bluuebunny/crossref_metadata_2025 huggingface dataset:
Screening for Dementia by Telephone Using the Memory Impairment Screen
Authors: Lipton Richard B. , Katz Mindy J. , Kuslansky Gail , Sliwinski Martin J. , Stewart Walter F. , Verghese Joe , Crystal Howard A. , Buschke Herman
Published: September 2003

Objectives: To develop and assess telephone‐based screening tests for dementia, especially Alzheimer's disease (AD).

Design: A cross‐sectional validation study nested within a longitudinal study of aging and dementia.

Setting: The Einstein Aging Study of the Albert Einstein College of Medicine, Bronx, New York.

Participants: Three hundred elderly community volunteers living in Bronx County, 27 of whom were diagnosed with dementia based on in‐person clinical evaluation. Of the 27 individuals with dementia, 18 had AD.

Measurements: A telephone battery was administered that included the Memory Impairment Screen by telephone (MIS‐T, a test of semantic memory), the Category Fluency Test (CF‐T), and the Telephone Instrument for Cognitive Status (TICS). An in‐person evaluation then followed that included a neurological examination, a neuropsychological battery, demographics, and medical history.

Results: The telephone battery was well accepted. The MIS‐T required 4 minutes; the CF‐T, 3 minutes; and the TICS, 10 minutes. The MIS‐T had excellent sensitivity and specificity when compared with the CF‐T and the TICS. Using cutscores on all three tests that provide a sensitivity of 78%, specificity was significantly higher for the MIS‐T (93%) than for the CF‐T (78%, P<.05) or the TICS (80%, P<.05). Combining the MIS‐T and CF‐T improved discriminative validity but increased screening time and the complexity of scoring. Normative data for the MIS‐T, the CF‐T, and the TICS for use in settings with different base rates (prevalence) of dementia are presented in this study.

Conclusion: The MIS‐T outperforms the CF‐T and the TICS as a valid and time‐efficient telephone screen for dementia. For applications that require optimal efficiency and accuracy, the MIS‐T is recommended.
Why Would Caregivers Not Want to Treat Their Relative's Alzheimer's Disease?
Authors: Karlawish Jason H. T. , Casarett David J. , James Bryan D. , Tenhave Tom , Clark Christopher M. , Asch David A.
Published: September 2003

Objectives: To determine family caregivers' willingness to use Alzheimer's disease (AD)‐slowing medicines and to examine the relationships between this willingness, dementia severity, and caregiver characteristics.

Design: Cross‐sectional survey.

Setting: In‐home interviews of patients from the Memory Disorders Clinic of the University of Pennsylvania's Alzheimer's Disease Center.

Participants: One hundred two caregivers of patients with mild to severe AD who were registered at an Alzheimer's disease center.

Measurements: Subjects participated in an in‐home interview to assess their willingness to use a risk‐free AD‐slowing medicine and a medicine with 3% annual risk of gastrointestinal bleeding.

Results: Half of the patients had severe dementia (n=52). Seventeen (17%) of the caregivers did not want their relative to take a risk‐free medicine that could slow AD. Half (n=52) did not want their relative to take an AD‐slowing medicine that had a 3% annual risk of gastrointestinal bleeding. Caregivers who were more likely to forgo risk‐free treatment of AD were older (odds ratio (OR)=1.7, P=.04), were depressed (OR=3.66, P=.03), had relatives living in a nursing home (OR=3.6, P=.02), had relatives with more‐severe dementia according to the Mini‐Mental State Examination (MMSE) (OR=2.29, P=.03) or Dementia Severity Rating Scale (DSRS) (OR=2.55, P=.002), and rated their relatives' quality of life (QOL) poorly on a single‐item global rating (OR=0.25, P=.001) and the 13‐item quality‐of‐life (QOL)‐AD scale (OR=0.38, P=.002). Caregivers who were more likely to forgo a risky treatment were nonwhite (OR=6.53, P=.005), had financial burden (OR=2.93, P=.02), and rated their relative's QOL poorly on a single‐item global rating (OR=0.61, P=.01) and the QOL‐AD (OR=0.56, P=.01).

Conclusion: These results suggest that caregivers are generally willing to slow the progression of their relative's dementia even into the severe stage of the disease, especially if it can be done without risk to the patient. Clinical trials and practice guidelines should recognize that a caregiver's assessment of patient QOL and the factors that influence it affect a caregiver's willingness to use AD‐slowing treatments.
Prognosis Communication in Serious Illness: Perceptions of Older Patients, Caregivers, and Clinicians
Authors: Fried Terri R. , Bradley Elizabeth H. , O'Leary John
Published: September 2003

Objectives:

To examine agreement between patients, caregivers, and clinicians regarding prognosis communication and to examine patients' and caregivers' desire for prognostic information.

Design: Cross‐sectional survey.

Setting: Participants' homes.

Participants: Two hundred fourteen persons aged 60 and older with a limited life expectancy secondary to cancer, congestive heart failure, or chronic obstructive pulmonary disease; caregivers; and clinicians.

Measurements: Patient–clinician and caregiver–clinician agreement about the occurrence of prognosis discussions and patient and caregiver desire for prognostic information.

Results: In 46% of patient/clinician and 34% of caregiver/clinician pairs, the clinician reported saying that the patient could die of the underlying disease, whereas the patient or caregiver reported no discussion. In 23% of patient/clinician and 30% of patient/caregiver pairs, the clinician reported discussing an approximate life expectancy, whereas the patient or caregiver reported no discussion. Of 205 patients who reported no life expectancy discussion, 40% did not want this discussion. Whereas 83% of those believing they had 1 year or less to live wanted to discuss prognosis, 79% of those believing they had 1 to 2 years, 53% of those believing they had 2 to 5 years, and 50% of those believing they had more than 5 years or who were unwilling to answer wanted this discussion (P=.007).

