bluuebunny/crossref_metadata_2025 huggingface dataset:
A longitudinal study of Alzheimer's disease: rates of cognitive and functional decline
Authors: Suh Guk‐Hee , Ju Young‐Su , Yeon Byeong Kil , Shah Ajit
Published: July 2004

Objective

To measure rates of decline in cognition and function in patients with Alzheimer's disease (AD) and to investigate their accelerating risk factors in Korea.

Methods

This study presents longitudinal data on a community‐based sample of 107 patients with AD, followed at 6 months and 12 months. The cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS‐cog), the Mini Mental State Examination (MMSE) and the Disability Assessment for Dementia Scale (DAD) were given. Mixed model analyses were conducted using the following independent variables: times of repeated assessment (0, 6 or 12 months), severity of dementia assessed by the Functional Assessment Staging (FAST) and individual indicators as covariates.

Results

Average annual rates of decline in the MMSE, the ADAS‐cog and the DAD were 2.3, 11.4 and 15.1 points, respectively. Neither gender, duration of formal education, nor duration of AD since onset was significant predictors of cognitive and functional decline. Patterns of functional decline in total DAD, instrumental ADLs, planning and organization and performance subscale are linear as MMSE score declines, while those of the basic ADLs and the initiation are curvilinear.

Conclusion

This naturalistic observational study measured rates of cognitive and functional decline in AD, and can provide reference data for further longitudinal studies or clinical trials. Further study will be necessary to determine whether linear or curvilinear pattern in functional decline is due to progression of AD itself or statistical artifact. Copyright © 2004 John Wiley & Sons, Ltd.
Telephone word‐list recall tested in the rural aging and memory study: two parallel versions for the TICS‐M
Authors: Hogervorst Eva , Bandelow Stephan , Hart John , Henderson Victor W.
Published: July 2004

Background

Parallel versions of memory tasks are useful in clinical and research settings to reduce practice effects engendered by multiple administrations. We aimed to investigate the usefulness of three parallel versions of ten‐item word list recall tasks administered by telephone.

Methods

A population based telephone survey of middle‐aged and elderly residents of Bradley County, Arkansas was carried out as part of the Rural Aging and Memory Study (RAMS). Participants in the study were 1845 persons aged 40 to 95 years. Word lists included that used in the telephone interview of cognitive status (TICS) as a criterion standard and two newly developed lists.

Results

The mean age of participants was 61.05 (SD 12.44) years; 39.5% were over age 65. 78% of the participants had completed high school, 66% were women and 21% were African‐American. There was no difference in demographic characteristics between groups receiving different word list versions, and performances on the three versions were equivalent for both immediate (mean 4.22, SD 1.53) and delayed (mean 2.35 SD 1.75) recall trials. The total memory score (immediate+delayed recall) was negatively associated with older age (beta = −0.41, 95%CI=−0.11 to −0.04), lower education (beta = 0.24, 95%CI = 0.36 to 0.51), male gender (beta = −0.18, 95%CI = −1.39 to −0.90) and African‐American race (beta = −0.15, 95%CI = −1.41 to −0.82).

Conclusions

The two RAMS word recall lists and the TICS word recall list can be used interchangeably in telephone assessment of memory of middle‐aged and elderly persons. This finding is important for future studies where parallel versions of a word‐list memory task are needed. (250 words). Copyright © 2004 John Wiley & Sons, Ltd.
Assessment of agitation in elderly patients with dementia: correlations between informant rating and direct observation
Authors: Cohen‐Mansfield Jiska , Libin Alexander
Published: July 2004

Background

Assessment of behavior problems in elderly persons with dementia is important for understanding and managing those behaviors. The most common method for assessing agitation is the use of informant ratings; however, these ratings may be affected by staff bias, inaccurate or insufficient memory, or stress. An alternative method is direct observation, which is more objective, but very costly and necessitates time sampling, thereby limiting the period covered by the assessment. To date, little research attention has been given to the degree to which these two methods converge.

Methods

In the present study, 175 elderly persons with dementia who manifested problem behaviors were recruited from 11 nursing home facilities in Maryland. The average age for the participants was 87 years; 78% were female. Two methods were employed for assessing agitation: the Agitated Behaviors Mapping Instrument (ABMI), which is based upon direct observations, and the Cohen‐Mansfield Agitation Inventory (CMAI), which is a frequency rating scale completed by a formal caregiver. The ABMI and CMAI contain some identical items for tapping behavior problems.

Results

Data analysis revealed significant Pearson correlations between identical items on the two assessment instruments, as well as significant correlations of summary measures based on these different instruments, demonstrating a strong convergence between informant ratings and direct observations.

Conclusions

Informant ratings can achieve moderate agreement with direct observation when valid instruments and informants are used. Copyright © 2004 John Wiley & Sons, Ltd.
Lifetime urban/rural residence, social support and late‐life depression in Korea
Authors: Kim Jae‐Min , Stewart Robert , Shin Il‐Seon , Yoon Jin‐Sang , Lee Hyung‐Yung
Published: July 2004

Background

Population ageing and rural–urban migration are accelerating in many non‐Western nations. This study aimed to investigate: (i) the association between lifetime urban/rural residence and late‐life depression in Korea and (ii) modification of associations between depression and social support by lifetime residence.

Methods

1204 urban/rural residents aged 65+were interviewed and GMS‐AGECAT diagnoses made. Previous areas of residence were recorded and social support deficits quantified.

Results

Depression was present in 9% and 21% of the rural and urban samples respectively. For the urban sample, depression was not associated with earlier urban/rural residence. Social support deficits were most strongly associated with depression in people with a lifetime rural residence, followed by urban residents with a rural birthplace.

