bluuebunny/crossref_metadata_2025 huggingface dataset:
Early Risk Factors for Postinjury Multiple Organ Failure
Authors: Sauaia Angela , Moore Frederick A. , Moore Ernest E. , Lezotte Dennis C.
Published: August 2002

Epidemiologic studies, based on retrospective data from heterogeneous populations with poor control of confounders, led early investigators to conclude that infection was the overriding risk factor for multiple organ failure (MOF). More recent studies have convincingly shown that MOF frequently occurs in the absence of infection. Consequently, we have shifted our research focus away from the traditional infectious models of MOF to the newer “one‐hit” and “two‐hit” inflammatory models. Clinically, we have chosen to study trauma patients because they are a relatively homogeneous group with a low incidence of common confounders. Trauma also permits a clear distinction between the first insult and the outcome, both temporally and with respect to the definition criteria. In this review we discuss the background, rationale, and our initial attempts to use indicators of the first insult (i.e., tissue injury quantification and clinical signs of shock) and indicators of the host response (i.e., systemic inflammatory response syndrome) to predict MOF early after injury.
Fibroblast Growth Factors and Their Receptors in Parathyroid Disease
Authors: Lambert Darren , Eaton Colby L. , Harrison Barnard J.
Published: August 2002

Fibroblast growth factors (FGFs) comprise a family of polypeptide growth factors implicated in the control of proliferation of glandular tissues. The aim of this study was to determine whether FGFs are produced in normal and abnormal parathyroid glands and if these tissues have the potential to respond to this growth factor family. We have examined the expression of FGF receptor (FGF‐R) types 1 and 2 and of FGFs 1, 2, 3, and 7 in a series of human parathyroid tissues using the reverse transcription polymerase chain reaction (RT‐PCR). Samples of 10 parathyroid adenomas and 10 hyperplastic glands from patients with renal hyperparathyroidism (HPT) were compared with samples from normal parathyroid glands from patients with primary HPT in the study. FGF‐R1 was expressed in all samples and FGF‐R2 in most. FGF1 and FGF2 were expressed in all samples at variable levels, with no correlation between disease type and amplified RT‐PCR product levels. FGF7 was expressed in normal parathyroid tissue and in all adenomas but was absent in all but one of the hyperplastic parathyroid glands from renal failure patients. FGF3 was expressed at low levels in normal tissue and variably expressed in diseased tissue, in some instances at high levels. These findings suggest that parathyroid tissue is potentially responsive to FGFs. The absence of FGF7 expression in all but one of the renal parathyroid samples compared with normal and adenomatous tissue requires further investigation. The presence of elevated levels of FGF3 expression in abnormal parathyroid tissue may be significant, as the FGF3 gene (int‐2 proto‐oncogene) is located on chromosome 11q13.3, a region already identified as being susceptible to rearrangement/mutation in parathyroid disease.
Lethality of Multiple Endocrine Neoplasia Type I
Authors: Doherty Gerard M. , Olson John A. , Frisella Margaret M. , Lairmore Terry C. , Wells Samuel A. , Norton Jeffrey A.
Published: August 2002

The lethality of the endocrine tumors associated with multiple endocrine neoplasia type I (MEN‐I), particularly the pancreatic islet cell tumors, has been controversial. We evaluated the cause and age of death in MEN‐I kindreds. Our database contains 34 distinct kindreds with 1838 members. Reliable death data are available for 103 people (excluding accidents and age < 18 years). We compared survival curves of MEN‐I patients who died from causes related to MEN‐I with those from MEN‐I carriers who died from a nonendocrine cause and unaffected kindred members. We also compared ages of death between affected and unaffected members of MEN‐I kindreds. Of 59 MEN‐I‐affected patients, 27 died directly of MEN‐I‐specific illness and 32 of non‐MEN‐I causes. The MEN‐I‐specific deaths occurred at a younger age (median 47 years) than either MEN‐I patients whose death was from some nonendocrine cause (median 60 years, p < 0.02) or than all kindred members who did not die of MEN‐I disease (median 55 years,p < 0.05). The causes of death of the MEN‐I patients included islet cell tumor (n= 12), ulcer disease (n= 6), hypercalcemia/uremia (n= 3), carcinoid tumor (n= 6), and nonendocrine malignancies (n= 9). There was no difference in survival between MEN‐I carriers and unaffected kindred members. Of our MEN‐I patients, 46% died from causes related to their endocrine tumors after a median age of 47 years, which was younger than family members who did not die from these tumors. Pancreatic islet cell tumors were the most common cause of death of MEN‐I patients. Management of kindreds with MEN‐I should include an aggressive screening program with early therapeutic intervention when a tumor is identified.
Neuroendocrine Tumor Imaging: Can 18F‐Fluorodeoxyglucose Positron Emission Tomography Detect Tumors with Poor Prognosis and Aggressive Behavior?
Authors: Pasquali Claudio , Rubello Domenico , Sperti Cosimo , Gasparoni Piero , Liessi Guido , Chierichetti Franca , Ferlin Giorgio , Pedrazzoli Sergio
Published: August 2002