Conclusion: Although clinicians report that they are discussing prognosis, patients and caregivers frequently do not corroborate these reports. Furthermore, many patients do not want prognostic information. Despite previous reports concluding that patients want full disclosure about their illness, many seriously ill older persons and caregivers may not be ready or able to receive prognostic information.
Selective Impairment of Frontal‐Executive Cognitive Function in African Americans with Cardiovascular Risk Factors
Authors: Pugh Kenneth G. , Kiely Dan K. , Milberg William P. , Lipsitz Lewis A.
Published: September 2003

Objectives: To determine whether a summary cardiovascular risk score is associated with an increased risk of frontal‐executive cognitive impairment.

Design: Cross‐sectional study.

Setting: Subjects were recruited from senior centers, senior housing complexes, and communities in the Boston metropolitan area.

Participants: Forty‐three predominantly female elderly African Americans.

Measurements: Cardiovascular risk factors were assessed during an interview and clinical examination. For each subject, the total number of cardiovascular (CV) risk factors was summed to compute a CV risk score. A battery of neuropsychological tests was administered that examined memory, visuospatial abilities, and frontal‐executive functions. Cognitive test scores were transformed into domain‐specific (memory, visuospatial, frontal‐executive) composite z scores. Cognitive impairment for each composite z score was defined as performance less than the median for the study group. Multivariate logistic regression was used to examine the relationship between the CV risk score and the risk for cognitive impairment in the three cognitive domains of interest.

Results: After controlling for age and education, the CV risk score was associated only with frontal‐executive cognitive impairment (odds ratio (OR)=2.44, 95% confidence interval (CI)=1.06–5.65). The CV risk score was not associated with the risk of memory (OR=1.30, 95% CI=0.64–2.67) or visuospatial impairment (OR=1.49, 95% CI=0.66–3.36). Greater CV risk scores were associated with an increased likelihood of having frontal‐executive cognitive impairment.

Conclusion: CV risk factors may exert a specific deleterious effect on frontal‐executive cognitive abilities as opposed to memory or visuospatial functions. Associated executive dysfunction may compromise the ability of patients with CV risk factors to comply with recommendations for risk reduction.
Vascular Disease and Cognitive Function: Evidence from the Whitehall II Study
Authors: Singh‐Manoux Archana , Britton Annie R. , Marmot Michael
Published: September 2003

Objectives: To test the hypothesis of an inverse association between indicators of vascular disease and cognitive function in the general, stroke‐free population.

Design: A longitudinal, British civil service–based cohort study. Measures of vascular disease examined were prevalent at baseline or traced over a median of 11 years, between Phases 1 (1985–1988) and 5 (1997–1999) of data collection. Cognitive function was assessed at Phase 5 of data collection.

Setting: Twenty London‐based Civil Service departments.

Participants: Four thousand one hundred forty‐one men and 1,681 women, aged 46 to 68 when tested for cognitive function.

Measurements: A battery of cognitive tests consisting of: memory test, Alice Heim 4, Mill‐Hill, phonemic, and semantic fluency.

Results: The occurrence of angina pectoris (P<.001), myocardial infarction (P=.02), all coronary heart disease (P<.001), and intermittent claudication (P=.004) was associated with poor cognitive function. These effects were independent of age and socioeconomic status. The association between indicators of vascular disease and cognitive function applied to the entire range of cognitive function measures examined in the study.

Conclusion: The findings support the view that vascular disease is predictive of poor cognitive function in the general population. The fact that presence of vascular disease was associated with diminished cognitive function even in a relatively young cohort has implications for the management of vascular disease.
Training Caregivers to Change the Sleep Hygiene Practices of Patients with Dementia: The NITE‐AD Project
Authors: McCurry Susan M. , Gibbons Laura E. , Logsdon Rebecca G. , Vitiello Michael , Teri Linda
Published: September 2003

Objectives: To examine the feasibility of training caregivers to implement sleep hygiene recommendations in dementia patients.

Design: A randomized, controlled trial.

Setting: Community.

Participants: Twenty‐two community‐dwelling patients with Alzheimer's disease (AD) and their family caregivers.

Interventions: All participants received written materials describing age‐ and dementia‐related changes in sleep and standard principles of good sleep hygiene. Caregivers in active treatment (n=10) also received specific recommendations about setting up and implementing a sleep hygiene program for the dementia patient. Control subjects (n=12) received general dementia education and caregiver support.

Measurements: Success implementing sleep hygiene recommendations was measured using daily log reports to calculate the percentage of days that caregivers reported that patients met individualized sleep scheduling, daytime‐napping, and walking goals.

Results: Caregivers in active treatment were more successful in setting goals related to sleep scheduling and increasing daytime activity than control caregivers who received written materials only. Among patients who were candidates for sleep hygiene changes, active treatment subjects were also significantly (P<.01) more likely than controls to maintain a consistent bedtime (83% vs 38% of days attempted) and a consistent rising time (96% vs 59%), to nap less during the day (70% vs 28%), and to walk daily (86% vs 7%).