Conclusions

Prevalence rates of depression were increased in the urban sample regardless of previous urban/rural residence. Reduced social support was particularly strongly associated with depression in people with a rural upbringing. Copyright © 2004 John Wiley & Sons, Ltd.
Efficacy and safety of long‐acting risperidone in elderly patients with schizophrenia and schizoaffective disorder
Authors: Lasser Robert A. , Bossie Cynthia A. , Zhu Young , Gharabawi Georges , Eerdekens Mariëlle , Davidson Michael
Published: July 2004

Background

Elderly patients are often an underserved population in terms of optimizing treatment outcomes. Long‐acting risperidone, the first long‐acting injectable atypical antipsychotic, can improve outcomes through continuous medication delivery.

Objective

To assess the efficacy and safety of long‐acting injectable risperidone in elderly patients with psychotic disorders.

Methods

This is a subanalysis of 57 patients aged ≥65 years enrolled in an open‐label study of long‐acting risperidone that included 725 symptomatically stable patients with schizophrenia or schizoaffective disorder. Patients were assigned to receive 25, 50, or 75 mg of long‐acting risperidone every 2 weeks for up to 50 weeks.

Results

Fifty‐seven elderly patients (mean ± SE age, 70.9 ± 0.7 years) were enrolled. Mean Positive and Negative Syndrome Scale (PANSS) total scores improved significantly throughout the study and at endpoint (p < 0.001). The PANSS factor scores (positive symptoms, negative symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression) also significantly improved (p < 0.01). Clinical improvement (≥20% reduction in PANSS total scores) was achieved by 49% of these stable patients, and 55% improved on the Clinical Global Impressions scale. Severity of movement disorders (Extrapyramidal Symptom Rating Scale scores) was reduced significantly. Adverse events reported in >10% of patients were insomnia (14%), constipation (12%), and bronchitis (12%).

Conclusions

Long‐acting risperidone was associated with significant symptom improvements in stable elderly patients with schizophrenia or schizoaffective disorder. Treatment was well tolerated. Copyright © 2004 John Wiley & Sons, Ltd.
Relationship of the Genomic Complexity of Hepatitis C Virus With Liver Disease Severity and Response to Interferon in Patients With Chronic Hcv Genotype 1B Interferon
Authors: López-Labrador Francesc-Xavier , Ampurdanès Sergi , Giménez-Barcons Mireia , Guilera Magdalena , Costa Josep , Jiménez de Anta María Teresa , Sánchez-Tapias Jose M. , Rodés Juan , Sáiz Juan-Carlos
Published: July 2004

In patients with chronic hepatitis C, the influence of the genetic heterogeneity of the hepatitis C virus (HCV) on the progression of liver disease and on the responsiveness to interferon therapy is a matter of controversy. In this study we evaluated the genetic complexity of HCV by single–strand conformation polymorphism (SSCP) analysis of amplicons from the hypervariable region 1 (HVR1) in 168 patients with chronic genotype 1b HCV infection, of whom 122 received a single course of interferon therapy (3 MU, three times weekly for 6 months). No correlation was observed between the degree of genetic complexity of HCV (indicated by the number of bands in the SSCP assay) and patient age, serum alanine aminotransferase activity, or serum HCV–RNA concentration, measured by competitive polymerase chain reaction. HCV genomic complexity was not related to gender nor to the presumed source of infection. The number of SSCP bands detected in serum samples from patients with chronic hepatitis, either mild (8.1 ± 3.9), moderate (8.0 ± 3.3), or severe (9.2 ± 3.3), and in patients with liver cirrhosis, either compensated (8.0 ± 2.9), decompensated (6.3 ± 2.9), or with superimposed hepatocellular carcinoma (9.5 ± 2.9), was similar. The number of SSCP bands detected in patients with sustained response (7.5 ± 3.9), transient response (8.3 ± 2.9), or no response (8.2 ± 3.6) to interferon administration was similar as well. These observations suggest that the genetic complexity of hypervariable region (HVR1) of HCV, as estimated by SSCP analysis, is not related to the severity of liver injury nor to the type of response to interferon therapy. Thus, information offered by SSCP analysis of HVR1 of HCV in chronic HCV genotype 1b infection does not appear to be useful in the clinical management of these patients.
Chronic Liver Disease in Central Harlem: the Role of Alcohol and Viral Hepatitis
Authors: Frieden Thomas R. , Ozick Lisa , McCord Colin , Nainan Omana V. , Workman Sara , Comer Gail , Lee Tai Ping , Byun Kwan-Soo , Patel Dhiren , Henning Kelly J.
Published: July 2004

For reasons not yet determined, chronic liver disease (CLD) has been a leading cause of excess morbidity and mortality in central Harlem. We conducted a case series and case–control analysis of demographic, clinical, epidemiological, and alcohol–intake-related information from patients with CLD and age– and sex–matched hospitalized control patients. Patients' sera were tested for markers of viral hepatitis. The presumed etiology of CLD among case–patients was as follows: both alcohol abuse and hepatitis C virus (HCV) infection, 24 persons (46% of case–patients); alcohol abuse alone, 15 (29%); HCV infection alone, 6 (12%); both alcohol abuse and chronic hepatitis B virus (HBV) infection, 3 (6%); and 1 each (2%) from: 1) schistosomiasis, 2) sarcoidosis, 3) unknown causes, and 4) alcohol abuse, chronic HBV, and HCV combined. In the case–control analysis, patients who had both alcoholism and either HBV (odds ratio [OR]: 6.3; 95% CI: 0.5–334) or HCV (OR: 2.9; 95% CI: 1.3–6.2) were at increased risk for CLD, whereas patients who had only one of these three factors were not at increased risk for CLD. Patients who tested positive for the hepatitis G virus (HGV) did not have a significantly increased risk of CLD, and neither severity of CLD nor mortality was greater among these patients. Most patients in central Harlem who had CLD had liver damage from a combination of alcohol abuse and chronic viral hepatitis. Alcohol and hepatitis viruses appear to be synergistically hepatotoxic; this synergy appears to explain both the high rate of CLD in central Harlem and the recent reductions in this rate. Persons at risk for chronic HBV and HCV infection should be counseled about their increased risk of CLD if they consume excessive alcohol. Morbidity and mortality from liver disease could be decreased further by a reduction in alcohol consumption among persons who have chronic HBV and HCV infection, avoidance of needle sharing, and hepatitis B vaccination.
Cerebral Herniation in Patients With Acute E Liver Failure Is Correlated With Arterial Ammonia Concentration
Authors: Clemmesen Jens Otto , Larsen Fin Stolze , Kondrup Jens , Hansen Bent Adel , Ott Peter
Published: July 2004

