Blood gene expression signatures predict exposure levels.

To respond to potential adverse exposures properly, health care providers need accurate indicators of exposure levels. The indicators are particularly important in the case of acetaminophen (APAP) intoxication, the leading cause of liver failure in the U.S. We hypothesized that gene expression patterns derived from blood cells would provide useful indicators of acute exposure levels. To test this hypothesis, we used a blood gene expression data set from rats exposed to APAP to train classifiers in two prediction algorithms and to extract patterns for prediction using a profiling algorithm. Prediction accuracy was tested on a blinded, independent rat blood test data set and ranged from 88.9% to 95.8%. Genomic markers outperformed predictions based on traditional clinical parameters. The expression profiles of the predictor genes from the patterns extracted from the blood exhibited remarkable (97% accuracy) transtissue APAP exposure prediction when liver gene expression data were used as a test set. Analysis of human samples revealed separation of APAP-intoxicated patients from control individuals based on blood expression levels of human orthologs of the rat discriminatory genes. The major biological signal in the discriminating genes was activation of an inflammatory response after exposure to toxic doses of APAP. These results support the hypothesis that gene expression data from peripheral blood cells can provide valuable information about exposure levels, well before liver damage is detected by classical parameters. It also supports the potential use of genomic markers in the blood as surrogates for clinical markers of potential acute liver damage.

Randomized, double-blind, dose-ranging trial of the oral neurokinin-1 receptor antagonist casopitant mesylate for the prevention of cisplatin-induced nausea and vomiting.

BACKGROUND: Casopitant mesylate is a novel, oral neurokinin-1 receptor antagonist with demonstrated antiemetic efficacy. We conducted a randomized, double-blind, controlled phase II trial to evaluate three casopitant doses as part of a triple-therapy regimen for the prevention of nausea and vomiting associated with high-dose cisplatin. The aim of the study was to detect a dose response. PATIENTS AND METHODS: A total of 493 patients with solid tumors receiving a first cycle of cisplatin > or =70 mg/m(2) were randomly assigned among six treatment arms. The primary analysis compared a control arm [ondansetron/dexamethasone (Ond/Dex)] with three investigational treatments (Ond/Dex plus oral casopitant 50, 100, or 150 mg administered daily for 3 days). Two exploratory arms were included: one evaluating a single oral casopitant dose of 150 mg added to standard Ond/Dex and another with 3-day oral aprepitant-based therapy (Ond/Dex plus aprepitant 125 mg day 1, 80 mg days 2-3). RESULTS: The complete response (CR) rate (defined as no vomiting, retching, rescue therapy, or premature discontinuation) was significantly increased in each casopitant arm relative to control over the 120-h evaluation period: 76% (50 mg), 86% (100 mg), 77% (150 mg), and 60% with control (P = 0.0036). The CR rate for the single oral dose regimen was similar to the CR rate reported for the 3-day regimens. No differences were observed in the incidence of nausea or significant nausea among groups in the primary analysis. The most common adverse events related to treatment included headache (n = 10) and hiccups (n = 14). CONCLUSION: All doses of oral casopitant as a 3-day regimen (and likely as a 150-mg single oral dose) in combination with Ond/Dex provided significant improvement in the prevention of cisplatin-induced emesis.

Transcriptional activity of the zinc finger protein NGFI-A is influenced by its interaction with a cellular factor.

NGFI-A is an immediate-early gene that encodes a transcription factor whose DNA-binding domain is composed of three zinc fingers. To define the domains responsible for its transcriptional activity, a mutational analysis was conducted with an NGFI-A molecule in which the zinc fingers were replaced by the GAL4 DNA-binding domain. In a cotransfection assay, four activation domains were found within NGFI-A. Three of the activation domains are similar to those characterized previously: one contains a large number of acidic residues, another is enriched in proline and glutamine residues, and another has some sequence homology to a domain found in Krox-20. The fourth bears no resemblance to previously described activation domains. NGFI-A also contains an inhibitory domain whose removal resulted in a 15-fold increase in NGFI-A activity. This increase in activity occurred in all mammalian cell types tested but not in Drosophila S2 cells. Competition experiments in which increasing amounts of the inhibitory domain were cotransfected along with NGFI-A demonstrated a dose-dependent increase in NGFI-A activity. A point mutation within the inhibitory domain of the competitor (I293F) abolished this property. When the analogous mutation was introduced into native NGFI-A, a 17-fold increase in activity was observed. The inhibitory effect therefore appears to be the result of an interaction between this domain and a titratable cellular factor which is weakened by this mutation. Downmodulation of transcription factor activity through interaction with a cellular factor has been observed in several other systems, including the regulation of transcription factor E2F by retinoblastoma protein, and in studies of c-Jun.

