bluuebunny/crossref_metadata_2025 huggingface dataset:
THE DRUG DEVELOPMENT PROCESS AND THE PREGNANT WOMAN
Authors: Frederiksen Marilynn C.
Published: February 2003

The drug development process in the United States includes extensive pre‐clinical testing and a series of clinical trials designed to explore the safety and efficacy of a new drug entity. As part of this process, animal studies are conducted to assess the effects of the new drug on the reproductive process. These studies, called developmental and reproductive toxicology studies, form the basis for the information included in the current pregnancy subsection of the drug label. The new drug's effects on the human fetus are gathered through post‐marketing studies, usually observational registries. There is usually no information regarding the dose appropriate for pregnancy. The usual adult dose is assumed to be appropriate. Proposed changes to the current pregnancy subsection would replace the categories with narrative text, allow more detailed clinical management advice, including inadvertent fetal exposure, and provide a summary of risks associated with the drug. The sections on fertility, pregnancy and lactation would be combined, since they are a continuum. A provision is also being made to incorporate information from pharmacokinetic and pharmacodynamic studies relevant to pregnancy.
HORMONE REPLACEMENT THERAPY: SHORT‐TERM VERSUS LONG‐TERM USE
Authors: Rousseau Mary Ellen
Published: February 2003

Midwives manage health care of women throughout the life cycle including prescribing hormone replacement therapy (HRT). This article presents a history of research on the use of HRT, as well as risks and benefits. Older research on the effects of HRT on heart disease, osteoporosis, and breast cancer is included. The results and recommendations of the Women's Health Initiative are examined.
ADDRESSING THE EPIDEMIC: PHARMACOTHERAPEUTIC MANAGEMENT OF DIABETES IN WOMEN
Authors: Reedy Nancy Jo
Published: February 2003

Diabetes is epidemic in the United States. More than half of the victims are women, and women from vulnerable populations have particularly high rates of diabetes. In addition, long‐term complications of diabetes are contributing factors to poverty, disability, and premature death, and complications of diabetes are more common and more serious in women. The provision of health care to women with diabetes must include knowledge of the pharmacotherapeutic agents used to treat diabetes to provide care that compliments and does not complicate diabetes management.
Endostatin inhibits murine colon carcinoma sinusoidal-type metastases by preferential targeting of hepatic sinusoidal endothelium
Authors: Solaun Miren S. , Mendoza Lorea , De Luca Marco , Gutierrez Virginia , López Mari-Paz , Olaso Elvira , Lee Sim Kim B. , Vidal-Vanaclocha Fernando
Published: February 2003

An angiogenic response originating from peritumoral sinusoids and portal tracts that leads to the formation of metastases with sinusoidal- and portal-type angiogenic patterns, respectively, occurs during the course of liver colonization by murine 51b colon carcinoma (51b-CC) cells. We found a 5-fold increase in endogenous endostatin levels from hepatic blood over baseline (25 ± 6 ng/mL) when micrometastatic foci had a detectable size and a 14-fold increase when macrometastases were developed. Despite this endogenous endostatin production, subcutaneous administration of recombinant human endostatin (rh-E; 50 mg/kg) decreased metastasis number by 60% when dosed from days 1 to 20 after 51b-CC cell injection, by 40% when given from days 10 to 20, and by 30% when administered as a single dose 30 minutes before 51b-CC cell injection compared with controls. In addition, administration of rh-E from days 10 to 20 decreased overall metastasis volume by 90% compared with controls. rh-E increased the number of necrotic sinusoidal-type metastases by 7-fold and decreased their intrametastatic CD31+-microvessel density by 80% without affecting portal-type metastases. Flow cytometry showed rh-E binding to mouse liver sinusoidal cells but not to CD45+ cells (leukocytes and Kupffer cells) or 51b-CC cells. Furthermore, rh-E induced sinusoidal endothelium cell apoptosis. In conclusion, despite the direct correlation between metastasis development and endogenous endostatin generation in the liver, administration of rh-E inhibited micrometastasis generation and macrometastasis growth very efficiently. The antiangiogenic mechanism was selective for sinusoidal-type metastases, in which the neovasculature originating from sinusoidal endothelium cells was targeted by rh-E.
Relationship between acetaldehyde levels and cell survival in ethanol-metabolizing hepatoma cells
Authors: Clemens Dahn L. , Forman Andrew , Jerrells Thomas R. , Sorrell Michael F. , Tuma Dean J.
Published: February 2003

We have created a number of recombinant Hep G2 cell lines, designated VA cells, that constitutively express alcohol dehydrogenase. Oxidation of ethanol by the VA cells results in the production and accumulation of acetaldehyde, and a dramatic increase in the nicotinamide adenine dinucleotide, reduced (NADH)/nicotinamide adenine dinucleotide (NAD+) ratio (redox-state). It is believed that production of acetaldehyde, and the increase in the redox-state of hepatocytes, are responsible for many of the dysfunctions associated with alcoholic liver disease. When the VA cells were cultured in the presence of ethanol, we observed a dramatic reduction in cell accumulation. This reduction was more pronounced in cells that metabolized ethanol more efficiently. Inhibition of alcohol dehydrogenase activity abolished this reduction, demonstrating that ethanol oxidation was required for this dysfunction. Subsequent investigations indicated that this ethanol oxidation-mediated reduction in cell accumulation was the result of both cytotoxicity and impaired DNA synthesis. To dissociate the increase in the cellular redox-state from acetaldehyde production, VA cells were cultured in the presence of isopropanol. The oxidation of isopropanol results in similar redox changes, but the metabolic by-product of isopropanol oxidation is acetone. The metabolism of isopropanol by VA cells resulted in very little reduction in cell number. Furthermore, treatment of ethanol-metabolizing VA cells with the aldehyde dehydrogenase inhibitor, cyanamide, increased the levels of acetaldehyde and resulted in an additional reduction in cell number. In conclusion, these studies indicated that exposure to acetaldehyde caused cytotoxicity, as well as the ethanol oxidation-mediated reduction in cell number.
Cellular response to conditional expression of hepatitis C virus core protein in Huh7 cultured human hepatoma cells
Authors: Li Kui , Prow Tarl , Lemon Stanley M. , Beard Michael R.
Published: February 2003