Conclusion: This study provides evidence that sleep hygiene interventions are feasible with community‐dwelling AD patients. Caregivers were able to help patients change sleep scheduling, napping, and walking routines, but clinicians who recommend sleep hygiene changes for their dementia patients should be aware that many caregivers need active assistance setting up and implementing a sleep hygiene program. Simply providing caregivers with education is often insufficient.
A Continuing Medical Education Initiative for Canadian Primary Care Physicians: The Driving and Dementia Toolkit: A Pre‐ and Postevaluation of Knowledge, Confidence Gained, and Satisfaction
Authors: Byszewski Anna M. , Graham Ian D. , Amos Stephanie , Man‐Son‐Hing Malcolm , Dalziel William B. , Marshall Shawn , Hunt Lynn , Bush Clarissa , Guzman Danilo
Published: September 2003

This study examined the effect of the Driving and Dementia Toolkit on physician knowledge and confidence gained and the anticipated change in patient assessment and evaluated the extent to which physicians found the material to be useful. Before receiving the driving toolkit, 301 randomly selected primary care physicians received a copy of the pretest questionnaire; 145 responded and met the eligibility criteria. This group was then sent the toolkit, a satisfaction a survey, and a posttest questionnaire. Physicians were faxed the questionnaires (with up to three reminders) and telephoned if necessary. Changes in pre‐ and posttest results were analyzed using the McNemar test and Wilcoxon signed rank test nonparametric procedures included in SPSS, Version 10.0, and paired‐samples t test. Pre‐ and posttest data were available and could be matched for 86 physicians (59.3%) response. Knowledge and confidence increased significantly (P≤.05) for most of the toolkit content questions. There was also a clear intent on the part of study participants to begin including additional pertinent questions in the patient/caregivers interview when assessing a patient's fitness to drive. On a scale from 1 (low) to 10 (high), overall satisfaction with the toolkit rated an average of 8.4. Use of the toolkit resulted in a clear improvement in physicians' reported knowledge of and confidence in dealing with dementia and driving. Future applications of similar innovative continuing education models can be used for other areas such as disclosure of dementia diagnosis, capacity assessments, or end‐of life issues.
A Novel Liver–Specific Zona Pellucida Domain Containing Protein That Is Expressed Rarely in Hepatocellular Carcinoma
Authors: Xu Zhi-Gang , Du Jian-Jun , Zhang Xin , Cheng Zhi-Hong , Ma Zhen-Zhong , Xiao Hua-Sheng , Yu Li , Wang Zhi-Qin , Li Yu-Yang , Huo Ke-Ke , Han Ze-Guang
Published: September 2003

We currently identified a liver–specific gene that encodes a novel zona pellucida (ZP) domain–containing protein named liver–specific ZP domain–containing protein (LZP). The full–length complementary DNA (cDNA) of human LZP has 2,255 bp with a complete open reading frame (ORF) of 1,635 bp. The gene is localized on chromosome 10q21.3 and spans 40 kb with 9 encoding exons and 8 introns. The deduced protein sequence has 545 amino acid residues, with an N–terminal signal peptide followed by 3 epidermal growth factor (EGF)–like domains and a ZP domain in C–terminal section. Interestingly, human LZP is expressed specifically in liver out of 23 tissues examined, and its mouse counterpart was detected at very early stage during embryo development. Moreover, LZP can be secreted into blood, albeit the protein was localized mainly on the nuclear envelop of hepatocytes. Most importantly, LZP is down–regulated in hepatocellular carcinoma (HCC) and HCC cell lines; meanwhile, the decreased level of hLZP messenger RNA (mRNA) could, at least in some HCC samples, be related to the methylation status of the putative LZP promoter. However, overexpression of hLZP in HCC cell line SMMC–7721 and human liver cell line L02 by stable cell transfection did not inhibit cell growth, implying that the down–regulation of hLZP in HCC might be a consequence of the dedifferentiation involved in hepatocarcinogenesis. In conclusion, these data suggest that LZP is a liver–specific protein involved possibly in hepatocellular function and development, and the protein could be used as potential negative biomarker for HCC pathologic diagnosis.
High Body Mass Index Is An Independent Risk Factor for Nonresponse to Antiviral Treatment in Chronic Hepatitis C
Authors: Bressler Brian L. , Guindi Maha , Tomlinson George , Heathcote Jenny
Published: September 2003

The aim of this study was to determine if body mass index (BMI) was an independent predictor of response to antiviral treatment in patients with chronic hepatitis C. A retrospective review was performed of all patients at a single center with chronic hepatitis C treated with antiviral medication from 1989 to 2000. A sustained response was defined as either negative hepatitis C virus (HCV) RNA by polymerase chain reaction and/or normal alanine aminotransferase (ALT) level (only in those treated before availability of HCV RNA testing) 6 months following completion of therapy. All patients were classified into one of 3 groups according to BMI (normal, <25 kg/m2; overweight, 25–30 kg/m2; obese, >30 kg/m2). A total of 253 patients were treated with either interferon (IFN) monotherapy or IFN in combination with ribavirin. Patients were excluded if predetermined clinical characteristics were unavailable. Using logistic regression, and after adjusting for the examined variables (age, sex, history of alcohol consumption >50 g/d, cirrhosis on pretreatment biopsy, and BMI), likelihood ratio tests showed significant differences in response to treatment according to BMI group (P = .01), genotype (P < .01), and cirrhosis (P < .01). Those with genotypes 2 or 3 had an odds ratio (OR) for success of 11.7 compared with those with genotype 1, cirrhotic patients had an OR of 0.15 compared with noncirrhotic patients, and obese patients had an OR of 0.23 compared with normal and overweight patients. Hepatic steatosis was not an independent risk factor for response to antiviral treatment. In conclusion, obesity, only when defined as a BMI greater than 30 kg/m2, is an independent (of genotype and cirrhosis) negative predictor of response to hepatitis C treatment.
Sensitivity of the 2–Oxoglutarate Carrier to Alcohol Intake Contributes to Mitochondrial Glutathione Depletion
Authors: Coll Olga , Colell Anna , García-Ruiz Carmen , Kaplowitz Neil , Fernández-Checa J. C.
Published: September 2003

