bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinicopathologic and Immunohistochemical Studies of Papillary Thyroid Microcarcinoma Presenting with Cervical Lymphadenopathy
Authors: Sugitani Iwao , Yanagisawa Akio , Shimizu Akira , Kato Mitsuyasu , Fujimoto Yoshihide
Published: August 2002

Although most papillary thyroid microcarcinomas (PMCs) are of little clinical significance, patients with PMCs occasionally have an unfavorable outcome, especially when they present with bulky nodal metastasis or distant metastasis. We have attempted to identify “high‐risk” PMCs by evaluating clinical, pathologic, and immunohistochemical prognostic factors. Among 190 patients with a PMC, 156 without clinically apparent nodal metastasis had a benign course. The remaining 34 patients, who presented with cervical lymphadenopathy of at least 1 cm, were studied. Three of the four patients who developed distant metastasis died of the disease, and the other died of local recurrence. All patients who developed distant metastasis or died of the disease had both nodal metastasis of at least 3 cm and a nonencapsulated type of primary lesion. All patients who developed distant metastasis showed both extracapsular extension of the metastatic lesions in lymph nodes and positive staining for transforming growth factor‐β3 (TGFβ3) (a potent growth inhibitor) in the primary lesion. The Ki‐67 (an indicator of cell proliferation) labeling indices in the primary and metastatic nodal lesions of patients who died of cancer were significantly higher than those of the others with nonfatal disease. None of the patients showed P53 (nuclear tumor‐suppressor phosphoprotein) overexpression. In conclusion, patients with PMC who have both 3 cm or larger lymphadenopathy and a nonencapsulated type of primary lesion may be regarded as high‐risk patients. Immunohistologic positivity for Ki‐67 and TGFβ3 in cancer cells is a potential indicator of aggressively malignant PMC.
Biliopancreatic Diversion
Authors: Scopinaro Nicola , Adami Gian Franco , Marinari Giuseppe M. , Gianetta Ezio , Traverso Enrico , Friedman Daniele , Camerini Giovanni , Baschieri Giorgio , Simonelli Alessandro
Published: August 2002

Biliopancreatic diversion (BPD) has made reacceptable the malabsorptive approach to the surgical treatment of obesity. The procedure, in a series of 2241 patients operated on during a 21‐year period, caused a mean permanent reduction of about 75% of the initial excess weight. The indefinite weight maintenance appears to be due to the existence of a threshold absorption capacity for fat and starch, and thus energy, and the weight loss is partly due to increased resting energy expenditure. Beneficial effects other than those consequent to weight loss or reduced nutrient absorption included permanent normalization of serum glucose and cholesterol without any medication and on totally free diet in 100% of cases, both phenomena being due to a specific action of the operation. Operative mortality was less than 0.5%. Specific late complications included anemia, less than 5% with adequate iron or folate supplementation (or both); stomal ulcer, reduced to 3.2% by oral H2‐blocker prophylaxis; bone demineralization, increasing up to the fourth year and tending to decrease thereafter, with need of calcium and vitamin D supplementation; neurologic complications, totally avoidable by prompt vitamin B administration to patients at risk; protein malnutrition, which was reduced to a minimum of 3% with 1.3% recurrence, in exchange with a smaller weight loss, by adapting the volume of the gastric remnant and the length of the alimentary limb to the patient's individual characteristics. It is concluded that the correct use of BPD, based on the knowledge of its mechanisms of action, can make the procedure an effective, safe one in all hands.
Socioeconomic Aspects
Authors: Rutkow Ira M.
Published: August 2002

Most surgeons conceptualize “surgical advance” as the introduction of a new operative technique or the presentation of a technologic breakthrough. However, the true landmark innovations of the past decade, with regard to effecting surgical health care delivery, have been the impact of economics and sociology in determining the profession's future. In the past, the surgeon's primary interests revolved around the art and science of surgery, and socioeconomic issues were deemed of secondary importance. Consequently, few of the investigations into “surgical socioeconomics” were conducted by surgeons, and the surgical establishment was more than mildly apathetic toward such social science research. All of this has changed, and it is now evident that there is an overwhelming need for surgeons to incorporate an understanding of sociologic and economic conditions into their clinical thinking. Basic tenets of surgical socioeconomics are presented, and their impact on various clinical situations is discussed.
Surgical Stress Response: Does Endoscopic Surgery Confer an Advantage?
Authors: Kehlet Henrik
Published: August 2002

“Open” surgical procedures are followed by profound changes in endocrine metabolic function and various host defense mechanisms, impaired pulmonary function, and hypoxemia. These physiologic changes are supposed to be involved in the pathogenesis of postoperative morbidity. Endoscopic surgery, mostly studied during laparoscopy, when compared with similar open operations, has no important effects on classic endocrine metabolic responses but may slightly reduce inflammatory responses and various immune functions, although the data are not consistent. In contrast, most data show improvement of postoperative pulmonary function and less hypoxemia with endoscopic operation. The slight modification of surgical stress responses by endoscopic surgery is in contrast to the common, though not universal, demonstration of less pain, shorter hospital stay, and less morbidity after endoscopic surgery. In conclusion, endoscopic surgery has so far not been demonstrated to have important modifying effects on classic endocrine metabolic responses and only a slight inhibitory effect on various inflammatory responses, but with improved pulmonary function and less hypoxemia. More data are needed from major operations where differences are more likely to be found. The clinical consequences of these findings in relation to allover surgical outcome remain to be defined, but effective pain treatment, stress reduction by other techniques, and provision of an active rehabilitation program with early mobilization and oral feeding may be more important than the choice between an endoscopic technique versus “open” operation per se to improve outcome.
Endoscopic Surgery: What Has Passed the Test?
Authors: Köhler L.
Published: August 2002