Cerebral edema leading to cerebral herniation (CH) is a common cause of death in acute liver failure (ALF). Animal studies have related ammonia with this complication. During liver failure, hepatic ammonia removal can be expected to determine the arterial ammonia level. In patients with ALF, we examined the hypotheses that high arterial ammonia is related to later death by CH, and that impaired removal in the hepatic circulation is related to high arterial ammonia. Twenty–two patients with ALF were studied retrospectively. In addition, prospective studies with liver vein catheterization were performed after development of hepatic encephalopathy (HE) in 22 patients with ALF and 9 with acute on chronic liver disease (AOCLD). Cerebral arterial–venous ammonia difference was studied in 13 patients with ALF. In all patients with ALF (n= 44), those who developed CH (n = 14) had higher arterial plasma ammonia than the non–CH (n = 30) patients (230 ± 58 vs. 118 ± 48 μmol/L; P< .001). In contrast, galactose elimination capacity, bilirubin, creatinine, and prothrombin time were not different (NS). Cerebral arterial–venous differences increased with increasing arterial ammonia (P < 001). Arterial plasma ammonia was lower than hepatic venous in ALF (148 ± 73 vs. 203 ± 108 μmol/L; P < .001). In contrast, arterial plasma ammonia was higher than hepatic venous in patients with AOCLD (91 ± 26 vs. 66 ± 18 μmol/L; P < .05). Net ammonia release from the hepatic–splanchnic region was 6.5 ± 6.4 mmol/h in ALF, and arterial ammonia increased with increasing release. In contrast, there was a net hepatic–splanchnic removal of ammonia (2.8 ± 3.3 mmol/h) in patients with AOCLD. We interpret these data that in ALF in humans, vast amounts of ammonia escape hepatic metabolism, leading to high arterial ammonia concentrations, which in turn is associated with increased cerebral ammonia uptake and CH.
Persistence of Viremia and the Importance of Long–Term Follow–Up After Acute Hepatitis C Infection
Authors: Villano Stephen A. , Vlahov David , Nelson Kenrad E. , Cohn Sylvia , Thomas David L.
Published: July 2004

The purpose of this investigation was to prospectively characterize acute hepatitis C virus (HCV) infections and to evaluate the hypothesis that the outcome is affected by identifiable clinical or viral factors. One hundred forty–two people with a history of illicit drug use who were HCV antibody-negative in 1988 were followed semiannually through 1996. HCV seroconversion (second generation enzyme immunoassay and recombinant immunoblot assay) was recognized in 43 (30%) of the participants, who were followed up for a median of 72 months. HCV RNA was detected and quantified by polymerase chain reaction in a median of 10 specimens per participant and showed two distinct patterns of viremia: viral clearance was noted in 6 (14%) of the participants, and viral persistence was observed in 37 (86%) of the participants. Subjects with viral clearance were more likely to be white (P = .004), have jaundice (P = .03), and have lower peak viral titer (P = .003). However, the outcome for a given person could not be predicted by clinical features, RNA level, or HCV subtype (as ascertained by analysis of core–E1 complementary DNA sequence). No acute infections were recognized by health care providers. At the time of seroconversion, HCV RNA was detectable in 81% of participants, and recombinant immunoblot assay (RIBA) was positive in 85% of participants. We conclude that approximately 85% of people with acute hepatitis C develop persistent viremia. However, acute infections are uncommonly recognized clinically, underscoring the importance of screening individuals at risk. Long–term follow–up, but no single laboratory test, is necessary to ascertain the outcome and in some cases make the diagnosis of acute HCV infection.
Long–Term Beneficial Effect of Interferon Therapy in Patients With Chronic Hepatitis B Virus Infection
Authors: Lin Shi-Ming , Sheen I-Shyan , Chien Rong-Nan , Chu Chia-Ming , Liaw Yun-Fan
Published: July 2004

To examine the long–term effect of interferon (IFN) therapy in patients with chronic hepatitis B virus (HBV) infection, particularly on survival and hepatocellular carcinoma (HCC) prevention, 101 male patients with chronic hepatitis B in a randomized controlled trial were followed up for 1.1 to 11.5 years after the end of therapy. Of the 101 patients, 34 patients received a placebo (control), and 67 patients were treated with IFN (31 patients were treated with IFN alone and 36 patients were treated with IFN after prednisolone priming). Follow–up studies included clinical, biochemical, and virological aspects and HCC screening every 3 to 6 months. Twenty–eight (42%) of the 67 IFN–treated patients and 8 (24%) of the 34 untreated patients seroconverted by the end of the trial. During follow–up, 22 (56%) of the 39 patients who did not seroconvert in the treated group and 5 (19%) of the 26 patients who did not seroconvert in the control group showed a delayed sustained response (P< .005). The cumulative incidence of sustained response was highest in the steroid priming group (P= .049 vs. the IFN-alone group;P= .028 vs. the control group). HCC was detected in 1 (1.5%) of the 67 treated patients and 4 (12%) of the 34 untreated patients (P= .043). The interval between entry and HCC detection was 3.5 to 8.2 years. The cumulative incidence of HCC development was significantly higher in the control group than in the treated group (P= .013). In contrast, the cumulative survival rate was higher in the treated group than the control group (P= .018). Multivariate analysis showed that IFN therapy, preexisting cirrhosis, and the patient's age at entry are significant independent factors for both survival and HCC development. The results suggest that IFN has long–term beneficial effects in terms of HBV clearance, reduction of HCC, and prolonging survival.
Hepatoprotective Effect of Endogenous Nitric Oxide During Ischemia–Reperfusion in the Rat
Authors: Cottart Charles-Henry , Do Louis , Blanc Marie-Céline , Vaubourdolle Michel , Descamps Geneviève , Durand Dominique , Galen François-Xavier , Clot Jean-Pierre
Published: July 2004

