bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanisms of hepatocyte protection against hypoxic injury by atrial natriuretic peptide
Authors: Carini Rita , De Cesaris Maria Grazia , Splendore Roberta , Domenicotti Cinzia , Nitti Maria Paola , Pronzato Maria Adelaide , Albano Emanuele
Published: February 2003

Atrial natriuretic peptide (ANP) reduces ischemia and/or reperfusion damage in several organs, but the mechanisms involved are largely unknown. We used freshly isolated rat hepatocytes to investigate the mechanisms by which ANP enhances hepatocyte resistance to hypoxia. The addition of ANP (1 μmol/L) reduced the killing of hypoxic hepatocytes by interfering with intracellular Na+ accumulation without ameliorating adenosine triphosphate (ATP) depletion and pH decrease caused by hypoxia. The effects of ANP were mimicked by 8-bromo-guanosine 3′, 5′-cyclic monophosphate (cGMP) and were associated with the activation of cGMP-dependent kinase (cGK), suggesting the involvement of guanylate cyclase-coupled natriuretic peptide receptor (NPR)-A/B ANP receptors. However, stimulating NPR-C receptor with des-(Gln18, Ser19,Gly20,Leu21,Gly22)-ANP fragment 4-23 amide (C-ANP) also increased hepatocyte tolerance to hypoxia. C-ANP protection did not involve cGK activation but was instead linked to the stimulation of protein kinase C (PKC)-δ through Gi protein- and phospholipase C-mediated signals. PKC-δ activation was also observed in hepatocytes receiving ANP. The inhibition of phospholipase C or PKC by U73122 and chelerythrine, respectively, significantly reduced ANP cytoprotection, indicating that ANP interaction with NPR-C receptors also contributed to cytoprotection. In ANP-treated hepatocytes, the stimulation of both cGK and PKC-δ was coupled with dual phosphorylation of p38 mitogen-activated protein kinase (MAPK). The p38 MAPK inhibitor SB203580 abolished ANP protection by reverting p38 MAPK-mediated regulation of Na+ influx by the Na+/H+ exchanger. In conclusion, ANP recruits 2 independent signal pathways, one mediated by cGMP and cGK and the other associated with Gi proteins, phospholipase C, and PKC-δ. Both cGK and PKC-δ further transduce ANP signals to p38 MAPK that, by maintaining Na+ homeostasis, are responsible for ANP protection against hypoxic injury.
Uroporphyria caused by ethanol in Hfe (−/−) mice as a model for porphyria cutanea tarda
Authors: Sinclair Peter R. , Gorman Nadia , Trask Heidi W. , Bement William J. , Szakacs Juliana G. , Elder George H. , Balestra Dominic , Sinclair Jacqueline F. , Gerhard Glenn S.
Published: February 2003

Two major risk factors for the development of porphyria cutanea tarda (PCT) are alcohol consumption and homozygosity for the C282Y mutation in the hereditary hemochromatosis gene (HFE). To develop an animal model, Hfe knockout mice were treated continuously with 10% ethanol in drinking water. By 4 months, uroporphyrin (URO) was detected in the urine. At 6 to 7 months, hepatic URO was increased and hepatic uroporphyrinogen decarboxylase (UROD) activity was decreased. Untreated Hfe(−/−) mice or wild-type mice treated with or without ethanol did not show any of these biochemical changes. Treatment with ethanol increased hepatic nonheme iron and hepatic 5-aminolevulinate synthase activity in Hfe(−/−) but not wild-type mice. The increases in nonheme iron in Hfe(−/−) mice were associated with diffuse increases in iron staining of parenchymal cells but without evidence of significant liver injury. In conclusion, the results of this study suggest that the uroporphyrinogenic effect of ethanol is mediated by its effects on hepatic iron metabolism. Ethanol-treated Hfe(−/−) mice seem to be an excellent model for studies of alcohol-mediated PCT.
Influence of hepatitis B virus genotypes on the progression of chronic type B liver disease
Authors: Sumi Hajime , Yokosuka Osamu , Seki Naohiko , Arai Makoto , Imazeki Fumio , Kurihara Tomoko , Kanda Tatsuo , Fukai Kenichi , Kato Masaki , Saisho Hiromitsu
Published: February 2003

To investigate the hepatitis B virus (HBV) genotype-related differences in the progression of liver disease, 585 patients with chronic HBV infection including 258 with histologically verified chronic liver disease (CLD) and 74 with hepatocellular carcinoma (HCC) were examined. The mean ages of both patients with advanced fibrosis (F3 or F4) and with HCC were significantly older in genotype B than in genotype C patients (P = .018, P = .024, respectively). Both the hepatitis B e antigen (HBeAg) negativity rate at biopsy and the cumulative HBe seroconversion rate in patients with CLD were significantly higher in genotype B patients than genotype C patients (P < .01, P = .022, respectively). Multivariate analysis revealed that genotype B, presence of precore mutation, high ALT levels, and severe histologic activity were independent factors for HBe seroconversion. Among all the biopsy-proven CLD patients, the ratio of patients with advanced fibrosis in genotype B was significantly lower than that in genotype C (4/30 vs. 74/224, respectively; P = .034). This difference was more remarkable in younger patients (≤45 years; 1/25 vs. 47/180, respectively; P = .020), and there was no difference in older patients (>45 years). The distribution of each genotype between CLD and HCC was very similar (B and C: 11.2% and 87.0% vs. 10.8% and 89.2%, respectively). In conclusion, our results suggest that, although the patients with genotype B experience earlier HBe seroconversion, slower progression of liver fibrosis, and slower development of HCC, the life-long risk of progression to advanced fibrosis and development of HCC may not differ among genotypes B- and C-related chronic liver disease.
Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival
Authors: Llovet Josep M. , Bruix Jordi
Published: February 2003