The use of endoscopic surgery has increased in gastrointestinal surgery since the introduction of laparoscopic cholecystectomy. It was the aim of this study to investigate the impact of endoscopic procedures in 1998. Laparoscopic cholecystectomy, fundoplication, repair of perforated peptic ulcer, gastric banding procedure, sigmoid resection for diverticulitis, and ileal pouch–anal anastomosis were investigated using techniques of technology assessment. Feasibility, efficacy, and effectiveness were used to evaluate the different types of operation. The statements were graded by three categories of evidence. Laparoscopic cholecystectomy and fundoplication have passed the test. Laparoscopic repair of perforated duodenal ulcer, gastric banding for morbid obesity, and sigmoid resection for diverticulitis are feasible and efficient but not effective today. Laparoscopy‐assisted ileal pouch–anal anastomosis has been shown to be feasible but is not yet efficient and effective.
Pancreatic Biopsy: Why? When? How?
Authors: Ihse Ingemar , Axelson Jan , Dawiskiba Sigmund , Hansson Lars
Published: August 2002

For final diagnosis of pancreatic cancer histologic or cytologic confirmation is needed. Tissue or cell material can be achieved by percutaneous puncture as part of the preoperative workup. During operation core‐needle, incisional, and wedge biopsies or fine‐needle aspiration cytology (FNAC) can be chosen. Sensitivity and diagnostic accuracy are high for both histologic and cytologic examinations, and false‐positive results are exceptional, giving a specificity of 100% in most published series. The complication rate is low, also for knife biopsies in recent reports, provided biopsy of seemingly normal tissue is avoided. Percutaneous puncture is currently restricted to patients found to have advanced disease and who are not candidates for laparotomy. Microscopic confirmation is required in all patients in whom chemotherapy, radiotherapy, or both are planned. However, for attempted radical surgery per se, biopsy is not mandatory if the clinical suspicion of cancer is high and the surgical team has documented low postoperative mortality and morbidity rates.
Outcomes Research: What to Measure
Authors: Wright James G.
Published: August 2002

Surgeons assess the outcomes of treatment to determine if treatment is effective. The most commonly used types of outcomes have been measures of disease process (or impairment measures) because surgery is often directed toward ameliorating abnormalities of structure or function. Patient‐based outcomes, such as measures of health or health‐related quality of life, are necessary, however, to determine if patients have been made better by treatment. Disease‐specific measures of health focus specifically on those aspects of the disease of most concern to patients, whereas generic measures of health and health‐related quality‐of‐life measures have a much broader focus. Patient satisfaction is an additional increasingly used outcome measure. Satisfaction may be directed toward the processes of care or the outcomes of care. Satisfaction with the outcomes of care is an important secondary outcome provided the aims of treatment have been achieved and the health of patients has been improved. In conclusion, different outcomes of treatment provide different and complementary information and all have a role to play in deciding if surgical treatments are effective.
Pylorus‐preserving Total Pancreatectomy for Pancreatic Cancer
Authors: Sugiyama Masanori , Atomi Yutaka
Published: August 2002

Standard total pancreatectomy (TP) combined with gastric resection often results in uncontrollable diabetes and malnutrition. Pylorus‐preserving total pancreatectomy (PPTP) and standard TP for pancreatic cancer were compared in terms of operative outcomes, nutritional recovery, and long‐term survival. Twenty‐four patients with pancreatic ductal adenocarcinoma (n= 14) or intraductal papillary mucinous carcinoma (N = 10) underwent PPTP (n= 10) or standard TP (n= 14). There were no significant differences in age, gender, or tumor type or stage between the PPTP and standard TP groups. Early (within 30 days of surgery) morbidity and mortality rates were 20% and 0% for PPTP and 29% and 7% for standard TP, respectively. Delayed gastric emptying occurred in 2 patients in each group. The incidence of late complications, including uncontrollable diabetes, diarrhea, and malnutrition, tended to be lower after PPTP (30%) than after standard TP (69%). Serum albumin and body weight at 6 months after surgery were significantly higher in the PPTP than in the standard TP group. Regardless of the tumor type, long‐term survival did not differ significantly between patients receiving PPTP and those with standard TP. PPTP for pancreatic cancer improves nutritional recovery, without compromising long‐term survival, compared with standard TP.
Therapeutic Splenectomy in Immune Thrombocytopenic Purpura
Authors: Wani Nazir A. , Parray Fazal Q.
Published: August 2002

The effects of splenectomy in 41 patients managed from 1982 to 1995 at Sher‐i‐Kashmir Institute of Medical Sciences, Srinagar (Jammu and Kashmir), India, were studied. Immune thrombocytopenic purpura (ITP) was the main indication for therapeutic splenectomy among all the hematologic disorders. The mean age was 30 years (range 7–64), and the male to female ratio was 1.05:1. The mean platelet count in the preoperative period was 31,751/mm3 (range 4000–85,000). All patients presented with thrombocytopenia, i.e., platelet count of <100,000/mm3. In addition, 5 patients presented with anemia, i.e., Hb <10 g%. Among the patients with thrombocytopenia, 30 patients presented with counts <50,000/mm3 and 11 patients presented with counts between 50,000–100,000/mm3. None of the patients presented with leukopenia. The morbidity observed was 15% and mortality was 2%. The response to splenectomy was complete for thrombocytopenia in 3 patients and partial in 5 patients; 4 patients failed to show any response. In anemic patients, 4 patients showed complete response and 1 patient showed no response. The prognosis was excellent in patients with platelet count >50,000/mm3, age <50 years, no concomitant disease, and disease of shorter duration.
Factors Affecting Recurrence following Incisional Herniorrhaphy
Authors: Anthony Thomas , Bergen Patricia C. , Kim Lawrence T. , Henderson Mark , Fahey Thomas , Rege Robert V. , Turnage Richard H.
Published: August 2002

