bluuebunny/crossref_metadata_2025 huggingface dataset:
Surface temperature of decomposing construction materials studied by laser‐induced phosphorescence
Authors: Omrane Alaa , Ossler Frederik , Aldén Marcus , Svenson Jenny , Pettersson Jan B. C.
Published: July 2004

Measurements of surface temperature and mass loss of decomposing construction materials during rapid pyrolysis are presented. Experiments have been performed with samples of low‐density fiberboard, medium‐density fiberboard, particleboard and poly(methyl methacrylate) in a single particle reactor at temperatures between 300° and 600°C. Ultraviolet laser light was used to excite micrometer‐sized thermographic phosphor particles that were deposited on the investigated materials, and the temperature was obtained from temporally resolved measurements of the laser‐induced emission. The wood‐based materials show a similar behavior, with small differences being attributed to differences in material properties. The surface temperature rapidly increases to about 400°C when a particle is introduced to the hot reactor. The initial phase is followed by rapid decomposition during which the surface temperature is 380°–540°C. The heating rate is slowed down during the rapid pyrolysis, and again increases as the remaining char is heated to the reactor temperature. The poly (methyl methacrylate), however, melts and at high temperatures can be characterized as a liquid with a boiling point of about 400°C. Thermographic phosphors are concluded to be suitable for high precision remote measurements of the surface temperature of decomposing construction materials, and possibilities for further studies and developments of the technique are discussed. Copyright © 2004 John Wiley & Sons, Ltd.
Correlates of resident psychosocial status in long‐term care
Authors: Gaugler Joseph E. , Leach Corinne R. , Anderson Keith A.
Published: July 2004

Objectives

This pilot study randomly selected five nursing homes, five assisted living facilities, and 16 family care homes from a South‐Central state in the US to identify correlates of resident psychosocial status.

Methods

In‐person and telephone interviews were conducted with administrators and resident‐family‐staff triads (n = 79) to gather information on setting, resident functional status, family involvement, sociodemographic context, and resident psychosocial status.

Results

Results indicated that type of facility, resident health conditions, resident race, and facility family orientation were significantly correlated with dimensions of resident psychosocial status.

Conclusions

The findings suggest that multiple informants are necessary to determine the processes that lead to residents' quality of life, and the consideration of diverse settings offers greater insight into how positive resident adaptation is achieved in long‐term care. Copyright © 2004 John Wiley & Sons, Ltd.
A failure of ‘Pop‐Out’ in visual search tasks in dementia with Lewy Bodies as compared to Alzheimer's and Parkinson's disease
Authors: Cormack Francesca , Gray Alistair , Ballard Clive , Tovée Martin J.
Published: July 2004

Objectives

The pattern of neural damage in dementia with Lewy Bodies (DLB) led us to hypothesize that patients with DLB would be particularly impaired on parallel (‘pop‐out’) search tasks, relative to serial search tasks, and that this would serve to distinguish DLB from other forms of neurodegenerative disease, particularly Alzheimer's disease (AD).

Methods

To explore this possibility we tested four groups of observers (DLB, Alzheimer's Disease, Parkinson's Disease and age‐matched controls) on parallel and serial search tasks, and a choice reaction time task.

Results

The DLB participants performed in a quantitatively and qualitatively different manner to the other groups. As predicted, they were particularly impaired on the parallel search task relative to the other observer groups.

Conclusions

This pattern of deficit may reflect damage in the occipital areas leading to deficits in figure‐ground segregation, and can assist differential diagnosis of DLB from other patients groups such as AD. Copyright © 2004 John Wiley & Sons, Ltd.
A randomized controlled trial of a behavior advisory service for hospitalized older patients with confusion
Authors: Mador Julie E. , Giles Lynne , Whitehead Craig , Crotty Maria
Published: July 2004

Objective

To determine whether individualized advice on non‐pharmacological strategies for hospitalized older patients with confusion and behavioral problems can improve levels of agitation and reduce the use of psychotropic medication.

Method

Pragmatic randomized controlled trial in two metropolitan teaching hospitals in South Australia. Seventy‐one older patients with confusion and a behavioral disturbance were randomly allocated to receive either an assessment and ongoing individualized advice from an extended practice nurse on non‐pharmacological strategies or usual care. Usual care included an assessment by a geriatrician.

Measurements

Primary outcomes were levels of agitation (Pittsburgh Agitation Scale), appropriateness of psychotropic medication prescribing (Medication Appropriateness Index) and levels of psychotropics administered (chlorpromazine and diazepam dose equivalents). Secondary outcomes were length of stay, discharge destination, number of falls, restraint use and satisfaction from nursing staff and next of kin.

Results

Levels of agitation were modest at baseline with mean PAS intervention group 3.4 (SD = 0.5) and control group 4.0 (SD = 0.4) and both groups improved over time to 1.7 (SD = 0.4) for the intervention group and 1.8 (SD = 0.3) for the control group on the final day of data collection. Median length of follow‐up was nine days. There was no effect of the intervention on levels of agitation, amount and appropriateness of psychotropic medication prescribed and administered, falls, length of stay, discharge destination, restraint use and nursing and next of kin satisfaction.

Conclusion

A nursing consultation service providing individualized non‐pharmacological advice does not improve patient agitation or use of psychotropic medication for older patients with confusion and behavioral problems in an acute hospital. Copyright © 2004 John Wiley & Sons, Ltd.
Does depression in old age increase only cardiovascular mortality? The Leiden 85‐plus Study
Authors: Vinkers David J. , Stek Max L. , Gussekloo Jacobijn , van der Mast Roos C. , Westendorp Rudi G. J.
Published: July 2004

Background

Depression in old age is associated with an increased mortality risk of cardiovascular disease but the mortality risk from non‐cardiovascular causes is disputed.