The mitochondrial pool of reduced glutathione (mGSH) is known to play a protective role against liver injury and cytokine–mediated cell death. However, the identification of the mitochondrial carriers involved in its transport in hepatocellular mitochondria remains unestablished. In this study, we show that the functional expression of the 2–oxoglutarate carrier from HepG2 cells in mitochondria from Xenopus laevis oocytes conferred a reduced glutathione (GSH) transport activity that was inhibited by phenylsuccinate, a specific inhibitor of the carrier. In addition, the mitochondrial transport of GSH and 2–oxoglutarate in isolated mitochondria from rat liver exhibited mutual competition and sensitivity to glutamate and phenylsuccinate. Interestingly, the kinetics of 2–oxoglutarate transport in rat liver mitochondria displayed a single Michaelis–Menten component with a Michaelis constant of 3.1 ± 0.3 mmol/L and maximum velocity of 1.9 ± 0.1 nmol/mg protein/25 seconds. Furthermore, the initial rate of 2–oxoglutarate was reduced in mitochondria from alcohol–fed rat livers, an effect that was not accompanied by an alcohol–induced decrease in the 2–oxoglutarate messenger RNA levels but rather by changes in mitochondrial membrane dynamics induced by alcohol. The fluidization of mitochondria by the fluidizing agent 2–(2–methoxyethoxy)ethyl 8–(cis–2–n–octylcyclopropyl) (A2C) restored the initial transport rate of both GSH and 2–oxoglutarate. Finally, these changes were reproduced in normal liver mitochondria enriched in cholesterol where the fluidization of cholesterol–enriched mitochondria with A2C restored the order membrane parameter and the mitochondrial 2–oxoglutarate uptake. In conclusion, these findings provide unequivocal evidence for 2–oxoglutarate as a GSH carrier and its sensitivity to membrane dynamics perturbation contributes in part to the alcohol–induced mGSH depletion.
Prevalence of Hbv Precore/Core Promoter Variants in the United States
Authors: Chu Chi-Jen , Keeffe Emmet B. , Han Steven-Huy , Perrillo Robert P. , Min Albert D. , Soldevila-Pico Consuelo , Carey William , Brown Robert S. , Luketic Velimir A. , Terrault Norah , Lok Anna S.F.
Published: September 2003

Variants in the precore (G1896A) and core promoter (A1762T, G1764A) regions of hepatitis B virus (HBV) may be related to serum HBV DNA levels and severity of liver disease. The aims of this nationwide study were to determine the prevalence of HBV precore/core promoter variants in the United States and the association between these variants and patient demographics, HBV genotypes, serum HBV DNA level, and severity of liver disease. A total of 694 consecutive chronic HBV–infected patients seen in 17 U.S. liver centers during a 1–year period were enrolled. Demographic, clinical, and laboratory data were collected. Sera were tested for HBV genotypes as well as precore and core promoter variants by line–probe assays. Quantitative HBV DNA levels were determined using Cobas Amplicor HBV Monitor kits. Precore and core promoter variants were found in 27% and 44% of patients with chronic HBV infection in the United States. Precore and core promoter variants were more common in hepatitis B e antigen (HBeAg)–negative than in HBeAg–positive patients (precore, 38% vs. 9%; core promoter, 51% vs. 36%; respectively, P < .001). The prevalence of these variants was related to ethnicity, place of birth, and HBV genotypes. Patients with core promoter variants were more likely to have hepatic decompensation. Precore and/or core promoter variants were associated with higher serum HBV DNA levels in HBeAg–negative but not in HBeAg–positive patients. In conclusion, HBV precore and core promoter variants are not rare in the United States. Physicians should be aware of the existence of HBV precore and core promoter variants and the clinical condition of “HBeAg–negative chronic hepatitis.”
Altered Expression of Genes Involved in Hepatic Morphogenesis and Fibrogenesis Are Identified by Cdna Microarray Analysis in Biliary Atresia
Authors: Chen Limin , Goryachev Andrew , Sun Jin , Kim Peter , Zhang Hui , Phillips James M. , Macgregor Pascale , Lebel Sylvie , Edwards Aled M. , Cao Qiongfang , Furuya Katryn N.
Published: September 2003

Biliary atresia (BA) is characterized by a progressive, sclerosing, inflammatory process that leads to cirrhosis in infancy. Although it is the most common indication for liver transplantation in early childhood, little is known about its etiopathogenesis. To elucidate factors involved in this process, we performed comprehensive genome–wide gene expression analysis using complementary DNA (cDNA) microarrays. We compared messenger RNA expression levels of approximately 18,000 human genes from normal, diseased control, and end–stage BA livers. Reverse–transcription polymerase chain reaction (RT–PCR) and Northern blot analysis were performed to confirm changes in gene expression. Cluster and principal component analysis showed that all BA samples clustered together, forming a distinct group well separated from normal and diseased controls. We further identified 35 genes and ESTs whose expression differentiated BA from normal and diseased controls. Most of these genes are known to be associated with cell signaling, transcription regulation, hepatic development, morphogenesis, and fibrogenesis. In conclusion, this study serves to delineate processes that are involved in the pathogenesis of BA.
Left Ventricular Hypertrophy in Rats With Biliary Cirrhosis
Authors: Inserte Javier , Perelló Antonia , Agulló Luis , Ruiz-Meana Marisol , Schlüter Klaus-Dieter , Escalona Noelia , Graupera Mariona , Bosch Jaume , Garcia-Dorado David
Published: September 2003

