bluuebunny/crossref_metadata_2025 huggingface dataset:
Factors Predicting Nutritional Derangements in Patients with Obstructive Jaundice: Multivariate Analysis
Authors: Padillo Francisco J. , Andicoberry Beatriz , Muntane Jordi , Lozano Jose M. , Miño Gonzalo , Sitges‐Serra Antonio , Pera‐Madrazo Carlos
Published: August 2002

Patients with obstructive jaundice (OJ) that requires surgery often have malnutrition associated with increased perioperative morbidity. This study investigated the factors influencing nutritional derangements in these patients. A series of 46 OJ patients were investigated prospectively (28 malignant tumors, 18 benign obstructions). A nutritional risk index of < 83.5 was used to define protein‐calorie malnutrition. Liver function, cholecystokinin (CCK), tumor necrosis factor‐α (TNFα), and endotoxin levels were determined. A multivariate analysis was performed, and an obstructive jaundice malnutrition index (OJMI) was obtained. Altogether, 22 (48%) OJ patients had malnutrition (33% with benign obstructions, 57% with malignant disease). Malnourished patients had higher serum bilirubin levels (258 ± 120 vs. 154 ± 62 mmol/L; p= 0.005), longer duration of jaundice (16 ± 9 vs. 9 ± 5 days; p= 0.03), and higher plasma levels of CCK (4.0 ± 1.3 vs. 1.7 ± 1.0 pmol/L; p= 0.005), alanine aminotransferase (ALT) (226 ± 209 vs. 187 ± 161 UI/L; p= 0.01), endotoxin (15 ± 10 vs. 6.5 ± 7.0 EU/L; p= 0.007), and TNFα (69 ± 82 vs. 23 ± 15 pg/ml; p= 0.008) than those without malnutrition. However, only serum bilirubin, CCK, ALT, and patient age were predictors for malnutrition by multivariate analysis. Malnutrition might be expected (95% confidence interval) in patients older than 68 years with increased bilirubin (> 290 mmol/L) and ALT (> 210 UI/L) levels that corresponded with an OJMI > 55. It was concluded that nutritional alterations in patients with obstructive jaundice were determined by the intensity of the biliary obstruction correlated with increased plasma CCK levels as well as with liver dysfunction and patient age.
Adrenalectomy for Treatment of Cushing Syndrome: Results in 122 Patients and Long‐Term Follow‐up Studies
Authors: Imai Tsuneo , Funahashi Hiroomi , Tanaka Yuji , Tobinaga Junichi , Wada Masaki , Morita‐Matsuyama Takako , Ohiso Yutaka , Takagi Hiroshi
Published: August 2002

Patients with Cushing syndrome (n= 122) who underwent adrenalectomy from 1957 through 1993 were reviewed for survival and complications. Of the 122 patients, 70 had adrenocortical adenoma, 30 Cushing's disease, 6 primary pigmented nodular adrenocortical disease (PPNAD), 7 other types of primary nodular hyperplasia, 5 adrenocortical carcinoma, and 4 ectopic ACTH syndrome. Sixty‐five patients with adrenocortical adenoma are alive, and the survival rate was equal to the age‐matched control population, when patients who died of the postoperative complication were excluded. Of the patients with Cushing's disease, 20 are alive; and 10 of 16 patients (63%) who were followed‐up and evaluated had skin pigmentation. Four of sixteen patients (25%) developed Nelson's syndrome. Four PPNAD patients and five with other types of nodular hyperplasia are alive. Most of these patients underwent bilateral total adrenalectomy, but some patients remitted after unilateral adrenalectomy. All of five adrenocortical carcinoma patients and four with ectopic ACTH syndrome died within 2 years after operation. The prognosis for patients with adrenocortical adenoma after unilateral adrenalectomy is excellent, though it is important to avoid operative complications. The rapid cure of signs and symptoms of glucocorticoid excess after total adrenalectomy is ensured, and prognosis is satisfactory under careful glucocorticoid replacement, making total adrenalectomy an alternative treatment for Cushing's disease.
Video‐assisted Thoracoscopic Surgery for Spontaneous Hemopneumothorax
Authors: Hsu Nan Yung , Hsieh Ming Jang , Liu Hui Ping , Kao Chiung Lun , Chang Jen Ping , Lin Pyng Jing , Chang Chau Hsiung
Published: August 2002

We operated on 403 patients with spontaneous pneumothorax between 1992 and 1996. Among these cases, 11 (2.7%) were spontaneous hemopneumothorax. The patients were all men, with ages ranging from 19 to 28 years (mean 23.8 years). The amount of blood drainage ranged from 650 to 2300 ml. Video‐assisted thoracoscopic surgery was performed on these patients within 1 day after admission. The sources of bleeding were in the parietal and visceral pleurae of ruptured bullae (n= 6), the parietal pleura (n= 4), or the visceral pleura (n= 1). During operation, the ruptured bullae can be managed by an endoscopic linear stapler for a bullectomy, and the bleeding parietal pleura of the torn adhesion can be coagulated directly. Postoperative recovery of the 11 patients was uneventful, and they were discharged 4 to 10 days after the operation. No recurrence of spontaneous hemopneumothorax or any other complications occurred during follow‐up. Thus spontaneous hemopneumothorax can be readily managed by cauterizing a bleeding site where appropriate, excising the apicocystic disease, and pleurodesis. As a minimally invasive method, video‐assisted thoracoscopic surgery may be considered an initial treatment procedure in patients with spontaneous hemopneumothorax.
Resection of Colorectal Liver Metastases: 25‐Year Experience
Authors: Ohlsson Björn , Stenram Unne , Tranberg K.‐G.
Published: August 2002