We evaluated the clinical value of positron emission tomography (PET) using 18F‐fluorodeoxyglucose (FDG) for neuroendocrine tumor (NET) detection. Sixteen patients with cytologically or histologically proved NETs were investigated. Patients were divided in two groups of eight patients each according to the clinicopathologic features related to prognosis: slow‐growing NETs and aggressive NETs. Results of FDG tumor uptake as detected by PET were compared with computed tomography (CT) scans and with scans obtained with 111In‐octreotide scintigraphy (n= 13). Tumor FDG uptake was increased in the primary lesion of all eight aggressive NETs; the tracer was shown also in lymph nodes, liver metastases, or both in five of six of them (83%). In four cases, additional unknown tumor sites undetected by CT scan were identified. A slight positivity was found in only one of eight cases with a slow‐growing NET. The overall octreotide scintiscan sensitivity was 85%, but in the aggressive NETs it failed to detect the primary lesion in two of seven cases. Uptake of the tracer in some but not all tumor lesions in the same patient was seen by both FDG‐PET and octreotide scintiscans. From our limited experience 18F‐FDG PET seems to be useful for identifying NETs characterized by rapid growth or aggressive behavior. Uptake of the FDG tracer by the tumor may be related to a worse prognosis. Despite the heterogeneity of tracer uptake in the various lesions of NETs with multiple tumor sites, FDG‐PET was able to detect unsuspected distant metastases, contributing to better staging of advanced disease.
Overview of Operations for Morbid Obesity
Authors: Deitel Mervyn
Published: August 2002

Massive obesity is prevalent and associated with serious co‐morbidities. For patients who cannot sustain weight loss, malabsorption and gastric reduction operations have been developed. Patients with the former operation require surveillance for protein malnutrition and other sequelae; those with gastric reduction require a permanent tiny reservoir and stoma. Long‐term follow‐up surveillance is necessary. Postoperatively, 15% to 40% of patients, depending on the operative procedure performed, fail to maintain adequate weight loss. Successful weight loss in most of these patients makes this challenging surgery worthwhile, with alleviation of devastating disease and marked improvement in quality of life.
Asymptomatic Cholelithiasis Revisited
Authors: Patiño José F. , Quintero G.A.
Published: August 2002

Elective cholecystectomy in the asymptomatic patient has elicited considerable controversy, going back to the prelaparoscopy cholecystectomy era. Surgical services often see patients with known or unidentified cholelithiasis who, having been asymptomatic, present with serious complications, potentially lethal, in whom emergency operations are associated with technical difficulties that lead to high conversion rates and significant mortality and morbidity. Elective cholecystectomy is a safe procedure associated with low morbidity and no mortality. Based on an analysis of our experience and a review of the literature, we discuss the indications for elective laparoscopic cholecystectomy in asymptomatic patients at high risk of developing complications of their asymptomatic disease. The following high‐risk criteria are proposed for elective cholecystectomy: life expectancy > 20 years; calculi > 2 cm in diameter; calculi < 3 mm and a patent cystic duct; radiopaque calculi; polyps in the gallbladder (GB); nonfunctioning GB; calcified (“porcelain”) GB; concomitant diabetes; women < 60 years; and individuals in geographic regions with a high prevalence of GB cancer.
Hemodynamic Patterns of Survivors and Nonsurvivors during High Risk Elective Surgical Operations
Authors: Shoemaker William C. , Wo Charles C.J. , Thangathurai Duraiyah , Velmahos George , Belzberg Howard , Asensio Juan A. , Demetriades Demetrios
Published: August 2002

Postoperative survivors' and nonsurvivors' hemodynamic and oxygen transport patterns have been extensively studied, and the early postoperative circulatory events leading to organ failures and death have been documented. Outcome was improved when potentially lethal circulatory patterns were treated during the early (the first 8–12 hours) postoperative period; but after the appearance of organ failure, reversal of nonsurvival patterns did not improve the outcome. The purpose of this study was to describe prospectively intraoperative circulatory deficiencies that precede shock, organ failures, and death. The ultimate aim was to elucidate nonsurvivor patterns at the earliest possible time to develop more effective preventive strategies for lethal organ failures. This approach is based on the assumption that it is easier and more effective to prevent the initiators of shock, such as hypovolemia, hypoxemia, poor tissue perfusion, and tissue hypoxia, than to treat the mediators of organ failure, such as cytokines, antigens, eicosinoids, and heat shock proteins. We monitored 356 high risk elective surgical patients with preoperative and intraoperative hemodynamic monitoring by the pulmonary artery (PA) thermodilution catheter. The conventionally monitored mean arterial pressure and heart rate remained in the normal range in both groups; the nonsurvivor pattern included decreased cardiac index, stroke index, stroke work, oxygen delivery, and oxygen consumption. Low oxygen consumption was partly compensated by increased oxygen extraction rates, and arterial pressures were maintained by increasing systemic vascular resistance. The early temporal pattern of nonsurvivors' changes were similar to those described during the postoperative period that preceded development of organ failure and death. This suggests that lethal circulatory dysfunctions may begin during the intraoperative period but become more apparent before and after organs fail during later postoperative stages.
Intraoperative Parathormone Measurement in Patients with Multiple Endocrine Neoplasia Type I Syndrome and Hyperparathyroidism
Authors: Tonelli Francesco , Spini Simona , Tommasi Mariasilvia , Gabbrielli Gianfranco , Amorosi Andrea , Brocchi Alessandro , Brandi Maria Luisa
Published: August 2002

