Summary. The clinical significance of elevated serum alpha‐fetoprotein (AFP) in patients with chronic hepatitis C virus (HCV) infection is not well defined. We analysed data from a population‐based cohort of patients with HCV infection to assess the prevalence of elevated serum AFP, to determine its association with clinical and virologic parameters and with clinical outcomes. We defined a slightly elevated serum AFP level as 8 to <15 and a high‐AFP level as ≥15 μg/L. Among 541 HCV‐RNA‐positive persons, 61 (11%) had a slightly elevated or high AFP at the time of consent. AFP ≥8 μg/L was associated with the older age, aspartate aminotransferase/alanine aminotransferase ratio >1, and higher alkaline phosphatase levels, but not with heavy alcohol use, IV drug use, genotype, viral load or duration of HCV infection. Among 192 persons with an AFP at liver biopsy, 17% had an AFP ≥8 μg/L. The sensitivity/specificity of an AFP level ≥8 in detecting Ishak 3–6 fibrosis was 39%/95%. Among 372 persons with a minimum of four AFP measurements over 6 years, 5% had persistently elevated AFP >8 μg/L, 19% had both elevated and normal AFP measurements, and 76% had persistently normal AFP. Elevated AFP at consent was associated with hepatocellular carcinoma (HCC) and end‐stage liver disease. Over 6 years of follow‐up, persistently elevated AFP was associated with the development of HCC; no person with AFP persistently <8 μg/mL developed HCC. Serial AFP measurements appear to be useful in identifying persons with advanced fibrosis and help to determine who needs periodic screening with liver ultrasound to detect HCC.

Summary. Liver biopsy is the primary method of assessing liver injury in hepatitis C patients. FIBRO Spect II (FS), a diagnostic panel of three extracellular matrix remodelling markers, may be useful as a noninvasive alternative to this procedure. The purpose of this study was to correlate FS results with liver fibrosis scores to determine if this test is sufficiently accurate to be a viable alternative to liver biopsy. A total of 142 serum specimens were evaluated for fibrosis with FS and were compared with Knodell and Ishak fibrosis scores. FS reports an index score ranging from 0.1 to 1.0, which corresponds to the probability of progressive liver fibrosis. Using a FS index cut‐off of 0.42, 50 of 54 patients with Ishak 3–6 were classified as having advanced fibrosis (METAVIR F2–F4) and 58 of 88 patients with Ishak 0–2 as having no/mild fibrosis (METAVIR F0–F1), resulting in a sensitivity of 93%, specificity of 66%, and an overall test accuracy of 76%. With a 38% prevalence of advanced fibrosis, the negative predictive value was 94% and positive predictive value was 63%. A biopsy length of ≥2 cm was associated with higher concordance between FS results and liver fibrosis scores ( P = 0.01). FS was clinically useful in ruling out advanced fibrosis in hepatitis C by identifying patients with mild disease in whom treatment could be deferred. The limitation of this test is its decreased sensitivity and specificity in the middle of the test's reporting range between scores of 0.42 and 0.80.

The aim of the present study was to identify a high affinity InsP4 receptor in membranes from cerebellum or brain from several species. In samples obtained from sheep, beef, human and rat, a 42 kDa protein represents an Ins(1,3,4,5)P4 receptor, similar to the InsP4 receptor from pig cerebellum, which we have described previously using an InsP4-photoaffinity analogue (Reiser et al., Biochem. J. 1991, 280, 533). CNBr cleavage of the pig receptor protein for peptide sequencing revealed peptide sequences which demonstrate that the 42 kDa InsP4 receptor is a novel protein. Two synthetic peptides derived from the pig receptor were used to generate peptide-specific antisera which recognized also the intact receptor protein from pig. The two antisera showed different reactivity with the InsP4 receptor purified from pig and human compared to sheep, beef and rat. This indicates a species heterogeneity of this protein.

We propose the use of a mean quadratic variation criteria to determine an optimal trading strategy in the presence of price impact. We derive the Hamilton Jacobi Bellman (HJB) Partial Differential Equation (PDE) for the optimal strategy, assuming the underlying asset follows Geometric Brownian Motion (GBM) or Arithmetic Brownian Motion (ABM). The exact solution of the ABM formulation is in fact identical to the static (price-independent) approximate solution for the mean–variance objective function in Almgren and Chriss (2000). The optimal trading strategy in the GBM case is in general a function of the asset price. The static strategy determined in the ABM formulation turns out to be an excellent approximation for the GBM case, even when volatility is large.