There is no standard treatment for patients with unresectable hepatocellular carcinoma (HCC). Survival benefits derived from medical interventions are controversial. The aim of this systematic review was to assess the evidence of the impact of medical treatments on survival. Randomized controlled trials (RCTs) that were published as full papers assessing survival for primary treatments of HCC were included. MEDLINE, the Cochrane Library, CANCERLIT, and a manual search from 1978 to May 2002 were used. The primary end point was survival, and the secondary end point was response to treatment. Estimates of effect were calculated according to the random effects model. Sensitivity analysis included methodological quality. We identified 61 randomized trials, but only 14 met the criteria to perform a meta-analysis assessing arterial embolization (7 trials, 545 patients) or tamoxifen (7 trials, 898 patients). Arterial embolization improved 2-year survival compared with control (odds ratio [OR], 0.53; 95% confidence interval [CI], 0.32-0.89; P = .017). Sensitivity analysis showed a significant benefit of chemoembolization with cisplatin or doxorubicin (OR, 0.42; 95% CI, 0.20-0.88) but none with embolization alone (OR, 0.59; 95% CI, 0.29-1.20). Overall, treatment induced objective responses in 35% of patients (range, 16%-61%). Tamoxifen showed no antitumoral effect and no survival benefits (OR, 0.64; 95% CI, 0.36-1.13; P = .13), and only low-quality scale trials suggested 1-year improvement in survival. In conclusion, chemoembolization improves survival of patients with unresectable HCC and may become the standard treatment. Treatment with tamoxifen does not modify the survival of patients with advanced disease.
Endoscopic screening for esophageal varices in cirrhosis: Is it ever cost effective?
Authors: Spiegel Brennan M. R. , Targownik Laura , Dulai Gareth S. , Karsan Hetal A. , Gralnek Ian M.
Published: February 2003

Current guidelines for the management of patients with compensated cirrhosis recommend universal screening endoscopy followed by prophylactic β-blocker therapy to prevent initial hemorrhage in those found to have esophageal varices. However, the cost-effectiveness of this recommendation has not been established. Our objective was to determine whether screening endoscopy is cost-effective compared with empiric medical management in patients with compensated cirrhosis. Decision analysis with Markov modeling was used to calculate the cost-effectiveness of 6 competing strategies: (1) universal screening endoscopy (EGD) followed by β-blocker (BB) therapy (EGD→BB) if varices are present, (2) EGD followed by endoscopic band ligation (EBL) (EGD→EBL) if varices are present, (3) selective screening endoscopy (sEGD) in high risk patients followed by BB therapy if varices are present (sEGD→BB), (4) selective screening endoscopy followed by EBL (sEGD→EBL) if varices are present, (5) empiric β-blocker therapy in all patients, and (6) no prophylactic therapy (“Do Nothing”). Cost estimates were from a third-party payer perspective. The main outcome measure was the cost per initial variceal hemorrhage prevented. The “Do Nothing” strategy was the least expensive yet least effective approach. Compared with the “Do Nothing” strategy, the empiric β-blocker strategy cost an incremental $12,408 per additional variceal bleed prevented. Compared with the empiric β-blocker strategy, in turn, both the EGD→BB and the EGD→EBL strategies cost over $175,000 more per additional bleed prevented. The sEGD→BB and sEGD→EBL strategies were more expensive and less effective than the empiric β-blocker strategy. In conclusion, empiric β-blocker therapy for the primary prophylaxis of variceal hemorrhage is a cost-effective measure, as the use of screening endoscopy to guide therapy adds significant cost with only marginal increase in effectiveness.
Modulation of cellular immune response against hepatitis C virus nonstructural protein 3 by cationic liposome encapsulated DNA immunization
Authors: Jiao Xuanmao , Wang Richard Y.-H. , Feng Zhiming , Alter Harvey J. , Shih James Wai-Kuo
Published: February 2003

A vaccine strategy directed to increase Th1 cellular immune responses, particularly to hepatitis C virus (HCV) nonstructural protein 3 (NS3), has considerable potential to overcome the infection with HCV. DNA vaccination can induce both humoral and cellular immune responses, but it became apparent that the cellular uptake of naked DNA injected into muscle was not very efficient, as much of the DNA is degraded by interstitial nucleases before it reaches the nucleus for transcription. In this paper, cationic liposomes composed of different cationic lipids, such as dimethyl-dioctadecylammonium bromide (DDAB), 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), or 1,2-dioleoyl-sn-glycerol-3-ethylphosphocholine (DOEPC), were used to improve DNA immunization in mice, and their efficiencies were compared. It was found that cationic liposome-mediated DNA immunization induced stronger HCV NS3-specific immune responses than immunization with naked DNA alone. Cationic liposomes composed of DDAB and equimolar of a neutral lipid, egg yolk phosphatidylcholine (EPC), induced the strongest antigen-specific Th1 type immune responses among the cationic liposome investigated, whereas the liposomes composed of 2 cationic lipids, DDAB and DOEPC, induced an antigen-specific Th2 type immune response. All cationic liposomes used in this study triggered high-level, nonspecific IL-12 production in mice, a feature important for the development of maximum Th1 immune responses. In conclusion, the cationic liposome-mediated gene delivery is a viable HCV vaccine strategy that should be further tested in the chimpanzee model.
Selective increase of brain lactate synthesis in experimental acute liver failure: Results of a [1H-13C] nuclear magnetic resonance study
Authors: Zwingmann Claudia , Chatauret Nicolas , Leibfritz Dieter , Butterworth Roger F.
Published: February 2003