Total or subtotal parathyroidectomy is considered the treatment of choice for multiple endocrine neoplasia type I (MEN‐I)‐associated primary hyperparathyroidism (HPT). However, persistent or recurrent HPT is frequently observed. The development of a rapid two‐site immunoradiometric assay (IRMA) method for measuring intact parathormone (PTH) has provided a valuable tool for recognizing possible surgical failures. Our experience includes 16 MEN‐I patients (10 females, 6 males) of mean age 35.5 years operated on between 1990 and 1996. Total parathyroidectomy (TPTX) with autotransplantation of parathyroid tissue was the standard treatment. Blood samples for PTH measurement were drawn at the induction of anesthesia (basal value), 10 and 20 minutes after the removal of each gland, and 60 minutes after TPTX. Rapid PTH measurement, which required only 15 minutes of incubation at 37°C, showed a highly significant correlation (p < 0.0001) with the standard method. Circulating PTH levels exhibited a stepwise decrease during TPTX, reaching a mean value of 22.3% of the baseline 20 minutes after removal of the last gland. Two patients showed a prompt decrease of PTH after removal of the single enlarged gland, featuring the kinetics observed in the adenomas. One of these two patients was successfully treated with more conservative surgery. None of the patients showed persistence or recurrence of HPT. In our experience, intraoperative measurement of PTH seems to be a valuable adjunct in both the diagnosis of multiglandular involvement and the prediction of surgical treatment in patients with primary parathyroid hyperplasia.
Various population fluctuation patterns of light‐attracted beetles in a tropical lowland dipterocarp forest in Sarawak
Authors: Kato M. , Itioka T. , Sakai S. , Momose K. , Yamane S. , Hamid A. A. , Inoue T.
Published: August 2002

The population fluctuation pattern of light‐attracted beetles was studied from August 1992 to September 1998 (for 73 months) using ultraviolet light‐traps set at three vertical levels in a tropical lowland dipterocarp forest in Sarawak, Malaysia. During our study, a general flowering occurred from April to July in 1996, and flowering on a small scale in 1997 and 1998. We analyzed the data for eight scarabaeid and six meloid species, some of which were anthophilous species. Various fluctuation patterns were observed among the beetle species in aspects of both seasonality and correlation with the supraannual phenological pattern. Three large chafer species (Scarabaeidae, Melolonthini) showed a clear seasonal fluctuation pattern with a peak once from March to May every year, the peak monthly catch greatly fluctuating annually. Other scarabaeid beetles did not show such a clear seasonal population pattern and hardly fluctuated annually. Populations of an anthophilous scarabaeid species, Parastasia bimaculata, a specific pollinator of Homalomena propinqua (Araceae), hardly fluctuated, probably because of its response to the constant flowering of its floral hosts. Monthly catches of an anthophilous scarabaeid, Anomala sp., and meloid beetles showed clear supraannual patterns in response to the general flowering and were significantly correlated with the flowering intensity with or without a lag of a month. The fluctuation pattern of meloids suggests a supraannual population fluctuation pattern of their hosts, i.e., megachilid/anthophorid bees.
The hepatic mitochondrial DNA depletion syndrome: Ultrastructural changes in liver biopsies
Authors: Mandel Hanna , Hartman Corina , Berkowitz Drora , Elpeleg Orli N. , Manov Irena , Iancu Theodore C.
Published: August 2002

Mitochondrial respiratory chain disorders are an established cause of liver failure in early childhood. In some patients, the levels of mitochondrial DNA are markedly reduced, a condition referred to as mtDNA depletion syndrome (MDS). We report here on the ultrastructural changes in the livers of 10 infants with the hepatic form of this syndrome. All patients displayed progressive liver failure, neurological abnormalities, hypoglycemia, and lactic acidosis that warranted investigation of respiratory chain disorder in liver tissue, specifically expressing the disease. Decreased activity of respiratory chain complexes containing mtDNA-encoded subunits (complexes I, III, IV) was shown in 5 patients. Mitochondrial DNA depletion was confirmed by Southern blot analysis in the livers of 6 patients. We found hepatocytes filled with mitochondria having aspects of “oncocytic transformation,” associated with numerous changes in shape, size, cristae, and matrix. The changes were virtually identical in all specimens. In many hepatocytes, microvesicular steatosis was the salient feature. Additional findings included cholestasis and focal cytoplasmic biliary necrosis (CBN), as well as cytosiderosis in hepatocytes and sinusoidal cells. In some hepatocytes the damage appeared extreme, but fibrosis was identified only in the few patients who died beyond 6 months of age. Although individual ultrastructural findings are not specific, when taken together, they show a diagnostic pattern highly suggestive of a respiratory chain disorder. In the appropriate clinical context, these findings can direct the clinician towards the diagnosis of hepatic MDS.
Endothelial cell-mediated uptake of a hepatitis B virus: A new concept of liver targeting of hepatotropic microorganisms
Authors: Breiner Klaus M. , Schaller Heinz , Knolle Percy A.
Published: August 2002

The liver is a target for many infectious agents, most notably hepatitis viruses. However, several receptor molecules identified so far for hepatitis viruses were found to be ubiquitously expressed and can thus not account for efficient liver targeting. Using a model hepatitis B virus, the duck hepatitis B virus (DHBV), we have obtained data indicating that scavenging liver sinusoidal endothelial cells (LSEC), rather than hepatocytes themselves, play the key role in the initial uptake of viral pathogens into the liver. Experiments with fluorescent viral particles and coated gold particles in test animals, as well as in primary liver cell culture, demonstrated a preferential uptake of the viral substrates into LSEC. Intracellularly, fluorescent virus particles internalized by LSEC colocalized with the DHBV receptor, carboxypeptidase D, suggesting receptor-mediated rescue from lysosomal degradation. To comply with the high efficiency by which hepatitis B viruses infect hepatocytes in vivo, we propose that viruses initially scavenged by LSEC are thereafter released to infect adjacent hepatocytes, the only cells capable of replicating these viruses. Such a model of primary uptake into LSEC may illustrate a general mechanism by which blood-borne hepatotropic agents are targeted to the hepatocytes in the liver.
Renal failure after upper gastrointestinal bleeding in cirrhosis: Incidence, clinical course, predictive factors, and short-term prognosis
Authors: Cárdenas Andrés , Ginès Pere , Uriz Juan , Bessa Xavier , Salmerón Joan Manuel , Mas Antoni , Ortega Rolando , Calahorra Blas , De Las Heras Dara , Bosch Jaime , Arroyo Vicente , Rodés Juan
Published: August 2002