Hepatitis C infection occurs in about 3% of the world's population. About 85% of primary infections with hepatitis C virus (HCV) become chronic, with fairly constant viraemia patterns despite vigorous host immune responses, and about 20% of patients with chronic hepatitis C eventually develop serious complications, such as liver cirrhosis, end-stage liver disease, hepatocellular carcinoma, and/or death due to liver failure. 1 Alter HJ To C or not to C: these are the questions. Blood. 1995; 85: 1681-1695 PubMed Google Scholar However, the efficacy of treatments for chronic hepatitis C has improved greatly over the past decade, with sustained response rates of about 80% when infections with genotypes 2 and 3 are treated with interferon plus ribavirin. 2 McHutchison JG Gordon SC Schiff ER et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C Hepatitis Interventional Therapy Group. N Engl J Med. 1998; 339: 1485-1492 Crossref PubMed Scopus (3337) Google Scholar Longitudinal studies have shown that HCV infection can be eradicated from the diseased host in over 90% of sustained responders, resulting in significant improvements in liver histology. 3 Marcellin P Boyer N Gervais A et al. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferonalpha therapy. Ann Intern Med. 1997; 127: 875-881 Crossref PubMed Scopus (567) Google Scholar However, over 50% of patients with HCV genotype 1 infection remain resistant to the best therapies.

Since the discovery of hepatitis C virus (HCV) by Choo et al. in the late 1980s,1 a plethora of research has helped illuminate the clinical importance of chronic hepatitis C throughout the world. The latest ‘‘silent epidemic’’ is now receiving much of the attention it deserves. However, there is a pressing need for prospective clinical trials to deepen our understanding of this important human infection, and any such trials will require accurate tests to quantify HCV replication in the infected host. In the current issue of HEPATOLOGY, Martinot-Peignoux et al. take an important step towards this goal in describing the standardization of HCV-RNA quantification, specifically for the pretreatment evaluation of patients slated to receive standard combination therapy (i.e., conventional dose interferon plus ribavirin). The investigators asked whether or not 3 different test methods could accurately identify patients as having low versus high pretreatment viral loads for the clinical purpose of predicting response. They present an excellent argument that the two commercially available test kits (i.e., Roche Monitor and Bayer Quantiplex, also known as bDNA 2.0) are equivalent to the noncommercial NGI SuperQuant test used in the recent clinical trials on combination therapy.2-4 The report offers important guidelines to both clinicians working with individual patients and clinical investigators who design and interpret research studies. For example, the investigators have recommended that specimens be diluted 100-fold before using the Roche Monitor assay, to improve assay discrimination. It should be emphasized that dilution effectively reduced the analytical sensitivity of the Roche PCR-based assay to that of the bDNA 2.0 assay (100,000 copies/mL for Monitor versus 200,000 equivalents/mL for bDNA 2.0). Nonetheless, both tests were 98% sensitive for HCV viremia before therapy, which may be acceptable from a clinical perspective. High-end quantification using quantitative polymerase chain reaction (PCR) tests (Monitor and SuperQuant) is often inaccurate without dilution before testing; reflexive testing of ‘‘off scale’’ specimens leads to an underestimation of viral load in high-titer specimens that do not register as ‘‘off scale’’ in the initial test (author’s unpublished data). At the University of Washington Medical Center, reflexive PCR testing is performed on all bDNA or Monitor-negative specimens to identify those patients with ‘‘very low’’ viral loads (e.g., 102 to 105 viral genomes/mL), because these patients may be the most likely to benefit from therapy. Furthermore, the United States Consensus Conference on Chronic Hepatitis C recognized qualitative reverse transcription–PCR as the best test for certifying the absence of HCV viremia during and after therapy. Neither the Roche Monitor test nor the Bayer bDNA 2.0 test offer sufficient sensitivity to rule out ‘‘very low level’’ viremia at the present time. However, the commercially available qualitative Roche Amplicor test is sufficiently sensitive for therapeutic monitoring. Regarding the issue of quantitative HCV-RNA assays during treatment, the data are intriguing but, as yet, insufficient to firmly recommend modifying the therapeutic approach based on quantitative changes in HCV viral load. It is important to mention the many contributions to date regarding the issue at hand, beginning with the early recognition by Lau et al.5 that HCV-RNA levels predicted response rates to interferon monotherapy, an observation that has held up extremely well over time and across different treatment approaches.6 More recently, Reichard et al.7 have performed a study similar to that of Martinot-Peignoux in the current issue of HEPATOLOGY; however, they reported predictive value only for monotherapy and not combination therapy. Several problems and unanswered questions remain to be resolved, only a few of which will be addressed here. Obviously, the assays are far from perfect in terms of sensitivity and linearity. For chronic hepatitis C, the ideal quantitative test will have a linear range extending from below 100 viral genomes/mL up to approximately 100 million genomes/mL. The reason for low-level sensitivity is obvious. A need for accuracy at the higher end is suggested by reports correlating high viral loads with disease activity in the transplant population. Although accuracy at the high end was not evaluated in the current study, we have previously reported problems of this kind with commercial kits,8 a finding that may have biased some previous studies. In this regard, the bDNA 2.0 test performs better at high viral loads than either the Monitor or SuperQuant assays.7 The present study only examined discrimination at a single reference point (i.e., 2 million ‘‘HCV genomes’’ per mL) in a single clinical context (pretherapy evaluation). Much more work is needed to fully understand the clinical significance of changes in HCV viremia over time during therapy, during natural infection, in patients with advanced disease, and in the setting of the immunocompromised host. Unfortunately, much of the previous work has either been noninformative or Abbreviations: HCV, hepatitis C virus; PCR, polymerase chain reaction. From the Virology Division, Harbor View Medical Center, Seattle, WA. Received January 14, 2000; accepted January 18, 2000. Address reprint requests to: David Gretch, M.D., Ph.D., Virology Division, Harbor View Medical Center, Box 359690, 325 9th Avenue, Seattle, WA 98104. E-mail: gretch@u.washington.edu; fax: 206-341-5203. Copyright r 2000 by the American Association for the Study of Liver Diseases. 0270-9139/00/3103-0035$3.00/0