Objective

To investigate the effect of depression on cardiovascular and non‐cardiovascular mortality in old age.

Methods

We prospectively followed 500 subjects from age 85 years onwards within the population‐based Leiden 85‐plus Study. Depressive symptoms were assessed annually with the 15‐item Geriatric Depression Scale (GDS‐15). Mortality risks were estimated in a Cox proportional‐hazards model with the annual assessment of depression (GDS‐15≥4 points) as a time‐dependent covariate.

Results

During 1654 person‐years of follow‐up (mean per person, 3.2 years), depression was associated with a two‐fold increase of all cause mortality [Relative Risk (RR), 1.83; 95% Confidence Interval (CI), 1.24–2.69] that was not explained by comorbid conditions. Both cardiovascular mortality and non‐cardiovascular mortality contributed equally to the excess mortality (RR 1.95 and 1.75 respectively).

Conclusion

Depression in old age contributes to an increase of both cardiovascular and non‐cardiovascular mortality. Motivational depletion may play an important role in the increased mortality in elderly with depression. Copyright © 2004 John Wiley & Sons, Ltd.
Antidepressant efficacy and cognitive effects of repetitive transcranial magnetic stimulation in vascular depression: an open trial
Authors: Fabre I. , Galinowski A. , Oppenheim C. , Gallarda T. , Meder J. F. , de Montigny C. , Olié J. P. , Poirier M. F.
Published: July 2004

Background

Beneficial effects of repetitive transcranial magnetic stimulation (rTMS) were demonstrated by many controlled studies in major depression. Moreover, this promising and non invasive therapeutic tool seems to be better tolerated than electroconvulsive therapy.

Vascular depression is a subtype of late‐life depression, associated with cerebrovascular disease and means a poorer response to antidepressant treatment. We employed rTMS over the left prefrontal cortex in 11 patients with late‐onset resistant vascular depression. The primary purpose of this two‐week open study was to examine antidepressant efficacy of rTMS in vascular depression. The secondary aim was to evaluate cognitive effects of rTMS in our sample.

Methods

Clinical status, as measured with the Hamilton Depression Rating Scale (HDRS), and cognitive effects, as evaluated by neuropsychological tests, were assessed at baseline and after two weeks of rTMS. Brain measurements to obtain an index of prefrontal atrophy were performed at both the motor cortex and prefrontal cortex.

Results

Five out of 11 resistant patients with late‐onset vascular depression were responders. They showed a clinically meaningful improvement in HDRS scores, with a decrease of 11, 4 points (p<0.01). Antidepressant response is correlated to the relative degree of prefrontal atrophy (p = 0.05). After two weeks, verbal fluency and visuospatial memory improved. No cognitive performance deteriorated except for verbal memory, as the delayed recall decreased significantly in the responders' group.

Conclusions

Our preliminary observations prompt to perform a subsequent controlled study to examine if rTMS may constitute an alternative to electroconvulsive therapy. Copyright © 2004 John Wiley & Sons, Ltd.
Effectiveness of a clinical pathway for the diagnosis and treatment of dementia and for the education of families
Authors: Kazui Hiroaki , Hashimoto Mamoru , Nakano Yoko , Matsumoto Keiji , Yamamura Shuhei , Nagaoka Kentaro , Mori Etsuro , Endo Hidetoshi , Tokunaga Hiromasa , Ikejiri Yoshitaka , Takeda Masatoshi
Published: July 2004

Aims

Clinical pathways (CPs) are rarely used in the treatment of dementia. We established a CP for a series of medical practices (diagnosis, treatment, establishment of a care system, and caregiver education) for patients with dementia hospitalized for a three‐week period, and evaluated its usefulness.

Methods

The length of hospital stay and hospital costs were compared between 23 consecutive patients with dementia hospitalized and treated using a CP and 20 controls treated by conventional medical practice without using a CP in a special ward for dementia patients. In the CP group, at the time of discharge, primary caregivers, physicians, and nurses were given a questionnaire to obtain their comments about the impression of treatment with the CP.

Results

The questionnaire survey indicated that the CP deepened the caregiver's understanding of the sequence of medical practices for the inpatient, the disorders of the inpatient, the treatment methods, and the methods for coping with the disorder. The CP was also useful for facilitating inpatient medical practice and promoting the establishment of a care system after discharge. The use of the CP significantly shortened the length of hospital stay and decreased hospital costs during hospitalization but increased the amount of work per day and made the medical staff feel that their freedom to choose medical procedures had been restricted.

Conclusions

The CP was useful for execution of inpatient medical practices for patients with dementia. Copyright © 2004 John Wiley & Sons, Ltd.
Combined effect of vision and hearing impairment on depression in elderly Chinese
Authors: Chou Kee‐Lee , Chi Iris
Published: July 2004

Background

Sensory impairment and depression are common in old age and the relation between depression and vision as well as hearing impairment have been established. However, few studies have directly compared their effects and examined the impact of dual sensory loss. The purpose of this study is to compare impacts of self‐reported hearing and vision loss as well as the effect of double sensory impairment on depression.

Method

This article analyzes cross‐sectional data collected from a representative community sample of 2,003 Chinese elderly people aged 60 or above in Hong Kong. Respondents were interviewed in a face‐to‐face format and data including vision and hearing impairment, socio‐demographic variables, health indicators, family support, and depression were obtained.

Results

Logistic regression analyses revealed that visual impairment was significantly related to depression even after age, gender, marital status, education, self‐reported health status, the presence of 11 diseases, functional limitation and family support were controlled but hearing loss was not. Hearing impairment did not add to the likelihood of depression where visual impairment was already present.