To assess the incidence, clinical course, predictive factors, and prognosis of renal failure in patients with cirrhosis and gastrointestinal bleeding, 175 consecutive episodes of gastrointestinal bleeding in 161 patients were analyzed. Renal failure occurred in 20 (11%) episodes and was transient in 8 episodes and nontransient in 12. Renal failure was more common in patients with cirrhosis than in a control population of bleeding patients without cirrhosis matched by age and severity of the bleeding episode. Among 39 clinical and laboratory variables obtained at admission or during hospitalization related with the bleeding episode or with liver and renal function, the presence of hypovolemic shock, number of packed red blood cells transfused, Child-Pugh class at admission, and baseline platelet count were independent predictors of renal failure. The development of renal failure and hypovolemic shock was the only independent predictors of in-hospital mortality. Mortality rate among the 20 episodes with renal failure was 55% (11 deaths) as compared with only 3% (5 deaths) in the 155 episodes without renal failure (P < .01). The development of nontransient renal failure entailed a much greater mortality as compared with transient renal failure (10 of 12 [83%] vs. 1 of 8 [12%]; P < .01). In conclusion, renal failure is a common event in patients with cirrhosis and gastrointestinal bleeding, the occurrence of which is mainly related to the severity of bleeding and baseline liver function. Renal failure is a strong predictor of mortality in patients with cirrhosis and gastrointestinal bleeding.
Intraductal papillary neoplasia of the liver associated with hepatolithiasis
Authors: Chen Tse-Ching , Nakanuma Yasuni , Zen Yoh , Chen Miin-Fu , Jan Yi-Yin , Yeh Ta-Sen , Chiu Cheng Tang , Kuo Tseng-Tong , Kamiya Jun-ichi , Oda Koji , Hamaguchi Michinari , Ohno Yoshiyuki , Hsieh Ling-Ling , Nimura Yuji
Published: August 2002

Intraductal papillary growth of neoplastic biliary epithelia with a fine fibrovascular stalk (intraductal papillary neoplasia of liver [IPN-L]) resembling intraductal papillary mucinous neoplasm of pancreas is occasionally associated with hepatolithiasis. In this study, 136 cases of hepatolithiasis in Taiwan, between January 1998 and March 2000, and an additional 21 cases of IPN-L before December 1998, were examined histologically. IPN-L was found in 41 of 136 hepatolithiasis cases (30.1%). Sixty-two IPN-L cases (42 women and 20 men; age range, 59.8 ± 10 years) were divided into 4 types (type 1, IPN-L with low-grade dysplasia, 23 cases; type 2, IPN-L with high grade dysplasia, 11 cases; type 3, IPN-L with in situ and microinvasive carcinoma, 13 cases; and type 4, IPN-L of types 2 and 3 with distinct invasive carcinoma, 15 cases). Intraductal spreading and glandular involvement were commonly observed in all types. About half of types 3 and 4 cases had mucobilia, and mucinous carcinoma was variably found in two thirds of group 4 patients. IPN-L frequently showed variable gastroenteric differentiation such as goblet cells and foveolar and colon-like metaplasia. IPN-L with goblet cells and colon-like metaplasia was frequently associated with overproduction of mucin and mucobilia (P < .01). In Japan, IPN-L was not frequent in hepatolithiasis (12 of 135 cases). In conclusion, IPN-L forms a spectrum of biliary neoplasm in hepatolithiasis. It often displays variable gastroenteric metaplasia and significant intraductal spread. IPN-L tends to progress to mucinous carcinoma. Formerly reported “mucin-producing intrahepatic cholangiocarcinoma” with a favorable prognosis is included in IPN-L.
Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats
Authors: Yoshiji Hitoshi , Kuriyama Shigeki , Yoshii Junichi , Ikenaka Yasuhide , Noguchi Ryuichi , Nakatani Toshiya , Tsujinoue Hirohisa , Fukui Hiroshi
Published: August 2002

The renin-angiotensin system (RAS) is frequently activated in patients with chronic liver diseases. Angiotensin-II (AT-II) has been suggested to play an important role in liver fibrogenesis. It induces hepatic stellate cell (HSC) proliferation and up-regulates the transforming growth factor β1 (TGF-β1) expression via AT-II type 1 receptor (AT1-R) in vitro. The aim of the present study was to examine the in vivo effect of candesartan (CA), a clinically used AT1-R blocker (ARB), and perindopril (PE), an angiotensin-converting enzyme (ACE) inhibitor (ACE-I), on pig serum-induced liver fibrosis development in rats. The clinically available comparable doses of CA and PE significantly attenuated the fibrosis development. These inhibitory effects of PE and CA were also found in the on-going liver fibrosis model. The hepatic hydroxyproline and serum fibrosis markers were significantly suppressed by CA and PE treatment. Furthermore, the α smooth muscle actin (α-SMA) positive cells in number were markedly suppressed by CA and PE treatment. Similarly, the hepatic TGF-β1 protein and messenger RNA (mRNA) levels were significantly suppressed. Our in vitro study showed that AT-II increased the TGF-β1 mRNA expression in the activated HSCs, and this effect was totally blocked by CA. These results suggested that the RAS, especially AT-II and AT1-R interaction plays a pivotal role in liver fibrosis development through HSC activation. Because both CA and PE are widely used in clinical practice without serious side effects, these drugs may provide an effective new strategy for anti-liver fibrosis therapy.
Tauroursodeoxycholic acid protects hepatocytes from ethanol-fed rats against tumor necrosis factor-induced cell death by replenishing mitochondrial glutathione
Authors: Colell Anna , Coll Olga , García-Ruiz Carmen , París Raquel , Tiribelli Claudio , Kaplowitz Neil , Fernández-Checa José C.
Published: August 2002