Portal hypertension induces neuroendocrine activation and a hyperkinetic circulation state. This study investigated the consequences of portal hypertension on heart structure and function. Intrahepatic portal hypertension was induced in male Sprague–Dawley rats by chronic bile duct ligation (CBDL). Six weeks later, CBDL rats showed higher plasma angiotensin–II and endothelin–1 (P < .01), 56% reduction in peripheral resistance and 73% reduction in pulmonary resistance (P < .01), 87% increase in cardiac index and 30% increase in heart weight (P < .01), and increased myocardial nitric oxide (NO) synthesis. In CBDL rats, macroscopic analysis demonstrated a 30% (P < .01) increase in cross–sectional area of the left ventricular (LV) wall without changes in the LV cavity or in the right ventricle (RV). Histomorphometric analysis revealed increased cell width (12%, P < .01) of cardiomyocytes from the LV of CBDL rats, but no differences in myocardial collagen content. Myocytes isolated from the LV were wider (12%) and longer (8%) than right ventricular myocytes (P < .01) in CBDL rats but not in controls. CBDL rats showed an increased expression of ANF and CK–B genes (P < .01). Isolated perfused CBDL hearts showed pressure/end–diastolic pressure curves and response to isoproterenol identical to sham hearts, although generated wall tension was reduced because of the increased wall thickness. Coronary resistance was markedly reduced. This reduction was abolished by inhibition of NO synthesis with N–nitro–L–arginine. Expression of eNOS was increased in CBDL hearts. In conclusion, portal hypertension associated to biliary cirrhosis induces marked LV hypertrophy and increased myocardial NO synthesis without detectable fibrosis or functional impairment. This observation could be relevant to patients with cirrhosis.
Interleukin 6 Is Important for Survival After Partial Hepatectomy in Mice
Authors: Blindenbacher Alex , Wang Xueya , Langer Igor , Savino Rocco , Terracciano Luigi , Heim Markus H.
Published: September 2003

The response to partial hepatectomy (PH) is impaired in interleukin 6 (IL–6)–deficient mice. IL–6 is well known for its role in the induction of the acute phase (AP) response, and the impairment of this response after surgery and hepatectomy could explain the defective hepatocyte regeneration. In addition, it was proposed that IL–6 has an important role in stimulating the reentry of quiescent cells into the cell cycle within the first 2 to 4 hours after PH. To further analyze the role for IL–6, we performed two third hepatectomies in wild–type mice, in IL–6 knockout (KO) mice, and in IL–6 KO mice that were treated 30 minutes before surgery with intravenous (IV) (short acting) or subcutaneous (SC) (long acting) injections of recombinant IL–6. The high postoperative mortality of IL–6–deficient mice could be completely prevented by SC, but not by IV IL–6 treatment, showing the requirement of a sustained action of IL–6. However, there is a subset of IL–6 KO mice that survives a PH in good health even without IL–6 treatment. When we analyzed these mice, we found an intact liver regeneration and no indication of a block in cell cycle reentry. We conclude that the major role of IL–6 is the induction of an adaptive response to PH that ensures body homeostasis and survival.
Antibody–Selected Mimics of Hepatitis C Virus Hypervariable Region 1 Activate Both Primary and Memory Th Lymphocytes
Authors: Frasca Loredana , Scottà Cristiano , Del Porto Paola , Nicosia Alfredo , Pasquazzi Caterina , Versace Ilaria , Masci Anna Maria , Racioppi Luigi , Piccolella Enza
Published: September 2003

An ideal strategy that leads to a vaccine aimed at controlling viral escape may be that of preventing the replication of escape mutants by eliciting a T– and B–cell repertoire directed against many viral variants. The hypervariable region 1 (HVR1) of the putative envelope 2 protein that presents B and T epitopes shown to induce protective immunity against hepatitis C virus (HCV), might be suitable for this purpose if its immunogenicity can be improved by generating mimics that induce broad, highly cross–reactive, anti–HVR1 responses. Recently we described a successful approach to select HVR1 mimics (mimotopes) incorporating the variability found in a great number of viral variants. In this report we explore whether these mimotopes, designed to mimic B–cell epitopes, also mimic helper T–cell epitopes. The first interesting observation is that mimotopes selected for their reactivity to HVR1–specific antibodies of infected patients also do express HVR1 T–cell epitopes, suggesting that similar constraints govern HVR1–specific humoral and cellular immune responses. Moreover, some HVR1 mimotopes stimulate a multispecific CD4+ T–cell repertoire that effectively cross–reacts with HVR1 native sequences. This may significantly limit effects as a T–cell receptor (TCR) antagonist frequently exerted by natural HVR1–variants on HVR1–specific T–cell responses. In conclusion, these data lend strong support to using HVR1 mimotopes in vaccines designed to prevent replication of escape mutants.
Acquired (non-Wilsonian) hepatocerebral degeneration: Complex management decisions
Authors: Wijdicks Eelco F.M. , Wiesner Russell H.
Published: September 2003

Portal systemic encephalopathy, in its many guises, can be reversible after medical management or liver transplantation. It is much less certain whether patients with a longstanding neurodegenerative syndrome (known in the medical vernacular as acquired hepatocerebral degeneration) can improve. Impressive neuroimaging abnormalities have been reported in this entity.1 However, the combination of a severe disabling neurologic deficit and widespread magnetic resonance abnormalities tempers the enthusiasm of transplant surgeons to proceed with liver transplantation. In our liver transplantation program, we were recently confronted with such a case, and present herein not only the characteristic magnetic resonance imaging findings but also some of the dilemmas of management. (Liver Transpl 2003;9:993-994.)
Acute Budd-Chiari syndrome during pregnancy: Surgical treatment and orthotopic liver transplantation with successful completion of the pregnancy
Authors: Grant Wendy J. , McCashland Timothy , Botha Jean F. , Shaw Byers W. , Sudan Debra L. , Mejia Alejandro , Iyer Kishore , Langnas Alan N.
Published: September 2003