AIM:We performed both a retrospective and prospective study to elucidate the types of glomerular diseases present in adults in Lima, Peru.MATERIAL AND METHODS:In the retrospective study, we analyzed 1,263 renal biopsies over a 10-year period (1985 -1995) that were processed at a central reference renal pathology laboratory in Lima. 101 cases were examined in the prospective study.RESULTS:The most common glomerular diseases observed were those due to systemic lupus erythematosus (30.2%), membranoproliferative glomerulonephritis (MPGN, 14.8%), and focal and segmental glomerulosclerosis (FSGS, 13.9%). Although mesangial-proliferative nephritis was observed in 9.5% of cases, IgA nephropathy was rare (0.9%). Examination of the year to year frequency showed that MPGN has tended to decrease in frequency with time whereas FSGS has been increasing. Although there is known to be a high frequency of infections in Peru, only 4.2% of the cases in the retrospective study were associated with infection. Furthermore, in the prospective study, only one case of hepatitis C and no cases of hepatitis B viral infection were detected, including in the 11 cases of MPGN observed.CONCLUSION:We conclude that the epidemiology of glomerular disease in Lima, Peru, is distinct from most areas of the world, but has similarities to certain regions in Africa, in that MPGN is common whereas IgA nephropathy appears to be rare. Further studies are necessary to elucidate the reasons why the patterns of glomerular disease are different from that observed in other parts of the world.

Unintegrated HIV-1 proviral DNA is one of the earliest detectable forms of HIV-1, and the influence of an antiretroviral drug on its appearance may reflect the efficacy of that agent in preventing infection of new cells. We characterized the dynamics of HIV-1 p24 (p24) antigen production, HIV-1 gag DNA, tandem long-terminal-repeat circular unintegrated proviral (2-LTR) HIV-1 DNA, HIV-1 tat mRNA, and cell viability in the presence of three antiretroviral agents: recombinant soluble CD4 (rsCD4), zidovudine, and saquinavir. Interference with HIV-1 entry by rsCD4 decreased p24 antigen levels modestly, decreased HIV-1 gag by twofold, and 2-LTR was detectable at the end of the culture period. Inhibition of reverse transcription by zidovudine decreased p24 antigen levels modestly, decreased HIV-1 gag by 19-fold, and inhibited detection of 2-LTR HIV-1 DNA. The protease inhibitor, saquinavir, had the greatest overall effect, with the lowest levels of p24 antigen and HIV-1 gag, and inhibition of 2-LTR. There was no detection of tat mRNA in the saquinavir-treated cultures. In addition, cell viability was significantly higher in cultures treated with saquinavir. In these experiments, 2-LTR HIV-1 DNA was indicative of the relative inhibitory effects of three antiretroviral agents acting at different steps of the HIV-1 replication cycle. We demonstrated in vitro that 2-LTR HIV-1 DNA was a useful indicator of an antiretroviral drug in preventing new cell infection and could be utilized as a dynamic marker of drug efficacy in HIV-l-infected patients. J. Mad. Virol. 58:165-173, 1999. (C) 1999 Wiley-Liss, Inc.