The aim of this retrospective study was to analyze survival and prognostic factors in 111 consecutive patients undergoing curative resection of liver metastases from colorectal cancer. In addition, the time periods 1971–1984 and 1985–1995 were compared; criteria for first liver resection did not change with time, whereas the attitude toward re‐resection was more aggressive during the latter period. Operative mortality was 6% during 1971–1984 and 0% during 1985–1995 (3.6% for all patients). The crude 5‐year actuarial survivals were 19% and 35% for patients operated during 1971–1984 and 1985–1995, respectively (25% for the whole period). Relapse at any site was observed in 52 patients (81%) operated during the first period and in 29 patients (67%) operated during the second period; re‐resection was performed in 12 (23%) and 15 (52%) of these patients, respectively. Five‐year survival after hepatic re‐resection was 29% (no operative mortality). In the univariate analysis, significant determinants for long‐term survival were, in descending order, a clear resection margin, high degree of fibrosis around the tumor, absence of extrahepatic metastases (including metastases to the liver hilum), use of an ultrasound dissector, low preoperative serum carcinoembryonic antigen (CEA) level, year of resection (1985–1995), and low/moderate grade of liver tumor. There were no 5‐year survivors when extrahepatic metastases were present, the liver tumor(s) had a low differentiation or satellites, or the resection margin was involved with tumor. In the multivariate analysis, the determinants were grade of liver tumor, absence of extrahepatic tumor, few intraoperative blood transfusions, low preoperative serum CEA level, and year of resection (1985–1995). It is concluded that: (1) an increased rate of hepatic re‐resection was partly responsible for the improved outcome after liver resection for colorectal metastases during recent years; (2) patients with extrahepatic metastases did not benefit from liver resection; and (3) surgery should be performed with a clear resection margin and minimal blood loss.
Cancer and Inflammatory Bowel Disease: Bias, Epidemiology, Surveillance, and Treatment
Authors: Solomon Michael J. , Schnitzler Margaret
Published: August 2002

Individuals with chronic ulcerative colitis are at increased risk of developing colorectal carcinoma, particularly if there is long‐standing disease or extensive colitis. It is generally accepted that the risk of colorectal cancer does not begin until 8 to 10 years after the time of diagnosis of ulcerative colitis. Thereafter it increases by approximately 0.5% to 1.0% per year. In patients with Crohn's disease, the risk of malignancy is smaller and less well defined. The most significant predictor of the risk of malignancy in patients with inflammatory bowel disease is the presence of dysplasia in colonic biopsies. There is considerable controversy in the literature regarding the efficacy of colonoscopic surveillance programs and the role of prophylactic surgery to prevent colorectal cancer. Surveillance certainly fails to detect carcinoma in some patients who are having regular colonoscopy. Concerns have also been raised as to the cost‐benefit of colonoscopic surveillance in patients with colitis. Randomized controlled trials of surveillance programs are highly unlikely in view of the low prevalence of IBD in the population, the long period of observation required, and the probability of contamination of surveillance programs by colonoscopy for assessment of disease activity. Despite the lack of clear guidelines, surveillance colonoscopy and biopsy continues to be widely practiced. Research is proceeding to identify genetic and biochemical markers that may prove clinically useful for predicting cancer risk. At present, however, surveillance programs are likely to continue according to institutional practice. It is important for those participating in such programs to be aware of the limitations of colonoscopy and biopsy as a means of reducing the risk of cancer in inflammatory bowel disease.
Strictureplasty for Crohn's Disease: Techniques and Long‐term Results
Authors: Hurst Roger D. , Michelassi Fabrizio
Published: August 2002

Strictureplasty for treatment of symptomatic intestinal strictures secondary to Crohn's disease is being performed with increasing frequency. To determine the overall clinical results after strictureplasty for Crohn's disease, all patients undergoing this procedure were prospectively studied. Between 6/1/89 and 2/1/97, 57 Crohn's disease patients underwent 60 operations utilizing strictureplasties. A total of 109 strictureplasties were performed (90 Heineke‐Mikulicz, 6 Finney, and 13 side‐to‐side isoperistaltic). The 30‐day perioperative morbidity was 12%, with complications being less common for patients undergoing elective versus unscheduled operations (p < 0.002). Recurrence of Crohn's disease requiring operation was seen in seven patients after a mean follow‐up of 38 months. The estimated cumulative recurrence rate after 2 years was 15 ± 6% (± standard error) and 22 ± 10% at 5 years. A recurrence developed at the site of the previous strictureplasty in only five cases. Strictureplasty is a safe, effective means of providing long‐term surgical palliation to selected patients with Crohn's disease. Perioperative complication rates are comparable to those seen with standard surgical treatment, and recurrences are not excessive.
Factors Determining Recurrence following Surgery for Crohn's Disease
Authors: Wolff Bruce G.
Published: August 2002

Many factors have been examined in an attempt to define groups at higher risk for recurrence or recrudescence of Crohn's disease. Among these factors are age and onset of disease, gender, site of disease, number of resections, symptomatic status at the time of surgery, length of small bowel resection, fistulizing versus obstructive forms of disease, proximal margin length, microscopic margin histology, strictureplasty, and number of sites of disease, as well as the presence of colonic only disease, the presence of granulomas, blood transfusions, family history, and prophylactic treatment. To date, only proctocolectomy with Brooke ileostomy versus other procedures for colonic only disease, and prophylactic treatment have been shown with some degree of confidence to lead to a lower recurrence rate after surgery for Crohn's disease.
Interleukin‐6 Levels in Colorectal Cancer Tissues
Authors: Komoda Hiroshi , Tanaka Yasuhiro , Honda Masaharu , Matsuo Yoshinobu , Hazama Kenji , Takao Tetsuto
Published: August 2002