Acute liver failure (ALF) results in alterations of energy metabolites and of glucose-derived amino acid neurotransmitters in brain. However, the dynamics of changes in glucose metabolism remain unclear. The present study was undertaken using 1H and 13C nuclear magnetic resonance (NMR) spectroscopy to determine the rates of incorporation of glucose into amino acids and lactate via cell-specific pathways in relation to the severity of encephalopathy and brain edema in rats with ALF because of hepatic devascularization. Early (precoma) stages of encephalopathy were accompanied by significant 2- to 4.5-fold (P < .001) increases of total brain glutamine and lactate concentrations. More severe (coma) stages of encephalopathy and brain edema led to a further significant increase in brain lactate but no such increase in glutamine. Furthermore, 13C isotopomer analysis showed a selective increase of de novo synthesis of lactate from [1-13C]glucose resulting in 2.5-fold increased fractional 13C enrichments in lactate at coma stages. [2-13C]glutamine, synthesized through the astrocytic enzyme pyruvate carboxylase, increased 10-fold at precoma stages but showed no further increase at coma stages of encephalopathy. 13C-label incorporation into [4-13C]glutamate, synthesized mainly through neuronal pyruvate dehydrogenase, was selectively reduced at coma stages, whereas brain GABA synthesis was unchanged at all time points. In conclusion, increased brain lactate synthesis and impaired glucose oxidative pathways rather than intracellular glutamine accumulation are the major cause of brain edema in ALF. Future NMR spectroscopic studies using stable isotopes and real-time measurements of metabolic rates could be valuable in the elucidation of the cerebral metabolic consequences of ALF in humans.
Low doses of isosorbide mononitrate attenuate the postprandial increase in portal pressure in patients with cirrhosis
Authors: Bellis Lia , Berzigotti Annalisa , Abraldes Juan G. , Moitinho Eduardo , García-Pagán Juan C. , Bosch Jaime , Rodés Juan
Published: February 2003

Postprandial hyperemia is associated with a significant increase in portal pressure in cirrhosis, which may contribute to progressive dilation and rupture of gastroesophageal varices. In cirrhosis, an insufficient hepatic production of nitric oxide (NO) may impair the expected hepatic vasodilatory response to increased blood flow, further exaggerating the postprandial increase in portal pressure. This study was aimed at investigating whether low doses of an oral NO donor might counteract the postprandial peak in portal pressure. Twenty-three portal hypertensive cirrhotics, 8 of them under propranolol therapy, were randomized to receive orally 5-isosorbide mononitrate (ISMN; 10 mg; n = 11) or placebo (n = 12) and a standard liquid meal 15 minutes later. Hepatic venous pressure gradient (HVPG), mean arterial pressure (MAP), and hepatic blood flow (HBF) were measured at baseline and 15, 30, and 45 minutes after a meal. ISMN significantly attenuated the postprandial increase in portal pressure as compared with placebo (peak HVPG increase: 2.4 ± 1.4 mm Hg vs. 5.2 ± 2.1 mm Hg, P = .002). Percentual increases in HBF were similar in both groups. MAP decreased slightly in ISMN group (−7.5% ± .5%; P < .01 vs. baseline). These effects were also observed in patients on chronic propranolol therapy. In conclusion, hepatic NO supplementation by low doses of ISMN effectively reduces the postprandial increase of portal pressure in cirrhosis, with only a mild effect on arterial pressure. The same was observed in patients receiving propranolol. Our results suggest that therapeutic strategies based on selective hepatic NO delivery may improve the treatment of portal hypertension.
Diagnosis of portopulmonary hypertension in candidates for liver transplantation: A prospective study
Authors: Colle Isabelle O. , Moreau Richard , Godinho Erica , Belghiti Jacques , Ettori Florence , Cohen-Solal Alain , Mal Hervé , Bernuau Jacques , Marty Jean , Lebrec Didier , Valla Dominique , Durand François
Published: February 2003

Portopulmonary hypertension represents a major risk factor for transplantation; therefore, preoperative detection is crucial. The aims of this study were to determine (1) whether Doppler echocardiography performed at evaluation is a reliable tool for detecting portopulmonary hypertension and (2) the incidence of acquired portopulmonary hypertension profile after evaluation. One hundred sixty-five patients had Doppler echocardiography and right heart catheterization at evaluation over a 9-year period. All patients had a prospective follow-up, and the results of catheterization at evaluation were compared with those obtained at the time of transplantation. Seventeen of 165 patients met the criteria for portopulmonary hypertension on Doppler echocardiography. Portopulmonary hypertension was confirmed by catheterization in 10 patients and ruled out in 7. There were no false negatives for echocardiography. Mean pulmonary artery pressure was significantly higher during the initial phase of transplantation than at evaluation (17.8 ± 4.3 vs. 20.3 ± 5.5 mm Hg, respectively, P < .0001), and there was no significant correlation between values obtained at these 2 time points. Three patients showed to have acquired portopulmonary hypertension profile while waiting for a graft within time intervals ranging from 2.5 to 5 months. In conclusion, Doppler echocardiography is a highly sensitive tool for detecting portopulmonary hypertension. However, because this technique has a poor positive predictive value, right heart catheterization is recommended for confirming portopulmonary hypertension. In addition, the absence of portopulmonary hypertension at evaluation does not exclude the occasional occurrence of acquired portopulmonary hypertension profile after listing.
Benzodiazepine-induced protein tyrosine nitration in rat astrocytes
Authors: Görg Boris , Foster Natalie , Reinehr Roland , Bidmon Hans J. , Höngen Andrea , Häussinger Dieter , Schliess Freimut
Published: February 2003