The aim of this study was to evaluate the protective or deleterious effects of endogenous nitric oxide (NO) on liver cells during hepatic ischemia–reperfusion (IR) in the rat. Injury to hepatocytes and endothelial cells was evaluated by determining cytolysis–marker activity in plasma (alanine transaminase [ALT]; aspartate transaminase [AST]) and plasma hyaluronic acid (HA) concentration. Clamping the hepatic pedicle for 45 minutes caused a significant increase in plasma AST and ALT activity after 30 minutes of reperfusion, which reached a maximum (+270% and +740%, respectively) after 6 hours of reperfusion. Plasma HA concentration was significantly higher (+130%) only after 6 hours of reperfusion. Administration of a nonselective NO synthase (NOS) inhibitor, Nω–nitro–L–arginine (L–NNA; 10 mg/kg iv), 30 minutes before IR, caused marked aggravation of postischemic liver injury, as shown by plasma ALT and AST activity and HA concentration. This deleterious effect was partially prevented by the simultaneous injection of L–arginine, the endogenous NO precursor (100 mg/kg iv). Interestingly, L–arginine alone limited postischemic damage (AST, -25%; ALT, -45%; HA, -21% vs. untreated IR rats at 6 hours reperfusion). Pretreatment with the Guanosine 3′:5′–cyclic monophosphate–independent vasodilator, prazosin, partially reversed L–NNA effects, but it did not protect untreated IR animals. Pretreatment with aminoguanidine, a selective inhibitor of inducible NOS, did not aggravate hepatic IR injury. Thus, endogenous NO, probably produced by an early and transient activation of a constitutive NOS, protects both hepatocytes and endothelial cells against liver ischemia-reperfusion injury, and this effect is not entirely a result of vasorelaxation.
Chronic Unexplained Hypertransaminasemia May Be Caused by Occult Celiac Disease
Authors: Bardella Maria Teresa , Vecchi Maurizio , Conte Dario , Del Ninno Ersilio , Fraquelli Mirella , Pacchetti Stefania , Minola Eliseo , Landoni Marina , Cesana Bruno Mario , De Franchis Roberto
Published: July 2004

In a subset of patients attending liver units, a chronic increase in serum transaminases may remain of undetermined cause despite thorough investigations. On the other hand, elevated levels of serum transaminases have been reported in about 40% of adult celiac patients. To evaluate the prevalence of subclinical celiac disease in patients with chronic unexplained hypertransaminasemia in comparison with that in the general population (0.5%), 140 consecutive patients with chronic increases of serum transaminases levels of unknown cause were tested for antigliadin and antiendomysium IgA antibodies. All patients with positive antibody tests were offered upper gastrointestinal endoscopy with distal duodenal biopsy. Thirteen patients (9.3%, 95% confidence interval 5.0–15.4) had positive antigliadin and antiendomysium antibodies. The prevalence of antibodies was 17% in women and 5.4% in men (8/47 vs. 5/93 respectively; relative risk 3.2, 95% confidence interval 1.1–9.1). Distal duodenal biopsy performed in all but one of the patients showed mild villous atrophy with increased intraepithelial lymphocytes in three cases, subtotal villous atrophy in six, and total villous atrophy in three. The prevalence of celiac disease in the patient group was significantly higher than that in the general population (P< .001) with a relative risk of 18.6 (95% confidence interval 11.1-31.2). On the basis of the present findings, screening for celiac disease is an important tool in the initial diagnostic work–up of patients with chronic unexplained hypertransaminasemia.
Changes in the Localization of the Rat Canalicular Conjugate Export Pump Mrp2 in Phalloidin–Induced Cholestasis
Authors: Rost Daniel , Kartenbeck Jürgen , Keppler Dietrich
Published: July 2004

Administration of phalloidin, one of the toxic peptides of the mushroom Amanita phalloides, leads to rapid and sustained cholestasis in rats. Although attributed to the interaction of phalloidin with microfilaments, the events leading to cholestasis are incompletely understood. The adenosine triphosphate (ATP)–dependent, apical conjugate export pump, termed multidrug resistance protein 2 (Mrp2) or canalicular multispecific organic anion transporter, is the major driving force for bile salt–independent bile flow. We investigated the role of Mrp2 in phalloidin–induced cholestasis. Bile flow decreased to 53% and 31% of control at 15 and 30 minutes after phalloidin (0.5 mg/kg), respectively. Mrp2–mediated [3H]leukotriene excretion into bile during the initial 45 minutes was reduced to 44% of control when [3H]LTC4 was injected 15 minutes after phalloidin treatment. Mrp2 was progressively lost from the hepatocyte canalicular membrane and detected predominantly on intracellular membrane structures together with other canalicular proteins including P–glycoproteins, ecto–ATPase, and dipeptidyl–peptidase IV. By contrast, structures involved in intercellular adhesion (zonula occludens, zonula adhaerens, and desmosomes) as well as intermediate filaments of the cytokeratin type appeared largely unaffected within 30 minutes after phalloidin. In line with the immunofluorescence analysis, immunoblots indicated a loss of Mrp2 and P–glycoproteins from the canalicular membrane and a 3– and 4.6–fold increase of these transport proteins in the microsomal fraction, respectively. Our results indicate that phalloidin induces marked alterations of the hepatocyte canalicular architecture and a loss of Mrp2 together with other proteins from the canalicular membrane. The resulting cholestasis can therefore be explained in part by the loss of export pumps, including Mrp2, from the canalicular membrane.
Tumor Necrosis Factor Increases Mitochondrial Oxidant Production and Induces Expression of Uncoupling Protein–2 in the Regenerating Rat Liver
Authors: Lee Janet F.Y. , Li Yunbo , Zhu Hong , Yang ShiQi , Lin Hui Zhi , Trush Michael , Diehl Anna Mae
Published: July 2004