Interleukin‐6 (IL‐6) levels in cancer tissues of 32 patients with colorectal cancer were measured and analyzed in relation to the clinicopathologic findings. The IL‐6 level in cancer tissues was 81.1 ± 118.0 pg/mg protein, which was significantly higher than the 11.2 ± 20.8 pg/mg protein in normal colorectal tissues (p= 0.028). IL‐6 levels in cancer tissues showed no correlation with the incidence of venous invasion, lymphatic invasion, lymph node involvement, or liver metastasis. The IL‐6 level in cancer tissue tended to decrease as the cancer penetration extended. Our results suggest that IL‐6 may play a role in human colorectal cancer growth.
Cost‐benefit Analysis for the Treatment of Severe Obesity
Authors: Martin Louis F. , White Steven , Lindstrom Walter
Published: August 2002

Cost‐benefit and cost‐effectiveness analyses (CEAs) are only now beginning to be used by business, government, and policymakers to evaluate various medical treatments. The evolution of why CEAs are being demanded is reviewed. To date, a formal CEA of obesity treatments has not been published. This article outlines how a CEA is performed, reviews data relevant to setting up a formal CEA of medical and surgical obesity treatments, and lists published reports that demonstrate the effectiveness of surgical obesity treatments. The general level of discrimination that society allows the obese to suffer also allows medical insurance companies, businesses, and government to not provide many obese Americans with obesity treatments that have established a level of effectiveness far surpassing many other forms of medical therapy. CEAs of obesity treatments, by themselves, cannot be expected to reverse this discrimination. This type of data, however, provides individual obese patients and their physicians with evidence to challenge policymakers’ decisions, especially when cost‐effective obesity treatments are excluded or placed at a lower priority than treatments with less proven effectiveness.
Are the Results of Pancreatectomy for Pancreatic Cancer Improving?
Authors: Tsiotos Gregory G. , Farnell Michael B. , Sarr Michael G.
Published: August 2002

Although pancreatectomy is still performed in a few patients with pancreatic cancer, and nearly all patients who develop pancreatic cancer eventually die of their disease, significant improvements have been made recently. Pancreatectomy is now safer, with major morbidity (hemorrhage, pancreatic anastomotic leak, intraabdominal sepsis) occurring in only about 20% and operative mortality of less than 5%. Two (seemingly subtle) issues cannot be overemphasized when someone carefully studies the literature: (1) There is a crucial difference between actuarial and actual survival, with the former generally being higher whereas the latter is true; and (2) careful re‐review of pathologic specimens (especially in long‐term survivors) initially diagnosed as pancreatic cancer, preferably by an independent pathologist before publishing long‐term results is essential. (Erroneous inclusion of patients with nonductal carcinoma substantially and artificially increases survival.) After curative resection, 5‐year actual survival is realistically about 10% with median survivals of 12 to 18 months. In certain subgroups with favorable pathologic characteristics (neoplasms < 2 cm without nodal or perineural invasion) the prognosis appears to be significantly better, with the 5‐year survival about 20%. The recent improvements in postoperative morbidity and mortality and long‐term outcome (resulting also in decreased cost of care of such patients) have occurred typically in centers with an invested interest in and proven record with pancreatic surgery. Further improvements in survival should be sought at the areas of earlier diagnosis and novel treatments designed to prevent locoregional recurrences; the role of extended resections must be determined by prospective, randomized trials.
Nerve‐sparing Surgery for Advanced Rectal Cancer Patients: Special Reference to Dukes C Patients
Authors: Saito Norio , Koda Keiji , Takiguchi Nobuhiro , Oda Kenji , Soda Hiroaki , Nunomura Masao , Sarashina Hiromi , Nakajima Nobuyuki
Published: August 2002

Several nerve‐sparing operations for advanced rectal cancer that aim to preserve genitourinary function without compromising tumor clearance have been developed in Japan. The aim of this study was to evaluate the survival and local recurrence of these procedures in Dukes B and C patients. A total of 177 patients with advanced rectal cancer underwent curative nerve‐sparing surgery (NSS) over the last 11 years; 52 were Dukes B patients and 54 were Dukes C. Altogether 36 had Dukes C1 and 18 had Dukes C2 tumors, 13 with lateral lymph node metastases, designated lateral LN(+). The 5‐year survival rate was 92% for Dukes B, 67% for Dukes C1, and 39% for Dukes C2 patients: 11% for Dukes C2 patients with lateral LN(+). The local recurrence rate was 6% for Dukes B, 11% for Dukes C1, and 33% for Dukes C2 patients: 20% for the lateral LN(−) group and 39% for the lateral LN(+) group. Almost all of the patients undergoing NSS could micturate spontaneously, but preservation of sexual function was not as successful. Although there is no guarantee of preserving satisfactory sexual function, our NSS is an acceptable procedure for Dukes B, C1, and C2 patients without lateral lymph node metastases.
The Cayley Trick, lifting subdivisions and the Bohne–Dress theorem on zonotopal tilings
Authors: Huber Birkett , Rambau Jörg , Santos Francisco
Published: August 2002

In 1994, Sturmfels gave a polyhedral version of the Cayley Trick of elimination theory: he established an order-preserving bijection between the posets of
coherent
mixed subdivisions of a Minkowski sum

\mathcal A_1+\cdots +\mathcal A_r

of point configurations and of
coherent
polyhedral subdivisions of the associated Cayley embedding

\mathcal C(\mathcal A_,...,\mathcal A_r)

. In this paper we extend this correspondence in a natural way to cover also
non-coherent
subdivisions. As an application, we show that the Cayley Trick combined with results of Santos on subdivisions of Lawrence polytopes provides a new independent proof of the Bohne–Dress theorem on zonotopal tilings. This application uses a combinatorial characterization of lifting subdivisions, also originally proved by Santos.
Complex Ginzburg-Landau equations in high dimensions and codimension two area minimizing currents
Authors: Lin Fanghua , Rivière Tristan
Published: August 2002