Recent studies indicate that ammonia and hypoosmotic astrocyte swelling can induce protein tyrosine nitration (PTN) in astrocytes with potential pathogenetic relevance for hepatic encephalopathy (HE). Because HE episodes are known to be precipitated also by sedatives, the effects of benzodiazepines on PTN in cultured rat astrocytes and rat brain in vivo were studied. In cultured rat astrocytes, diazepam, PK11195, Ro5-4864, and the benzodiazepine binding inhibitor (DBI), which acts on peripheral-type benzodiazepine receptors, induced PTN. Clonazepam, a specific ligand of the central benzodiazepine receptor, failed to induce PTN. Nanomolar concentrations of DBI and PK11195 were sufficient to increase PTN, and diazepam effects were already observed at concentrations of 1 μmol/L. Diazepam-induced PTN was insensitive to NOS inhibition and uric acid but was blunted by MK-801, BAPTA-AM, W13, and catalase, suggesting an involvement of NMDA-receptor activation, elevation of the cytosolic Ca2+ concentration [Ca2+]i, and hydrogen peroxide. Diazepam induced a plateau-like increase in [Ca2+]i and the generation of reactive oxygen intermediates (ROIs), which are both blunted by MK-801 and BAPTA-AM. The expression of functional N-methyl-D-aspartate (NMDA) receptors on cultured rat astrocytes was confirmed by reverse transcriptase polymerase chain reaction, Western blot analysis, immunhistochemistry, and receptor autoradiography. Astroglial PTN is also found in brains from rats challenged with diazepam, indicating the in vivo relevance of the present findings. In conclusion, production of ROIs and increased PTN by benzodiazepines may alter astrocyte function and thereby contribute to the precipitation of HE episodes.
The nitric oxide donor, V-PYRRO/NO, protects against acetaminophen-induced hepatotoxicity in mice
Authors: Liu Jie , Li Chengxiu , Waalkes Michael P. , Clark James , Myers Page , Saavedra Joseph E. , Keefer Larry K.
Published: February 2003

The liver-selective nitric oxide (NO) donor, O
2-vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO), is metabolized by P-450 enzymes to release NO in the liver, and is shown to protect the liver from tumor necrosis factor α (TNF-α)-induced apoptosis and D-glactosamine/endotoxin-induced hepatotoxicity. This study was undertaken to examine the effects of V-PYRRO/NO on acetaminophen-induced hepatotoxicity in mice. Mice were given V-PYRRO/NO via osmotic pumps (1.8-5.4 mg/mL, 8 μL/h) 4 to 16 hours before a hepatotoxic dose of acetaminophen (600 mg/kg, intraperitoneally [ip]). V-PYRRO/NO administration dramatically reduced acetaminophen-induced hepatotoxicity in a dose- and time-dependent manner, as evidenced by reduced serum alanine aminotransferase (ALT) activity, reduced hepatic congestion, apoptosis, and improved hepatocellular pathology. The protection afforded by V-PYRRO/NO does not appear to be caused by a decrease in the formation of toxic acetaminophen metabolites, which consumes glutathione (GSH), because V-PYRRO/NO did not alter acetaminophen-induced hepatic GSH depletion. Acetaminophen-induced lipid peroxidation, as determined by the concentrations of 4-hydroxyalkenals (4-HNE) and malondialdehyde (MDA), was reduced significantly by V-PYRRO/NO treatment. Although pretreatment was most effective, administration of V-PYRRO/NO simultaneously with acetaminophen also was able to reduce acetaminophen hepatotoxicity. Genomic analysis of the liver samples 10 hours after acetaminophen intoxication showed the enhanced expression of genes associated with stress/oxidative stress, apoptosis/cell death, and DNA damage/repair. Acetaminophen-induced alterations in gene expression were attenuated significantly by V-PYRRO/NO. Real-time reverse-transcription polymerase chain reaction (RT-PCR) and Western-blot analysis confirmed microarray results. In conclusion, V-PYRRO/NO is effective in blocking acetaminophen-induced hepatotoxicity in mice. This protection may involve the reduction of oxidative stress, the inhibition of apoptosis, and possibly the maintenance of hepatic vasculature to prevent congestion.
Induction of cellular resistance against Kupffer cell-derived oxidant stress: A novel concept of hepatoprotection by ischemic preconditioning
Authors: Schauer Rolf J. , Gerbes Alexander L. , Vonier Daniel , op den Winkel Mark , Fraunberger Peter , Bilzer Manfred
Published: February 2003

Ischemic preconditioning (IP) triggers protection of the liver from prolonged subsequent ischemia. However, the underlying protective mechanisms are largely unknown. We investigated whether and how IP protects the liver against reperfusion injury caused by Kupffer cell (KC)-derived oxidants. IP before 90 minutes of warm ischemia of rat liversin vivosignificantly reduced serum alanine aminotransferase (AST) levels and leukocyte adherence to sinusoids and postsinusoidal venules during reperfusion. This protective effect was mimicked by postischemic intravenous infusion of glutathione (GSH), an antioxidative strategy against KC-derived H2O2. Interestingly, no additional protection was achieved by infusion of GSH to preconditioned animals. These findings and several additional experiments strongly suggest IP mediated antioxidative effects: IP prevented oxidant cell injury in isolated perfused rat livers after selective KC activation by zymosan. Moreover, IP prevented cell injury and pertubations of the intracellular GSH/GSSG redox system caused by direct infusion of H2O2(0.5 mmol/L). IP-mediated resistance against H2O2could neither be blocked by the adenosine A2a antagonist DMPX nor mimicked by A2a agonist CGS21680. In contrast, H2O2resistance was abolished by the p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB203580, but induced when p38 MAPK was directly activated by anisomycin. In conclusion, we propose a novel concept of hepatoprotection by IP: protection of liver cells by enhancing their resistance against KC-derived H2O2. Activation of p38 MAPK and preservation of the intracellular GSH/oxidized glutathione (GSSG) redox system, but not adenosine A2a receptor stimulation, seems to be pivotal for the development of H2O2resistance in preconditioned livers.
Functional significance of hepatic arterial flow reserve in patients with cirrhosis
Authors: Zipprich Alexander , Steudel Norbert , Behrmann Curd , Meiss Frank , Sziegoleit Ursula , Fleig Wolfgang E. , Kleber Gerhard
Published: February 2003