Mitochondrial glutathione (GSH) plays a key role against tumor necrosis factor α (TNF)-induced apoptosis because its depletion is known to sensitize hepatocytes to TNF. The present study examined the role of tauroursodeoxycholic acid (TUDCA) administration to chronic ethanol-fed rats on mitochondrial GSH levels and kinetics, mitochondrial membrane physical properties, TNF-induced peroxide formation, and subsequent hepatocyte survival. TUDCA selectively increased the levels of GSH in mitochondria without an effect on cytosolic GSH. This outcome was accompanied by improved initial rate of GSH transport examined at low (1 mmol/L) and high (10 mmol/L) GSH concentrations both in intact mitochondria and mitoplasts prepared from ethanol-fed livers. Assessment of membrane fluidity revealed an increased order parameter in mitochondria and mitoplasts from ethanol-fed rats compared with pair-fed controls, which was prevented by TUDCA administration. Compared with hepatocytes from pair-fed rats, TNF stimulated peroxide generation in hepatocytes from ethanol-fed rats, preceding TNF-induced cell death. Administration of TUDCA to ethanol-fed rats prevented TNF-induced peroxide formation and cell death, an effect that was reversed on depletion of the recovered mitochondrial GSH levels by (R,S)-3-hydroxy-4-pentenoate before TNF treatment. The protective effect of TUDCA against TNF was not because of activation of phosphatidylinositol 3-kinase, discarding a role for a survival-dependent pathway. Thus, these findings reveal a novel role of TUDCA in protecting hepatocytes in long-term ethanol-fed rats through modulation of mitochondrial membrane fluidity and subsequent normalization of mitochondrial GSH levels.
Combination of interferon induction therapy and ribavirin in chronic hepatitis C
Authors: Ferenci Peter , Brunner Harald , Nachbaur Karin , Datz Christian , Gschwantler Michael , Hofer Harald , Stauber Rudolf , Hackl Franz , Jessner Wolfgang , Rosenbeiger Martha , Munda-Steindl Petra , Hegenbarth Karin , Gangl Alfred , Vogel Wolfgang
Published: August 2002

The initial clearance of hepatitis C virus (HCV) during interferon-alfa therapy is dose-dependent. Therefore, higher initial interferon doses (induction therapy) may improve treatment results. This concept was tested in a prospective, randomized controlled trial. Previously untreated patients with chronic hepatitis C were randomized to receive 3 different interferon doses during the first 14 weeks of therapy (Group A, n = 130: 10 MU IntronA [AESCA-Schering Plough, Traiskirchen, Austria]/day for 2 weeks, followed by 10 MU/2 days for 12 weeks; Group B, n = 124: 5 MU/day for 14 weeks; Group C, n = 119; 5 MU/2 days for 14 weeks) followed in all by 5 MU/2 days for 24 weeks. Throughout the whole study all patients received 1 to 1.2 g ribavirin/day. On treatment, no differences in viral clearance rates were observed. Sustained response rates were also not different among the groups (A: 48.5%, B and C: 41.3%, intent to treat). When data were analyzed according to genotypes, sustained response was almost twice as high in patients with genotype 1 receiving high-dose interferon induction therapy (A: 44.2%, B: 28.6%, C: 27%, P < .05). In contrast, results were not different in genotype 3a patients (A: 61.3%, B: 75.9%, C: 56.3%; P > .1). These data indicate that high-dose interferon induction therapy may improve the outcome of interferon/ribavirin combination therapy in genotype 1 patients.
TAK1/JNK and p38 have opposite effects on rat hepatic stellate cells
Authors: Schnabl Bernd , Bradham Cynthia A. , Bennett Brydon L. , Manning Anthony M. , Stefanovic Branko , Brenner David A.
Published: August 2002

After liver injury, hepatic stellate cells (HSCs) undergo a process of activation with expression of smooth muscle α-actin (α-SMA), an increased proliferation rate, and a dramatic increase in synthesis of type I collagen. The intracellular signaling mechanisms of activation and perpetuation of the activated phenotype in HSCs are largely unknown. In this study the role of the stress-activated protein kinases, c-Jun N-terminal kinase (JNK) and p38, were evaluated in primary cultures of rat HSCs. The effect of JNK was assessed by using an adenovirus expressing a dominant negative form of transforming growth factor β (TGF-β)-activated kinase 1 (TAK1) (Ad5dnTAK1) and a new selective pharmacologic inhibitor SP600125. The effect of p38 was assessed with the selective pharmacologic inhibitor SB203580. These kinases were inhibited starting either in quiescent HSCs (culture day 1) or in activated HSCs (culture day 5). Although blocking TAK1/JNK and p38 decreased the expression of α-SMA protein in early stages of HSC activation, no effect was observed when TAK1/JNK or p38 were inhibited in activated HSCs. JNK inhibition increased and p38 inhibition decreased collagen α1(I) mRNA level as measured by RNase protection assays, with maximal effects observed in early stages of HSC activation. Furthermore, TAK1/JNK inhibition decreased HSC proliferation, whereas p38 inhibition led to an increased proliferation rate of HSCs, independently of its activation status. These results show novel roles for the TAK1/JNK pathway and p38 during HSC activation in culture. Despite similar activators of TAK1/JNK and p38, their functions in HSCs are distinct and opposed.
Contractile hyporesponsiveness of hepatic arteries in humans with cirrhosis: Evidence for a receptor-specific mechanism
Authors: Schepke Michael , Heller Jörg , Paschke Sebastian , Thomas Julia , Wolff Martin , Neef Markus , Malago Max , Molderings Gerhard J. , Spengler Ulrich , Sauerbruch Tilman
Published: August 2002