Abstract. There is an obvious topological obstruction for a finite energy unimodular harmonic extension of a

S^1

-valued function defined on the boundary of a bounded regular domain of

R^n

. When such extensions do not exist, we use the Ginzburg–Landau relaxation procedure. We prove that, up to a subsequence, a sequence of Ginzburg–Landau minimizers, as the coupling parameter tends to infinity, converges to a unimodular harmonic map away from a codimension-2 minimal current minimizing the area within the homology class induced from the

S^1

-valued boundary data. The union of this harmonic map and the minimal current is the natural generalization of the harmonic extension.
Convex integration with constraints and applications to phase transitions and partial differential equations
Authors: Müller Stefan , Šverák Vladimír
Published: August 2002

Abstract. We study solutions of first order partial differential relations Du]K, where u:Q²ÂnMÂm is a Lipschitz map and K is a bounded set in m2n matrices, and extend Gromov's theory of convex integration in two ways. First, we allow for additional constraints on the minors of Du and second we replace Gromov's P-convex hull by the (functional) rank-one convex hull. The latter can be much larger than the former and this has important consequences for the existence of 'wild' solutions to elliptic systems. Our work was originally motivated by questions in the analysis of crystal microstructure and we establish the existence of a wide class of solutions to the two-well problem in the theory of martensite.
Almost invariant submanifolds for compact group actions
Authors: Weinstein Alan
Published: August 2002

Abstract. We define a C1 distance between submanifolds of a riemannian manifold M and show that, if a compact submanifold N is not moved too much under the isometric action of a compact group G, there is a G-invariant submanifold C1-close to N. The proof involves a procedure of averaging nearby submanifolds of riemannian manifolds in a symmetric way. The procedure combines averaging techniques of Cartan, Grove/Karcher, and de la Harpe/Karoubi with Whitney's idea of realizing submanifolds as zeros of sections of extended normal bundles.
Extinction of marine renewable resources: a demographic analysis
Authors: Punt A. E.
Published: August 2002

A simple (deterministic) population dynamics model is used to examine the level of fishing mortality at which a population is expected to be driven to extinction (Fcrash). Values for Fcrash are determined for six marine fish species (Cape hake, blue grenadier, blue warehou, school shark, gummy shark, and orange roughy) subject to commercial harvest. The sensitivity of the value of Fcrash to changing the selectivity pattern of the fishery and the relationship between the size of the reproductive component of the population and subsequent births to allow for depensatory effects is examined. Fcrash is greatest for highly productive species and when the fishery does not target immature animals. The ratio of Fcrash to the fishing mortality at which maximum sustainable yield is achieved, FMSY, is a decreasing function of the productivity of the population. The possibility of depensation has little impact on FMSY but can substantially reduce the ratio Fcrash/FMSY. A series of stochastic simulations is conducted to assess the probability of detecting that the extent of fishing exceeds Fcrash using the current IUCN A criterion. The results of these simulations are also used to determine the probability that the IUCN A criteria will be triggered when fishing takes place at FMSY. The results indicate that there are substantial probabilities of incorrectly identifying species being harvested at FMSY as being threatened during the ‘fishing down’ phase and also of not identifying species actually at risk of extinction if fishing mortality is not reduced.
Localized outbreak of a willow leaf beetle: plant vigor or natural enemies?
Authors: Björkman C. , Bengtsson B. , Häggström H.
Published: August 2002

The possible roles of plant quality (vigor) and natural enemies in the development of a localized out‐break of the leaf beetle Galerucella lineola (Coleoptera: Chrysomelidae) in a stand of Salix cinerea were investigated. Caged and uncaged larvae on six bushes in the outbreak area were compared with caged and uncaged larvae on six bushes in an adjacent nonoutbreak area in terms of performance. In 1997, when the studies were performed, the natural density of the insect (beetles plus eggs) was six times higher in the outbreak area compared with the nonoutbreak area. Even though the vigor (measured as shoot length) of bushes in the outbreak was 72% higher than that of bushes in the nonoutbreak area, we found no difference between areas in the performance (survival, developmental time, pupal weight) of caged larvae or in the willingness of caged females to lay eggs. Among larvae exposed to natural enemies, the disappearance rate was significantly higher in the nonoutbreak area. The density of generalist predators was significantly higher in the nonoutbreak than in the outbreak area. We conclude that differences in plant quality, despite the observed difference in plant vigor, could not explain the observed difference in beetle density between areas. Lower predation pressure in the outbreak area could, however, not be excluded as a possible reason for the higher density of leaf beetles in this area.
Microscopic Acanthosis Nigricans in Type 2 Diabetes
Authors: McManus R. M. , Gottschalk R. , Alanen K. , Shum D. T. , Grundy P.
Published: August 2002

Background

Acanthosis nigricans (AN) has been associated with insulin resistance. Individuals with type 2 diabetes are insulin-resistant and, therefore, could be expected to manifest AN. However, the prevalence and predictors of AN are unknown in this population.

Objective

An outpatient population with Type 2 diabetes (DM) was compared with matched controls (C) for microscopic and clinical AN along with measurement of body habitus, insulin, glucose, and androgen levels.

>Methods

Twenty-four individuals with DM (12M, 12F) from a tertiary care center were compared with 24 C (12M, 12F). Fasting glucose, insulin, sex hormone binding globulin, androstenedione, dihydroepiandrosterone sulfate, and testosterone were measured. Height, weight, waist/hip measures, and a clinical survey for acanthosis were recorded. A 2-mm skin biopsy from midaxilla of the nondominant arm was taken for pathological review.