Data suggesting that the hepatitis C virus (HCV) core protein influences normal cellular processes remain controversial. To determine the effects of core on cellular gene expression in hepatocytes, we developed a human hepatoma (Huh7)-derived cell line with tightly regulated core expression under the control of a tetracycline-regulated promoter. Cells expressing core did not have impaired proliferative abilities. Changes in gene expression profiles in response to core expression were determined using commercial oligonucleotide microarrays (Affymetrix GeneChip). Significant increases were observed in the abundance of mRNA-encoding members of the metallothionein (MT) family, as well as nicotinamide N-methyltransferase (NNMT) and glutathione peroxidase-like protein (GPLP). These changes did not result from removal of tetracycline from growth media, and were confirmed in reverse-transcription polymerase chain reaction (RT-PCR) assays. They suggest that core protein expression leads to intracellular oxidative stress, and that vital cellular functions are, in turn, protected by up-regulation of cellular antioxidant defense mechanisms. In conclusion, these findings can explain many potentially conflicting prior observations concerning the effects of core on cellular physiology, and are of relevance to the role of core protein in the pathogenesis of HCV-related fibrosis and hepatocellular carcinoma.
Mitochondrial oxidative stress and CD95 ligand: A dual mechanism for hepatocyte apoptosis in chronic alcoholism
Authors: Miñana Juan B. , Gómez-Cambronero Luis , Lloret Ana , Pallardó Federico V. , Del Olmo Juan , Escudero Amparo , Rodrigo José M. , Pellíin Antonio , Viña Juan R. , Viña José , Sastre Juan
Published: February 2003

Apoptosis plays an important role in the progression of alcohol-induced liver disease to cirrhosis. Oxidative stress is an early event in the development of apoptosis. The major aim of this study was to study the conditions in which oxidative stress occurs in chronic alcoholism and its relationship with apoptosis of hepatocytes. We have found that oxidative stress is associated with chronic ethanol consumption in humans and in rats, in the former independently of the existence of alcohol-induced liver disease. Ethanol or acetaldehyde induces apoptosis in hepatocytes isolated from alcoholic rats, but not in those from control rats. Inhibition of aldehyde dehydrogenase, but not of cytochrome P450 2E1, prevents ethanol-induced cell death. Ethanol-induced apoptosis is caused by increased reactive oxygen species (ROS) driven by increased availability of the reduced form of nicotinamide-adenine dinucleotide (NADH) owing to mitochondrial acetaldehyde metabolism and it is prevented by blocking the opening of mitochondrial permeability transition (MPT) pores with cyclosporine A. Inhibition of nitric oxide (NO) synthase or addition of antioxidant vitamins C and E completely prevented ethanol-induced apoptosis. Mitochondrial oxidative stress, which occurs during chronic alcoholism, renders hepatocytes susceptible to apoptosis. On the other hand, the CD95 ligand expression was up-regulated by acetaldehyde. In conclusion, ethanol induces apoptosis via 2 different pathways: MPT and up-regulation of the expression of CD95-Fas ligand. The overproduction of ROS by mitochondria, driven by acetaldehyde metabolism, is a common trigger of both mechanisms.
Extended preservation of rat liver graft by induction of heme oxygenase-1
Authors: Redaelli Claudio A. , Tian Ying-Hua , Schaffner Thomas , Ledermann Monika , Baer Hans U. , Dufour Jean-François
Published: February 2003

Livers can be preserved only for a short period without jeopardizing the transplantation outcome. Heat shock proteins (HSPs) protect against ischemia and reperfusion injury. We studied whether their induction and, in particular, the induction of heme oxygenase 1 (HO-1), improves transplantation survival after an extended time of cold storage. Rats were subjected to heat preconditioning (42°C for 20 minutes). Livers were harvested 24 hours later, preserved in cold University of Wisconsin solution for 44 hours, and transplanted in isogeneic rats (arterialized transplantation). HO-1 was specifically induced and inhibited by cobalt protoporphyrin and tin protoporphyrin, respectively. All animals receiving a graft without preconditioning and subjected to 44 hours of cold preservation died within 3 days, whereas 89% of rats who received a graft exposed to heat survived for 3 weeks (P = .0004). Preconditioning reduced serum aspartate transaminase (AST) and lactate dehydrogenase activities after reperfusion, improved bile flow, and decreased the histologic lesions of reperfusion injury. These significant effects of heat preconditioning were prevented by administration of tin protoporphyrin and could be reproduced by administration of cobalt protoporphyrin. In grafts without preconditioning, only a small fraction (<5%) of hepatocytes were positive with the terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) assay, and even less expressed activated caspase 3. Preconditioning tended to reduce the number of positive cells and to stimulate the expression of antiapoptotic Bcl-XL. In conclusion, heat preconditioning and, specifically, overexpression of HO-1 improve posttransplantation survival and graft function after prolonged cold ischemia preservation. The mechanism underlying these beneficial effects does not appear to be prevention of apoptosis.
Hepatocellular carcinoma and survival in patients with primary biliary cirrhosis
Authors: Shibuya Akitaka , Tanaka Katsuaki , Miyakawa Hiroshi , Shibata Minoru , Takatori Masao , Sekiyama Kazuhiko , Hashimoto Naoaki , Amaki Shuuichi , Komatsu Tatsuji , Morizane Toshio
Published: February 2003