Endoscopic treatment of patients with portal hypertension.

This article discusses endoscopic treatment of patients with sequelae from portal hypertension. The literature on endoscopic therapy for primary and secondary prophylaxis of esophageal varices is reviewed. Therapeutic approaches to less commonly seen entities, such as portal gastropathy and portal colopathy, are discussed.

Impact of dialysis and older age on survival after liver transplantation.

Because creatinine is heavily weighed in the MELD (model for end-stage liver disease) score, we sought to determine the impact of MELD-based organ allocation on outcomes after transplantation in the pre- and post-MELD eras, focusing on recipients over age 65 on dialysis prior to transplant. A total of 20 196 patients from the UNOS database were analyzed. Comparing the pre-MELD to MELD era, there was a 41% increase in patients on dialysis (p<0.0001), and a 117% increase in combined liver/kidney transplants (p<0.0001). In the pre-MELD era, 1-year patient survival in recipients greater and less than age 65 on dialysis who received liver transplant alone was 56.8% and 76.4%, respectively (p=0.13). In the MELD era these rates were 50.7% and 77.8% (p=0.04). In the pre-MELD era, 1-year patient survival in recipients greater and less than age 65 on dialysis who underwent combined liver/kidney transplantation was 25.0% and 83.2%, respectively (p=0.0002). In the MELD era, these rates were 67.0% and 82.5% (p=0.18). In conclusion, a greater proportion of patients in the MELD era are on dialysis prior to transplant, and more receive combined liver/kidney transplants compared with the pre-MELD era. Candidates over age 65 who are on dialysis at the time of transplant have decreased survival after isolated liver transplantation.

Should patients with chronic hepatitis C who have normal ALT levels be treated?

Up to 25% of patients with chronic hepatitis C have persistently normal serum alanine aminotransferase (ALT) levels. Reports from some studies indicate that patients with normal ALT levels are more likely to be female and nondrinkers. Patients with persistently normal aminotransferase levels often have mild disease on liver biopsy with little or no fibrosis, but a small number of patients may have substantial fibrosis or cirrhosis. Treatment with interferon monotherapy has been disappointing. Combination therapy with interferon and ribavirin is controversial, but early clinical results have shown good response rates. Currently, therapy for chronic HCV patients with normal ALT levels should be based upon results from liver biopsy and preferably be done in the context of a clinical trial.

Identification of NAB1, a repressor of NGFI-A- and Krox20-mediated transcription.

NGFI-A (also called Egr1, Zif268, or Krox24) and the closely related proteins Krox20, NGFI-C, and Egr3 are zinc-finger transcription factors encoded by immediate-early genes which are induced by a wide variety of extracellular stimuli. NGFI-A has been implicated in cell proliferation, macrophage differentiation, synaptic activation, and long-term potentiation, whereas Krox20 is critical for proper hindbrain segmentation and peripheral nerve myelination. In previous work, a structure/function analysis of NGFI-A revealed a 34-aa inhibitory domain that was hypothesized to be the target of a cellular factor that represses NGFI-A transcriptional activity. Using the yeast two-hybrid system, we have isolated a cDNA clone which encodes a protein that interacts with this inhibitory domain and inhibits the ability of NGFI-A to activate transcription. This NGFI-A-binding protein, NAB1, is a 570-aa nuclear protein that bears no obvious sequence homology to known proteins. NAB1 also represses Krox20 activity, but it does not influence Egr3 or NGFI-G, thus providing a mechanism for the differential regulation of this family of immediate-early transcription factors.

A national survey of practice patterns of gastroenterologists with comparison to the past two decades.