The purpose of this study was to determine the influence of chronic illness, obesity, and type of repair on the likelihood of recurrence following incisional herniorrhaphy. The medical records of 77 patients who underwent elective repair of a midline incisional hernia at the Dallas Veterans Affairs Medical Center between 1991 and 1995 were reviewed. Demographic data, presence of chronic illnesses, type of repair, and presence of recurrence were noted. Ninety‐six percent of the patients were men, with an average age of 59 years. More than 50% of the patients had chronic lung or cardiac diseases and more than 40% weighed ≥120% of their ideal body weight and had a body mass index (BMI) ≥30. Sixty‐two percent of the patients underwent primary reapproximation of the fascia (tissue repair), whereas 38% underwent repair with prosthetic material (prosthetic repair). The overall recurrence rate was 45%, with a median follow‐up of 45 months (range 6–73). Seventy‐four percent of the recurrences presented within 3 years of repair. The recurrence rate for those patients undergoing a tissue repair was 54%, whereas the recurrence rate following prosthetic repair was 29%. The incidence of recurrence for patients with pulmonary or cardiac disease or diabetes mellitus was similar to that of patients without these illnesses. The percent ideal body weight and BMI of patients who developed a recurrent hernia, particularly following a prosthetic repair, were significantly greater than those of patients whose repairs remained intact. These data strongly support the use of prosthetic repairs for incisional hernias, particularly in patients who are overweight.
Trends in Perforated Peptic Ulcer: Incidence, Etiology, Treatment, and Prognosis
Authors: Svanes Cecilie
Published: August 2002

After increasing steeply at the beginning of the twentieth century, ulcer perforation incidence during the last decades has declined in the young and in men, and it has risen among the elderly and in women. These changes can be attributed to a cohort phenomenon: Ulcer perforation risk is particularly common in the cohorts born after the turn of the twentieth century and is less common in previous and succeeding birth cohorts. A decline in total incidence is expected with the death of the high risk cohorts. Most ulcer perforations among subjects < 75 years of age can be attributed to smoking. Subjects with a history of ulcer perforation therefore have poorer long‐term survival than the general population, most pronounced for younger generations. About one of four ulcer perforations can be attributed to the use of nonsteroidal antiinflammatory drugs, a risk factor of particular importance in the elderly. Ulcer perforation was frequently treated by gastric resection in former days, whereas suture, being the first method introduced in 1887, is the method of choice today. The introduction of antibiotics improved the prognosis of ulcer perforation surgery greatly. Postoperative lethality decreased until 1950 but has remained stable since then. Lethality is higher in the elderly and is higher after gastric than after duodenal perforation. The delay before surgical treatment is a strong determinant for lethality, complication rates, and hospital costs. Treatment delay seems to have increased during the last few decades and is higher among women and the elderly. The prognosis of ulcer perforation is poorer in women owing to longer treatment delay.
Long‐term Prognosis after Partial Gastrectomy for Gastroduodenal Ulcer
Authors: von Holstein Christer Staël
Published: August 2002

The decline in duodenal ulcer disease and the established relation of peptic ulcer to Helicobacter pylori have virtually abolished the need for elective ulcer surgery. However, a substantial proportion of the population around retirement age has previously been subjected to partial gastric resection due to peptic ulcer, and the long‐term outcome of these patients is of continuing relevance. Patients subjected to elective surgery could represent a selected group of healthy subjects with a lower overall morbidity, but reports indicate that patients operated on for peptic ulcer have more advanced disease associated with excess smoking and a different pattern of social behavior. The surgical procedure induces enterogastric reflux, leading to profound changes in the remnant mucosa and the formation of carcinogens in the gastric juice. In addition, metabolic abnormalities are common, especially fat malabsorption. Evaluation of the impact of these factors on morbidity and mortality is difficult. Increased mortality in gastrointestinal tumors (especially gastric stump carcinoma), respiratory diseases and other smoking‐related malignancies, and suicide are found in the long‐term follow‐up after partial gastric resection due to peptic ulcer. However, these hazards to life are offset by a decreased mortality in cardiovascular disease. Preventive measures against suicide and especially tobacco smoking are recommended to improve the outcome for this cohort.
Effects of Medical Treatment on Gastric Mucosal Abnormalities in Gastroduodenal Ulcer Disease
Authors: Aoki Teruaki , Takayama Sumio , Nimura Hiroshi , Tsutsumi Jun
Published: August 2002

