cases of visualization of the right atrial appendix (RAA). All had disease involving the right side of the heart, such as mitral stenosis (four cases), congenital heart disease (two), cor pulmonale (one), and primary myocardial disease (one). The RAA was identified from multiple projections in all cases and sometimes confirmed by radionuclide angiocardiography. The RAA was seen at the right upper aspect of the ventricles and was distinguishable from them. Evidence derived from ECG, chest radiographs, and cardiac catheterization, indicated that the most important factor in the visualization might be the displacement of the RAA to a more anterior position.

Tachyarrhythmia provoked by coughing and other stimuli.

A rare case of cough-induced tachyarrhythmia is described. The effectiveness of atropine sulfate, and worsening of the arrhythmia resulting from administration of digitalis, suggests that vagal reflex might be the mechanism responsible for the tachyarrhythmia.

Ruptured chordae tendineae of the tricuspid valve due to nonpenetrating trauma. Echocardiographic findings.

A case of traumatic tricuspid insufficiency is presented. In the diagnosis of ruptured chordae tendineae of the tricuspid valve, two-dimensional echocardiography was an essential diagnostic procedure, while M-mode echocardiography showed no specific findings. Ruptured chordae tendineae of the tricuspid valve were confirmed at operation.