Previous surveys on the practice of gastroenterology collected limited data on practice demographics. Gastroenterology practices may have changed over the past decade as a result of changes in health care delivery. The authors sought to describe the practice composition and demographics of today's gastroenterologist, and also to make comparisons to prior studies to determine whether changes have occurred. A nationwide cross-sectional survey was performed in 1997 of 900 American Gastroenterological Association (AGA) members selected randomly from the AGA directory. A total of 767 AGA members were eligible for the study, and 376 responded (response rate, 49%). The mean age was 46 years old and the mean year training was completed was 1982. The majority of gastroenterologists were in solo or group practice (57%) and in an urban setting (55%). Respondents were fairly equally represented from different regions of the country. The most common diagnosis seen was irritable bowel syndrome ([IBS] 19%), followed by esophageal reflux (17%) and inflammatory bowel disease (14%). Functional disorders as a group (IBS, nonulcer dyspepsia, and other functional disorders) were, by far, the most common disorders (35%), which is similar to findings in prior studies of gastrointestinal practices. Only 3% of gastroenterologists believed that managed care has made it easier to deliver quality health care to patients with IBS. Despite changes that have occurred in health care over the past decade, the types of diagnoses seen in gastroenterology practices has remained the same. Most gastroenterologists feel that managed care has not made it easier to deliver quality health care.

Cost-effectiveness analysis of transjugular intrahepatic portosystemic shunt (TIPS) versus endoscopic therapy for the prevention of recurrent esophageal variceal bleeding.

For the prevention of recurrent esophageal variceal bleeding, studies show that patients treated with transjugular intrahepatic portosystemic shunt (TIPS) have lower rebleeding rates compared with endoscopic therapy. However, TIPS is associated with higher rates of portosystemic encephalopathy and possibly higher costs. The aim of this study was to conduct a cost-effectiveness analysis comparing TIPS with endoscopic sclerotherapy and endoscopic ligation for the prevention of recurrent esophageal variceal bleeding. Data for rates of rebleeding, death, complications, and crossover from endoscopy to TIPS were obtained from the literature. Costs for procedures and hospitalizations were obtained from two medical centers. Sensitivity analyses were performed varying probabilities of key variables. The patient population consisted of a hypothetical cohort of cirrhotic patients successfully treated for esophageal variceal bleeding with endoscopic sclerotherapy who received prophylactic sclerotherapy, ligation, or TIPS over 1 year. Endoscopic patients would receive propranolol. Mortality was similar for the three groups. The number of bleeds per patient for sclerotherapy, ligation, and TIPS would be 0.39, 0.32, and 0.07, respectively. The total annual costs per patient for sclerotherapy, ligation, and TIPS were $23,459, $23,111, and $26,275, respectively. The incremental cost per bleed prevented for TIPS compared with sclerotherapy and ligation was $8,803 and $12, 660, respectively. The incremental cost per bleed prevented for TIPS compared with sclerotherapy or ligation was sensitive to the cost of TIPS and the TIPS stenosis rate. Ligation had lower costs and lower recurrent bleeding rates than sclerotherapy. Compared with endoscopic therapy, TIPS leads to lower recurrent variceal bleeding rates and it is more cost effective in the short term for the prevention of recurrent esophageal variceal bleeding.

Identification of residues in the nucleotide binding site of the epidermal growth factor receptor/kinase.

We have purified the epidermal growth factor receptor/kinase from A431 membrane vesicles which had been affinity labeled with the ATP analog, 5'-p-fluorosulfonylbenzoyl[8-14C]adenosine. The resulting purified, affinity labeled receptor/kinase preparation has been subjected to reduction and carboxymethylation followed by tryptic digestion. From this digest, we have isolated and sequenced the tryptic peptide containing the major site of labeling by the ATP analog. The sequence of this peptide is Ile-Pro-Val-Ala-Ile-X-Glu-Leu, where X corresponds to Lys 721 of the derived sequence of the EGF receptor/kinase.

Effectiveness and economic impact of screening for colorectal cancer by mass fecal occult blood testing.