Results

C and DM were matched for age and body mass index (BMI). Prevalence of microscopic AN in C was 12% (3/24) and in DM was 21% (5/24; NS). In C, AN was predicted by waist, waist/hip ratio, and fasting insulin measures, while none of the variables examined was predicative of AN in DM.

Conclusions

Microscopic acanthosis nigricans was found in similar numbers of people with DM when compared with C. Fasting insulin levels most strongly predicted the presence of AN in C, while no significant predictors of AN were found in the population with DM.
The Role of Liver Biopsy in Chronic Hepatitis C
Authors: Saadeh Sherif , Cammell Greg , Carey William D. , Younossi Zobair , Barnes David , Easley Kirk
Published: August 2002

Hepatitis C virus (HCV) is a major cause of chronic liver disease worldwide, affecting 175 million people globally. Over 80% of acutely infected patients go on to develop chronicity, but only 20% to 25% will develop end–stage liver disease and its complications. The sequelae of HCV–induced chronic liver disease accounts for 8,000 to 10,000 deaths annually in the United States and is currently the leading indication for liver transplantation. To date, there are no accurate noninvasive markers of disease activity and fibrosis. Liver biopsy is indicated to exclude other forms of liver pathologies and to establish the stage of liver disease. In this study, the role of liver biopsy in chronic hepatitis C was evaluated. Additionally, we calculated a discriminant score to predict cirrhosis in chronic hepatitis C infection. Our results showed that additional diagnoses or unsuspected diagnoses are less frequent than clinicians' suspected. We confirmed that the discriminant score for predicting cirrhosis is inferior to liver biopsy. In conclusion, the majority of patients with chronic hepatitis C will require a liver biopsy, which has an important implication on staging of the liver disease, prognosis, and possibly further management options.
Bacterial Lipopolysaccharide Enhances Aflatoxin B1 Hepatotoxicity in Rats by A Mechanism That Depends on Tumor Necrosis Factor α
Authors: Barton Charles C. , Barton Eva X. , Ganey Patricia E. , Kunkel Steven L. , Roth Robert A.
Published: August 2002

Exposure to a nontoxic dose of bacterial endotoxin (lipopolysaccharide [LPS]) potentiates the hepatotoxicity of aflatoxin B1 (AFB1). Because some of the pathophysiologic effects associated with LPS are mediated through tumor necrosis factor α (TNF–α), this study was conducted to explore the role of TNF–α in the AFB1/LPS model. Male Sprague–Dawley rats (250–300 g) were treated with either 1 mg AFB1/kg, intraperitoneally, or its vehicle (0.5% dimethyl sulfoxide [DMSO]/water), and 4 hours later with either Escherichia coli lipopolysaccharide (7.4 × 106EU/kg, intravenously) or its saline vehicle. LPS administration resulted in a marked rise in TNF–α levels at 6 hours, which preceded the onset of liver injury. TNF–α messenger RNA (mRNA) in liver was increased by LPS treatment. The mRNA of receptors (R1 and R2) for TNF–α was also examined. R1 mRNA levels were not altered; however, R2 mRNA levels were increased by either AFB1 or LPS administration. To determine if TNF–α plays a causal role in the development of liver injury, the increase in TNF–α was attenuated by administration of either pentoxifylline or anti–TNF–α serum, and liver injury was assessed. Administration of either of these agents resulted in protection. LPS treatment resulted in the upregulation of gene transcription for cyclooxygenase–2 (COX–2). However, administration of the selective COX–2 inhibitor NS–398 did not decrease injury. TNF–α and COX–2 inhibitors did not affect hepatic sequestration of neutrophils. Furthermore, it did not appear that TNF–α contributed to injury through inhibition of tissue repair. These data support the hypothesis that LPS–induced expression of TNF–α underlies the potentiation of AFB1–induced hepatotoxicity.
Hepatitis C Virus Core Protein Enhances the Activation of the Transcription Factor, Elk1, in Response to Mitogenic Stimuli
Authors: Fukuda Katsuhiko , Tsuchihara Katsuya , Hijikata Makoto , Nishiguchi Shuhei , Kuroki Tetsuo , Shimotohno Kunitada
Published: August 2002

Mitogen–activated protein kinase (MAPK) pathways play key roles in cell proliferation, transformation of mammalian cells, and the stress response. We and other investigators showed that hepatitis C virus (HCV) core protein has an oncogenic potential, but its mechanism has remained unknown. We previously demonstrated that the MAPK–extra–cellular signal—regulated kinase (ERK) kinase (MEK)–ERK pathway and its downstream target, the serum response element (SRE), is activated in BALB/3T3 cells producing HCV core protein. To elucidate the precise mechanism by which HCV core protein activates the MEK–ERK pathway, we transiently expressed HCV core protein in several cell lines and studied the signal transduction of the pathway, using Gal4–Elk1 luciferase assay, in vitro kinas assay of MAPK, and Western blotting analysis. We discovered that, in the presence of mitogenic signal, HCV core protein enhanced Elk1 activation working downstream of MEK without affecting ERK activity and Elk1 phosphorylation. Our data suggest that HCV core protein may activate Elk1 through a pathway alternative to the typical phosphorylation cascade. These findings might give new insights into the role of HCV in hepatocarcinogenesis.
Gene Therapy of Orthotopic Hepatocellular Carcinoma in Rats Using Adenovirus Coding for Interleukin 12
Authors: Barajas Miguel , Mazzolini Guillermo , Genové Guillem , Bilbao Roberto , Narvaiza Iñigo , Schmitz Volker , Sangro Bruno , Melero Ignacio , Qian Cheng , Prieto Jesús
Published: August 2002

