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Objective: To survey the levels of Golgi glycoprotein (GP73), a hepatocellular carcinoma (HCC) marker, in residents of Qidong and determine the correlation of detected GP73 concentration ranges with outcome at two-year follow-up., Methods: A total of 12,378 individuals (age range: 35-69 years old) from Qidong were enrolled in the study. All participants were tested for hepatitis B virus (HBV) by detecting hepatitis B surface antigen (HBsAg) in serum. One-tenth of the participants were assigned to a stratified-random sample group (those with identification numbers ending with "0") to represent a "subgroup of the natural population" (HBsAgPop, n = 1227). All HBsAg carriers were stratified as a "subgroup of positivity" (HBsAgPve, n = 1025). One-tenth of all HBsAg-negative individuals were assigned to a stratified-random sample group to represent a "subgroup of negativity" (HBsAgNve, n = 1132). Enzyme-linked immunoassay was used to measure the serum GP73 and alpha-fetoprotein (AFP) levels; the distribution, medians (50th percentile), and 95th percentiles of GP73 were determined for the three subgroups. A two-year follow-up was carried out to observe the differential incidence of HCC between the HBsAgPve and HBsAgNve subgroups., Results: A positively skewed distribution of the GP73 values was observed for all three subgroups. The medians for HBsAgPve, HBsAgNve, and HBsAgPop were 67 mug/L, 54 mug/L, and 55 mug/L; the 95th percentiles were 174 mug/L, 108 mug/L, and 114 mug/L, respectively. The AFP positivity rates were 7.23% (37/512) for carriers whose GP73 values were above the median level and 0.78% (4/513) for carriers with GP73 values below the median level, with a highly significant difference between the two (P less than 0.01). A the two-year follow-up, 23 (4.49%) of the 512 carriers with GP73 more than or equal to 67 mug/L had developed HCC, while only one patient (0.19%) of the 513 carriers with GP73 less than 67 mug/L developed HCC, which yielded a relative risk value of 23.6. In the non-carriers, no HCC cases had occurred, regardless of serum GP73 level., Conclusion: Serum GP73 has a higher potential as a diagnostic/prognostic marker of HCC in individuals with HBsAg positivity. In follow-up of HBsAg carriers, GP73 may help in the early detection of liver cancer.

Objective: To describe and analyze the charecteristics and trends of liver cancer mortality during the past fifty years in Qidong, China., Methods: Retrospective mortality survey was conducted to get the data on liver cancer death in the period of 1958-1971, and the data from 1972 to 2007 were obtained from the records of cancer registration in Qidong. The crude mortality rate (CR) of liver cancer, and age-standardized rate by Chinese population (CASR) and by world population (WASR) were calculated and analyzed. The total percent changes (PC) and annual percent changes (APC) were used for evaluating the increasing trends of the mortality. The sex-specific rate, age-specific rate, truncated rate of the age group 35 - 64, cumulative rate of the age group 0-74, cumulative risk, period-rate, and the rate for age-birth cohort were compared., Results: The natural death rate in Qidong residents for the past five-decade period experienced a wave interval of 8.62‰ in 1958 down to 5.37‰ in 1979, and up to 7.75‰ in 2007. The mortality rate for all-site cancers was increased from 56.69 per 100, 000 to 234.97 per 100, 000. The mortality rate of liver cancer, being 20.45 per 100, 100 in 1958 was increased to 49.04 per 100, 000 in 1972, and up to 69.29 per 100, 000 in 2007. According to the registration data of 1972 - 2007, the death from liver cancer was accounted for 34.88% of all deaths due to cancers, with a CR of 58.86 per 100, 000, CASR of 38.36 per 100, 000, and WASR, 49.37 Per 100, 000 in Qidong. The truncated rate for the age group 35 - 64 was 117.08 per 100, 000, and the cumulative rate for the age group 0-74 and the cumulative risk were 5.15% and 5.02%, respectively. The CRs for males was 90.52 per 100, 000 and for females was 27.93 per 100, 000, with a sex ratio of 3.24:1. For the period of 1972 - 2007, the PC for CR was 49.71%, and APC was +1.41%, showing an increasing variation tendency. The APCs for CASR and WASR, however, were decreasing, with a percentage of -1.11%, and -0.84%, respectively. The age-specific mortality rates by period showed a decreasing trend for those under age of 44. Moreover, age-birth cohort analysis showed a more rapid lowering mortality in the age groups 35-, 30-, 25-, and 15-, that is, those born after 1950's., Conclusions: Liver cancer remains the leading death cause due to cancers in Qidong, with a continuing higher crude mortality rate. Yet the age-standardized mortality rate has presented a declining posture. The liver cancer mortality in young people in Qidong demonstrates a continuously falling trend. The campaign for the control of liver cancer in Qidong has achieved initial success.