Conclusion

The impact of visual impairment on psychological well‐being among elderly Chinese is more robust than hearing loss. Therefore, aged care service practitioners must take this risk factor into consideration in their preventive intervention and treatment for psychological well‐being. Copyright © 2004 John Wiley & Sons, Ltd.
Long–Term Ursodeoxycholic Acid Delays Histological Progression in Primary Biliary Cirrhosis
Authors: Angulo Paul , Batts Kenneth P. , Therneau Terry M. , Jorgensen Roberta A. , Dickson Rolland E. , Lindor Keith D.
Published: July 2004

Primary biliary cirrhosis (PBC) is a progressive cholestatic liver disease frequently leading to development of cirrhosis and its complications. Ursodeoxycholic acid (UDCA) is a beneficial medical therapy for patients with PBC. Improvement in some histological features, but not in histological stage, has been reported after 2 years of UDCA therapy. Thus, longer follow–up may be necessary to determine whether UDCA has a favorable effect on histological stage of disease and progression to cirrhosis. Our aim was to determine the long–term effects of UDCA therapy on histological stage and progression to cirrhosis in patients with PBC. Sixteen unselected patients with noncirrhotic PBC who had been on long–term UDCA therapy (13–15 mg/kg/d) for 6.6 ± 0.4 years (range, 5–9 years) were identified and their histological finding during treatment compared with that of 51 noncirrhotic patients with PBC who had received ineffective therapy (d–penicillamine [DPCA] or placebo) for 5.6 ± 0.07 years (range, 5–8 years). Histological stage was determined using the Ludwig classification. The rate of progression to cirrhosis (stage 4) was significantly less in the UDCA group than in the control group (13% vs. 49%P= .009). Although the overall rate of progression of histological stage was less in the UDCA group than in the control group (50% vs. 71%), this difference was not significant (P= .1). A marked improvement in liver biochemistries and Mayo risk score was noted in all patients during UDCA therapy; however, this improvement was not significantly different between patients who progressed and those who did not. In conclusion, long–term UDCA therapy appeared to delay the development of cirrhosis in PBC.
Transjugular Intrahepatic Portosystemic Shunt: Short–Term and Long–Term Effects on Hepatic and Systemic Hemodynamics in Patients With Cirrhosis
Authors: Lotterer Erich , Wengert Arthur , Fleig Wolfgang E.
Published: July 2004

The aim of this prospective, nonrandomized study was to assess the short– and long–term effects of transjugular intrahepatic portosystemic shunt (TIPS) on hepatic and systemic hemodynamics and on gastroesophageal collateral flow in patients with cirrhosis and failure of chronic sclerotherapy. Cardiac output (CO), free and wedged pulmonary artery pressure (FPAP and WPAP) systemic vascular resistance (SVR) azygos venous blood flow (AzVBF), and the relative (portal minus vena cava) pressure in the portal vein (rel.PP) were determined immediately before, 30 minutes, 1 week, 3 months, and 1 year after TIPS implantation in 21 patients with alcoholic and biliary cirrhosis with repeated bleeding from esophageal varices despite chronic sclerotherapy. TIPS was inserted when patients were in a stable hemodynamic condition. Palmaz stents were dilated to a 10–mm to 14–mm diameter until gastroesophageal collaterals were no longer visible on direct splenoportography. Relative portal pressure decreased from 21 ± 5 mm Hg to 11 ± 5 mm Hg 30 minutes after the procedure (P< .001). CO increased from 7.1 ± 1.5 L/min at baseline to 8.9 ± 2.0 L/min (P < .005) at 30 minutes, 8.2 ± 2.0 L/min (P< .01) at 1 week, and 8.0 ± 2.0 L/min (P< .01) at 3 months after TIPS, and returned to 7.2 ± 1.3 L/min (ns) after 1 year. Before TIPS, SVR was 990 ± 285 dyne · sec · cm-5 and decreased to 856 ± 252 dyne · sec · cm-5 (P< .05) and 866 ± 267 dyne · sec · cm-5
P< .05) at 30 minutes and 1 week after the procedure, and increased again to 903 ± 208 dyne · sec · cm-5 (s) and 1,016 ± 260 dyne · sec · cm-5 (ns) at 3 months and 1 year, respectively. AzVBF continuously decreased from 474 ± 138 mL/min before TIPS to 335 ± 116 mL/min, 289 ± 147 mL/min, 318 ± 157 mL/min, and 250 ± 104 mL/min (all P < .005) at 30 minutes, 1 week, 3 months, and 1 year after TIPS. Portal decompression after TIPS is associated with a significant increase of CO for at least 3 months, which is only partly explained by a transient decrease of SVR. After 1 year, CO had returned to baseline levels. Despite an immediate decrease in portal pressure, the reduction of blood flow through gastroesophageal collaterals is delayed and not complete before 1 year after TIPS. In contrast to previous short–term observations, TIPS does not seem to cause long–term aggravation of the hyperkinetic circulation in patients with cirrhosis.
Interleukin–2-Activated Natural Killer Cells Can Induce Both Apoptosis and Necrosis in Rat Hepatocytes
Authors: Blom Marty W. , De Bont Hans J.G.M. , Meijerman Irma , Kuppen Peter J.K. , Mulder Gerard J. , Nagelkerke Fred J.
Published: July 2004