The growth–stimulatory actions of tumor necrosis factor α (TNF–α) after partial hepatectomy (PH) are difficult to reconcile with its well–established role in the genesis of liver injury. The lethal actions of TNF are thought to involve the induction of oxidant production by mitochondria. It is not known if TNF initiates mitochondrial oxidant production after PH. Furthermore, if this potentially toxic response follows PH, it is not clear how hepatocytes defend themselves sufficiently so that replication, rather than death, occurs. These studies test the hypothesis that TNF does increase mitochondrial oxidant production after PH but that these oxidants primarily promote the induction of antioxidant defenses in regenerating hepatocytes. Consistent with this concept, H2O2production by liver mitochondria increases from 5 minutes to 3 hours after PH, beginning before the transient inductions of hepatic NF kB activity (which peaks at 30 minutes post–PH) and uncoupling protein–2 (UCP–2) (which begins around 30 minutes and peaks from 6–24 hours post–PH). Pretreatment with neutralizing anti–TNF antibodies, which inhibits hepatocyte DNA synthesis after PH, also reduces post–PH hepatic mitochondrial oxidant production by 80% and inhibits NF κB activation and UCP–2 induction by 50% and 80%, respectively. In contrast, pretreatment with D609, an agent that inhibits phosphatidylcholine–specific phospholipase C, neither inhibits regenerative induction of mitochondrial oxidant production, UCP–2 expression, nor hepatocyte DNA synthesis, although it inhibits NF κB activation by 50%. Given published evidence that NF κB is antiapoptotic and that UCP–2 may decrease mitochondrial oxidant production in some cells, these results suggest that TNF–dependent increases in oxidant production by liver mitochondria promote the induction of antioxidant defenses in the regenerating liver.
Altered Microtubule–Associated Tau Messenger Rna Isoform Expression in Livers of Griseofulvin– and 3,5–Diethoxycarbonyl–1,4–Dihydrocollidine-Treated Mice
Authors: Kenner Lukas , Zatloukal Kurt , Stumptner Cornelia , Eferl Robert , Denk Helmut
Published: July 2004

Tau proteins belong to the family of microtubule–associated proteins (MAPs), which so far have been mostly detected in neuronal cells. Different domains on the protein serve different functions. By alternative splicing, several mRNAs and tau isoforms are created from one gene, which contain these functionally important domains to various degrees, and thus differ in their microtubule–related properties. In the present article, several novel observations are reported. Tau mRNA and proteins have been identified and further characterized in mouse liver. It is shown on the basis of mRNA determinations that at least three tau isoforms differing particularly with respect to their amino–terminal domains are present in mouse liver. The major and predominant isoform (isoform 1) lacks portions encoded by exons 2 and 3, which are responsible for cross–talk of microtubules with their environment (“projection domain”). Moreover, mRNA encoding tau protein with four repeats of the microtubule binding domain predominate in embryonal as well as adult mouse liver in contrast to brain, in which a shift from the predominant three–repeat isoform to the four–repeat isoform characterizes the transition from the embryonic to the adult stage. Intoxication with griseofulvin (GF) or 3,5–diethoxycarbonyl–1,4–dihydrocollidine (DDC) significantly affects in a reversible manner the levels of tau mRNA as well as isoform ratios in mouse liver, but not in mouse brain. Tau mRNAs are significantly increased in intoxicated mouse livers. Moreover, a shift to isoform 1 lacking exons 2 and 3 occurs. However, the increase in liver tau protein was less than expected from increased mRNA levels, which could be the result of translational or posttranslational regulation. The consequences on microtubular function are as yet unclear, but impairment can be expected because the overexpressed tau mRNA isoform lacks the domain that mediates interaction of microtubules with their environment. On the other hand, the ratio of polymerized (microtubules) to nonpolymerized tubulin remained unaffected.
Twelve–Year Follow–Up of A Prospective Randomized Trial of Hepatitis B Recombinant Dna Yeast Vaccine Versus Plasma–Derived Vaccine Without Booster Doses in Children
Authors: Yuen Man-Fung , Lim Wei-Ling , Cheng Chi-Chung , Lam Shiu-Kam , Lai Ching-Lung
Published: July 2004

A total of 318 children were prospectively randomized in group 1 with two 5–μg doses of recombinant vaccine given at 0 and 1 month; in group 2 with three 5–μg doses of recombinant vaccine given at 0, 1, and 6 months; or in group 3 with three doses of plasma–derived vaccine given at 0, 1, and 6 months. Eleven subjects with a hepatitis B surface antigen antibody (anti–HBs) titer of less than 10 mIU/mL at 12 months were given an extra dose of vaccine and were excluded from analysis. No booster doses were given to any other subjects. All children were followed up yearly for the level of anti–HBs titers and for the detection of hepatitis B infection. At the 12th year of follow–up, there were significantly fewer subjects with anti–HBs of 10 mIU/mL or above in group 1 (60.4%) when compared with group 2 (81.4%; P = .0287) and group 3 (79.0%; P = .0381). The geometric mean titers (GMTs) of subjects of group 1 were significantly lower than those of group 2 and group 3 throughout the 12 years of follow–up. A total of 65 subjects had one or more episodes of anamnestic response. No subject became positive for hepatitis B surface antigen (HBsAg); 2 became positive for hepatitis B core antigen antibody (anti–HBc). In conclusion, the long–term protective immunity was better with three doses of hepatitis B vaccine (either the recombinant or plasma–derived) than with two doses. However, protection from hepatitis B infection could be equally achieved by either two doses or three doses of the vaccine. Booster doses were not necessary, probably because of effective anamnestic response.
Occult Lifelong Persistence of Infectious Hepadnavirus and Residual Liver Inflammation in Woodchucks Convalescent From Acute Viral Hepatitis
Authors: Michalak Tomasz I. , Pardoe Ingrid U. , Coffin Carla S. , Churchill Norma D. , Freake Dion S. , Smith Paula , Trelegan Colleen L.
Published: July 2004