The development of carcinoma in cases of gastric ulcer disease during long‐term H2‐blocker treatment is slowly increasing, and ulcers that require such treatment exhibit the characteristics of intractable conditions, including linear ulcers, simultaneous gastric and duodenal ulcers, immature intestinal metaplasia of the gastric epithelium, and atrophic gastritis accompanied with multiple ulcer cicatrices. The incomplete form of intestinal metaplasia resembling Filipe's type III lesions and showing structural atypia developed in the background gastric mucosa in such cases, and the characteristics of this metaplasia included structural atypia, a residuum of gastric‐type mucous cells, rapid proliferative activity, and in some areas abnormal expression of P53 protein. In addition, in rat studies it was demonstrated that prolonged administration of H2‐blockers while gastric ulcers were present accelerated cell proliferation in the background gastric mucosa in the long term. Accordingly, it was considered possible that the development of the incomplete form of intestinal metaplasia, which was strongly suggested to have some relation to the sites where intestinal‐type gastric carcinoma appeared, was accelerated by mucosal injury due to chronic ulcers and by persistent elevation in intragastric pH. The results of the present study of gastric carcinoma as a complication of peptic ulcer disease indicated the possibility that Helicobacter pylori was a major contributory factor to the development of the incomplete form of intestinal metaplasia from damage to the background mucosa, but it was unclear whether H. pylori made any direct contribution to carcinogenesis.
Influence of Two‐dimensional and Three‐dimensional Imaging on Endoscopic Bowel Suturing
Authors: Hanna George B. , Cuschieri Alfred
Published: August 2002

Several three‐dimensional (3‐D) video‐endoscopic systems have been introduced in surgical practice to enhance depth perception during minimal access surgery (MAS), but the facilitation of endoscopic manipulations by the current 3‐D systems remains unproved. The aim of the study was to investigate the influence of 2‐D and 3‐D imaging modalities on intracorporeal suturing. The standard task consisted of suture closure of 60 mm enterotomies made in porcine small bowel with continuous seromuscular 3/0 Polysorb. Ten experienced surgeons participated in the study. The imaging systems were Storz (2‐D), Welch Allyn (3‐D), and Zeiss (as both 2‐D and 3‐D). Each surgeon performed two tasks with each modality in a random sequence. The outcome measures were execution time, suture line leakage pressure, and suture placement score. In addition, the participating surgeons assigned subjective scores on the image quality and the adverse effects of the imaging systems. There was no significant difference in the execution time, leakage pressure, and suture placement score among the various imaging modalities. Depth perception was rated as similar with 2‐D and 3‐D imaging. Surgeons experienced visual strain with the three systems, but it was rated higher with 3‐D imaging. With the current technology, we have not documented any significant difference in task efficiency and quality of endoscopic bowel suturing by trained surgeons between 2‐D and 3‐D imaging systems.
Standard and Nonstandard Applications of Sentinel Node‐guided Melanoma Surgery
Authors: Schachter Jacob , Laish Avishag , Mekhmandarov Sergey , Feinmesser Meora , Fenig Eyal , Tamir Gabriel , Gutman Haim
Published: August 2002

Identification and histologic study of the sentinel node (SN) is an acceptable, yet not firmly established, guide for treating intermediate‐thickness melanoma. This study widens the range of applications of this technique. We included 97 patients with intermediate‐thickness melanoma lesions or lesions for which there is no standard treatment. Fifty‐six underwent preoperative lymphoscintigraphy, and all underwent intraoperative lymphatic mapping (IOLM) using blue dye, followed by frozen section study and total node processing by serial sections. Elective lymph node dissection was performed in cases of metastasis to the sentinel node or technical failures with high risk. Four categories were defined: (A) intermediate‐thickness lesions (mean 2.27 mm) (n= 45); (B) thin lesions (mean 1.14 mm) with risk factors of regional failure (n= 27); (C) lesion thickness close to but more than 4 mm (n= 10); and (D) lesions of undetermined thickness (n= 15). Median follow‐up was 30 months (range 13–51 months). Intraoperative lymphatic mapping successfully identified the sentinel node (SN) in 93% of basins explored. Metastases were detected in 11 SNs. There were three lymph basin recurrences in patients with previously negative SNs, all salvaged by therapeutic lymph basin dissection and are NED (no evidence of disease). Two SN+ patients had systemic recurrences; one died of his disease, and the other is alive with disease. One SN− patient died NED owing to other cause. This technique spared 83% of category A patients from lymph node dissection. It allowed better staging and better decision making for treatment in categories B and D; and it prevented early regional recurrences in category C patients. Intraoperative lymphatic mapping with SN guidance is a novel, low‐morbidity approach applicable and advantageous for a wide range and subgroups of melanoma patients.
Estimate of population extinction risk and its application to ecological risk management
Authors: Iwasa Y. , Hakoyama H. , Nakamaru M. , Nakanishi J.
Published: August 2002

Environmental threats, such as habitat size reduction or environmental pollution, may not cause immediate extinction of a population but may shorten the expected time to extinction. We developed a method to estimate the mean time to extinction for a density‐dependent population with environmental fluctuation and to compare the impacts of different risk factors. We first derived a formula of the mean extinction time for a population with logistic growth and environmental and demographic stochasticities expressed as a stochastic differential equation model (canonical model). The relative importance of different risk factors is evaluated by the decrease in the mean extinction time. We studied an approximated formula for the reduction in habitat size that enhances extinction risk by the same magnitude as a given decrease in survivorship caused by toxic chemical exposure. In a large population (large K) or in a slowly growing population (small r), a small decrease in survivorship can cause the extinction risk to increase, corresponding to a significant reduction in the habitat size. Finally, we studied an approximate maximum likelihood estimate of three parameters (intrinsic growth rate r, carrying capacity K, and environmental stochasticity σ2e) from time series data. By Monte Carlo sampling, we can remove the bias very effectively and determine the confidence interval. We discuss here how the reliability of the estimate changes with the length of time series. If we know the intrinsic rate of population growth r, the mean extinction time is estimated quite accurately even when only a short time series is available for parameter estimation.
Contribution to antimitochondrial antibody production: Cleavage of pyruvate dehydrogenase complex-E2 by apoptosis-related proteases
Authors: Matsumura Shuji , Van De Water Judy , Kita Hiroto , Coppel Ross L. , Tsuji Takao , Yamamoto Kazuhide , Ansari Aftab A. , Gershwin Eric M.
Published: August 2002