Natural killer (NK) cells play a crucial role in the elimination of virus–infected or transformed cells in the liver. In this article, we describe the mechanism by which liver cells are killed by NK cells. Interleukin–2–activated natural killer (A–NK) cells from the rat induced apoptotic cell death in 30% of freshly isolated rat hepatocytes within 60 minutes. Recognition by the A–NK cells of the hepatocytes as nonself was established by masking the major histocompatibility complex (MHC) class I molecules on the hepatocytes with the OX18 antibody. During the killing process, a decrease of the mitochondrial membrane potential (MMP), formation of blebs, phosphatidyl serine (PS) externalization, chromatin condensation, and nuclear fragmentation were observed. The hepatocytes became apoptotic before permeabilization of the plasma membrane occurred, suggesting that the observed cytolysis was caused by secondary necrosis. The apoptotic process was completely abolished by the caspase inhibitors, Z–Val–Ala–DL–Asp fluormethylketone (zVAD–fmk) and Ac–Asp–Glu–Val–aldehyde (DEVD–cho). However, under these conditions, A–NK cells killed a smaller fraction of the hepatocytes by (primary) necrosis. These results indicate that apoptosis is the major cytotoxic process induced by A–NK cells in hepatocytes. If apoptosis is prevented, a more limited necrotic effect is induced. Therefore, this study shows that NK cells are fully equipped to induce both apoptosis and necrosis in hepatocytes, but appear to prefer the apoptotic route.
Role of C– Kit Receptor Tyrosine Kinase in Development of Oval Cells in the Rat 2–Acetylaminofluorene/Partial Hepatectomy Model
Authors: Matsusaka Satoshi , Tsujimura Tohru , Toyosaka Akihiro , Nakasho Keiji , Sugihara Ayako , Okamoto Eizo , Uematsu Kunio , Terada Nobuyuki
Published: July 2004

Oval cells that develop in the rat 2–acetylaminofluorene/partial hepatectomy (AAF/PH) model express the c–kit receptor tyrosine kinase (KIT) and its ligand, stem cell factor (SCF). We investigated the role of the SCF/KIT system in the development of oval cells using Ws/Ws rats, whose c–kit kinase activity was severely impaired owing to a small deletion in the kinase domain. On days 7, 9, and 13 after PH in the AAF/PH model, the development of oval cells was remarkably suppressed in Ws/Ws rats when compared with that of the control normal (+/+) rats. However, oval cells that developed in Ws/Ws rats expressed marker proteins of oval cells, such as α–fetoprotein (AFP), cytokeratin–19 (CK–19), and flt–3 receptor tyrosine kinase, similar to those of +/+ rats. Furthermore, labeling with [3H]–thymidine and immunostaining of Ki–67 showed that the proliferative activity of oval cells that developed in Ws/Ws rats was comparable with that of +/+ rats. The present results indicate that the signal transduction of the SCF/KIT system plays a crucial role in the development of oval cells, at least, in the rat AAF/PH model, and suggest that KIT–mediated signal transduction plays only a small role in determining the phenotype and in the proliferative activity of oval cells.
The Human P53 Gene Mutated At Position 249 Per Se Is Not Sufficient to Immortalize Human Liver Cells
Authors: Schleger Claudia , Becker Roger , Oesch Franz , Steinberg Pablo
Published: July 2004

A particular point mutation of the tumor suppressor gene p53, namely a G→T transversion at the third base of codon 249, is frequently detected in primary hepatocellular carcinomas from patients living in areas where the levels of dietary exposure to aflatoxin B1 and the rates of infection with the hepatitis B virus are very high. Very recently, a nontumorigenic liver epithelial cell line (HACL–1) with a finite life–span and expressing a number of hepatocyte–specific markers was established from a human hepatocellular adenoma in our laboratory. To analyze the role of mutated p53 in the immortalization of human liver cells, we transfected HACL–1 cells with an expression vector containing a human p53 complementary DNA mutated at the third base of codon 249 and analyzed the consequences of this gene transfer on the growth properties of this cell line. HACL–1 cells transfected with mutant p53 showed no increase in their life–span (when compared with HACL–1 cells transfected with the antibiotic resistance gene alone) and did not grow in soft agar, whereas transfection of wild–type p53 into HACL–1 cells led to a proliferation stop. Thus, these results strongly support the view that the mutation at codon 249 of the p53 gene may serve as a fingerprint for aflatoxin B1–induced hepatocellular carcinomas, but is not, by itself, sufficient to immortalize human liver cells.
Suppressive Effects of Estradiol on Dimethylnitrosamine–Induced Fibrosis of the Liver in Rats
Authors: Yasuda Mitugi , Shimizu Ichiro , Shiba Masako , Ito Susumu
Published: July 2004

As a model for the analysis of the fibrosuppressive role of estradiol, hepatic fibrosis was induced in male and female rats by the administration of a single dose of dimethylnitrosamine (DMN). The fibrotic response of the male liver after DMN treatment was significantly stronger than that of the female liver. In the male DMN model, estradiol reduced hepatic mRNA for type I and III procollagens and the tissue inhibitor of metalloproteinase–1 (TIMP–1), as well as deposition of type I and III collagen protein total hepatic collagen and malondialdehyde (MDA), a product of lipid peroxidation. Concomitant administration of a neutralizing antibody against rat estradiol enhanced fibrogenesis, as judged by the same parameters. Ovariectomy in the female model had a fibrogenic effect, inducing the hepatic expression of both types of procollagen and TIMP–1; in addition, the number of α–smooth muscle actin (α–SMA)-positive cells in the liver increased; estradiol replacement was fibrosuppressive in the castrated–female model. In rat hepatic stellate cells incubated in primary culture with estradiol, cell number, type I collagen production, and α–SMA expression were all reduced. These findings suggest that estradiol suppressed the induction of hepatic fibrosis, and may in part underlie the more rapid progression in males of hepatic fibrosis and its complications.
Viral Load and Clinicopathological Features of Chronic Hepatitis C (1B) in A Homogeneous Patient Population
Authors: Fanning Liam , Kenny Elizabeth , Sheehan Margaret , Cannon Bridin , Whelton Michael , O'Connell Joe , Collins Kevin J. , Shanahan Fergus
Published: July 2004