Traces of hepatitis B virus (HBV) genome can persist for years following recovery from hepatitis B. To determine overall duration, molecular characteristics, and pathological implications of this serologically undetectable form of hepadnaviral carriage, we have analyzed the expression of transcriptionally active virus genomes, their infectivity, and examined liver alterations during the natural lifespan of woodchucks convalescent from acute infection with HBV– related woodchuck hepatitis virus (WHV). In this study, we document lifelong persistence of scanty amounts of replicating virus both in the liver and lymphatic system after spontaneous resolution of an episode of experimental hepadnaviral hepatitis. Antibodies to virus nucleocapsid (core) were found to be the most reliable immunovirological marker coexisting with occult infection. In the majority of convalescent woodchucks, serial liver biopsies showed protracted minimal to mild necroinflammation with periods of normal morphology; however, hepatocellular carcinoma (HCC) ultimately developed in 2 of 9 animals studied. Inocula derived from lymphoid cells of convalescent animals induced classical acute hepatitis in virus–naive woodchucks that progressed to chronic hepatitis and HCC in 1 of the animals, demonstrating infectivity and pathogenic competence of the carried virus. Our results reveal that low levels of infectious WHV and residual hepatic inflammation usually continue for life after resolution of hepatitis and that this recovery does not avert HCC development. They also demonstrate that, in addition to the liver, the lymphatic system is the site of the occult lifelong maintenance of replicating hepadnavirus.
Liver–Associated Lymphocytes Expressing Nk1.1 Are Essential for Oral Immune Tolerance Induction in A Murine Model
Authors: Trop Shivti , Samsonov Dimitri , Gotsman Israel , Alper Ruslana , Diment Judith , Ilan Yaron
Published: July 2004

Oral tolerance is the induction of immunological hyporesponsiveness towards orally administered antigens. Tolerance initiation involves induction of anti–inflammatory (Th2) lymphocytes, with downregulation of pro–inflammatory (Th1) lymphocytes. The liver was previously shown to play a critical role in oral tolerance induction. The aim of the present study was to test whether liver–associated-lymphocytes expressing the NK1.1 marker (NK1.1+ LAL) are substantial for induction of oral tolerance in an experimental colitis model. Colitis was induced in C57 mice by intracolonic instillation of trinitrobenzensulfonic acid (TNBS). Mice received five oral doses of colonic proteins extracted from TNBS–colitis colonic wall. Anti–NK1.1 monoclonal antibodies were injected before tolerance induction. Colitis was assessed by standard clinical, macroscopic, and microscopic scores. Serum IFN–γ, TGF–β1, and IL4 levels were measured by enzyme–linked immunosorbent assay. To evaluate the role of NK1.1+ LAL in keeping the balance between immunogenic and tolerogenic subsets of cells, we tested whether peripheral lymphocytes harvested from tolerized and NK1.1–depleted nontolerized mice can adoptively transfer the tolerance into naive irradiated rats. Depletion of NK1.1+ LAL prevented immune tolerance induction in the experimental colitis model. NK1.1+ LAL-depleted nontolerized mice, disclosed severe clinical, macroscopic, and microscopic parameters of colitis. These mice had significantly lower TGF–β1, IL4, and higher IFN–γ serum levels, and their lymphocytes failed to transfer the tolerance into naive animals. In contrast, the feeding of colitis–extracted proteins, without NK1.1+ LAL depletion, markedly alleviated the disease. Tolerized mice had higher IL4 and TGF–β1 and lower IFN–γ serum levels, and adoptive transfer of their suppressor splenocytes markedly alleviated colitis in naive recipients. NK1.1+ LAL plays a critical role in oral tolerance induction. Depletion of this subset of LAL prevents a shift from Th1 to a Th2 type of immune response, hindering the ability to induce immune tolerance.
High Prevalence of 1762T 1764A Mutations in the Basic Core Promoter of Hepatitis B Virus Isolated From Black Africans With Hepatocellular Carcinoma Compared With Asymptomatic Carriers
Authors: Baptista Marina , Kramvis Anna , Kew Michael C.
Published: July 2004

The purpose of this study was to identify mutations in the basic core promoter and enhancer II region of the hepatitis B virus (HBV) that might cause the HBV e antigen (HBeAg)–negative phenotype and contribute to hepatocarcinogenesis in black African carriers of the virus. The basic core promoter/enhancer II overlaps with the X gene. HBV DNA from serum of 47 asymptomatic carriers and 50 patients with hepatocellular carcinoma and from 28 tumor and 10 nontumor liver tissues was amplified and sequenced directly. That part of the enhancer II region not overlapping the basic core promoter was completely conserved in all samples. Missense mutations at nucleotides 1809 and 1812 in the basic core promoter were found in 80% of all sequences and may represent wild–type sequence in Southern African isolates. Nucleotide and amino acid divergences were higher in the basic core promoter of hepatocellular carcinoma patients when compared with asymptomatic carriers (P < .0001). This applied particularly to the paired 1762 adenine to thymine (1762T) and 1764 guanine to adenine (1764A) missense mutations, the prevalence of which was 66% in patients with hepatocellular carcinoma compared with 11% in asymptomatic carriers (P < .0001). There was no association between the presence of 1762T1764A and HBeAg negativity, although these mutations suppressed HBeAg titers in HBeAg–positive patients. Suppression of HBeAg expression as well as alteration of the amino acid sequence of the X protein may play a role in hepatocarcinogenesis.
Hepatitis B Virus X Protein Transactivates the Inducible Nitric Oxide Synthase Promoter
Authors: Amaro Maria José , Bartolomé Javier , Carreño Vicente
Published: July 2004