Patients with PBC produce a directed, specific response to a single immunodominant autoepitope of PDC-E2 within the inner lipoyl domain. In contrast, immunized animals react to multiple epitopes and rarely recognize the inner lipoyl domain. In other autoimmune diseases, apoptosis plays a critical role in antigen presentation; the caspases and granzyme B are the key proteases in the generation of autoepitopes. To determine the specific cleavage pattern of full-length recombinant PDC-E2, we performed in vitro digestion with caspases-3, -6, -8 and granzyme B. The resulting fragments were immunoblotted and probed with an extensive panel of monoclonal anti-PDC-E2 antibodies and sera from patients with PBC. Interestingly, on granzyme B digestion, PDC-E2 lost reactivity, suggesting the destruction of the immunodominant epitope. Because this site contains the major epitope for both B cells and T cells, it suggests that granzyme B is unlikely to be involved in generation of autoepitopes in primary biliar cirrhosis (PBC). In contrast, following treatment with the caspase enzymes, immunoreactive fragments were generated. Indeed, by confocal microscopy, activated caspase-3 is found in the marginal hepatocytes and bile ducts. Moreover, caspase-3 staining was strongest in the small intrahepatic bile ducts, the major site of tissue destruction in PBC. In conclusion, these data suggest that following apoptosis, the caspase family of proteolytic enzymes have the potential to generate immunogenic fragments that contribute to the autoantigen reservoir and the production of antimitochondrial antibodies. These findings are also consistent with the generation of an autoimmune response against an intracellular antigen that evades catabolism during apoptosis.
Stimulation and proliferation of primary rat hepatic stellate cells by cytochrome P450 2E1-derived reactive oxygen species
Authors: Nieto Natalia , Friedman Scott L. , Cederbaum Arthur I.
Published: August 2002

The alcohol-inducible cytochrome P450 2E1 (CYP2E1) is expressed mainly in hepatocytes and generates reactive oxygen species (ROS). To better understand how hepatic stellate cells (HSC) become activated in the presence of oxidative stress and evaluate whether CYP2E1-derived ROS activate stellate cells, we coincubated primary stellate cells with HepG2 cells, which do (E47 cells) or do not (C34 cells) express CYP2E1. Morphologic changes and loss of lipid droplets were more apparent in the stellate cells cocultured with E47 cells. There was a more pronounced increase in α-smooth muscle actin (α-sma), intracellular and secreted collagen type I protein, and intra- and extracellular H2O2 and lipid peroxidation products in stellate cells coincubated with E47 cells. Expression of collagen in stellate cells did not change when cocultured with HepG2 cells expressing a different P450, CYP3A4. Stellate cells cultured on Matrigel expressed increased α-sma and collagen when incubated with E47 cells. The increase in collagen production by coculture with E47 cells was prevented by antioxidants, by CYP2E1 inhibitors, and by transfected antisense CYP2E1. The addition of arachidonic acid plus ferric nitrilotriacetate (Fe-NTA), agents that potentiate oxidative stress, further induced collagen protein in the E47 coculture. Stellate cell proliferation was greater in the E47 coculture, and this was partially abrogated by catalase and vitamin E. These results show that hepatocytes containing CYP2E1 release diffusible mediators including ROS, which can activate HSC. Thus, besides perturbing the homeostasis of hepatocytes, CYP2E1-derived diffusible oxidants may also interact with stellate cells and contribute to hepatic fibrosis.
Fine specificity of autoantibodies to soluble liver antigen and liver/pancreas
Authors: Herkel Johannes , Heidrich Birgit , Nieraad Nicole , Wies Ingrid , Rother Michael , Lohse Ansgar W.
Published: August 2002

Autoantibodies to soluble liver antigen and liver pancreas (SLA/LP) have been described as specific markers for Autoimmune Hepatitis (AIH), occurring in about 20% of patients with AIH. The high degree of specificity for SLA/LP in autoimmune liver disease suggests a possible role in its pathogenesis. This study aims to map the exact epitope(s) recognized by SLA/LP autoantibodies and to assess the role of molecular mimicry between microbial antigens and self-epitopes. Using SLA/LP-reactive sera of 18 individual AIH patients and a pool of 15 patient sera, we found the dominant immune reactivity directed to peptide p395-414 and a less prominent immune response to 2 other epitopes adjacent to the dominant epitope. Immunodominance of peptide p395-414 was confirmed by absorption experiments. The SLA/LP autoantibodies of all tested AIH patients were mainly of the IgG1 type, suggesting that SLA/LP autoantibodies may arise by a common and specific underlying immune stimulus. Based on sequence homologies of the SLA/LP antigenic region with viral proteins, it was hypothesized that molecular mimicry may drive autoimmunity to SLA/LP. However, the homologous virus-derived peptides were not recognized by SLA/LP autoantibodies. Similarly, the only known procaryotic homologue, MJ0610 of Methanococcus jannaschii, was only weakly recognized by SLA/LP-positive sera. Thus, no evidence could be found for molecular mimicry being the causative mechanism for the development of SLA/LP autoantibodies. In conclusion, the exquisite epitope specificity and IgG subtype are evidence for the maturity of the SLA/LP autoantibody response; a specific autoantigen-driven process underlying the immunopathogenesis is likely.
Activation of the Raf-1/MEK/ERK cascade by bile acids occurs via the epidermal growth factor receptor in primary rat hepatocytes
Authors: Rao Yi-Ping , Studer Elaine J. , Stravitz Todd R. , Gupta Seema , Qiao Liang , Dent Paul , Hylemon Phillip B.
Published: August 2002