Monitoring the progression of hepatitis C virus (HCV) includes clinical, biochemical, and histological parameters. Quantitation of viral load by reverse–transcription polymerase chain reaction (RT–PCR) may offer a more reliable marker of disease status. Conflicting reports on viral titers may reflect heterogeneity of patient population, mode of infection, and viral type/subtype. The aim of this study was to correlate quantitative serum viral load with alanine transaminase (ALT) and histological status in a homogenous population. The study population consisted of 77 Rhesus–negative women with chronic hepatitis C type 1b. Homogenous features of this study population included: same defined source of infection (contaminated anti–D immunoglobulin); same duration of disease (17 years at the time of study); same viral type/subtype; same ethnic origin; all healthy child–bearing females at the time of infection; and an absence of competing risk factors for infectious and other liver diseases. None of the patients had received antiviral treatment at the time of study. Liver biopsy was performed on all patients. All biopsies were scored by a single histopathologist who was blinded to the clinical and viral status of each patient. A weak, but statistically significant, correlation (r
s = .26; P < .05) between serum viral load and the degree of inflammation (mean value: 3.87 ± 2.17 [SD]) was found. There was no significant correlation between serum viral load and the degree of fibrosis (mean value: 0.84 ± 0.8 [SD]; P = .06). There was no significant correlation between serum viral load and ALT, although there was a correlation between ALT and the degree of inflammation (r
s = .241; P = .035)
Efficacy of Lamivudine in Patients With Hepatitis B E Antigen-Negative/Hepatitis B Virus Dna-Positive (Precore Mutant) Chronic Hepatitis Befficacy of Lamivudine in Patients With Hepatitis B E Antigen-Negative/Hepatitis B Virus Dna-Positive (Precore Mutant) Chronic Hepatitis Befficacy of Lamivudine in Patients With Hepatitis B E Antigen-Negative/Hepatitis B Virus Dna-Positive (Precore Mutant) Chronic Hepatitis Befficacy of Lamivudine in Patients With Hepatitis B E Antigen-Negative/Hepatitis B Virus Dna-Positive (Precore Mutant) Chronic Hepatitis Bb
Authors: Tassopoulos Nicolaos C. , Volpes Riccardo , Pastore Giuseppe , Heathcote Jenny , Buti Maria , Goldin Robert D. , Hawley Sasha , Barber Judy , Condreay Lynn , Gray Fraser D.
Published: July 2004

This placebo controlled, double–blind study evaluated the efficacy and safety of lamivudine in patients with hepatitis B e antigen (HBeAg)–negative/hepatitis B virus (HBV) DNA-positive chronic hepatitis B. Patients were randomized to receive 100 mg lamivudine orally once daily for 52 weeks (n = 60) or placebo for 26 weeks (n = 65). Patients who were HBV DNA positive at week 24 were withdrawn at week 26. The primary efficacy endpoint was loss of serum HBV DNA plus normalization of alanine transaminase (ALT) at week 24. A significantly higher proportion of patients receiving lamivudine (63%) had a complete response at week 24 compared with patients receiving placebo (6%) (P < .001). Secondary efficacy parameters included histological response from baseline to week 52 in the lamivudine–treated patients. At week 52, 60% of lamivudine–treated patients with liver biopsy specimens available showed histological improvement (≥2–point reduction in Knodell necro–inflammatory score), 29% showed no change, and 12% worsened. In a ranked assessment of pretreatment and post–treatment biopsy pairs 11% improved, 86% showed no change, and 2% worsened in fibrosis. At week 52, 27% of patients receiving lamivudine had YMDD (tyrosine–methionine–aspartate–aspartate amino acid motif of HBV polymerase) variant HBV. The incidence of adverse events and laboratory abnormalities was similar in both groups. In conclusion, lamivudine treatment results in a significant virological and biochemical improvement compared with placebo, induces an improvement or no change in histology in most patients, and is well tolerated. The response to lamivudine therapy in HBeAg–negative patients is similar to the response reported in previous studies of patients with HBeAg–positive chronic hepatitis B.
Correction of Hypozincemia Following Liver Transplantation in Children Is Associated With Reduced Urinary Zinc Loss
Authors: Narkewicz Michael R. , Krebs Nancy , Karrer Frederick , Orban-Eller Kathy , Sokol Ronald J.
Published: July 2004

Zinc deficiency is a relatively common problem in children with chronic liver disease. We have previously shown inappropriate urinary zinc excretion in children with chronic liver disease and hypozincemia. This study was designed to determine if zinc deficiency and inappropriate urinary zinc losses are corrected in children with liver disease by liver transplantation. Thirty–three patients (age 1–19 years) underwent 35 liver transplants for acute and chronic liver disease. At the time of transplant, 17 patients had low plasma zinc (hypozincemic) (plasma zinc, 45.4 ± 1.8 μg/dL), whereas 18 had normal plasma zinc (75.7 ± 3.8). Before transplant, patients with zinc deficiency had higher urinary zinc to creatinine ratio compared with those with normal zinc status (6.6 ± 1.9 vs. 2.2 ± 0.6;P= .03) and lower serum albumin concentrations (low: 2.8 ± 0.1 vs. normal: 3.3 ± 0.2;P= .02). After transplant, there was a significant reduction in urinary zinc losses in the hypozincemic group followed by normalization of plasma zinc levels by 7 days posttransplant. These data suggest that the abnormal renal zinc homeostasis that is present in approximately 50% of pediatric patients undergoing liver transplant is rapidly improved and biochemical zinc deficiency is reversed after liver transplantation.
Endothelial Cells Lining Transjugular Intrahepatic Portasystemic Shunts Originate in Hepatic Sinusoids: Implications for Pseudointimal Hyperplasia
Authors: Sanyal Arun J. , Mirshahi Faridoddin
Published: July 2004