In cirrhosis, hepatic arterial vasodilatation occurs in response to reduced portal venous blood flow. However, although the hepatic arterial flow reserve is high in patients with cirrhosis, its impact on hepatic function is unknown. This study investigated the effect of adenosine-induced hepatic arterial vasodilatation on different markers of liver function. In 20 patients with cirrhosis (Child-Pugh class A/B/C: n = 2/7/11) adenosine (2-30 μg · min−1 · kg body wt−1) was infused into the hepatic artery and hepatic arterial average peak flow velocities (APV), pulsatility indices (PI), and blood flow volumes (HABF) were measured using digital angiography and intravascular Doppler sonography. Indocyanine green (ICG), lidocaine, and galactose were administered intravenously in doses of 0.5, 1.0, and 500 mg/kg body weight in the presence of adenosine-induced hepatic arterial vasodilatation and, on a separate study day, without adenosine. ICG disappearance, galactose elimination capacity (GEC), and formation of the lidocaine metabolite monoethylglycinxylidide (MEGX) were assessed. Adenosine markedly increased APV and HABF and markedly decreased PI. Serum MEGX concentrations were 63.7 ± 18.2 (median, 62; range, 36-107) and 99.0 ± 46.3 (82.5; 49-198) ng/mL in the absence and presence of adenosine infusion, respectively (P = .001). Adenosine-induced changes in MEGX concentrations were correlated inversely to changes in APV (r = −0.5, P = .02) and PI (r = −0.55, P = .01) and were more marked in Child-Pugh class C compared with Child-Pugh class A patients (57.4 ± 49.9 [44; −14 to 140] vs. 8.4 ± 16.5 [13; −11 to 35] ng/mL, P < .01). In conclusion, hepatic arterial vasodilatation provides substantial functional benefit in patients with cirrhosis. The effect does not depend directly on hepatic arterial macroperfusion and is observed preferentially in patients with decompensated disease.
Effect of cold preservation on intracellular calcium concentration and calpain activity in rat sinusoidal endothelial cells
Authors: Upadhya Aravinda G. , Topp Stefan A. , Hotchkiss Richard S. , Anagli John , Strasberg Steven M.
Published: February 2003

This study was performed to determine the role of intracellular calcium concentration and calpain activity on the cellular events that occur in rat sinusoidal endothelial cells (SEC) in the cold. Intracellular calcium concentrations were measured in isolated cold preserved rat SEC. Dantrolene or 1,2-bis(o-Aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetra(acetoxymethyl) ester (BAPTA-AM) was added in some studies. In other studies, calpain activity and m-calpain and μ-calpain expression were measured during cold preservation in the presence or absence of calpain inhibitors. The effect of addition of dantrolene to preservation solutions on function of whole livers after preservation was determined. Cold preservation caused an increase in intracellular calcium concentration first detected at 1 hour of preservation. This was associated with cell rounding and actin disassembly. Dantrolene and BAPTA-AM prevented the increase in intracellular calcium concentration and reduced cell rounding and actin disassembly. Cold preservation also resulted in increased calpain activity and expression on SEC. Calpain expression was reduced by dantrolene. Calpain inhibitors N-acetyl-leu-leu-norleucinal (ALLN) and N-acetyl-leu-leu-methioninal (ALLM) reduced calpain activity and expression and restored SEC cell shape and actin morphology. Dantrolene improved function of livers preserved in Eurocollins (EC) solution when tested on the isolated perfused rat liver (IPRL). In conclusion, exposure of SEC to cold results sequentially in elevated intracellular calcium concentration, increased calpain activity, and actin disassembly.
A recombinant adenovirus encoding hepatitis C virus core and E1 proteins protects mice against cytokine-induced liver damage
Authors: Lasarte Juan José , Sarobe Pablo , Boya Patricia , Casares Noelia , Arribillaga Laura , de Cerio Ascensión López-Díaz , Gorraiz Marta , Borrás-Cuesta Francisco , Prieto Jesús
Published: February 2003

Hepatitis C virus (HCV) infection has a strong tendency to evolve to chronicity despite up-regulation of proapoptotic cytokines in the inflamed liver. The mechanisms responsible for persistent viral replication in this inflammatory environment are obscure. It is conceivable that viral replication would be facilitated if the infected hepatocytes are rendered resistant to cytokine-induced cytotoxicity. In this study, we investigated if an adenovirus encoding HCV core and E1 (RAdCE1) could reduce liver cell injury in different in vivo models of cytokine-mediated hepatotoxicity in mice. We show that RAdCE1 markedly attenuates hepatocellular apoptosis and the increase in serum transaminase levels after concanavalin A (con A) challenge. This protective effect is accompanied by an inhibition of nuclear translocation of nuclear factor κB (NF-κB); reduced expression of inducible nitric oxide synthase (iNOS); decreased hepatic messenger RNA levels of chemokines macrophage inflammatory protein 2 (MIP-2), monocyte chemoattractant protein 1 (MCP-1), and interferon-inducible protein 10 (IP-10); and abrogation of liver leukocyte infiltration. RAdCE1 also causes a reduction in serum transaminase levels and inhibits hepatocellular apoptosis in mice given tumor necrosis factor (TNF)-α plus d-galactosamine. In conclusion, HCV structural antigens can protect liver cells against the proapoptotic effects of proinflammatory cytokines. The antiapoptotic status of infected liver cells may represent a mechanism favoring viral persistence. Our findings also suggest that, in chronic hepatitis C, the burden of hepatocellular damage mainly affects noninfected liver cells.
Effect of early arterialization of the porcine liver allograft on reperfusion injury, hepatocellular injury, and endothelial cell dysfunction
Authors: van As A. B. , Lotz Z. , Tyler M. , Kahn D.
Published: February 2003