The incidence of hepatocellular carcinoma (HCC) in patients with primary biliary cirrhosis (PBC) is not well known. The aims of this study are to determine HCC incidence and survival, and to identify risk factors associated with these outcomes in patients with PBC. We collected information on 396 patients with PBC at enrollment and followed-up from 6 to 271 months. They were all negative for hepatitis B and C virus markers. HCC was detected by scanning with ultrasonography, computed tomography, or both every 4 to 6 months. Life expectancy (LE) was approximated with the declining exponential approximation of LE. A total of 14 patients developed HCC. The cumulative appearance rate of HCC in patients with advanced-stage PBC (Scheuer's stage III or IV) was significantly higher than that for patients with early-stage (stage I or II) (12.3% and 7.7% by the tenth year, respectively. P = .021). Proportional hazards analysis showed 3 factors are independently associated with the development of HCC: age at the time of diagnosis, male gender, and history of blood transfusion. Age, male gender, and advanced-stage PBC were associated with survival, but HCC development was not. The disease-specific annual mortality rate was estimated to be 0.008 for women and 0.028 for men with advanced-stage PBC. In conclusion, HCC develops in old patients with advanced-stage PBC, but HCC does not affect the patients' survival.
A tamoxifen-inducible chimeric Cre recombinase specifically effective in the fetal and adult mouse liver
Authors: Tannour-Louet Mounia , Porteu Arlette , Vaulont Sophie , Kahn Axel , Vasseur-Cognet Mireille
Published: February 2003

The spatiotemporal control of somatic mutagenesis in mice is considered a promising step to determine the function of a given gene product in a defined population of cells at any given time during animal life and also to generate better mouse models of human diseases. To introduce defined mutations in a temporally controlled manner in the liver, we established transgenic mice expressing a tamoxifen-inducible Cre recombinase under the control of the transthyretin promoter (TTR-Cre ind). The recombinase activity was examined on 2 different floxed alleles by crossing TTR-Cre ind mice with either the reporter strain ROSA 26 or with homozygous mice carrying floxed catalytic α2 subunit of the adenosine monophosphate (AMP)-activated protein kinase gene. By placing 2 mutated hormone-binding domains of murine estrogen receptor (Mer) at both termini of the Cre, we show that the fusion protein is active only on administration of the synthetic estrogen antagonist 4-hydroxytamoxifen (4-OHT) without any background in the absence of the inducing agent. The recombination is specific of the fetal and adult liver, and we show that the efficiency of recombination reached 80% to 100% after treatment with 4-OHT. In conclusion, TTR-Cre ind transgenic mice represent a valuable tool for temporally controlling the desired gene modifications in vivo in the fetal and adult liver. This would certainly help to understand the physiologic functions of genes in the liver, to create various mouse models mimicking human diseases, and to contribute to liver cancer-specific suicide gene therapy studies.
Functional and genomic implications of global gene expression profiles in cell lines from human hepatocellular cancer
Authors: Lee Ju-Seog , Thorgeirsson Snorri S.
Published: February 2003

Global gene expression profiles in cancer have impacted both classification of tumors and definition of molecular pathways in neoplasia. To explore the possibility of employing human tumor cell lines to obtain information on the functional genomics of the early stages of tumorigenesis, we have characterized variation in gene-expression patterns in a cytogenetically well-defined series of cell lines derived from human hepatocellular carcinoma (HCC). Microarrays containing 6,720 sequence-verified human cDNAs were used in this study. Nineteen well-characterized HCC cell lines were analyzed, and a nontumorigenic liver-derived epithelial cell line (Chang) was used as a reference. Each sample was examined at least twice by switching fluorescent dyes, Cy-5 and Cy-3, and average values of 2 experiments on each sample were used for further analysis. Analysis of the clustered data revealed 2 distinctive subtypes of gene-expression patterns among the 19 cell lines, suggesting a degree of heterogeneity among the gene-expression profiles of cell lines. Remarkably, expression of α-fetoprotein (AFP) was highly correlated with the molecular subtypes of HCC. Although the 3 most distinctive gene-expression modules represented the signatures of 2 different subgroups of HCC, most of the cell lines shared many coexpressed genes. However, sets of coexpressed genes that are specific for the subtypes of HCC were identified. Furthermore, our results indicate that the comparison between gene-expression patterns and structural alterations in chromosomes is potentially useful in identifying genes critical in early stages of tumorigenesis. In conclusion, these results not only identified unrecognized subtypes of HCC, but also provided potential molecular markers for each subtype that can be useful for diagnostic and/or therapeutic purposes.
HFE mutations, hepatic iron, and fibrosis: Ethnic-specific association of NASH with C282Y but not with fibrotic severity
Authors: Chitturi Shivakumar , Weltman Martin , Farrell Geoffrey C. , McDonald David , Liddle Christopher , Samarasinghe Dev , Lin Rita , Abeygunasekera Shehan , George Jacob
Published: February 2003