The phenotype of the endothelial cells (ECs) in the pseudointima of transjugular intrahepatic portasystemic shunts (TIPS) and the mechanisms of pseudointima formation after TIPS were unknown. We hypothesized that TIPS were lined by hepatic sinusoidal ECs, which stimulated the migration of smooth muscle cells (SMCs) into the pseudointima and their proliferation. Studies were done with the following specific aims: (1) isolation of ECs from TIPS pseudointima and comparison of their phenotype with human cirrhotic sinusoidal and vascular ECs derived from hepatic and portal veins as well as aorta, and (2) testing of the effects of TIPS ECs on TIPS–derived SMC migration and proliferation. ECs were isolated from eight TIPS retrieved from liver explants by immunomagnetic separation using monodispersed magnetizable polystyrene beads (Dynabeads M–450) coated with Ulex Europeus 1. EC phenotypes were examined by transmission electron microscopy, factor VIII-related antigen, CD31, CD14, and CD34 expression, uptake of acetylated LDL and secretion of type IV collagen. The effects of EC–conditioned media on SMC migration and proliferation were tested in multiwell chemotaxis chambers and by cell counting, respectively. ECs were obtained from TIPS pseudointima with >95% purity. The phenotype of TIPS–derived ECs matched that of cirrhotic sinusoidal endothelium (both expressed CD14) and differed from that of vascular endothelium (CD14 negative, Weibel–Palade positive). Conditioned media from both stenosed (n = 3) and nonstenosed (n = 3) TIPS–derived endothelial cells produced a marked (>100%) P < .001 increase in migration as well as (up to 88%) P < .01 proliferation of SMCs from both stenosed (n = 3) as well as nonstenosed TIPS (n = 3). These data indicate that TIPS pseudointima are lined by hepatic sinusoidal endothelial cells, which stimulate pseudointima formation by increasing SMC migration and proliferation.
Inhibition of Macrophages With Gadolinium Chloride Alters Intercellular Adhesion Molecule–1 Expression in the Liver During Acute Endotoxemia in Rats
Authors: Ahmad Nosheen , Gardner Carol R. , Yurkow Edward J. , Laskin Debra L.
Published: July 2004

Cell adhesion molecules are important for localized accumulation of phagocytes at sites of tissue damage. In the present studies, we analyzed the effects of blocking hepatic macrophages on expression of β2 integrins and intercellular adhesion molecule–1 (ICAM–1) adhesion molecules on liver cells during acute endotoxemia. Flow cytometric analysis revealed distinct subpopulations of macrophages from control animals that varied on the basis of their size and density. In contrast, hepatocytes and endothelial cells were relatively homogeneous. Treatment of rats with endotoxin (5 mg/kg, intravenously) resulted in a time–dependent increase in the percentage of small, dense macrophages and a progressive loss of larger, less–dense cells. In contrast, no major effects were observed on the physical properties of hepatocytes or endothelial cells. ICAM–1 was found to be constitutively expressed on endothelial cells and hepatocytes, as well as on macrophages. Induction of acute endotoxemia resulted in a time–dependent increase in ICAM–1 expression on hepatocytes, which was observed within 3 hours and reached a maximum after 24 hours. An increase in ICAM–1 expression was also observed on endothelial cells and on macrophages at 3 hours, followed by a decrease at 24 to 48 hours. Macrophages and endothelial cells also constitutively expressed β2 integrins. Induction of acute endotoxemia had no effect on β2 integrin expression by these cells. Pretreatment of rats with gadolinium chloride (GdCl3 ), a macrophage inhibitor known to block endotoxin–induced liver injury, abrogated the effects of endotoxin on ICAM–1 expression by hepatocytes and macrophages. In contrast, ICAM–1 expression on endothelial cells increased. Interestingly, treatment of rats with GdCl3 alone resulted in a marked increase in expression of ICAM–1 on endothelial cells and hepatocytes, and of β2 inteegrins on macrophages and endothelial cells. Taken together, these data suggest that ICAM–1 is involved in mediating macrophage adherence and accumulation in the liver during endotoxemia. Furthermore, macrophages appear to regulate expression of this cell adhesion molecule on parenchymal cells.
Carbohydrate–Deficient Transferrin, A Sensitive Marker of Chronic Alcohol Abuse, Is Highly Influenced by Body Iron
Authors: De Feo Tullia Maria , Fargion Silvia , Duca Lorena , Mattioli Michela , Cappellini Maria Domenica , Sampietro Maurizio , Cesana Bruno Mario , Fiorelli Gemino
Published: July 2004