The capability of hepatitis B virus (HBV) to increase the transcription of the human hepatic inducible nitric oxide synthase (iNOS) by transactivating its promoter has been studied. We have observed by reverse–transcription polymerase chain reaction (RT–PCR) that although the mRNA for the iNOS was almost undetectable in the human hepatoblastoma cell line, HepG2, it was constitutively expressed in the 2.2.15 cell line (a derivative of the HepG2 that produces complete HBV particles). Transfection of HepG2 and 2.2.15 cells with the p1iNOS–CAT plasmid (containing a 1.1–kb fragment of the iNOS promoter) resulted in an increase in chloramphenicol acetyl transferase (CAT) activity in 2.2.15 cells. Similar results were observed when HepG2 and Chang liver cell lines were cotransfected with the p1iNOS–CAT plasmid and the complete HBV genome. It was shown that pX was responsible for the transactivation by cotransfection of HepG2 cells with the p1iNOS–CAT and plasmids expressing the HBV–encoded pX protein, core antigen, and e antigen. Cotransfection of HepG2 cells with the pX expression plasmids and a series of deletion mutants of the 1.1–kb iNOS promoter fragments established that transactivation by pX depends on the presence of at least one nuclear factor–κB (NF–κB) binding site. This was further confirmed by cotransfecting cells with a plasmid expressing the NF–κB inhibitor, IκB.
Ymdd Motif in Hepatitis B Virus Dna Polymerase Influences on Replication and Lamivudine Resistance: A Study By In Vitro Full–Length Viral Dna Transfection
Authors: Ono-Nita Suzane Kioko , Kato Naoya , Shiratori Yasushi , Masaki Tsutomu , Lan Keng-Hsin , Carrilho Flair José , Omata Masao
Published: July 2004

Recently, lamivudine used to treat patients with hepatitis B virus (HBV) infection was revealed to have potent antiviral activity. However, HBV resistance to lamivudine has been reported and shown to have amino acid substitutions in the methionine residue of the conserved tyrosine (Y), methionine (M), aspartate (D), aspartate (D) motif of RNA–dependent DNA polymerase. To explore the consequences of substitutions in this motif (YMDD), we made 7 variants by substituting the methionine of the YMDD motif with isoleucine (I), valine (V), alanine (A), leucine (L), lysine (K), arginine (R), and threonine (T). Replication ability of these variants was evaluated by transfection into human hepatoma cells. Sensitivity to lamivudine was tested for replication–competent variants. Four variants with hydrophobic substitutions (I, V, A, and L) remained replication–competent, whereas 3 others with hydrophilic substitutions (K, R, and T) exhibited impaired replication. Of the 4 replication–competent variants, 2 (I and V) were resistant, and 2 (A and L) were sensitive to lamivudine. Because the polymerase and the surface gene overlap, the introduction of these mutations affected the secretion of hepatitis B surface antigen (HBsAg), namely 4 variants (I, V, L, and R) secreted HBsAg, whereas 3 variants (A, K, and T) did not. Our study elucidated that only one amino acid substitution in the YMDD motif was sufficient to cause lamivudine resistance in vitro. As a result of replication competence and lamivudine sensitivity, only viruses having YIDD or YVDD sequences may appear during treatment with lamivudine. This in vitro system could be used to study HBV mutations, replication competence, and their susceptibility to antivirals.
Functions of the Fibrinolytic System in Human Ito Cells and Its Control by Basic Fibroblast and Platelet–Derived Growth Factor
Authors: Fibbi Gabriella , Pucci Marco , Grappone Cecilia , Pellegrini Giulia , Salzano Renata , Casini Alessandro , Milani Stefano , Del Rosso Mario
Published: July 2004

During liver fibrogenesis, hepatic stellate cells (HSC) proliferate and migrate under the influence of growth factors, including platelet–derived growth factor (PDGF) and basic–fibroblast growth factor (b–FGF). The plasminogen activation system regulates extracellular matrix (ECM) catabolism and cell movement. We evaluated the expression and biological functions of the plasminogen activation system in human HSC and its interaction with PDGF and b–FGF. Urokinase–plasminogen activator receptors (u–PAR) were measured by radioligand binding, cell cross–linking, immunoassay, and RNAse protection assay. u–PA and plasminogen activator inhibitors (PAIs) expression and activities were analyzed by zymography, immunoassay, and RNase protection assay. Cell migration and proliferation, studied in Boyden chambers and by microscopic counting, were evaluated after the addition of PDGF, b–FGF, and blockade with anti-u–PA, anti-u–PAR antibodies, and antisense oligodeoxynucleotides (aODN) against u–PAR mRNA. We have shown that HSC produce u–PAR, u–PA, and PAI–1. PDGF and b–FGF up–regulate u–PA and u–PAR, but not PAI–1, and exogenous addition of u–PA stimulates HSC proliferation, chemotaxis, and chemoinvasion. Inhibition of u–PA/u–PAR with antibodies against u–PA or u–PAR and with u–PAR aODN inhibit the proliferative, chemotactic, and chemoinvasive activity of PDGF and b–FGF. These findings indicate that u–PA and u–PAR are required for the mitogenic and chemoinvasive activity of PDGF and b–FGF on HSC.
Anti–Idiotypic Antibodies to Anti-Pdc–E2 in Primary Biliary Cirrhosis and Normal Subjects
Authors: Chen Qiao-yi , Rowley Merrill J. , Mackay Ian R.
Published: July 2004