There is conflicting evidence regarding inheritance of hemochromatosis gene (HFE) mutations and influence of hepatic iron deposition as cofactors for development of fibrosis in patients with nonalcoholic steatohepatitis (NASH). We studied hepatic iron content (Perls’ stain grade), frequency of HFE mutations, and serum iron indices in 93 patients with NASH from a multiethnic background; 59 (63%) were of Anglo-Celtic origin. Data on C282Y mutations were available for all 93 patients and on H63D for 69 patients. Respective controls were 206 (for C282Y, 141 [69%] of whom were Anglo-Celtic) and 180 (for H63D) blood donors. Hyperferritinemia was present in 38 patients (40%) with NASH, but transferrin saturation was increased (>55%) in only 5 (5%). Liver biopsy specimens showed advanced fibrosis in 31 (33%) (cirrhosis in 20%). Altogether, 9 biopsy specimens (10%) showed increased iron: 7 (8%) with grade 2 and 2 (2%) with grade 3 iron staining. Only 1 biopsy specimen with increased iron showed advanced fibrosis. The frequency of C282Y heterozygosity was increased in Anglo-Celtic patients with NASH compared with ethnic blood donor controls (22% vs. 9.2%; P = .035); there were no C282Y homozygotes in the NASH cohort. Although there was a trend toward higher serum ferritin levels among C282Y heterozygotes with NASH, there were no differences in histologic grades of steatosis, inflammation, or fibrosis between individuals with and without C282Y. The frequencies of compound C282Y/H63D heterozygotes (n = 1) or H63D heterozygotes (n = 10) were not increased in NASH. Multivariate analysis identified female sex, diabetes mellitus, and more severe liver inflammation but not HFE mutations, serum ferritin, iron saturation, or hepatic iron staining as independent predictors of hepatic fibrosis. In conclusion, hepatic iron is not a factor linked to hepatic fibrogenesis in patients with NASH. HFE mutations do not confer an additional risk of hepatic fibrosis in this disorder.
Management strategies using pharmacogenomics in patients with severe HCV-1b infection: A decision analysis
Authors: Moriguchi Hisashi , Uemura Takamoto , Kobayashi Makoto , Chung Raymond T. , Sato Chifumi
Published: February 2003

The management of interferon (IFN) therapy for histologically severe chronic hepatitis C virus genotype 1b (HCV-1b [F3]) is controversial. A decision analysis using the Markov decision analysis model was performed for 6 disease management strategies by using clinical data from a Japanese teaching hospital and available published data. The results of base case analyses showed that IFN monotherapy was considered favorable for patients aged 40 to 60 years with HCV-1b (F3). For the sensitivity analyses, to support the results of base case analyses, HCV-1b (F3) patient quality-of-life (QOL) score must be 0.5 or greater for those 40 to 50 years old and 0.4 to 0.5 or greater for those 60 years old. When patients with HCV-1b (F3) were judged as nonresponsive (NR) after IFN monotherapy, the transition probabilities of liver diseases at 40, 50, and 60 years of age had to be such that the progression of liver diseases was controlled at an annual rate of 7.51% to 8.82% or lower, 7.77% to 8.27% or lower, and 6.39% to 6.60% or lower, respectively, and the sustained virologic response (SVR) rate for IFN monotherapy must be 3.0% to 5.51% or greater, 5.57% to 5.93% or greater, and 10.6% to 11.21% or greater, respectively. It is likely that IFN monotherapy could be applied to patients with HCV-1b (F3) aged 40 years at a dose of at least 432 MU. However, IFN monotherapy did not appear useful for patients with HCV-1b (F3) aged 50 and 60 years if they had no amino acid mutation in NS5A 2209 to 2248 and HCV RNA levels exceeded 1.0 mEq/mL. In conclusion, use of decision analysis models can help in therapeutic decisions for patients with HCV-1b.
Reduced glutathione depletion causes necrosis and sensitization to tumor necrosis factor-α-induced apoptosis in cultured mouse hepatocytes
Authors: Nagai Hidenari , Matsumaru Katsuhiko , Feng Guoping , Kaplowitz Neil
Published: February 2003

The effect of reduced glutathione (GSH) depletion by acetaminophen (APAP), diethylmaleate (DEM), or phorone on the mode of cell death and susceptibility to tumor necrosis factor (TNF)-induced cell death was studied in cultured mouse hepatocytes. Dose-dependent necrosis was the exclusive mode of cell death with APAP alone, but the addition of TNF-α induced a switch to about half apoptosis without changing total loss of viability. This effect was seen at 1 and 5 mmol/L but was inhibited at 10 and 20 mmol/L APAP. The switch to apoptosis was associated with increased caspase activities, release of cytochrome c, and DNA laddering and was inhibited by caspase inhibitors. DEM and phorone also induced dose-dependent necrosis. Treatment with TNF-α under these conditions lead to incremental cell death in the form of apoptosis at 0.25 and 0.5 mmol/L DEM and 0.1 and 0.2 mmol/L phorone. At 1.0 and 2.0 mmol/L DEM and 0.5 mmol/L phorone, 90% to 100% necrosis was observed with resistance to TNF-α effects. The apoptosis with TNF-α plus DEM was confirmed by DNA laddering and inhibition by caspase inhibitors. However, in the presence of caspase inhibitors, the increment in cell death induced by TNF-α persisted as an increase in necrosis. A combination of antioxidants, vitamin E, and butylated hydroxytoluene (BHT) markedly inhibited necrosis induced by APAP or DEM alone, but the sensitization to TNF-α-induced apoptosis was unaffected. GSH monoethylester (GSH-EE) protected against necrosis and apoptosis. In conclusion, depletion of GSH by APAP, DEM, or phorone causes oxidative stress-induced necrosis and sensitizes to an oxidative stress independent TNF-α-induced apoptosis.
Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B
Authors: Perrillo Robert P. , Lai Ching-Lung , Liaw Yun-Fan , Dienstag Jules L. , Schiff Eugene R. , Schalm Solko W. , Heathcote Jenny E. , Brown Nathaniel A. , Atkins Mark , Woessner Mary , Gardner Stephen D.
Published: February 2003