The use of gene therapy to enhance antitumor immunity has emerged as a promising procedure to fight cancer. In this study we have tested the ability of an adenovirus carrying interleukin 12 (IL–12) gene (AdCMVIL–12) to eliminate tumoral lesions in 3 animal models of orthotopic hepatocellular carcinoma (HCC). Intratumoral injection of AdCMVIL–12 in animals with a single big tumor nodule implanted in the liver resulted in significant inhibition of tumor growth in a dose–dependent manner. Fifty percent of animals that received a dose of 5 × 109 plaque–forming units, showed complete regression of the tumor 2 weeks after treatment. In animals with 2 independent tumor nodules in the left liver lobe, injection in only one of them of 5 × 109 pfu AdCMVIL–12 induced, 15 days after therapy, complete regression of 50% of treated tumors and also of 50% of untreated lesions, with 60% long–term survival. Rats that were tumor free after therapy with AdCMVIL–12 showed protection against tumor rechallenge. A group of rats received the carcinogen diethylnitrosamine and developed multiple hepatic dysplasic nodules of 1 to 5 mm in diameter. These animals were treated by intrahepatic artery injection of either AdCMVIL–12 (5 × 109 pfu) or control vector. In this model AdCMVIL–12 induced complete tumor regression in 20% of treated rats and inhibited tumor growth in 60% of cases with an increase in rat survival. Activation of natural killer (NK) cells and inhibition of angiogenesis were found to be antitumor mechanisms set in motion by AdCMVIL–12. Our data indicate that experimental HCC can be efficiently treated by intratumoral or intravascular injection of adenovirus expressing IL–12.
Outcome of Hospital Care of Liver Disease Associated With Hepatitis C in the United States
Authors: Kim Ray W. , Gross John B. , Poterucha John J. , Locke Richard G. , Dickson Rolland E.
Published: August 2002

We describe mortality and resource utilization for inpatient care of hepatitis C (HCV) in comparison to alcohol–induced liver disease (ALD) in the United States and identify factors that affect outcomes. The Healthcare Cost and Utilization Project database, a national inpatient sample was used to identify hospitalization records with diagnoses related to liver disease from HCV and ALD. Outcome of hospitalizations was analyzed in terms of in–hospital deaths and health care resource utilization. For 1995, we estimate that there were 26,700 hospitalizations and 2,600 deaths in acute, nonfederal hospitals in the United States for liver diseases caused by HCV. Total charges for these hospitalizations were $514 million. In comparison, ALD was associated with 101,200 hospitalizations, 13,400 deaths, and $1.8 billion in charges. Simultaneous HCV and alcohol abuse was associated with younger ages at the time of hospitalization and death compared with HCV or ALD alone. In a logistic regression analysis, alcohol abuse (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.2–1.5) and human immunodeficiency virus (HIV) infection (OR, 4.5; 95% CI, 4.0–4.9) were associated with an increased risk of death among those with HCV. Liver transplantation and patient death were associated with the largest increase in hospitalization charges. Major complications of cirrhosis, such as variceal bleeding, encephalopathy, and hepatorenal syndrome, and sociodemographic factors, such as race and health insurance, were also significantly associated with the risk of death and hospitalization charges, which were similar in HCV and ALD. This study provides new estimates regarding the public health impact of HCV, for use in health policy decisions and cost–effectiveness analyses of preventive and therapeutic interventions.
Differential Role of IκB Kinase 1 and 2 in Primary Rat Hepatocytes
Authors: Schwabe Robert F. , Bennett Brydon L. , Manning Anthony M. , Brenner David A.
Published: August 2002

Nuclear factor–κB (NF–κB) protects hepatocytes from undergoing apoptosis during embryonic development and during liver regeneration. Activation of NF–κB is mediated through phosphorylation of its inhibitor, IκB, by a kinase complex that contains 2 IκB kinases. We analyzed the differential role of IκB kinase 1 (IKK1) and IκB kinase 2 (IKK2) in tumor necrosis factor α (TNF–α)– and interleukin–1β (IL–1β)–mediated NF–κB activation in primary rat hepatocytes. Maximal induction of IKK activity was observed 5 minutes after TNF–α and 15 minutes after IL–1β treatment, and activated IKK was able to phosphorylate GST–IκB (1–54) and GST–p65 (354–551), but not a GST–p65 (354–551) substrate with a serine–to–alanine substitution at position 536. Infection with an adenovirus containing catalytically inactive IKK2K44M (Ad5IKK2dn) completely blocked both TNF–α– and IL–1β–induced GST–IκB and GST–p65 phosphorylation, IκB degradation, and NF–κB DNA binding. Adenovirally transduced, catalytically inactive IKK1K44M (Ad5IKK1dn) reduced IKK activity and NF–κB DNA binding only slightly. Accordingly, Ad5IKK2dn induced apoptosis in 75% (±6%) of hepatocytes after 12 hours of TNF–α, which was accompanied by activation of caspases 3 and 8, nuclear fragmentation, and DNA laddering. In contrast, Ad5IKK1dn led to 21% (±2%) apoptosis in TNF–α–treated hepatocytes after 12 hours and comparatively low activity of caspases 3 and 8. Furthermore, Ad5IKK2dn completely blocked the induction of inducible nitric oxide synthase (iNOS), whereas Ad5IKK1dn had no influence on the expression of iNOS. Thus, IKK2 is the main mediator for cytokine–induced NF–κB activation in primary hepatocytes and protects against TNF–α–induced apoptosis, whereas IKK1 kinase activity is not required for NF–κB activation.
Antiviral Activity of Clevudine [L–Fmau, (1–(2–Fluoro–5–Methyl–β, L–Arabinofuranosyl) Uracil)] Against Woodchuck Hepatitis Virus Replication and Gene Expression in Chronically Infected Woodchucks ( Marmota Monax )
Authors: Peek Simon F. , Cote Paul J. , Jacob James R. , Toshkov Ilia A. , Hornbuckle William E. , Baldwin Betty H. , Wells Frances V. , Chu C. K. , Gerin John L. , Tennant Bud C. , Korba Brent E.
Published: August 2002