Anti–idiotypic antibodies may regulate the immune system and influence pathogenic autoimmunity. We investigated idiotype-anti–idiotype interactions in sera of patients with primary biliary cirrhosis (PBC), normal subjects and animals immunized with pyruvate dehydrogenase complex (PDC) or its derivatives. IgG autoantibody to the E2 subunit of PDC (PDC–E2) was derived by affinity–purification from sera of 12 patients with PBC, and F(ab)2 was prepared (anti-PDC–E2–F[ab]2). This was used as a reactant by enzyme–linked immunosorbent assay (ELISA) with sera from patients with PBC, normal subjects, or immunized animals. Results were that IgG antibody to anti-PDC–E2–F(ab)2 was detectable at low concentration in 12 PBC sera (mean optical density [OD] ± SD: 1.02 ± 0.26), and also in 19 normal sera (mean OD ± SD: 0.97 ± 0.35) using a serum dilution of 1:20; background OD was 0.09 to 0.10, whereas antisera from animals immunized with PDC or PDC–E2 were nonreactive. There was a significant inverse correlation (r = -.59, P = .04) between the levels of anti-PDC–E2 in PBC sera (but not normal sera), and anti–idiotypic antibody reactive with anti-PDC–E2–F(ab)2. Anti–idiotypic antibody existed as a complex with anti-PDC–E2, because the removal of anti-PDC–E2 from serum resulted in decreased reactivity to anti-PDC–E2–F(ab)2. Reactivity between PDC–E2 and anti-PDC–E2 from PBC serum was not inhibited by normal sera, indicating that anti–idiotypic antibody from normal sera with anti-PDC–E2 reacts with the framework of F(ab) rather than the paratope. The conclusions are that PBC and normal sera contain IgG class anti–idiotypic antibodies to anti-PDC–E2, the characteristic autoantibody in PBC. Anti-PDC–E2 in immunized animals does not contain an idiotype cross–reactive with human anti-PDC–E2. Anti–idiotypic antibody in PBC is complexed with anti-PDC–E2 and in part accounts for immune complexes demonstrable in PBC. Anti–idiotypic antibody in PBC may regulate levels of anti-PDC–E2.
Gadolinium Blocks Rat Kupffer Cell Calcium Channels: Relevance to Calcium–Dependent Prostaglandin E2 Synthesis and Septic Mortality
Authors: Roland Claude R. , Naziruddin Bashoo , Mohanakumar T. , Flye Wayne M.
Published: July 2004

Hepatic Kupffer cells (KC), the major tissue macrophage population, produce the septic response mediators, tumor necrosis factor α (TNF–α) and prostaglandin E2 (PGE2 ), and have been shown to internalize gadolinium chloride (GD), a rare earth metal of the lanthanide series. Because GD pretreatment of rats has been shown to inhibit the mortality of sepsis, we studied the secretory response to lipopolysaccharide (LPS) by KC isolated from rats injected with either saline or GD (7 mg/kg, intravenously) on the 2 days before KC isolation. Using culture conditions modified to reflect the intrasinusoidal milieu of arginine (RPMI–1640 media with 10 or 100 μmol/L arginine), KC from GD–treated rats responded to LPS (0.0025 μg/mL) with significantly (P < .01) reduced PGE2 release. In contrast, TNF–α release by treated KC was significantly (P < .05) enhanced, consistent with the loss of PGE2 autocoid inhibition of TNF–α. Calcium flux is an early signaling event in eicosanoid synthesis, and GD is known to block calcium channels. Therefore, KC were loaded with fura–2–AM to study the effect of GD on KC calcium flux. GD prevented ionomycin and platelet–activating factor (PAF)–mediated [Ca++]i increase and calcium–dependent PGE2 synthesis, while GD did not affect PGE2 synthesis when protein kinase C (PKC) was directly activated with tetradecanoylphorbolacetate (TPA). The inhibition of calcium flux and calcium–dependent PGE2 synthesis in the major cell of the monocytic phagocytic system by GD may explain the previously reported ability of this lanthanide to prevent the mortality of endotoxemia.
Liver Resection and Needle Liver Biopsy Cause Hematogenous Dissemination of Liver Cells
Authors: Louha Malek , Nicolet Jérome , Zylberberg Herve , Sabile Abdelmajid , Vons Corinne , Vona Giovanna , Poussin Karine , Tournebize Monique , Capron Frédérique , Pol Stanislas , Franco Dominique , Lacour Bernard , Bréchot Christian , Paterlini-Bréchot Patrizia
Published: July 2004

We have investigated whether liver resection and needle liver biopsy cause dissemination of liver cells into peripheral blood circulation, using a reverse–transcription polymerase chain reaction (RT–PCR)–based assay targeted against α–fetoprotein (AFP) mRNA. Twelve patients with and 16 without primary liver cancer (PLC) undergoing liver resection were tested before skin incision, after liver mobilization, after hepatic parenchyma transection, after abdominal wall suture, and 4 days after surgery. Two patients with and 20 without PLC were tested before, 20 minutes after, and 24 hours after needle liver biopsy. Six of 14 patients with and 0 of 36 patients without PLC scored positive before intervention (P < .001). Liver cell spreading was induced at different times after surgery and liver biopsy in 14 of 14 patients with but also 23 of 36 without PLC (P < .05). We conclude that liver resection and needle liver biopsy induce release of cells from the liver, which are not necessarily liver tumor cells, into the peripheral blood circulation. This may be, however, an important mechanism of liver cancer cell dissemination deserving further investigations.