Elevated alanine transaminase (ALT) levels and low serum hepatitis B virus (HBV) DNA predict a higher likelihood of hepatitis B e antigen (HBeAg) loss in patients with chronic hepatitis B treated with interferon. Predictors of HBeAg loss in patients treated with lamivudine are not known. The objective of this analysis of 4 lamivudine-controlled Phase III trials was to determine patient-dependent or laboratory variables that predict HBeAg loss. Predictors of HBeAg loss in patients treated with interferon, lamivudine plus interferon, or placebo are also described. A total of 805 adults with chronic hepatitis B were treated either with lamivudine (n = 406), matching placebo (n = 196), interferon (n = 68), or the combination of lamivudine plus interferon (n = 135). Demographic and baseline disease characteristics were used in stepwise multivariate analyses to identify features that were predictive of lamivudine-induced HBeAg loss. HBeAg loss correlated with increased pretreatment ALT levels in all groups. The rate of HBeAg loss was highest among patients with pretreatment ALT levels greater than 5 times the upper limit of normal (ULN) and was most pronounced in the lamivudine group (56%). Multivariate modeling indicated that elevated baseline ALT levels (P < .001) and histologic activity index (HAI) score (P < .001) were important predictors of HBeAg loss in response to lamivudine. The effect of pretreatment ALT levels on HBeAg loss was similar for Asians and Caucasians. In conclusion, elevated pretreatment ALT levels and/or active histologic disease were the most important predictors of lamivudine-induced HBeAg loss. Asians and Caucasians had similar rates of response to lamivudine at comparable ALT levels.
Ursodeoxycholic acid diminishes Fas-ligand-induced apoptosis in mouse hepatocytes
Authors: Azzaroli Francesco , Mehal Wajahat , Soroka Carol J. , Wang Lin , Lee John , Crispe Nicholas , Boyer James L.
Published: February 2003

Ursodeoxycholic acid (UDCA) can protect hepatocytes from apoptosis induced by a variety of stimuli including anti-Fas antibody. However, in vivo the Fas receptor is activated by its natural ligand, Fas-L, whereas anti-Fas antibodies are not a physiologic stimulus. We therefore have assessed the anti-apoptotic effects of UDCA and other bile acids in a novel coculture model where apoptosis is induced in murine hepatocytes by membrane-bound Fas-L expressing fibroblasts. Primary hepatocytes were cultured overnight on collagen-coated coverslips with increasing concentrations of different bile acids and overlaid with either NIH 3T3 Fas-L+ or Fas-L− expressing fibroblasts. After 6 hours cells were fixed and apoptosis was evaluated by TUNEL assay and DAPI staining using digital imaging. Fas-L protein expression and Fas trimerization were evaluated by Western blot analysis. FITC-UDCA and Mitotracker Red were used to evaluate UDCA localization with mitochondria. UDCA (up to 100 μmol/L, P < .0001), TUDCA (up to 400 μmol/L, P < .0001), and TCDCA (up to 200 μmol/L, P < .0001), but not TCA (up to 500 μmol/L), significantly protected hepatocytes in Fas-L+ cocultures. UDCA had no significant effect on hepatocytes in Fas-L− cocultures. TUDCA, 50 μmol/L (P < .001) and TCDCA up to 200 μmol/L (P < .0001) also reduced the hepatocytes apoptotic rate in Fas-L− cocultures. Bile acids did not affect Fas-L expression in fibroblasts or Fas trimerization. FITC-UDCA colocalized with the mitochondrial probe. In conclusion, UDCA, TUDCA, and TCDCA but not TCA are capable of protecting hepatocytes from Fas-L-induced apoptosis. This protective effect is not associated with reductions in Fas trimerization, but may be related to a direct effect on the mitochondrial membrane.
Hepatitis C infection and the patient with end-stage renal disease
Authors: Fabrizi Fabrizio , Poordad Fred F. , Martin Paul
Published: February 2003

Hepatitis C virus (HCV) remains common in patients with end-stage renal disease (ESRD) and is an important cause of liver disease in this population. Acquisition of HCV infection continues to occur in dialysis patients because of nosocomial spread. The natural history of HCV in dialysis patients remains controversial because the course of HCV typically extends over decades, whereas dialysis patients have higher morbidity and mortality rates than those of the general population limiting long-term follow-up. However, recent reports suggest that HCV infection affects the survival of chronic dialysis patients as well as renal transplant (RT) recipients. The severity of preexisting liver disease on pretransplantation liver biopsy may provide useful prognostic information about clinical outcome after RT; liver biopsy should be incorporated in the evaluation and management of RT candidates with HCV. Recent surveys with long-term follow-up have documented adverse effects of HCV on patient and graft survival. Use of renal grafts from HCV-infected donors in recipients with HCV does not appear to result in a greater burden of liver disease albeit with short-term follow-up. There is only limited data about interferon (IFN) therapy in chronic dialysis patients, although sustained responses are reported. Preliminary data on IFN plus ribavirin therapy in dialysis patients with hepatitis C have given encouraging results, but randomized trials are needed. Interferon remains contraindicated post-RT because of concern about precipitating graft dysfunction.
The effect of donor body mass index on primary graft nonfunction, retransplantation rate, and early graft and patient survival after liver transplantation
Authors: Yoo Hwan Y. , Molmenti Ernesto , Thuluvath Paul J.
Published: February 2003