Bile acids have been reported to activate several different cell signaling cascades in rat hepatocytes. However, the mechanism(s) of activation of these pathways have not been determined. This study aims to determine which bile acids activate the Raf-1/MEK/ERK cascade and the mechanism of activation of this pathway. Taurodeoxycholic acid (TDCA) stimulated (+235%) the phosphorylation of p74 Raf-1 in a time (5 to 20 minutes) and concentration-dependent (10 to 100 μmol/L) manner. Raf-1 and ERK activities were both significantly increased by most bile acids tested. Deoxycholic acid (DCA) was the best activator of ERK (3.6-fold). A dominant negative Ras (N17) construct expressed in primary hepatocytes prevented the activation of ERK by DCA. The epidermal growth factor receptor (EGFR)-specific inhibitor (AG1478) significantly inhibited (˜81%) the activation of ERK by DCA. DCA rapidly (30 to 60 seconds) increased phosphorylation of the EGFR (˜2-fold) and Shc (˜4-fold). A dominant negative mutant of the EGFR (CD533) blocked the ability of DCA to activate ERK. In conclusion, these results show that DCA activates the Raf-1/MEK/ERK signaling cascade in primary hepatocytes primarily via an EGFR/Ras-dependent mechanism.
Adenosine triphosphate infusion increases liver energy status in advanced lung cancer patients: An in vivo 31P magnetic resonance spectroscopy study
Authors: Leij-Halfwerk Susanne , Agteresch Hendrik J. , Sijens Paul E. , Dagnelie Pieter C.
Published: August 2002

We recently observed inhibition of weight loss in patients with advanced nonsmall-cell lung cancer after intravenous infusion of ATP. Because liver ATP levels were found to be decreased in lung cancer patients with weight loss, the present 31P magnetic resonance spectroscopy (MRS) study was aimed at investigating whether ATP infusion restores liver energy status in these patients. Nine patients with advanced nonsmall-cell lung cancer (stage IIIB/IV) were studied 1 week before (baseline) and at 22 to 24 hours of continuous ATP infusion (37-75 μg/kg/min). Localized hepatic 31P MR spectra (repetition time 15 seconds), obtained in the overnight-fasted state, were analyzed for ATP and Pi content. Ten healthy subjects (without ATP infusion) served as control. Liver ATP levels in lung cancer patients increased from 8.8 ± 0.7% (relative to total MR-detectable phosphate; mean ± SE) at baseline to 12.2 ± 0.9% during ATP infusion (P < .05), i.e., a level similar to that in healthy subjects (11.9 ± .9%). The increase in ATP level during ATP infusion was most prominent in patients with ≥5% weight loss (baseline: 7.9 ± 0.7%, during ATP infusion: 12.8 ± 1.0%, P < .01). In conclusion, ATP infusion restores hepatic energy levels in patients with advanced lung cancer, especially in weight-losing patients. These changes may contribute to the previously reported beneficial effects of ATP infusion on the nutritional status of lung cancer patients.
Interferon-γ inhibits replication of subgenomic and genomic hepatitis C virus RNAs
Authors: Frese Michael , Schwärzle Verena , Barth Kerstin , Krieger Nicole , Lohmann Volker , Mihm Sabine , Haller Otto , Bartenschlager Ralf
Published: August 2002

Persistent infection with hepatitis C virus (HCV) is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. All treatments known so far rely on the antiviral activity of interferon alfa (IFN-α) that is given alone or in combination with ribavirin. Unfortunately, only a fraction of the patients clear the virus during therapy and for those who do not respond there is currently no alternative treatment. Selectable subgenomic HCV RNAs (replicons) have been recently used to investigate the effect of IFN-α on HCV replication. However, it has not yet been analyzed whether other cytokines also play a role in the innate immune response against HCV. Here we show that IFN-γ inhibits protein synthesis and RNA replication of subgenomic and genomic HCV replicons. We further show that the inhibitory action of IFN-γ does not rely on the production of nitric oxide or the depletion of tryptophan. In conclusion, our results suggest that cytotoxic T cells and natural killer cells may contribute to HCV clearance not only by cell killing but also by producing IFN-γ, thereby enhancing the intracellular inhibition of viral replication.
The in vivo apoptotic effect of interferon alfa-2b on rat preneoplastic liver involves Bax protein
Authors: de Luján Alvarez María , Cerliani Juan Pablo , Monti Juan , Carnovale Cristina , Ronco María Teresa , Pisani Gerardo , Lugano María Cristina , Carrillo María Cristina
Published: August 2002