Carbohydrate–deficient transferrin(CDT) a microheterogeneous form of serum transferrin (Tf) has been proposed as the most reliable marker of chronic alcohol consumption, although unexplained false–positive and –negative results have been reported.We investigated whether body iron influenced CDT serum levels by studying alcohol abusers with or without iron overload and nonabusers with iron deficiency or iron overload caused by genetic hemochromatosis (GH).In alcohol abusers, CDT was significantly lower in the presence of iron overload than in the absence (24.6 ±16.5 U/L vs.33.3 ±11.7 U/L; P<.01) with false–negative results almost exclusively in patients with iron overload. Similarly, in nonabusers with GH, CDT was lower than in normal controls (9.6±2.2 U/L vs.15.7 ± 3.3 U/L;P<.0001) whereas, patients with iron deficiency anemia had significantly higher levels than controls (28.1±5.8 U/L vs.15.7±3.3 U/L;P<.0001).In nonabusers, iron supplementation therapy significantly decreased CDT levels in patients with iron deficiency anemia (33.7±6.6 U/L vs.21.7± 5.2 U/L;P=.0007) while iron–depletion treatment significantly increased CDT levels in patients with GH (9.7 ± 2.0 U/L vs. 14.7 ± 4.0 U/L;P=.001).Alcohol abusers had a significant relationship between liver iron concentration (LIC)and the reciprocal of CDT (r=.65;P <.0001) while in nonabusers, there was a significant correlation between Tf and CDT (r=.72;P<.0001).In conclusion, CDT serum levels are markedly affected by the patient's iron status, with iron overload reducing its sensitivity in alcohol abusers and iron deficiency its specificity in nonabusers. CDT can be considered a reliable marker of alcohol abuse only when iron stores are normal.
A Histone Deacetylase Inhibitor, Trichostatin A, Suppresses Myofibroblastic Differentiation of Rat Hepatic Stellate Cells in Primary Culture
Authors: Niki Toshiro , Rombouts Krista , De Bleser Pieter , De Smet Karen , Rogiers Vera , Schuppan Detlef , Yoshida Minoru , Gabbiani Giulio , Geerts Albert
Published: July 2004

Hepatic stellate cells are the major cellular sources of extracellular matrix in chronic liver diseases leading to fibrosis. We explored the antifibrogenic effect of two histone deacetylase inhibitors, sodium butyrate and trichostatin A (TSA), on this cell typein vitro.Primary hepatic stellate cells as well as culture activated cells were exposed to butyrate (0.01–1 mmol/L) or TSA (1–100 nmol7sol;L); their effect on collagen types I and III and smooth muscle α–actin was examined by quantitative immunoprecipitation and by Northern analysis. Their antiproliferative effect was examined by3H–thymidine incorporation and cell counting. Hyperacetylation of histones was demonstrated by acid urea/Triton–X–100 (AUT) polyacrylamide gel electrophoresis. Possible cytotoxic effects were judged on stellate cells by evaluatingde novototal protein synthesis, and on hepatocytes by measuring lactate dehydrogenase (LDH) leakage, albumin secretion, and epoxide hydrolase and ethoxycoumarinO–deethylase activity. TSA at 100 nmol/L and butyrate at 1 mmol/L retarded the morphological changes characteristic for activation of primary stellate cells. TSA at 100 nmol/ inhibited synthesis of collagen types I and III and smooth muscle α–actin by 62%, 70%, and 88%. Butyrate at 1 mmol/L showed a modest inhibitory effect on collagen type III and smooth muscle α–actin, but had no effect on collagen type I. Northern analysis suggested that these inhibitory effects on collagen type III and smooth muscle α–actin were transcriptional, while the effect on collagen type I was largely posttranscriptional. At 100 nmol/L, TSA strongly suppressed proliferation of primary hepatic stellate cells. Inhibition of activation of stellate cells was preceded by hyperacetylation of histone H4. When tested on cells at day 14 in culture, butyrate had no inhibitory effects on the synthesis of collagens or smooth muscle α–actin. One hundred or 10 nmol/L TSA modestly inhibited the synthesis of collagens type I (-24%,-22%) and III (-34%,-22%), and smooth muscle α–actin (-27%,-12%). We conclude that TSA inhibits transdifferentiation of stellate cells into myofibroblasts by interfering with the level of acetylation of histone H4.
A P53 Genetic Polymorphism As A Modulator of Hepatocellular Carcinoma Risk in Relation to Chronic Liver Disease, Familial Tendency, and Cigarette Smoking in Hepatitis B Carriers
Authors: Yu Ming-Whei , Yang Shi-Yi , Chiu Yueh-Hsia , Chiang Yi-Ching , Liaw Yun-Fan , Chen Chien-Jen
Published: July 2004

This study evaluated whether the codon 72 p53 polymorphism was related to hepatocellular carcinoma (HCC). Genotypes of p53 were determined in 80 incident cases of HCC and 328 controls nested in a cohort study of 4,841 male chronic hepatitis B carriers. No overall increase in HCC risk with the Pro variant allele of the p53 polymorphism was apparent. However, there were synergistic effects on HCC development for the Pro allele with chronic liver disease and family history of HCC in first–degree relatives. Compared with subjects without the Pro allele and chronic liver disease, the increase in HCC risk associated with chronic liver disease among those without the Pro allele was only threefold. Subjects with both chronic liver disease and the Pro allele were at an increased risk of 7.60 (95% CI = 2.28–25.31). When subjects without family history of HCC and the Pro allele were considered as the reference group, there was no apparent increased risk of HCC for those without the Pro allele who had family history of HCC. Among those with both factors, there was a significantly increased risk of 3.29 (95% CI = 1.10–9.85). Both cigarette smoking and glutathione S–transferase M1 genotype modified the risk of HCC associated with the p53 polymorphism. Significantly increased risk associated with the p53 genotype was observed only among smokers who were glutathione S–transferase-null (Pro/Pro vs. Arg/Arg: odds ratio = 6.46; 95% CI = 1.55–26.94). The p53 polymorphism also interacted with the cytochrome P450 1A1 and carotenoid levels in smoking–related hepatocarcinogenesis.
Features of Alagille Syndrome in 92 Patients: Frequency and Relation to Prognosis
Authors: Emerick Karan M. , Rand Elizabeth B. , Goldmuntz Elizabeth , Krantz Ian D. , Spinner Nancy B. , Piccoli David A.
Published: July 2004