Hepatitis C virus (HCV) infection is highly prevalent among chronic dialysis patients (10% to 40%) and is the most common cause of chronic liver disease. However, there are no studies estimating the risk for death among dialysis patients infected with HCV compared with those not infected. We conducted a prospective cohort study to estimate the risk for death among chronic dialysis patients infected with HCV compared with those not infected. In 1992, 200 patients (91%) who had been undergoing dialysis therapy for at least 6 months consented to be screened for HCV infection by enzyme immunoblot assay and polymerase chain reaction (PCR). Information about potential confounders and potential risk factors for death and HCV infection was obtained from the dialysis center database. Patient outcomes collected included death, transplantation, and loss to follow-up. The Cox proportional hazards model was used to estimate the odds of death among dialysis patients who were positive for the HCV antibody and HCV RNA compared with negative patients. Forty-four patients (22%) were HCV antibody positive. Thirty-four patients (17%) were HCV RNA positive. Patients in the HCV RNA-positive group were more likely to be younger (51.8+/-12.6 v 57.2+/-17.3 years of age), men (77% v 54%), and black (65% v 37%). None of the home hemodialysis or peritoneal dialysis patients were HCV RNA positive, whereas one of the home hemodialysis and one of the peritoneal dialysis patients were HCV antibody positive. Two patients became infected with HCV during the follow-up period. Patients who were HCV RNA positive and those who were HCV antibody positive were at increased risk for death compared with patients who were negative (adjusted relative risk [aRR]=1.78; 95% confidence interval [CI], 1.01 to 3.14; P=0.045; and aRR=1.97; 95% CI, 1.16 to 3.33; P=0.012, respectively), after adjusting for time on dialysis, race, transplantation, and age. We conclude that HCV infection increased the risk for death during the study period compared with those not infected. Further studies should assess the measures used to prevent and treat HCV infection. (Am J Kidney Dis 1998 Oct;32(4):629-34)

Background. Although most studies have not demonstrated decreased patient or graft survival in kidney-alone allograft recipients infected with hepatitis C virus (HCV), the impact of HCV infection on patient and graft survival in HCV-infected kidney-pancreas recipients has not been studied. Methods. We undertook a retrospective cohort analysis of 137 kidney-pancreas transplant recipients who were transplanted between January 1989 and May 1996. HCV infection was determined by a positive polymerase chain reaction. Relative risk of death and graft failure was calculated using the Cox proportional hazards model with time-dependent covariates. Relative risks were adjusted (aRR) to control for the number of OKT3-treated rejections and cytomegalovirus status of the recipient at the time of transplantation. Results. Mean length of follow-up was 30.4 months in the HCV-infected patients compared with 31.7 months in noninfected patients. Seven (5.1%) patients were infected with HCV before transplant, one (1%) relapsed after transplantation, and four (2.9%) acquired the infection after transplantation. The HCV-infected group had a 3.7-fold (95% confidence interval [CI], 1.0-13.5) increased risk of death after transplant compared with the HCV-negative group, with an aRR of 5.5 (95% CI, 1.5-20.0). Death in the HCV-infected group (n=3) was generally the result of liver failure and sepsis, whereas death for those in the uninfected group (n=11) was primarily of cardiovascular origin. Patients infected with HCV were 3.4-fold (95% CI, 1.1-10.1) more likely to develop kidney graft failure than HCV-negative patients with an aRR of 5.1 (95% CI, 1.7-15.4). The risk of pancreatic allograft failure was not significantly increased. Conclusions. We conclude that HCV infection in kidney-pancreas transplant patients results in a significantly increased risk of kidney allograft failure and death.