To determine whether interferon alfa (IFN-α) prevents in vivo oncogenesis in very-early-stage cancer cells, we evaluated the action of IFN-α2b over preneoplastic foci in rats. Animals were divided into 6 groups: subjected to a 2-phase model (diethylnitrosamine [DEN] plus 2-acetylaminofluorene [2-AAF]) of preneoplasia development (group 1), treated with IFN-α2b during the 2 phases (group 2), only during initiation with DEN (group 3), only during administration of 2-AAF (group 4), subjected only to an initiation stage (group 5), and treated with IFN-α2b during this period (group 6). The numbers of placental form of rat glutathione S-transferase (rGST-P)-positive foci per liver and the foci as percentage of liver were significantly reduced in groups 2, 3, and 6 but not in group 4. Rats treated with IFN-α2b showed a higher apoptotic index (AI) in altered hepatic foci (AHF). Levels of p53 and Bax protein in liver lysates were significantly increased in those animals. Similarly, levels of antiapoptotic proteins Bcl-2 and Bcl-xL in mitochondrial fraction were decreased. Finally, increased levels of Bax protein were localized in the mitochondria of rats that received IFN-α2b, at least during the DEN phase (groups 2, 3, and 6), whereas mitochondrial Bax expression was not increased in group 4. In conclusion, the preneoplastic hepatocytes in rats that received IFN-α2b during the initiation stage undergo programmed cell death as a primary result of a significant increase in the amount and translocation to the mitochondria of Bax protein.
Lower risk for alcohol-induced cirrhosis in wine drinkers
Authors: Becker Ulrik , Grønbæk Morten , Johansen Ditte , Sørensen Thorkild I. A.
Published: August 2002

Although there is a well-known relationship between total alcohol intake and future risk for cirrhosis, other factors such as the type of alcohol consumed are sparsely studied. The aim of this study was to assess the effects of wine compared with other types of alcoholic beverages on risk for alcohol-induced cirrhosis. In 3 prospective studies, 30,630 participants from the Copenhagen area were followed-up for a total observation time of 417,325 person-years. Information on weekly intake of beer, wine, and spirits, and sex, age, body mass index, smoking habits, and education was obtained from questionnaires. The primary outcome measures were first admission or death, with alcohol-induced cirrhosis obtained from death certificates and from the National Hospital Discharge Register. Data were analyzed by means of multiplicative Poisson regression models. We confirmed the increasing risk for cirrhosis with increasing alcohol intake. Individuals who drank more than 5 drinks per day had a relative risk of 14 to 20 for developing cirrhosis compared with non- or light drinkers. However, compared with individuals who drank no wine (relative risk set at 1.0), individuals drinking 16% to 30% wine of their total intake had a relative risk of 0.4 (95% confidence limits, 0.3-0.6) and those drinking 51% or more of wine had a relative risk of 0.3 (95% confidence limits, 0.2-0.5) for developing cirrhosis. In conclusion, the results suggest that a high intake of all 3 types of alcohol conveys an increased risk for cirrhosis, but wine drinkers are at a lower risk than beer and spirits drinkers.
The MDR phenotype is associated with the expression of COX-2 and iNOS in a human hepatocellular carcinoma cell line
Authors: Fantappiè Ornella , Masini Emanuela , Sardi Iacopo , Raimondi Laura , Bani Daniele , Solazzo Michela , Vannacci Alfredo , Mazzanti Roberto
Published: August 2002

The presence of multiple drug resistance (MDR1) and angiogenic phenotypes negatively affect patients' prognosis with cancer even when treated with drugs that are not transported by the MDR1 gene product. It is possible to suggest a link between the MDR1 and angiogenic phenotypes. Because prostaglandins (PGs) and nitric oxide (NO) have been proposed to be involved in angiogenesis in vivo, the production of PGs and NO and the behavior of inducible NO synthase (iNOS), cyclooxygenase 1 (COX-1), and inducible cyclooxygenase (COX-2) were studied in parental drug-sensitive (P5) liver cancer cell lines and in P5-derived MDR1 cells P1(0.5). Immunohistochemical evaluation, Northern and Western blot analysis of COX-2 and iNOS, and assessment of cell proliferation were performed in basal conditions and after the exposure to stimulants or to specific inhibitors of COX-2 and iNOS. The messenger RNA and protein levels of COX-2 and iNOS were in basal conditions higher in P1(0.5) cells than the parental P5 cells. The exposure to lipopolysaccharide (LPS) or epidermal growth factor (EGF) determined an increase of PG and NO production in both cell lines and this increase was strongly reduced by COX-2 inhibitors such as celecoxib (CLX) and nimesulide (NIME). The inhibition of NO production by COX-2 inhibitors suggests cross-talk between COX-2 and iNOS pathways. CLX and NIME also inhibited cell proliferation, but only in MDR1 cells. A specific inhibitor of iNOS, N
6-(1-iminoethyl)-L-lysine, had only a mild effect on cell proliferation in both cell lines. In conclusion, these data support the hypothesis that the MDR1 and angiogenic phenotypes are linked to each other in human liver cancer cell lines.
Peripheral blood count abnormalities among patients with hepatitis C in the United States
Authors: Streiff Michael B. , Mehta Shruti , Thomas David L.
Published: August 2002

An estimated 2.7 million people in the United States are infected with the hepatitis C virus (HCV), yet the influence of HCV infection on the peripheral blood count remains unknown. To investigate the prevalence of low peripheral blood counts among HCV-infected adults in the United States general population, we analyzed data collected in the third National Health and Nutrition Examination Survey (NHANES III). The study population consisted of 16,196 individuals age 18 or older who had peripheral blood counts and data on HCV infection. The lowest fifth percentile of each component of the peripheral blood was designated a priori as being low. HCV infection was assessed by antibody reactivity. HCV antibody-positive individuals were 3-fold more likely to have low neutrophil counts (HCV positive, 9% vs. HCV negative, 3%, P < .0001) and 2.6-fold more likely to have low platelet counts (HCV positive, 13% vs. HCV negative, 5%, P < .0001) independent of other evaluated factors. HCV infection was observed in more than 20% of persons with neutrophil counts below 1.0 × 109/L or platelet counts less than 100 × 109/L. No association was detected between anti-HCV status and anemia or other peripheral blood cell components. In conclusion, HCV-infected persons in the general population of the United States are more likely to have low neutrophil and platelet counts, and HCV testing should be considered for persons with unexplained neutrophil counts below 1.0 × 109/L or platelet counts less than 100 × 109/L. Alternate causes of anemia should be considered for HCV-infected persons with low red blood cell counts.
Inhibition of the MAPK and PI3K pathways enhances UDCA-induced apoptosis in primary rodent hepatocytes
Authors: Qiao Liang , Yacoub Adly , Studer Elaine , Gupta Seema , Pei Xin Yan , Grant Steven , Hylemon Philip B. , Dent Paul
Published: August 2002