Previous studies have suggested that moderate donor liver steatosis is associated with an increased incidence of primary graft nonfunction (PGNF), delayed graft function, early graft loss, and retransplantation rates. The objective of our study was to determine the effect of donor body mass index (dBMI), after adjusting for other known confounding variables, on PGNF, early graft failure, retransplantation rate, and patient survival. The United Network for Organ Sharing (UNOS) database (1987 to 2001) of 22,303 adult patients, excluding patients of pediatric age (age less than 18 years) and those with multiple organ transplantations, living donors, and retransplantations, was used for this study. Based on the BMI (kg/m2) of the organ donor, transplant recipients were divided into four groups as follows: BMI < 25 (group 1, n = 11,660), 25 to 29.9 (group 2, n = 7418), 30 to 34.9 (group 3, n = 2301), and ≥ 35 (group 4, n = 924). Information on donor liver histology was available for 1603 patients who underwent transplantation after 1999, and this subgroup was divided into three groups based on severity of steatosis (group A, < 20%; group B, 20% to 35%; group C, > 35%). Incidence of PGNF and early retransplantation rates were similar in groups 1 to 4 and in groups A, B, and C. Logistic regression analysis showed that dBMI or severity of steatosis was not a predictor of PGNF and early retransplantation. Cox regression analysis, after adjusting for confounding variables, showed similar patient and graft survival at 1 month and 1, 2, and 5 years for groups 1 to 4, and at 1 month and 6 months for groups A, B, and C. Severe donor obesity or moderate steatosis did not influence short-term and long-term outcome of liver transplantation.
ABO-incompatible liver transplantation with no immunological graft losses using total plasma exchange, splenectomy, and quadruple immunosuppression: Evidence for accommodation
Authors: Hanto Douglas W. , Fecteau Annie H. , Alonso Maria H. , Valente John F. , Whiting James F.
Published: February 2003

ABO-incompatible liver transplants (LTX) have been associated with a high risk of antibody-mediated rejection, poor patient and graft survival, and a high risk of vascular thrombosis and ischemic bile duct complications. We used pretransplantation and posttransplantation double-volume total plasma exchange (TPE), splenectomy, and quadruple immunosuppression (cyclophosphamide or mycophenolate mofetil, prednisone, cyclosporine or tacrolimus, and OKT3 induction) in 14 patients receiving ABO-incompatible LTX between June 1992 and February 2001: A1 to O (seven), B to O (two), B to A (two), A to B (one), AB to A (one), and AB to O (one). Actuarial 1- and 5-year patient and graft survival rates are 71.4% and 61.2 % and 71.4% and 61.2%, respectively, with a mean follow-up of 62.9 ± 39.4 months. Ten acute cellular rejections occurred, and the mean time to the first episode was 62 ± 33 days. All were steroid sensitive. No antibody-mediated rejection or vascular thromboses occurred. Pretransplantation pre-TPE immunoglobulin (Ig) G mean isohemagglutinin titers were 262 ± 326, compared with pretransplantation post-TPE titers of 65 ± 103 (P = .04). Eight of nine patients with measurable titers before and after TPE achieved a reduction in titers. The mean number of posttransplantation TPE was 5.5 ± 4.1 (range, 0 to 12), and the last TPE was on postoperative day 9.4 ± 5.3. IgG isohemagglutinin titers 2 weeks posttransplantation had increased to 153 ± 309 (P = .03 compared with pretransplantation pre-TPE IgG). ABO-incompatible liver transplantations can be performed with acceptable patient and graft survival rates with a low risk of antibody-mediated rejection with a combination of TPE, splenectomy, and quadruple immunosuppression. Recovery of isohemagglutinin antibody levels without humoral rejection suggests that accommodation may be the protective mechanism preventing late antibody-mediated rejection.
Assessment of the Motor Power in Older Children with Obstetric Brachial Plexus Palsy
Authors: AL-QATTAN M. M.
Published: February 2003

The King Saud University (KSU) muscle grading system used for assessing the upper limb in older children with obstetric brachial plexus palsy is presented and compared to other muscle grading systems.
Obstetric Brachial Plexus Lesions: A Study of 74 Children Registered with the British Paediatric Surveillance Unit (March 1998–March 1999)
Authors: BISINELLA G. L. , BIRCH R.
Published: February 2003

Seventy-four children with obstetric brachial plexus palsy registered with the British Paediatric Surveillance Unit were prospectively followed for a minimum of 2 years. Thirty-nine (52.7%) spontaneously recovered to normal or nearly normal levels and a further 29 (39.3%) regained good function in the upper limb. The most important secondary deformity involved the gleno-humeral joint and 20 patients (27%) needed surgical correction. Two more children await operation for shoulder deformity. The brachial plexus was explored in nine patients (12.2%) and repaired in seven.
Avulsion Fractures from the Base of the Proximal Phalanges of the Fingers
Authors: SHEWRING D. J. , THOMAS R. H.
Published: February 2003

Thirty-three patients with avulsion fractures from the base of the proximal phalanges were treated during a 6-year period. All eight fractures treated conservatively failed to unite and subsequently required surgery. The remaining 25 patients were treated with primary internal fixation using a single lag screw through a palmar approach. Surgery gave excellent results in all cases and all patients achieved a full range of movement within 3 weeks.
Restoration of Pinch Grip in Ulnar Nerve Paralysis: Extensor Carpi Radialis Longus to Adductor Pollicis and Abductor Pollicis Longus to First Dorsal Interosseus Tendon Transfers
Authors: FISCHER T. , NAGY L. , BUECHLER U.
Published: February 2003

A double tendon transfer was used to restore thumb pinch in nine consecutive patients. The extensor carpi radialis longus was transferred to the adductor pollicis tendon and one slip of the abductor pollicis longus was transferred to the first dorsal interosseus tendon. The patients were followed for 6 (range, 2–10) years and there were no instances of transfer rupture. Selective recruitment of the motors of the transfers was possible in all cases. Their amplitude was considered adequate for all the cases of adductor transfers but was limited in all of the first dorsal interosseus ones. Key pinch was 73% (range, 41–104%), the pulp-to-pulp pinch was 72% (range, 50–95%) and the power grip was 73% (range, 35–91%) of the opposite hand. The force of thumb adduction was 63% (range, 27–132%) and of index finger abduction was 58% (range, 21–104%) of the unaffected side.
A Comparison of ex vivo and in vitro Sutter Metacarpophalangeal Prostheses
Authors: JOYCE T. J. , MILNER R. H. , UNSWORTH A.
Published: February 2003