Splanchnic vasodilatation and vascular hyporesponsiveness to vasopressors are characteristic features of patients with cirrhosis. Although the vascular response to different vasopressors has been shown to be attenuated in cirrhosis, alterations on the receptor level are discussed controversially. Thus, impaired postreceptor signaling has been postulated. However, so far this has not been studied in human splanchnic vessels. Therefore, we assessed the vascular response of human hepatic arteries after activating the G-protein-dependent signal transduction pathway by stimulation with angiotensin II, the thromboxane A2 analog U46619, or by G-protein activation with NaF/AlCl3. After endothelium denudation, cumulative isometric concentration contraction curves were obtained for hepatic arteries from 32 cirrhotic patients undergoing liver transplantation and from 40 organ donors after stimulation with either angiotensin II (10−11-10−5 mol/L), U46619 (10−10-10−6 mol/L) or AlCl3 (30 μmol/L)/NaF (10−4-3 × 10−2 mol/L). Hepatic arteries from cirrhotic patients were markedly less responsive to angiotensin II (P < .0001) than those from organ donors. Both stimulation of the G-protein phospholipase C pathway via the thromboxane A2 receptor and receptor-independent G-protein stimulation with AlCl3/NaF, induced an intact contractile response. In conclusion, the G-protein-dependent signal transduction system itself is unaltered in cirrhosis. Hence, the cause of the hyporesponsiveness to some vasoconstrictors in cirrhosis appears to be a receptor-specific phenomenon localized upstream from the G-protein level.
Lipopolysaccharide results in a marked decrease in hepatocyte nuclear factor 4α in rat liver
Authors: Wang Bin , Cai Shi-Rong , Gao Cuihua , Sladek Frances M. , Ponder Katherine Parker
Published: August 2002

The acute-phase response can result in decreased liver-specific functions and death as a result of liver failure. We show here that lipopolysaccharide (LPS), an endotoxin that induces the acute-phase response, results in a marked decrease in the major isoforms of the transcription factor, hepatocyte nuclear factor 4α (HNF-4α), in livers of rats. HNF-4α is a nuclear receptor that is critical for the expression of several liver-specific genes. This decrease in HNF-4α is primarily the result of a posttranscriptional mechanism, because mRNA levels are normal, and there are no major changes in the splicing patterns. This decrease was of functional significance, because expression of a gene that is highly dependent on HNF-4α, HNF-1α, was reduced. Interleukin-1β (IL-1β) is a cytokine whose levels are increased in vivo in response to LPS. IL-1β resulted in a decrease in HNF-4α levels in HepG2 cells. This IL-1β-induced decrease was likely caused by degradation via the proteasome, because it was prevented by the addition of the proteasome inhibitor, MG132. We conclude that the decrease in HNF-4α that occurs in vivo after the administration of LPS may be the result of IL-1β-induced degradation, and likely contributes to the liver insufficiency that occurs. IL-1β antagonists or proteasome inhibitors might increase HNF-4α protein levels in the acute-phase response, which could result in increased liver function and survival.
Hepatitis B virus X protein increases expression of p21Cip-1/WAF1/MDA6 and p27Kip-1 in primary mouse hepatocytes, leading to reduced cell cycle progression
Authors: Qiao Liang , Leach Kevin , McKinstry Robert , Gilfor Donna , Yacoub Adly , Park Jong Sung , Grant Steven , Hylemon Philip B. , Fisher Paul B. , Dent Paul
Published: August 2002

Previously, we have linked prolonged intense mitogen-activated protein kinase (MAP kinase; MAPK) signaling in hepatocytes to increased expression of p21Cip-1/WAF1/MDA6 (p21) and p16INK4a (p16), that leads to a p21-dependent growth arrest. In this study, we investigated the impact of hepatitis B virus X protein (pX) expression on MAPK-modulated cell cycle progression in primary mouse hepatocytes. In hepatocytes, expression of pX enhanced protein levels of p21 and p27, but not of p16. The elevated levels of p21 and p27 correlated with reduced DNA synthesis in wild-type (+/+) hepatocytes and with a weak stimulation of DNA synthesis in p21 null (−/−) cells. Antisense p27 messenger RNA (mRNA) (p27as) increased DNA synthesis in +/+ and p21 −/− cells, and pX blunted this effect in +/+ cells. In p21 −/− cells, however, p27as permitted pX to further stimulate DNA synthesis. These data argue that a reduced ability to enhance expression of both p21 and p27 is required to fully reveal the growth-potentiating properties of pX. This finding also implies that depending on the functional status of the p21 and p27 genes, expression of pX can have 2 very different effects on hepatocyte proliferation. Prolonged intense MAPK signaling reduced DNA synthesis in +/+ cells and enhanced DNA synthesis in p21 −/− cells. The enhancement of DNA synthesis in p21 −/− cells was blocked by pX, and the effect of pX was abrogated by p27as. Furthermore in p21 −/− cells, overexpression of p16 blocked MAPK-stimulated DNA synthesis, and this effect was partially reversed by p27as. These data argue that p27 can also cooperatively interact with p16 to inhibit DNA synthesis in hepatocytes. Collectively, our findings show that reduced expression of p16, p21, and p27, which can occur during hepatocellular carcinoma, enhances the ability of MAPK signaling and pX to cause proliferation in hepatocytes. Thus loss of cyclin kinase inhibitor function may play an important role in the process of tumor progression after chronic hepatitis B virus infection.
Interferon and ribavirin combination therapy for chronic hepatitis C in human immunodeficiency virus-infected patients with congenital coagulation disorders
Authors: Sauleda Silvia , Juárez Alberto , Esteban Juan I. , Altisent Carmen , Ruiz Isabel , Puig Lluís , Esteban Rafael , Guardia Jaime
Published: August 2002