The mechanisms by which bile acids induce apoptosis in hepatocytes and the signaling pathways involved in the control of cell death are not understood fully. Here, we examined the impact of mitogen-activated protein kinase (MAPK) and phosphatidyl inositol 3-kinase (PI3K) signaling on the survival of primary hepatocytes exposed to bile acids. Treatment of hepatocytes with deoxycholic acid (DCA), chenodeoxycholic acid (CDCA) or ursodeoxycholic acid (UDCA) caused sustained MAPK activation that was dependent on activation of the epidermal growth factor receptor (EGFR). Activation of MAPK was partially blocked by inhibitors of PI3K. Inhibition of DCA-, CDCA-, and UDCA-stimulated MAPK activation resulted in ˜20%, ˜35%, and ˜55% apoptosis, respectively. The potentiation of DCA- and CDCA-induced apoptosis by MEK1/2 inhibitors correlated with cleavage of procaspase 3, which was blocked by inhibitors of caspase 8 (ile-Glu-Thr-Asp-p-nitroanilide [IETD]) and caspase 3 (DEVD). In contrast, the potentiation of UDCA-induced apoptosis weakly correlated with procaspase 3 cleavage, yet this effect was also blocked by IETD and DEVD. Incubation of hepatocytes with the serine protease inhibitor AEBSF reduced the death response of cells treated with UDCA and MEK1/2 inhibitor to that observed for DCA and MEK1/2 inhibitor. The apoptotic response was FAS receptor- and neutral sphingomyelinase-dependent and independent of FAS ligand expression, and neither chelation of intracellular and extracellular Ca2+ nor down-regulation of PKC expression altered the apoptotic effects of bile acids. In conclusion, bile acid apoptosis is dependent on the production of ceramide and is counteracted by activation of the MAPK and PI3K pathways.
NF-κB inhibition sensitizes hepatocytes to TNF-induced apoptosis through a sustained activation of JNK and c-Jun
Authors: Liu Hailing , Lo Chau R. , Czaja Mark J.
Published: August 2002

Hepatocyte resistance to tumor necrosis factor α (TNF)-induced apoptosis is dependent on activation of the transcription factor nuclear factor κB (NF-κB). To determine the mechanism by which NF-κB protects against TNF toxicity, the effect of NF-κB inactivation on the proapoptotic c-Jun NH2-terminal kinase (JNK) signaling pathway was examined in the rat hepatocyte cell line RALA255-10G. Adenovirus-mediated NF-κB inactivation led to a prolonged activation of JNK and increased activating protein-1 (AP-1) transcriptional activity in response to TNF treatment. Inhibition of the function of the JNK substrate and AP-1 subunit c-Jun blocked cell death from NF-κB inactivation and TNF as determined by measures of cell survival, numbers of apoptotic and necrotic cells, and DNA hypoploidy. Inhibition of c-Jun function blocked mitochondrial cytochrome c release and activation of caspase-3 and -7. NF-κB therefore blocks the TNF death pathway through down-regulation of JNK and c-Jun/AP-1. In conclusion, sustained JNK activation that occurs in the absence of NF-κB initiates apoptosis through a c-Jun-dependent induction of the mitochondrial death pathway.
Tie2 vascular endothelial receptor expression and function in hepatocellular carcinoma
Authors: Tanaka Shinji , Sugimachi Keishi , Yamashita Yo-ichi , Ohga Takefumi , Shirabe Ken , Shimada Mitsuo , Wands Jack R. , Sugimachi Keizo
Published: August 2002

Hepatocellular carcinoma (HCC) is generally characterized as a hypervascular tumor of rapid growth. We have previously reported that angiopoietin (Ang), a ligand for Tie2 vascular endothelial-specific receptor tyrosine kinase, may play a role in the progression of human HCC (J Clin Invest 1999;103:341-345) and matrix proteinase expression (Cancer Res 2001;61:2145-2153). However, the role of Tie2 receptor in hepatic oncogenesis is unknown. The Tie2 receptor protein was overexpressed in the neovascular endothelium of 31 of 39 (80%) human HCC tumors by immunohistochemical analysis with significant correlation to cell dedifferentiation and tumor size (P < .05). In vitro expression of a dominant-negative construct, containing a soluble Tie2 ectodomain (sTie2), led to Ang protein interaction, inhibition of endogenous Tie2 phosphorylation in vascular endothelial cells and matrix metalloproteinase 9 (MMP-9) suppression. In conclusion, tumorigenicity with neovascularization was suppressed by in vivo gene transfer and sTie2 expression in a murine HCC model, suggesting a possible role for Tie2 expression in the induction of HCC neovascularization and disease progression. Inhibition of the Ang/Tie2 signal transduction cascade is a promising approach for tumor treatment.