The conventional technique of liver transplantation involves the initial perfusion of the graft with portal blood. However, recent evidence suggests that initial arterialization of the graft may be better. The aim of this study is to evaluate the timing of arterialization on reperfusion injury, hepatocellular injury, and endothelial cell function after liver transplantation. Large white X Landrace pigs (n = 24) were subjected to orthotopic liver transplantation. The animals were randomly assigned to 4 groups, ranging from late arterialization (60 minutes after portal reperfusion) to early rearterialization (20 minutes before portal reperfusion). Aspartate aminotransferase levels continued to increase 4 hours posttransplantation in group 1 (late arterialization), but remained stable after 1 hour posttransplantation in group 4 (early rearterialization). Levels of malondialdehyde doubled in all groups after portal reperfusion with the exception of group 4, in which the liver received arterial blood before portal reperfusion. Vitamin A levels decreased in all groups after revascularization, but the decrease was more pronounced and prolonged in groups 1 and 2 (late arterialization) compared with groups 3 and 4 (early rearterialization). Hyaluronic acid levels continued to increase in all groups until 1 hour posttransplantation except in group 4, in which the level decreased from 20 minutes posttransplantation. Results of this study show that early rearterialization is associated with less hepatocellular damage, less reperfusion injury, and improved liver endothelial cell function. In conclusion, our results indicate that early rearterialization of the graft is beneficial to the transplanted liver.
Combined cardiac surgery and liver transplantation
Authors: Eckhoff Devin E. , Frenette Luc , Sellers Marty T. , McGuire Brendan M. , Contreras Juan L. , Bynon John S. , McGiffin David C.
Published: February 2003

During evaluation for liver transplantation, a 63-year-old man with cirrhosis secondary to hepatitis C was diagnosed with severe aortic stenosis (aortic valve area, 0.87 cm2) and coronary artery disease. A combined procedure involving aortic valve replacement (pericardial xenograft), coronary artery bypass surgery, and orthotopic liver transplantation was performed. Convalescence was uneventful, and at 2 years after the procedure, the patient has normal cardiac function, good prosthetic valve function, and biochemically normal liver function.
Natural history of vancomycin-resistant enterococcal colonization in liver and kidney transplant recipients
Authors: Patel Robin , Allen Sharlene L. , Manahan Janice M. , Wright Alan J. , Krom Ruud A.F. , Wiesner Russell H. , Persing David H. , Cockerill Franklin R. , Thompson Rodney L.
Published: February 2003

At Mayo Medical Center (Rochester, MN), surveillance rectal (and other-site) cultures have been routinely collected from liver transplant recipients as part of a selective bowel decontamination program. Beginning in 1995, vancomycin-resistant enterococcus (VRE) colonization and infection were identified in Mayo Clinic liver and kidney transplant patients through our surveillance cultures. The purpose of this study is to describe the natural history of VRE colonization in this patient population. Fifty-two patients with VRE colonization (predominantly with a single vanB clone) were identified from September 1995 through December 1997. Five hundred ninety cultures were reviewed for this study (mean, 11.3 cultures/patient). The median time from initial VRE colonization to the last surveillance culture obtained was 306 days (range, 1 to 1,393 days). VRE infection was documented in 6 patients (11.3%). Eighteen patients (35%) met the criteria for clearance of VRE colonization, defined as VRE-negative rectal culture results on at least 3 consecutive occasions greater than 1 week apart. However, VRE was detected on subsequent surveillance cultures from 2 of these patients (11% relapse rate). Of the remaining 34 patients, 16 remained colonized with VRE and 18 did not meet the definition for clearance of VRE colonization because of incomplete follow-up. This study documents that VRE colonization usually persists for months to years in liver and kidney transplant patients.
Successful outcome of orthotopic liver transplantation in patients with preexisting malignant states
Authors: Saigal Sanjiv , Norris Suzanne , Srinivasan Parthi , Muiesan Paolo , Rela Mohamed , Heaton Nigel , O’Grady John
Published: February 2003

Preexisting malignancy is considered a relative contraindication to orthotopic liver transplantation (OLT) because of the risk of tumor recurrence. The purpose of this study is to assess the outcome of OLT in patients with a preexistent malignant state. Of 1,097 OLTs performed between 1989 and 1999 at King’s College Hospital (London, UK), 18 patients had a pretransplantation malignant state, including 6 cases of myeloproliferative disorder (MPD) presenting as Budd-Chiari syndrome. Those patients with solid-organ malignancies had their tumor detected at an early stage and underwent curative treatment before or during OLT. Patients were followed up for a median of 71 months (range, 1 to 119 months) post-OLT, and the rates of rejection and malignancy were compared with those of transplant recipients without preexisting malignancy during the same period. One patient had a recurrence of his primary malignancy (non-Hodgkin’s lymphoma) after 27 months, whereas another patient developed a de novo posttransplant lymphoproliferative disorder after 57 months. One patient with MPD developed acute leukemia 72 months after OLT. In comparison, of 1,079 OLTs performed in patients without preexisting malignancy during the same period, there were 34 cases of de novo malignancies. The rate of rejection in patients with and without preexisting malignancy was similar. Successful medium-term outcome after OLT can be achieved in carefully selected patients with preexisting malignancy providing the malignancy is amenable to curative treatment before or at OLT. Primary MPDs responsible for Budd-Chiari syndrome should not be considered a contraindication to OLT.
Modified Supracricoid Partial Laryngectomy with Cricohyoidopexy: Series Report and Analysis of Results
Authors: Adamopoulos George , Yiotakis John , Stavroulaki Pelagia , Manolopoulos Leonidas
Published: February 2003