l–FMAU [1–(2–fluoro–5–methyl–β,l–arabinofuranosyl) uracil] has been shown to be an effective inhibitor of hepatitis B virus (HBV) and duck hepatitis B virus replication in cell culture and duck hepatitis B virus replication in acutely infected Peking ducks. The woodchuck hepatitis virus (WHV) and its natural host, the Eastern woodchuck (Marmota monax), have been established as a predictive model for the evaluation of antiviral therapies against chronic HBV infection. In this report, the antiviral activity of l–FMAU against WHV replication in chronically infected woodchucks is described. Four weeks of once–daily oral administration of l–FMAU significantly reduced viremia, antigenemia, intrahepatic WHV replication, and intrahepatic expression of woodchuck hepatitis virus core antigen (WHcAg) in a dose–dependent manner. At the highest dose administered (10 mg/kg/d), significant reductions of intrahepatic WHV RNA and covalently closed circular (ccc)WHV–DNA levels also were observed. The reduction in viremia was remarkably rapid at the higher doses of l–FMAU, with greater than 1,000–fold reductions in WHV–DNA serum levels observed after as little as 2 to 3 days of therapy. Following the withdrawal of therapy, a dose–related delay in viremia rebound was observed. At the highest doses used, viremia remained significantly suppressed in at least one half of the treated animals for 10 to 12 weeks' posttreatment. No evidence of drug–related toxicity was observed in the treated animals. l–FMAU is an exceptionally potent antihepadnaviral agent in vitro and in vivo, and is a suitable candidate for antiviral therapy of chronic HBV infection.
Reck Gene Expression in Hepatocellular Carcinoma: Correlation With Invasion–Related Clinicopathological Factors and Its Clinical Significance
Authors: Furumoto Katsuyoshi , Arii Shigeki , Mori Akira , Furuyama Hiroaki , Gorrin Rivas Manuel J. , Nakao Teizou , Isobe Naoki , Murata Toru , Takahashi Chiaki , Noda Makoto , Imamura Masayuki
Published: August 2002

The RECK (reversion–inducing–cysteine–rich protein with Kazal motifs) gene was initially isolated as a transformation suppressor gene. It encodes a membrane–anchored glycoprotein with multiple serine protease inhibitor–like domains. The RECK gene is expressed widely in normal organs but is undetectable in many tumor–derived cell lines. When artificially expressed in such cell lines, RECK suppresses their invasive and metastatic activities. Clinical implications of these findings, however, remained undefined because of the lack of studies using fresh human tumor samples. In the present study, we have addressed this issue by analyzing the levels of RECK gene expression in hepatocellular carcinoma (HCC). RECK mRNA was detectable by RNA blot hybridization in all the tumorous and contiguous nontumorous tissues obtained from 64 patients with HCC. In 26 cases, the RECK expression in tumorous tissues was higher than that in nontumorous tissues. The expression of RECK protein in these tissues could also be demonstrated by immunohistochemistry. Patients with high RECK mRNA expression in tumorous tissues tended to show better survival (P = .02), and such tumors had a tendency to be less invasive. Univariate and multivariate analysis revealed that the RECK mRNA expression is a novel and independent variable affecting overall survival (P = .01). These findings support the hypothesis that RECK has negative effects on the invasiveness of HCC cells and suggest the feasibility of RECK mRNA as a promising prognostic molecular marker for HCC.
Visual Demonstration of Hepatitis C Virus–Specific Memory Cd8+ T–Cell Expansion in Patients With Acute Hepatitis C
Authors: Sobao Yuji , Tomiyama Hiroko , Nakamura Saburo , Sekihara Hisahiko , Tanaka Katsuaki , Takiguchi Masafumi
Published: August 2002

Hepatitis C virus (HCV)–specific CD8+ T cells in peripheral blood mononuclear cells (PBMCs) from patients infected with HCV were quantitatively analyzed by flow cytometry using an HLA–B*3501–HCV epitope tetrameric complex. In chronic hepatitis C, tetramer+CD8+ T cells were detected at frequencies ranging from 0.05% to 0.12% of total CD8+ T cells. The number of tetramer+CD8+ T cells in acute phase PBMCs from patients with acute hepatitis C was about 3 to 5 times higher than in recovery phase PBMCs from the same patients and in PBMCs from patients with chronic hepatitis C. Expanding tetramer+CD8+ T cells in PBMCs from patients with acute hepatitis C express a CD28+CD45RA- memory T–cell phenotype. In contrast, tetramer+CD8+ T cells in PBMCs from patients with chronic hepatitis C did not predominantly express this phenotype. These tetramer+CD8+ T cells did not have perforin in their cytoplasma. The present study visually showed that a high number of circulating HCV–specific CD8+ T cells in acute phase PBMCs from patients with acute hepatitis C are mostly memory T cells.
A Multicenter United States—Canadian Trial to Assess Lamivudine Monotherapy Before and After Liver Transplantation for Chronic Hepatitis B
Authors: Perrillo Robert P. , Wright Teresa , Rakela Jorge , Levy Gary , Schiff Eugene , Gish Robert , Martin Paul , Dienstag Jules , Adams Paul , Dickson Rolland , Anschuetz Gaya , Bell Steve , Condreay Lynn , Brown Nathaniel
Published: August 2002