A 26-year-old woman presented with acute Budd-Chiari syndrome 18 weeks into a pregnancy. She was found to be heterozygous for the G20210A prothrombin gene mutation. She was treated with portacaval shunt placement and successfully completed the pregnancy, with a healthy baby delivered at 31 weeks’ gestation. She developed progressive liver failure after delivery of the child, likely associated with clotting of the shunt, which occurred in the face of full anticoagulation. The patient subsequently underwent a technically complicated orthotopic liver transplantation, but died 10 months after transplantation. This case illustrates the challenges involved in the treatment of Budd-Chiari syndrome, in addition to difficulties balancing the health of a mother and an unborn child. It is the only case of surgical treatment of Budd-Chiari syndrome during pregnancy reported in the literature. (Liver Transpl 2003;9:976-979.)
Beta tryptase levels are not elevated in patients undergoing liver transplantation
Authors: Woehlck Harvey J. , Johnson Christopher P. , Roza Allan M. , Adams Mark B.
Published: September 2003

Reperfusion syndrome during liver transplantation and anaphylaxis are clinical syndromes that share similarities in physiological responses. The liver and intestine contain a variety of immunologically active cells, including mast cells. The purpose of this study is to investigate the possibility that mast-cell degranulation occurs routinely during transplantation and thereby contributes to hemodynamic instability and coagulopathy. Beta tryptase, an enzyme released by mast cells during degranulation, is a reliable marker for mast-cell-mediated events. Six patients undergoing liver transplantation had beta tryptase levels assayed in blood immediately before and after reperfusion of the liver. No patient showed an increase in beta tryptase levels at 15 or 60 minutes after reperfusion. In conclusion, it is unlikely that clinically significant mast-cell degranulation occurs routinely in patients undergoing liver transplantation. (Liver Transpl 2003;9:980-982.)
An evaluation of long-term outcomes after liver transplantation for cryptogenic cirrhosis
Authors: Heneghan Michael A. , Zolfino Teresa , Muiesan Paolo , Portmann Bernard C. , Rela Mohammed , Heaton Nigel D. , O’Grady John G.
Published: September 2003

Patients with cryptogenic cirrhosis (CC) comprise a significant proportion of liver transplant recipients. Poor outcome after transplantation has been reported by some centers, with fibrosis occurring in a significant proportion of patients. Outcome of 46 patients with CC who underwent transplantation between 1989 and 1999 at King’s College Hospital London were compared with time-matched recipients who underwent transplantation for hepatitis C virus (HCV) cirrhosis (n = 58) and patients with alcohol-related cirrhosis (AC, n = 53) during the same time period. Mean follow-up was 46 ± 37 months for CC patients, 41 ± 31 months for AC patients, and 49 ± 31 months for HCV patients. No protocol liver biopsy specimens were obtained, and biopsies were performed only for investigation of biochemical abnormalities. Acute cellular rejection occurred in 30% of CC, 26% of AC, and 37% of HCV patients (P = NS). Overall patient and graft survival at 1 year was 85% and 80% for CC patients, 87% and 81% for AC patients, and 91% and 82% for patients with HCV (P = NS). Five-year patient and graft survival was 81% and 77% for CC patients, 60% and 48% for AC patients, and 79% and 57% for HCV patients (Log rank; P = .369). Twenty-two percent of CC patients had inflammation on last evaluable liver biopsy, compared with 25% of patients who underwent transplantation for AC and 68% of patients who underwent transplantation for HCV. No patient who underwent transplantation for CC had histologic evidence of cirrhosis on last evaluable biopsy, compared with 2% of patients who underwent transplantation for AC and 16% of patients who underwent transplantation for HCV (Chi-squared = 13.053, P = .0015). These results suggest that CC is a favorable indication for OLT and that although a proportion of patients develop inflammation in the liver allograft, this does not result in significant graft dysfunction or loss. (Liver Transpl 2003;9:921-928.)
The role of complex hepatic artery reconstruction in orthotopic liver transplantation
Authors: Soliman Thomas , Bodingbauer Martin , Langer Felix , Berlakovich Gabriela A. , Wamser Peter , Rockenschaub Susanne , Muehlbacher Ferdinand , Steininger Rudolf
Published: September 2003