Aiming to improve voice quality and to facilitate swallowing rehabilitation, we modified the supracricoid partial laryngectomy with cricohyoidopexy by preserving the posterior segment of the true vocal cord on the less involved side of the larynx. Between 1983 and 1994, 13 patients with supraglottic cancer were treated with this modified procedure. The possibility of incomplete tumor excision was eliminated by careful patient selection and intraoperative reconfirmation of tumor extent with frozen sections. Our results have been promising, with a 76.9% 3‐year survival rate and a 69.2% laryngeal preservation rate. There were 7 recurrences, 3 local (2 at the superior border of the cricoid and 1 at the cricoarytenoid region) and 4 nodal, in 5 patients. Distant metastases developed in another patient. Three patients, 2 with local and nodal recurrence and 1 with distant metastases, died of disease. Functional outcomes were also good, with all patients achieving normal swallowing by the end of the first year, although 5 patients required temporary gastrostomy for transient swallowing impairment. Early decannulation and satisfactory voice quality were achieved in all cases. We believe that with proper patient selection this modified procedure is effective both for tumor control and for preserving a more functional larynx.
Pain in the Neck after Neck Dissection
Authors: Talmi Yoav P. , Horowitz Zeev , Pfeffer M. Raphael , Stolik‐Dollberg Orit C. , Shoshani Yitzhak , Peleg Michael , Kronenberg Jona
Published: February 2003

BACKGROUND

Reports of disability after neck dissection have been directed toward shoulder dysfunction and pain. We could find no report addressing the issue of pain localized to the actual operative site. We have conducted a combined prospective and retrospective study of pain in patients undergoing neck dissection.

METHODS

Eighty‐eight disease‐free patients were evaluated in 3 groups for neck pain. One group was followed up prospectively for 1 to 8 months after surgery, and 2 retrospective groups were followed up for more than 2 years or for 6 months to 2 years. Pain was assessed by a body map and visual analog scale.

RESULTS

None of 31 patients followed up for more than 2 years reported neck pain. Four of 27 patients followed up for 6 to 24 months had pain, with a mean visual analog scale score of 3.7. Seventy percent of the prospective group of 30 patients had pain during the first postoperative week, and only 1 patient had pain persisting for more than 2 months. Shoulder pain and disability after radical neck dissection were encountered in all groups, comparable with the incidence reported in the literature. No postoperative neuromas were found.

CONCLUSIONS

Chronic pain localized to the operative site is an uncommon occurrence even after radical neck dissection. Chronic pain in the shoulder region may follow radical neck dissection, whereas modified neck dissection is usually a painless procedure.
Pitfalls in the Surgical Management of Cancer of the Larynx and Hypopharynx
Authors: Thabet M. Hossam , Talaat Mohammed , Rizk Adel M.
Published: February 2003

This article is based on findings in 180 patients with cancer of the larynx and hypopharynx. Positive margins were found in 12.2% (22/180) of all tumors, 12.5% (8/64) of supraglottic tumors, 16% (4/25) of transglottic tumors, 5.3% (2/38) of glottic tumors, 11.1% (2/18) of pyriform fossa tumors, 50% (3/6) of posterior pharyngeal wall tumors, and 10.6% (3/29) of postcricoid tumors. The relationship between the inadequate surgical margins of the specimens, tumor spread, preoperative CT findings, and surgical procedures performed have been correlated. (Otolaryngol Head Neck Surg 2000;123:482‐7.)
Endoscopic Surgery for a Parathyroid Functioning Adenoma Resection with the Neck Region‐Lifting Method
Authors: Myers Eugene N. , Kitano Hiroya , Fujimura Masaki , Hirano Masamitu , Kataoka Hideyuki , Kinoshita Takashi , Seno Satoshi , Kitajima Kazutomo
Published: February 2003

Recently, endoscopic surgery has been applied to cervical exploration. We have developed new techniques for endoscopic neck surgery. We reported on a 53‐year‐old Japanese man with functioning parathyroid adenoma resected by endoscopic surgery with a neck region‐lifting method. A 10‐mm midline trocar for the endoscope and two 5‐mm lateral trocars were inserted from the anterior chest wall to avoid neck scars. There were no intraoperative complications. The incisions were completely covered by the patient's undergarments. (Otolaryngol Head Neck Surg 2000;123:465‐6.)
Cautery‐Assisted Palatal Stiffening Operation for the Treatment of Obstructive Sleep Apnea Syndrome
Authors: Wassmuth Zachary , Mair Eric , Loube Daniel , Leonard David
Published: February 2003