We have studied 92 patients with Alagille syndrome (AGS) to determine the frequency of clinical manifestations and to correlate the clinical findings with outcome. Liver biopsy specimens showed paucity of the interlobular ducts in 85% of patients. Cholestasis was seen in 96%, cardiac murmur in 97%, butterfly vertebrae in 51%, posterior embryotoxon in 78%, and characteristic facies in 96% of patients. Renal disease was present in 40% and intracranial bleeding or stroke occurred in 14% of patients. The presence of intracardiac congenital heart disease was the only clinical feature statistically associated with increased mortality (P< .001). Initial measures of hepatic function in infancy including absence of scintiscan excretion were not predictive of risk for transplantation or increased mortality. The hepatic histology of these AGS patients showed a significant increase in the prevalence of bile duct paucity (P= .002) and fibrosis (P< .001) with increasing age. Liver transplantation for hepatic decompensation was necessary in 21% (19 of 92) of patients with 79% survival 1–year posttransplantation. Current mortality is 17% (16 of 92). The factors that contributed significantly to mortality were complex congenital heart disease (15%), intracranial bleeding (25%), and hepatic disease or hepatic transplantation (25%). The 20–year predicted life expectancy is 75% for all patients, 80% for those not requiring liver transplantation, and 60% for those who required liver transplantation.
Elevated Circulating Cardiac Troponin I in Patients With Cirrhosis
Authors: Pateron Dominique , Beyne Pascale , Laperche Thierry , Logeard Damien , Lefilliatre Pascale , Sogni Philippe , Moreau Richard , Langlet Philippe , Elman Annie , Bernuau Jacques , Valla Dominique , Erlinger Serge , Lebrec Didier
Published: July 2004

It has been shown that certain patients with cirrhosis have asymptomatic cardiac abnormalities that have not yet been explained. Thus, cardiac troponin I, a specific marker of myocardial injury, has been measured in patients with cirrhosis without previous cardiac disease. Thirty–two consecutive patients (age 49 ± 11) with cirrhosis and normal ECG were selected, 22 of which were alcoholic. Hemodynamic investigations were performed. Left ventricular function and mass were evaluated by echocardiography. Serum creatine kinase MB mass, myoglobin, and cardiac troponin I concentrations were measured. Cardiac troponin I concentrations were elevated in 10 patients (32%) (range 0.06–0.25 μg/L) whereas creatine kinase MB mass and myoglobin were normal in all patients. Abnormal troponin I values were not related to the severity of cirrhosis, to the degree of portal hypertension, or to other hemodynamic values. In contrast, elevated serum cardiac troponin I concentrations were related to a decreased stroke–volume index (P < .05) and a decreased left ventricular mass (P < .05). These results show a high prevalence of slightly elevated serum cardiac troponin I in patients with cirrhosis, especially in those with alcoholic cirrhosis. Elevated troponin I is associated with subclinical left ventricular myocardial damage. These findings may be linked to a lack of left ventricular adaptation in certain patients with cirrhosis and alcoholic cardiomyopathy.
Control of the Tissue Inhibitor of Metalloproteinases–1 Promoter in Culture–Activated Rat Hepatic Stellate Cells: Regulation by Activator Protein–1 Dna Binding Proteins
Authors: Bahr Matthias J. , Vincent Karen J. , Arthur Michael J.P. , Fowler Andrew V. , Smart David E. , Wright Matthew C. , Clark Ian M. , Benyon Christopher R. , Iredale John P. , Mann Derek A.
Published: July 2004

In the injured liver hepatic stellate cells (HSCs) undergo a dramatic phenotypic transformation known as “activation” in which they become myofibroblast–like and express high levels of the tissue inhibitor of metalloproteinase 1 (TIMP–1). HSC activation is accompanied by transactivation of the TIMP–1 promoter. Truncation mutagenesis studies delineated a minimal active promoter consisting of nucleotides -102 to +60 relative to the major start site for transcription. Removal of an AP–1 site located at nucleotides -93 to -87 caused almost a complete loss of promoter activity. Analysis of AP–1 DNA binding activities during culture activation of HSCs initially indicated transient expression of proteins capable of forming a low mobility AP–1 DNA binding complex (lmAP–1). lmAP–1 was maximally induced at 24 hours of culture and then fell to undetectable levels at 120 hours. Western blot studies showed that both c–Fos and c–Jun underwent similar transient inductions. These temporal changes in c–Fos and c–Jun activities were unexpected because TIMP–1 mRNA expression is not detected in HSCs until culture day 3 to 5 and is thereafter sustained at a high level. Previous work in other cell lineages has established a key role for Pea3 binding proteins (Ets–1) in AP–1 mediated transactivation of the TIMP–1 promoter. We show that HSCs express relatively low levels Ets–1 and Ets–2 and show that mutagenesis of the Pea3 DNA binding site in the TIMP–1 promoter has less than a twofold effect on its activity in activated HSCs. Further analysis of AP–1 DNA binding activities in 7– to 14–day culture activated HSCs led to the discovery of high mobility AP–1 complexes (hmAP–1). hmAP–1 DNA binding activities were sequence specific with respect to AP–1 and absent from freshly isolated HSCs. Supershift EMSA and Western blot studies identified JunD, Fra2, and FosB as potential components of the HMAP–1. Mutations of the AP–1 site of the TIMP–1 promoter that prevented formation of hmAP–1 caused a 70% loss of activity in transfected activated HSCs. Taken together the data indicate that sustained upregulation of TIMP–1 gene expression may be at least partially controlled by a novel AP–1 dependent regulation of TIMP–1 promoter activity.