Forty-one Sutter metacarpophalangeal prostheses were implanted into 11 hands of nine patients. Twelve of these prostheses were revised from three patients after a mean period of 42 months. Of the 12 prostheses, 11 showed fracture at the junction of the distal stem and the central hinge region. Two Sutter metacarpophalangeal prostheses were tested on a single station finger simulator and both failed due to fracture at the junction of the hinge and the distal stem.
Minimally Displaced Colles’ Fractures: A Prospective Randomized Trial of Treatment With a Wrist Splint or a Plaster Cast
Authors: O’CONNOR D. , MULLETT H. , DOYLE M. , MOFIDI A. , KUTTY S. , O’SULLIVAN M.
Published: February 2003

Sixty-six adult patients with minimally displaced distal radial fractures were randomly assigned to treatment with either a plaster cast or a lightweight removable wrist splint. Outcome assessment was by clinical and radiological evaluation and an independent physiotherapy assessment. There were significant differences between the treatments for cast satisfaction, cast problems and the functional assessment score at 6 weeks, with the removable splint scoring better in all cases.
Carpal Tunnel Syndrome – Is High-Frequency Ultrasound a Useful Diagnostic Tool?
Authors: LEONARD L. , RANGAN A. , DOYLE G. , TAYLOR G.
Published: February 2003

This study assessed the clinical use of three ultrasound measurements; median nerve cross-sectional area, median nerve flattening ratio and palmar displacement of the flexor retinaculum, for the diagnosis of carpal tunnel syndrome. The measurements were made in 20 carpal tunnel sufferers and 20 controls. The sensitivity, specificity and predictive values of each were calculated in various clinical settings. Values for each of the three variables were significantly different in the patient and control populations. The differences we recorded were smaller than those found in previous studies. The tests had a sensitivity of 72% and a specificity of 90%. Alterations in the morphology of the carpal tunnel in patients with carpal tunnel syndrome can be measured in the district general hospital setting. The measurements described maybe a useful non-invasive confirmatory test in patients in whom there is a strong clinical suspicion of carpal tunnel syndrome. However, they would be of no benefit in epidemiological surveys of populations with a low incidence of carpal tunnel syndrome.
An Analysis of Time and Staff Utilization for Open Versus Percutaneous Tracheostomies
Authors: Kaylie David M. , Andersen Peter E. , Wax Mark K.
Published: February 2003

OBJECTIVE

We examined staff utilization and procedure length for percutaneous and open bedside tracheostomies in an intensive care setting

STUDY DESIGN

Prospective clinical outcomes study.

METHODS

Intensive care unit (ICU) tracheostomy consults meeting criteria for bedside procedures were randomized to open or percutaneous procedures. The Cook percutaneous kit and a prepackaged tracheostomy tray were used. ICU nursing and respiratory therapy staff was present for all procedures. The total resident time, staff time, and procedure length were recorded. Twelve patients underwent percutaneous tracheostomy, and 12 received an open tracheostomy.

RESULTS

An operating room nurse was present for 7 of the open procedures. Ancillary medical staff was present for 3 open tracheostomies: anesthesia for 2 and critical care for 1. Ancillary medical staff was present for 4 percutaneous tracheostomies: anesthesia staff for 1 and critical care for 3. The average resident presence, staff presence, and procedure length for open tracheostomies were 47, 30, and 12 minutes, respectively. For percutaneous tracheostomies, the times were 39, 29, and 12 minutes, respectively. One intraoperative complication occurred during a percutaneous procedure and 2 perioperative complications occurred: 1 in the open group and 1 in the percutaneous group.

CONCLUSIONS

There was no significant difference in procedure length, resident time, or staff time between the 2 procedures. Ancillary staff was occasionally used but was not thought to be necessary for the majority of procedures. Both procedures can be safely and expediently performed in the ICU.
A Population‐Based Analysis of Survival Factors in Differentiated and Medullary Thyroid Carcinoma
Authors: Bhattacharyya Neil
Published: February 2003

OBJECTIVE

The study purpose was to determine survival and prognostic factors for differentiated thyroid carcinoma (DTC).

METHODS

Cases of DTC were extracted from the Surveillance, Epidemiology and End Results database from 1988 through 1998. Kaplan‐Meier survival analysis was conducted for papillary, follicular, and medullary histologies. Cox proportional hazard analysis was used to examine the influence of age, gender, tumor size, local extension, and cervical node involvement on overall survival.

RESULTS

A total of 18,118 cases were identified, including 15,820 (87.3%) papillary carcinomas, 1799 (9.9%) follicular carcinomas, and 499 (2.8%) medullary carcinomas. Mean survival (10‐year survival) was 122 (87.7%), 117 (80.2%), and 108 (73.7%) months for papillary, follicular, and medullary tumors, respectively. For each histology, increasing age, male gender, and degree of local extension substantially reduced survival. Cervical metastasis did not influence survival for papillary or follicular carcinomas but approached significance for medullary carcinoma (P = 0.065).

CONCLUSIONS

Degree of local extension in thyroid carcinoma should be subclassified to more accurately determine prognosis. Treatment of the neck should be considered for medullary thyroid carcinoma.
Increased Independence and Decreased Vertigo after Vestibular Rehabilitation
Authors: Cohen Helen S. , Kimball Kay T.
Published: February 2003

OBJECTIVE

We sought to determine the effectiveness in decreasing some symptoms, such as vertigo, and increasing performance of daily life skills after vestibular rehabilitation.