We have conducted an open, prospective trial to assess the safety and efficacy of interferon alfa-2b and ribavirin in combination for the treatment of chronic hepatitis C in human immunodeficiency virus (HIV)-infected hemophiliacs. Twenty hemophiliacs coinfected with HIV and hepatitis C virus (HCV), 18 of them under highly active antiretroviral therapy (HAART), with a mean CD4+ cell count of 490 ± 176 cells/mm3 and undetectable (n = 9) or low-level HIV RNA (<10,000 copies/mL; n = 11), were treated with interferon-alfa2b (3 MU thrice weekly) and ribavirin (800 mg/d) for 6 or 12 months according to virologic response. Patients were monitored for tolerance and response at 4, 8, 12, 24, 36, and 48 weeks during treatment and every other month thereafter. All 20 patients enrolled completed at least 6 months of treatment with no major side effect requiring treatment withdrawal, dose reduction, or modification of HAART. Overall, 8 patients (40%) achieved a sustained virologic response at the end of the 6-month post-treatment follow-up. Sustained responders had lower baseline HCV-RNA levels (5.7 ± 0.8 vs. 6.3 ± 0.4 log10 IU/mL, P = .041) but were otherwise similar to nonresponders. All sustained responders had a decrease in HCV-RNA level of at least 1 log per month during the first 2 months and undetectable levels at 6 months. In conclusion, our results provide evidence that combination therapy with interferon and ribavirin is safe in HIV-infected hemophiliacs with stable CD4 cell count and undetectable or low-level HIV replication, and leads to eradication of HCV in 40% of these patients.
Activation of caspase-8 during N -(4-hydroxyphenyl)retinamide-induced apoptosis in fas-defective hepatoma cells
Authors: You Kyung-Ran , Shin Myung-Nym , Park Rae-Kil , Lee Seung-Ok , Kim Dae-Ghon
Published: August 2002

We observed that N-(4-hydroxyphenyl)retinamide (4HPR), a chemopreventive and chemotherapeutic agent, effectively induced apoptosis in hepatoma cells. Interestingly, Fas-negative (Hep 3B and PLC/PRF/5) hepatoma cells were shown to be more susceptible to apoptosis induced by 4HPR than were Fas-positive (Hep G2 and SK-HEP-1) hepatoma cells. Thus, we explored the mechanisms underlying 4HPR-induced apoptosis in Fas-defective hepatoma cells. Hep 3B cells stably expressing the dominant-negative Fas-associated death domain (dnFADD) showed no alteration in 4HPR drug susceptibility, but when stably expressing E1B19K, Crm A, or dominant-negative FLICE (dnFLICE), Hep 3B cells were resistant, suggesting that 4HPR-induced apoptosis was mediated by caspase-8 activation. Furthermore, apoptosis could be completely blocked by Z-VAD-FMK (a general caspase inhibitor) or by IETD-CHO (a caspase-8 inhibitor), but was only partially blocked by Ac-DEVD-CMK (a caspase-3 inhibitor), by N-acetyl-L-cysteine (NAC) (an antioxidant), by N-acetyl-leucyl-leucyl-norleucinal (ALLN) (a calpain inhibitor I), or by Z-LEHD-FMK (a caspase-9 inhibitor). Time-sequence analysis of the induction of apoptosis by 4HPR revealed that an initial caspase-8 activation was followed by late mitochondrial cytochrome c release and minor caspase-9 activation, which suggested that caspase-8 activation is the primary upstream regulatory point. Activation of Bid or induction of proapoptotic Bax was not observed during apoptosis. In contrast, Bcl-xL expression was decreased during 4HPR-induced apoptosis. Taken together, these results indicate that 4HPR may be a potential chemotherapeutic drug, which is able to induce apoptosis in Fas-defective hepatoma cells through caspase-8 activation.
Hepatic and intestinal cytochrome P450 3A activity in cirrhosis: Effects of transjugular intrahepatic portosystemic shunts
Authors: Chalasani Naga , Gorski Christopher J. , Patel Nilesh H. , Hall Stephen D. , Galinsky Raymond E.
Published: August 2002

Transjugular intrahepatic portosystemic shunt (TIPS) is performed to treat some complications of cirrhosis. This study investigated the effects of cirrhosis and TIPS on intestinal and hepatic cytochrome P450 3A (CYP3A) activity. Nine volunteers were cirrhotic patients with TIPS, 9 were cirrhotic controls (matched for sex, age, etiology, and Child-Pugh class), and 9 were sex- and age-matched healthy volunteers. Simultaneous doses of midazolam were given intravenously (0.05 mg/kg) and orally (3 mg of [15N3]midazolam). Peripheral and portal venous blood samples were assayed for midazolam and [15N3]midazolam. The systemic clearance of midazolam was significantly greater (P < .05) in healthy volunteers (0.42 ± 0.10 L · h−1 · kg−1) compared with cirrhotic controls (0.20 ± 0.05) and with cirrhotic patients with TIPS (0.21 ± 0.09). Hepatic availability followed the same trend. The bioavailability of midazolam was significantly higher (P < .05) in cirrhotic patients with TIPS (0.76 ± 0.20) compared with cirrhotic controls (0.27 ± 0.14) and with healthy volunteers (0.30 ± 0.10). The intestinal availability was significantly greater (P < .05) in cirrhotic patients with TIPS (0.83 ± 0.17) compared with cirrhotic controls (0.32 ± 0.16) and with healthy volunteers (0.42±0.15). As expected, hepatic CYP3A activity was reduced in cirrhosis. However, in cirrhotic patients with TIPS, there was a marked loss in first-pass metabolism of midazolam as a result of diminished intestinal CYP3A activity.
Carcinoembryonic antigen-related cell adhesion molecule 1 is the 85-kilodalton pronase-resistant biliary glycoprotein in the cholesterol crystallization promoting low density protein-lipid complex
Authors: Jirsa Milan , Muchová Lucie , Dráberová Lubica , Dráber Petr , Šmíd František , Kuroki Masahide , Mareček Zdenčk , Groen Albert K.
Published: August 2002