Cautery‐assisted palatal stiffening operation (CAPSO) is a recently developed single office‐based procedure performed with local anesthesia for the treatment of palatal snoring. A midline strip of soft palate mucosa is removed, and the wound is allowed to heal by secondary intention. The flaccid palate is stiffened, and palatal snoring ceases. This prospective study evaluated the ability of CAPSO to treat obstructive sleep apnea syndrome (OSAS). Twenty‐five consecutive patients with OSAS underwent CAPSO. Responders were defined as patients who had a reduction in apnea‐hypopnea index (AHI) of 50% or more and an AHI of 10 or less after surgery. By these strict criteria, 40% of patients were considered to have responded to CAPSO. Mean AHI improved from 25.1 ± 12.9 to 16.6 ± 15.0 (P = 0.010). The Epworth Sleepiness Scale, a subjective measure of daytime sleepiness, improved from 12.7 ± 5.6 to 8.8 ± 4.6 (P < 0.001). These results indicate that CAPSO is as effective as other palatal surgeries in the management of OSAS.
Magnetic Resonance Imaging versus Clinical Palpation in Evaluating Cervical Metastasis from Head and Neck Cancer
Authors: Hao Sheng‐Po , Ng Shu‐Hang
Published: February 2003

We prospectively compared the value of MRI and clinical palpation for detecting cervical metastases in patients with primary cancer of the head and neck. Sixty patients with squamous cell carcinoma of the upper aerodigestive tract were evaluated with MRI and clinical palpation before undergoing a total of 81 neck dissections. The results of preoperative clinical palpation and MRI were compared with the histopathologic outcome. The sensitivity and specificity were 75.6% and 97.5%, respectively, for clinical palpation and 73.2% and 95%, respectively, for MRI. The rate of occult cervical metastasis was 24% with clinical palpation and 26.8% with MRI. The use of MRI did not improve the rate of early detection of occult metastasis, nor did it improve the detection of extracapsular spread. Our findings show that we could not depend on palpation or MRI alone to determine the need for elective neck dissection. However, MRI can be used to improve the preoperative grading of cervical lymph nodes. In selected cases, this may direct surgeons to convert the treatment plan to choose a more conservative neck dissection or, after sentinel node sampling and frozen‐section control, to convert the treatment to a more radical dissection.
Quality of Life for Children with Obstructive Sleep Apnea
Authors: Franco Ramon Arturo , Rosenfeld Richard M. , Rao Madu
Published: February 2003

The caregivers of 61 eligible children (6 months to 12 years old) completed a 20‐item (OSA‐20) health‐related quality‐of‐life survey after polysomnography was performed to psychometrically validate the OSA‐20. Excellent test‐retest reliability was obtained for the individual survey items (R > 0.74). Construct validity was shown by significant correlation of the mean survey score with the respiratory distress index (R = 0.43) and adenoid size (R = 0.43). Two items with poor validity were dropped, reducing the survey to 18 items (OSA‐18). The relationship between the OSA‐18 summary score and respiratory distress index remained significant when adjusted for tonsil size, adenoid size, body mass index, and child age. On the basis of the total survey score, the impact of OSAS on quality of life was small for 20 children (33%), moderate for 19 (31%), and large for 22 (36%). The OSA‐18 is a practical means of office‐based determination of quality‐of‐life impact for obstructive sleep apnea syndrome in children.
Comparative External Versus Endoscopic Dacryocystorhinostomy: Results in 115 Patients (130 Eyes)
Authors: Cokkeser Yasar , Evereklioglu Cem , Er Hamdi
Published: February 2003

BACKGROUND

Epiphora is an annoying symptom, embarrassing the patient both socially and functionally. The two widely accepted treatment modalities of epiphora resulting from obstruction of the nasolacrimal ductus are external and endoscopic dacryocystorhinostomy (DCR).

OBJECTIVE

The aim was to compare the results, operative time, and complications of external and videoendoscopic endonasal DCR performed between December 1994 and December 1998.

METHODS

In group 1, conventional primary external DCR with or without silicone tube intubation was performed in 79 patients (66 women and 13 men) with unilateral dacryocystitis. In group 2, endoscopic primary endonasal DCR with hammer‐chisel removal of bone located over the lacrimal sac was performed in 51 eyes of 36 patients, 33 women and 3 men (15 bilateral procedures).

RESULTS

The follow‐up period was 6 to 48 months (mean 25 months) after surgery. The age range was from 4 to 76 years (mean 38.5 years). The success rates of external and endoscopic hammer‐chisel DCR were found to be 89.8% and 88.2%, respectively. A lower complication rate was observed in the endoscopic group, with minimal morbidity and shorter operative time compared with the external approach.

CONCLUSIONS

Hammer‐chisel endoscopic DCR is practical, less traumatic, less time‐consuming, and cosmetically more convenient than the external approach. The success rate of the endoscopic DCR procedure is comparable with that of traditional external DCR, and it also allows simultaneous correction of any intranasal pathology.
Does the Severity of Sinus Computed Tomography Findings Predict Outcome in Chronic Sinusitis?
Authors: Stewart Michael G. , Donovan Donald T. , Parke Robert B. , Bautista Marilyn H.
Published: February 2003

OBJECTIVES:

We studied the association between the severity of pretreatment CT scan findings and the improvement in symptoms of chronic sinusitis after treatment.

METHODS:

We analyzed data from an ongoing prospective, nonrandomized clinical outcomes study of patients treated for chronic sinusitis at a tertiary‐care academic medical center (n = 57, mean age 46.8 years). Disease‐specific symptom severity was measured with a validated health status instrument, and CT stage was quantified with the Harvard CT staging system.

RESULTS:

In a multivariate analysis, symptom severity based on CT findings emerged as a strong predictor of both improvement in symptom score outcome (β = 0.47, P = 0.01) and absolute symptom level after treatment (P = −0.58, P = 0.001).

CONCLUSIONS:

Severity as assessed by a pretreatment CT scan is a strong predictor of outcome. Patients with higher symptom severity based on CT scans showed significantly larger improvement and lower absolute levels of symptom severity after treatment. This study links CT scan findings and subjective patient‐based outcomes (symptom scores) using a validated outcomes instrument.