STUDY DESIGN AND SETTING

Patients who had chronic vertigo due to peripheral vestibular impairments were seen at a tertiary care center. They were referred for vestibular rehabilitation and were assessed on vertigo intensity and frequency with the use of the Vertigo Symptom Scale, the Vertigo Handicap Questionnaire, the Vestibular Disorders Activities of Daily Living Scale, and the Dizziness Handicap Inventory. They were then randomly assigned to 1 of 3 home program treatment groups.

RESULTS

Vertigo decreased and independence in activities of daily living improved significantly. Improvement was not affected by age, gender, or history of vertigo.

CONCLUSION

For many patients a simple home program of vestibular habituation head movement exercises is related to reduction in symptoms and increasing independence in activities of daily living.
Allergy and Chronic Rhinosinusitis
Authors: Krause Helen Fox
Published: February 2003

Allergy and its relationship to chronic rhinosinusitis are important contemporary topics in the practice of otolaryngology. The relationship may go unrecognized. It is important to understand the current knowledge.
Development of Interface in Hydroxyapatite Implanted in the Middle Ear of the Rat: A Light and Scanning Microscopy Study
Authors: Pinilla M. , Ramírez‐Camacho R. , Salas C. , González F. , López‐Cortijo C. , Vergara J.
Published: February 2003

OBJECTIVE

The aim of this work is to study the chronology in the biological covering of the hydroxyapatite bioprostheses in the healthy middle ear of the rat.

STUDY DESIGN AND SETTING

Dense hydroxyapatite is implanted into the middle ear of 45 Long‐Evans rats, between stapes and tympanic membrane. The sample was divided into 3 groups for morphologic, functional, and chemical studies at 15 days, 3 months, and 6 months after surgery, respectively.

RESULTS

The short‐term studies reveal that the prostheses is surrounded by a fibrous epithelial tissue referred as the interface; it presents a marked inflammatory reaction that decreases gradually in the medium‐term and long‐term studies; in this way, we observe a progressive adhesion between implant and the contact tissues.

CONCLUSIONS AND SIGNIFICANCE

This model has enabled us to study the cell reaction produced by the contact of the prostheses with bone and soft tissue and their impact on the functional qualities of the prostheses.
Activity of Matrix Metalloproteinases‐2 and ‐9 in Advanced Laryngeal Cancer
Authors: Bogusiewicz Michal , Stryjecka‐Zimmer Marta , Szymanski Marcin , Rechberger Tomasz , Golabek Wieslaw
Published: February 2003

OBJECTIVES

Matrix metalloproteinases‐2 and ‐9 (MMP‐2 and MMP‐9) are proteolytic enzymes that digest collagen type IV and other components of the basement membrane. They play a key role in local invasion and the formation of distant metastases by malignant tumors. The aim of this study was to evaluate the activity of MMP‐2 and MMP‐9 in stage III and IV laryngeal cancers.

STUDY DESIGN

In the study we used specimens of laryngeal cancer and surrounding normal mucosa obtained from 23 patients undergoing surgical treatment as a primary therapy. After extraction of MMP‐2 and MMP‐9 from tissue samples, their activity was assessed with zymography.

RESULTS

Greater activity of MMP‐2 and MMP‐9 and a higher active/latent MMP‐2 ratio were found in cancer compared with normal mucosa. Moreover, N2 tumors revealed greater activity of MMP‐2 in comparison with N1 and N0 tumors.

CONCLUSIONS

Results of the study indicate that both MMP‐2 and MMP‐9 may be involved in the expansion of laryngeal cancer. MMP‐2 may also play an important role in the lymphatic spread of some laryngeal tumors.
The eigenvalue problem for the p‐Laplacian‐like equations
Authors: Chen Zu-Chi , Luo Tao
Published: February 2003

We consider the eigenvalue problem for the following p‐Laplacian‐like equation: −div(a(|Du|p)|Du|p−2Du) = λf(x, u) in Ω,
u = 0 on ∂Ω, where Ω ⊂ ℝn is a bounded smooth domain. When λ is small enough, a
multiplicity result for eigenfunctions are obtained. Two examples
from nonlinear quantized mechanics and capillary phenomena,
respectively, are given for applications of the theorems.
On the spectra of non‐selfadjoint differential operators and their adjoints in direct sum spaces
Authors: Ibrahim Sobhy El-Sayed
Published: February 2003

The general ordinary quasidifferential expression Mp of nth
order, with complex coefficients and its formal adjoint on any finite number of intervals
Ip = (ap, bp), p = 1, …,
N, are considered in the setting of the direct sums of
‐spaces of functions defined on each of the separate intervals. And a number of results concerning the location of the point spectra and regularity fields of general differential operators generated by such expressions are obtained.
Hilbert series and applications to graded rings
Authors: Altinok Selma
Published: February 2003

This paper contains a number of practical remarks on Hilbert
series that we expect to be useful in various contexts. We use the
fractional Riemann‐Roch formula of Fletcher and Reid to write out
explicit formulas for the Hilbert series P(t) in a number of
cases of interest for singular surfaces (see Lemma 2.1) and 3‐folds. If X is a ℚ‐Fano 3‐fold and S ∈   | − KX| a K3 surface in its anticanonical
system (or the general elephant of X), polarised with D = 𝒪S (−KX), we determine the relation between PX(t) and PS,D(t). We discuss the denominator
of P(t) and, in particular, the question of
how to choose a reasonably small denominator. This idea has
applications to finding K3 surfaces and Fano 3‐folds whose
corresponding graded rings have small codimension. Most of the
information about the anticanonical ring of a Fano 3‐fold or
K3 surface is contained in its Hilbert series. We believe that,
by using information on Hilbert series, the classification of
ℚ‐Fano 3‐folds is too close. Finding K3 surfaces are
important because they occur as the general elephant of a
ℚ‐Fano 3‐fold.