A pronase resistant 85-kd glycoprotein in the Concanavalin A-binding fraction (CABF) of biliary glycoproteins has been reported to act as a promotor of cholesterol crystallization. De Bruijn et al. (Gastroenterology 1996;110:1936-1944) found this protein in a low-density protein-lipid complex (LDP) with potent cholesterol crystallization promoting activity. This study identifies and characterizes this protein. An LDP was prepared from CABF by discontinuous gradient ultracentrifugation. Proteins were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), blotting and immunochemical staining with anti-carcinoembryonic antigen, CEA-related adhesion molecule 1 (CEACAM1) cross-reacting antibodies. Biliary concentrations of CEA cross-reacting proteins were determined in patients with and without gallstones. Two isoforms of CEACAM1 (85- and 115-kd bands), CEA and 2 CEA cross-reacting protein bands of 40 and 50 kd were found in human bile. All bands were also present in CABF, but only a subfraction of the 85-kd band found in the LDP was resistant to digestion with pronase. CEACAM1-85 exhibited potent cholesterol crystallization promoting activity in vitro and accounted for most of the activity in CABF. Total CEA cross-reacting protein concentrations were the same in gallbladder biles from patients with cholesterol and pigment gallstones but only half of those in biles from nongallstone subjects. In conclusion, we have identified the protein component of the cholesterol crystallization promoting LDP to be CEACAM1-85.
Accuracy of bile duct changes for the diagnosis of chronic liver allograft rejection: Reliability of the 1999 Banff schema
Authors: Sebagh Mylène , Blakolmer Karin , Falissard Bruno , Roche Bruno , Emile Jean-Francois , Bismuth Henri , Samuel Didier , Reynès Michel
Published: August 2002

Chronic rejection (CR) after liver transplantation is thought to be a dynamic and potentially reversible process. The Banff working group has developed recommendations for its histopathologic staging. The 1999 Banff classification of CR (i.e., bile duct dystrophy >50% and/or bile duct loss >20%) was applied to: 1) biopsies from patients retransplanted for CR (N = 19) and pathologies other than CR (N = 21) to evaluate its specificity and sensitivity, especially of the early stage lesions of CR; and 2) biopsies from nonretransplanted patients (N = 21) to evaluate the evolution of CR lesions. Atypical forms of CR were also described. Including an early stage into the definition of CR has resulted in a much higher sensitivity for its diagnosis, as compared with the former classification (i.e., bile duct loss >50%) (89% vs. 33%; P = .0001), while keeping an acceptable specificity (74% vs. 100%; P = .03). In 55% of the nonretransplanted patients, CR lesions were reversible. No histologic feature reliably predicted CR outcome. Transient lobular hepatitis, unrelated to viral infection, and veno-occlusive disease were seen significantly more often in the CR group (P = .04 and P = .03, respectively). We conclude that the application of the 1999 Banff classification is superior to the previous classification for the diagnosis of CR. However, limited information can be drawn regarding the outcome of CR based on histology alone. Transient lobular hepatitis, unrelated to viral infection and veno-occlusive disease, may be an unusual expression of CR.
Failure of a reinforced triple course of hepatitis B vaccination in patients transplanted for HBV-related cirrhosis
Authors: Angelico Mario , Di Paolo Daniele , Trinito Massimo O. , Petrolati Alessandra , Araco Antonio , Zazza Settimio , Lionetti Raffaella , Casciani Carlo U. , Tisone Giuseppe
Published: August 2002

Long-term immunoprophylaxis with anti-HBs immunoglobulins (HBIg) is used to prevent hepatitis B (HBV) reinfection after liver transplantation for HBV-related cirrhosis. This approach is highly expensive. A recent report proposed posttransplant HBV vaccination with a reinforced schedule as an alternative strategy to allow HBIg discontinuation. We investigated the efficacy of a reinforced triple course of HBV vaccination in 17 patients transplanted for HBsAg—positive cirrhosis 2 to 7 years earlier. The first cycle consisted of 3 double intramuscular doses (40 μg) of recombinant vaccine at month 0, 1, and 2, respectively. This was followed, in nonresponders, by a second cycle of 6 intradermal 10 μg doses every 15 days. All nonresponders then received a third cycle identical to the first one. Vaccination started 4.5 months after HBIg discontinuation, and lamivudine (100 mg/day) was given throughout the study. All patients were seronegative for HBsAg and HBV-DNA (by PCR) and positive for anti-HBe, and 7 were positive for anti-HDV. After the first cycle one patient (#5, 53 years old, male) developed an anti-HBs titer of 154 IU/L, another (#12) reached a titer of 20 IU/L and the remainder had titers <10 IU/L. At month 7, patient #5 reached a titer of 687 IU/L. After the second cycle only one additional patient (#9) had a slight response (an anti-HBs titer of 37 IU/L). After the third cycle patient #9 rose to an anti-HBs titer of 280 IU/L, patient #12 dropped to 10 IU/L, and no other patient responded. In conclusion, a highly reinforced HBV vaccination program is effective only in a few patients who had liver transplants for HBV—related cirrhosis.