OBJECTIVES: Fecal occult blood testing has been shown to reduce mortality from colorectal cancer in large randomized, controlled trials conducted in the United States, Denmark, and the United Kingdom, and mathematical simulation modeling found it to be cost-effective relative to other health care services. Before making a concerted effort to implement mass fecal occult blood testing based on this evidence alone, however, we considered it prudent to critically re-evaluate the effectiveness and economic impact of screening in the US population as a whole. METHODS: To assess the effectiveness of screening, we projected published outcomes from each of the three large randomized controlled trials of fecal occult blood testing to the US population, as if each clinical trial had been done in the population as a whole. We then determined the resource costs of detection and treatment that would be associated with the outcomes predicted from each trial. RESULTS: More than 1 million colorectal cancers could be expected to arise over 10 yr in the cohort of US residents eligible to enter a screening program in 1997, and trial outcomes indicate that > or = 60% of these cancers would be fatal. If the 60-67% compliance rate of the population-based randomized controlled trials were achieved, a fecal occult blood testing program would detect 30% of known colorectal cancers and save 100,000 lives over 10 yr. Screening would incur total costs of $3-4 billion over 10 yr, or $2,500 per life-year saved. CONCLUSIONS: Mass fecal occult blood testing is cost-effective, and, although not inexpensive, many would consider the total cost acceptable. Even with a concerted effort to achieve compliance, however, the effectiveness of fecal occult blood testing would be limited to saving the lives of < or = 15% of those who otherwise would die from their cancer in the first 10 yr after beginning mass screening. The limitations of fecal occult blood testing suggest the need to further evaluate the role of endoscopy in screening, and to develop more effective, noninvasive screening tools.

Plasma selenium levels and the risk of colorectal adenomas.

Previous research has suggested that selenium may protect against the development of colorectal neoplasia. We examined the potential chemopreventive properties of selenium against colorectal adenomas while controlling for a number of dietary and life-style factors. We conducted a cross-sectional study among patients referred for colonoscopy to University of North Carolina Hospitals. Cases had one or more pathologically confirmed adenomas, and noncases had none. Plasma selenium levels were determined using graphite furnace atomic absorption spectrometry with Zeeman background correction and platform technique. Odds ratios were calculated using logistic regression analysis adjusting for potential confounders. The mean plasma selenium concentrations for cases (n = 37) and noncases (n = 36) were 107 and 120 micrograms/l, respectively (p = 0.06). Those in the fourth quartile of plasma selenium level had 0.24 times the risk (95% confidence interval = 0.06-1.04) for colorectal adenomas of those in the first quartile. The adjusted odds ratio for colorectal adenomas was 0.58 (95% confidence interval = 0.31-1.08) for a 30 microgram/l increase in plasma selenium level. Lower plasma selenium levels were associated with multiple adenomas but not with adenoma size or location. These data support a protective effect of selenium against colorectal adenomas after adjustment for possible confounders. Selenium might be a potentially useful chemopreventive agent for colorectal neoplasia.

Payer status, but not race, affects the cost of liver transplantation.

Prior studies evaluating the impact of race and payer on cost of liver transplantation did not adjust for clinical factors known to increase cost. We analyzed the impact of race and payer on the cost of liver transplantation after controlling for clinical factors. We analyzed data obtained on patient and graft survival, cost, race, age, sex, payer, and United Network for Organ Sharing (UNOS) status from 153 consecutive liver transplants in 130 patients performed at University of North Carolina Hospitals from September 1991 through December 1996. Race was classified as white or nonwhite, and payer status was classified as commercial or Medicare/Medicaid. Multivariate linear regression was used to compare costs, adjusting for age, sex, race, payer, and UNOS status. For the 130 patients, 1-year patient and graft survival rates were 88% and 82%, respectively. There were no significant differences in patient and graft survival or in the unadjusted average cost of liver transplantation by race or payer. After adjusting for demographic and clinical factors, the cost of transplantation was $28,494 more for Medicare/Medicaid recipients compared with the commercial insurance recipients (P = .02). The Medicare/Medicaid group had higher intensive care unit costs compared with the commercial insurance group ($17,807 and $9,359, respectively; P = .03), and a longer length of stay (41 and 31 days, respectively; P = .04). There was no significant difference in cost between whites and nonwhites adjusting for these factors. Medicare or Medicaid patients had a higher cost of transplantation compared with those with commercial insurance. The cost of liver transplantation was similar for whites and nonwhites.