The goal of this study was to analyze the influence of multiple anastomosis on outcome in orthotopic liver transplantation (OLT) and its implications for split-liver and living related liver transplantation programs. In a retrospective study, 683 first OLTs in adults were analyzed. Complex hepatic artery reconstruction was defined as revascularization of the graft requiring additional anastomosis between donor hepatic arteries. OLT was performed in a standard manner. All patients had daily ultrasound examination. In this series we found 72 grafts (10.5%) with anatomic arterial variations that required complex hepatic artery reconstruction. There was no difference in primary organ function and demographic data compared with patients with simple arterial reconstruction. However, hepatic artery thrombosis (HAT) occurred in 9.7% of patients (7 of 72) with complex reconstruction in contrast to 2.0% in the control group (12 of 638; P < .001). Statistical analysis identified multiple anastomoses (P < .002) and primary nonfunction (P < .02) as significant risk factors for HAT. Three patients underwent successful thrombectomy for HAT, all others had to undergo retransplantation. Although in the group with complex arterial reconstruction increased graft loss caused by HAT was found early postoperatively, the overall 5-year patient and graft survival was not different for both groups. Although complex reconstruction is a risk factor for HAT, early diagnosis of HAT by daily ultrasound and early repeat OLT can provide similar 5-year survival as for patients with simple reconstruction. We conclude that complex hepatic artery reconstruction challenges conventional OLT as well as split-liver and living related liver transplantation, but does not necessarily affect its long-term outcome
Liver transplantation for primary sclerosing cholangitis in the Nordic countries: Outcome after acceptance to the waiting list
Authors: Brandsæter Bjørn , Broomé Ulrika , Isoniemi Helena , Friman Styrbjörn , Hansen Bent , Schrumpf Erik , Oksanen Antti , Ericzon Bo-Göran , Höckerstedt Krister , Mäkisalo Heikki , Olsson Rolf , Olausson Michael , Kirkegaard Preben , Bjøro Kristian
Published: September 2003

Primary sclerosing cholangitis (PSC) is a common indication for liver transplantation, but evaluation of patients and timing of liver transplantation remain as major problems. Data from PSC and control patients listed for liver transplantation from 1990 through 2000 in the Nordic countries were recorded prospectively. Outcomes from the waiting list and after transplantation have been recorded for both groups. For PSC patients, regression analyses have been performed to analyze predictors of outcome. A total of 255 PSC and 610 control patients were accepted on the liver transplantation waiting list from 1990 to 2000. In the PSC group, 223 patients (87%) received a first liver allograft, and 32 patients (13%) died without transplantation. The corresponding figures for the control group were 89% and 10%. For PSC patients, the 5- and 10-year survival from the time of acceptance was 68% and 58%, respectively. A higher Model for End-Stage Liver Disease score and a shorter duration of PSC predicted death on the waiting list for PSC patients. PSC is a frequent indication for liver transplantation. In our material, serum bilirubin or Model for End-Stage Liver Disease score and PSC duration are predictors of outcome including survival of the waiting list.
Combined heart and liver transplantation for familial amyloidotic neuropathy: Considerations from the hepatic point of view
Authors: Grazi Gian Luca , Cescon Matteo , Salvi Fabrizio , Ercolani Giorgio , Ravaioli Matteo , Arpesella Giorgio , Magelli Carlo , Grigioni Francesco , Cavallari Antonino
Published: September 2003

Few cases of combined heart and liver transplantation (CHLT) for familial amyloidotic polyneuropathy have been reported, and the technique for the operation is far from being consolidated. Three patients with amyloidogenic transthyretin (ATTR)-related (variant Glu89Gln to ATTR Glu89Gln) cardiomyopathy underwent CHLT at our institution. Patient 1 had no serious involvement of other organs, whereas patients 2 and 3 had evident peripheral neuropathy and gastrointestinal motility alterations. Patient 3 also had high-grade orthostatic hypotension. All three patients underwent cardiac and sequential hepatic transplantation using the piggyback technique with organs procured from the same donor. Venovenous bypass (VVB) was used only in patient 1, with an uncomplicated procedure. After CHLT, his cardiac performance remained normal, and no progression of amyloidosis was observed. Patient 2 had no intraoperative complications, but experienced postoperative bleeding, renal failure, sepsis, and heart failure and eventually died of multiorgan failure 2 months after transplantation. In patient 3, right hemicolectomy was required intraoperatively because of intestinal ischemia without significant hemodynamic perturbations, whereas extracardiac symptoms of amyloidosis gradually worsened postoperatively. Two patients (no. 1 and 3) currently are alive after 38 and 18 months, respectively. CHLT for ATTR Glu89Gln can be performed successfully, even in patients with advanced disease. However, the most compromised patients are more exposed to intraoperative risks, postoperative complications, and worsening of extracardiac and extrahepatic symptoms. The need for VVB remains to be evaluated
Hypoglycemia in nondiabetic patients undergoing albumin dialysis by molecular adsorbent recirculating system
Authors: Khoo Ai-Leng , Tham Lai-San , Lim Gek-Kee , Lee Kang-Hoe
Published: September 2003

It was observed that patients developed episodes of hypoglycemia during molecular adsorbent recycling system (MARS) treatment. The aim of this study is to assess the effect of MARS treatment on blood glucose concentration to formulate appropriate dextrose replacement guidelines during MARS dialysis. Five patients with liver failure each underwent a 6- to 8-hour MARS treatment. No patient had a history of diabetes or was administered insulin or oral antihyperglycemic agents throughout the period of albumin dialysis. There was no active intervention or restriction on glucose intake. Rather, a dextrose drip and boluses were allowed based on each patient’s condition and the clinical judgment of the attending physician. Blood glucose concentration was monitored hourly during the period of MARS treatment. Glucose loss in dialysate fluid was quantified hourly by measuring the total volume of dialysate fluid and assaying the glucose concentration in dialysate fluid. Mean glucose removal during a 6-hour MARS session was 37.19 ± 5.58 g. Mean glucose removal rate was 6.20 ± 0.93 g/h. In addition to a maintenance drip supporting the caloric requirement of patients, a dextrose replacement drip that paralleled the rate of glucose removal would prevent patients from experiencing episodes of hypoglycemia during MARS treatment. Dextrose replacement at a mean rate of 6 g/h (range, 5 to 7 g/h) in patients without diabetes undergoing albumin dialysis by MARS is recommended
A carboxyl-terminal interaction of lamin B1 is dependent on the CAAX endoprotease Rce1 and carboxymethylation
Authors: Maske Christopher P. , Hollinshead Michael S. , Higbee Niall C. , Bergo Martin O. , Young Stephen G. , Vaux David J.
Published: September 2003