Seventy–seven liver transplant candidates were enrolled in a multicenter study in which patients were treated with lamivudine (100 mg daily) without the adjunctive use of hepatitis B immune globulin. Treatment was begun while patients awaited liver transplantation and continued after transplantation. All were hepatitis B surface antigen (HBsAg) positive, and 61% had detectable hepatitis B e antigen (HBeAg) and HBV DNA when treatment was begun. Forty–seven underwent liver transplantation and 30 did not. Median study participation was 38 months (range, 2.7–48.5) in the transplanted patients and 26 months (range, 0.1–37) in the nontransplanted group. Twenty–five of 42 (60%) transplanted patients with 12 or more weeks of posttransplantation follow–up were HBsAg negative at the last study visit. At treatment week 156, 13 of 22 (59%) remained HBsAg negative, and all 9 reinfected patients were HBV–DNA positive before treatment. In the nontransplanted patients, HBeAg was initially detectable in 20 of 27 (74%) but this decreased to 3 of 17 (18%) after 104 weeks of treatment, and significant improvement in biochemical parameters was observed. HBV–DNA polymerase mutants were detected in 15 (21%) and 6 (20%) of the transplanted and nontransplanted patients, respectively. When compared with historical cohorts, lamivudine–treated patients appeared to have improved survival, and transplanted patients had a decrease in the rate of recurrent HBV infection. Lamivudine therapy was partially effective in preventing recurrent HBV infection when given before and after transplantation. Thus, future trials using a combination of HBIg and lamivudine are needed to assess the optimal prophylactic therapy.
Efficacy and Safety of Pegylated (40–Kd) Interferon α–2A Compared With Interferon α–2A in Noncirrhotic Patients With Chronic Hepatitis C
Authors: Reddy Rajender K. , Wright Teresa L. , Pockros Paul J. , Shiffman Mitchell , Everson Gregory , Reindollar Robert , Fried Michael W. , Purdum Preston P. , Jensen Donald , Smith Coleman , Lee William M. , Boyer Thomas D. , Lin Amy , Pedder Simon , DePamphilis Jean
Published: August 2002

Administration of interferon (IFN) 3 times weekly in patients with chronic hepatitis C (CHC) is associated with low sustained responses, which may be, in part, related to this regimen's inability to maintain IFN concentrations sufficient to suppress viral replication. An enhanced IFN molecule produced by the covalent attachment of a branched 40–kd polyethylene glycol moiety to IFN α–2a (PEG[40kd] IFN α–2a) exhibits sustained absorption, a restricted volume of distribution, and reduced clearance compared with unmodified IFN α–2a. One hundred fifty–nine patients with CHC participated in a randomized, ascending–dose (45 or 90, 180, 270 μg) study comparing PEG(40kd) IFN α–2a administered once weekly with 3 MIU IFN α–2a administered 3 times weekly for 48 weeks to determine the most appropriate PEG(40kd) IFN α–2a dose for subsequent clinical trials. Efficacy was assessed by measuring hepatitis C virus (HCV) RNA following a 24–week treatment–free period. Sustained virological responses for PEG(40kd) IFN α–2a once weekly were 10% (45 μg; not significant), 30% (90 μg; P = .009), 36% (180 μg; P = .0006), and 29% (270 μg; P = .004), compared with 3% for the 3–times–weekly 3–MIU IFN α–2a regimen. The types and frequencies of adverse events and laboratory abnormalities were similar among all groups. In conclusion, once–weekly PEG(40kd) IFN α–2a was associated with a higher number of sustained virological responses compared with IFN α–2a 3 times weekly in patients with CHC, but had a similar safety profile. The 180–μg PEG(40kd) IFN α–2a dose appeared to be the optimal dose based on sustained virological response and its associated side–effect profile.
Pathogenesis of Experimental Neonatal Woodchuck Hepatitis Virus Infection: Chronicity As An Outcome of Infection Is Associated With A Diminished Acute Hepatitis That Is Temporally Deficient for the Expression of Interferon Gamma and Tumor Necrosis Factor–Alpha Messenger Rnas
Authors: Nakamura Ikuo , Nupp James T. , Cowlen Matthew , Hall William C. , Tennant Bud C. , Casey John L. , Gerin John L. , Cote Paul J.
Published: August 2002

Surgical biopsies of the liver were obtained from woodchuck hepatitis virus (WHV)–infected neonatal woodchucks at 2 time points before the self–limited or chronic outcomes became obvious by serologic criteria. Following segregation of outcomes, livers were analyzed for intrahepatic type 1 cytokine messenger RNAs (mRNAs) (interleukin 2 [IL–2], interferon gamma [IFN–γ], tumor necrosis factor–alpha [TNF–α]) and leukocyte inflammatory phenotype (IgG+ plasma cells, lysozyme+ macrophages, CD3+ T cells). Baselines were assessed using age–matched uninfected control livers. At week 8 (early acute phase), intrahepatic type 1 cytokine mRNAs were similarly low in both outcome settings and no different from age–matched uninfected controls. This was consistent with the minimal initial viral loads and lack of histologic inflammation at this time. At week 14 (mid–acute phase), changes in viral load between outcome groups related inversely to the intrahepatic inflammatory responses. Animals that eventually became resolved had increased intrahepatic expression of IFN–γ and TNF–α mRNAs and robust inflammation by CD3+ T cells, plasma cells, and macrophages. At the same time point of infection, animals that eventually became chronic carriers had an acute hepatitis involving the same cell types, but at diminished levels, and markedly deficient intrahepatic expression of IFN–γ and TNF–α mRNAs. IL–2 mRNA remained at baseline control levels in both outcome groups. These cotemporal comparisons map a critical deviation in host response to the acute stage of an evolving chronic infection. They strongly suggest that increasing viral load and chronicity as an outcome of neonatal WHV infection result from a temporal deficiency in the acute intrahepatic effector mechanisms mediated by IFN–γ and TNF–α.