The mammalian nuclear lamina protein lamin B1 is posttranslationally modified by farnesylation, endoproteolysis, and carboxymethylation at a carboxyl-terminal CAAX motif. In this work, we demonstrate that the CAAX endoprotease Rce1 is required for lamin B1 endoproteolysis, demonstrate an independent pool of proteolyzed but nonmethylated lamin B1, as well as fully processed lamin B1, in interphase nuclei, and show a role for methylation in the organization of lamin B1 into domains of the nuclear lamina. Deficiency in the endoproteolysis or methylation of lamin B1 results in loss of integrity and deformity of the nuclear lamina. These data show that the organization of the nuclear envelope and lamina is dependent on a mechanism involving the methylation of lamin B1, and they identify a potential mechanism of laminopathy involving a B-type lamin.
Closed product formulas for extensions of generalized Verma modules
Authors: Biagioli Riccardo
Published: September 2003

We give explicit combinatorial product formulas for the polynomials encoding the dimensions of the spaces of extensions of

(
g
,
p
)

(g,p)

-generalized Verma modules, in the cases when

(
g
,
p
)

(g,p)

corresponds to an indecomposable classic Hermitian symmetric pair. The formulas imply that these dimensions are combinatorial invariants. We also discuss how these polynomials, defined by Shelton, are related to the parabolic

R
R

-polynomials introduced by Deodhar.
Vassiliev invariants for braids on surfaces
Authors: González-Meneses Juan , Paris Luis
Published: September 2003

We show that Vassiliev invariants separate braids on a closed oriented surface, and we exhibit a universal Vassiliev invariant for these braids in terms of chord diagrams labeled by elements of the fundamental group of the surface.
Exponential sums on 𝐀ⁿ, II
Authors: Adolphson Alan , Sperber Steven
Published: September 2003

We prove a vanishing theorem for the

p
p

-adic cohomology of exponential sums on

A

n

\mathbf {A}^n

. In particular, we obtain new classes of exponential sums on

A

n

\mathbf {A}^n

that have a single nonvanishing

p
p

-adic cohomology group. The dimension of this cohomology group equals a sum of Milnor numbers.
Orientational Order of the Lamellipodial Actin Network as Demonstrated in Living Motile Cells
Authors: Verkhovsky Alexander B. , Chaga Oleg Y. , Schaub Sébastien , Svitkina Tatyana M. , Meister Jean-Jacques , Borisy Gary G.
Published: September 2003

Lamellipodia of crawling cells represent both the motor for cell advance and the primary building site for the actin cytoskeleton. The organization of actin in the lamellipodium reflects actin dynamics and is of critical importance for the mechanism of cell motility. In previous structural studies, the lamellipodial actin network was analyzed primarily by electron microscopy (EM). An understanding of lamellipodial organization would benefit significantly if the EM data were complemented and put into a kinetic context by establishing correspondence with structural features observable at the light microscopic level in living cells. Here, we use an enhanced phase contrast microscopy technique to visualize an apparent long-range diagonal actin meshwork in the advancing lamellipodia of living cells. Visualization of this meshwork permitted a correlative light and electron microscopic approach that validated the underlying organization of lamellipodia. The linear features in the light microscopic meshwork corresponded to regions of greater actin filament density. Orientation of features was analyzed quantitatively and compared with the orientation of actin filaments at the EM level. We infer that the light microscopic meshwork reflects the orientational order of actin filaments which, in turn, is related to their branching angle.
Phosphoinositides, Ezrin/Moesin, and rac1 Regulate Fusion of Rhodopsin Transport Carriers in Retinal Photoreceptors
Authors: Deretic Dusanka , Traverso Valerie , Parkins Nilda , Jackson Fannie , de Turco Elena B. Rodriguez , Ransom Nancy
Published: September 2003

The post-Golgi trafficking of rhodopsin in photoreceptor cells is mediated by rhodopsin-bearing transport carriers (RTCs) and regulated by the small GTPase rab8. In this work, we took a combined pharmacological-proteomic approach to uncover new regulators of RTC trafficking toward the specialized light-sensitive organelle, the rod outer segment (ROS). We perturbed phospholipid synthesis by activating phospholipase D with sphingosine 1-phosphate (S1P) or inhibiting phosphatidic acid phosphohydrolase by propranolol (Ppl). S1P stimulated the overall rate of membrane trafficking toward the ROS. Ppl stimulated budding of RTCs, but blocked membrane delivery to the ROS. Ppl caused accumulation of RTCs in the vicinity of the fusion sites, suggesting a defect in tethering, similar to the previously described phenotype of the rab8T22N mutant. Proteomic analysis of RTCs accumulated upon Ppl treatment showed a significant decrease in phosphatidylinositol-4,5-bisphosphate–binding proteins ezrin and/or moesin. Ppl induced redistribution of moesin, actin and the small GTPase rac1 from RTCs into the cytosol. By confocal microscopy, ezrin/moesin and rac1 colocalized with rab8 on RTCs at the sites of their fusion with the plasma membrane; however, this distribution was lost upon Ppl treatment. Our data suggest that in photoreceptors phosphatidylinositol-4,5-bisphosphate, moesin, actin, and rac1 act in concert with rab8 to regulate tethering and fusion of RTCs. Consequentially, they are necessary for rhodopsin-laden membrane delivery to the ROS, thus controlling the critical steps in the biogenesis of the light-detecting organelle.