We studied the effects of starvation and re-feeding on the levels of plasma IGF-1, IGFBP-1 and expressions of hepatic IGF-1 mRNA and muscle IGF-1R mRNA in Carassius auratus gibelio. During the two week starvation period, both the levels of plasma IGF-1 and IGFBP-1 decreased and were significantly lower on day 14 (P <0.05). On the first day of re-feeding, the level of plasma IGF-1 increased sharply, to the level of control group, and had no significant changes for the remaining days. While the level of plasma IGFBP-1 was still greatly lower than that of control group at the first day of re-feeding, it increased significantly higher than that of control group by day 14 (P <0.05). During the starvation period, expression of IGF-1 mRNA in liver decreased, but it was not statistically different from that of the control group (P>0.05). During the early period of re-feeding, the abundance of IGF-1 mRNA was still significantly lower than that of control group (P <0.05), then increased to the level of control group on day 7. IGF-1R mRNA showed a decreasing trend after starvation, and reached a significantly low value on day 3 (P <0.05). After re-feeding, the abundance of IGF-1R mRNA increased to peak at day 14. These results indicate that the higher level of IGFBP-1 in serum and IGF-1R mRNA in muscle after re-feeding could improve the promoting growth effect of IGF-1 to participate in the regulation of compensatory growth.

Aims: To investigate the effect of zinc sulfate on pharmacokinetics of cephalexin when administered concurrently or at strategically spaced dosing times designed to avoid the potential interaction in healthy volunteers., Methods: In this study, all subjects (n= 12) were randomized to receive the following four treatments, separated by a wash-out period of 7 days: cephalexin 500mg alone, concomitantly with zinc 250mg, 3h after zinc 250mg or 3h before zinc 250mg., Results: All subjects completed the study safely. Zinc supplements administered concurrently with cephalexin significantly decreased the peak serum concentration (C(max) ), area under the plasma concentration-time curve from zero to infinity (AUC(0-∞) ) and the time for which the plasma concentration of the drug remained above the minimal inhibitory concentration of the pathogenic organism (T > MIC) of cephalexin [mean percentage decrease (95% confidence intervals) of 31.05% (22.09-40.01%), 27.40% (18.33-36.47%) and 22.33% (12.51-32.16%), respectively; P < 0.05] compared with administration of cephalexin alone. Also, administration of zinc 3h before cephalexin decreased the C(max) , AUC(0-∞) and T > MIC of the drug compared with administration of cephalexin alone [mean percentage decrease (95% confidence intervals) of 11.48% (3.40-19.55%), 18.12% (9.63-26.60%) and 23.75% (14.30-33.20%), respectively; P < 0.05]. In contrast, the pharmacokinetics of cephalexin was not notably altered by administration of zinc 3h after cephalexin dosing (P > 0.05)., Conclusions: The significant interaction between zinc and cephalexin might affect the clinical outcome of cephalexin therapy. The dosing recommendation is that zinc sulfate can be safely administered 3h after a cephalexin dose., (© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.)

A sensitive method using liquid chromatography with tandem mass spectrometric detection (LC-MS/MS) was developed and validated for the analysis of antihistamine drug azatadine in human plasma. Loratadine was used as internal standard (IS). Analytes were extracted from human plasma by liquid/liquid extraction using ethyl acetate. The organic phase was reduced to dryness under a stream of nitrogen at 30 °C and the residue was reconstituted with the mobile phase. 5 μL of the resulting solution was injected onto the LC-MS/MS system. A 4.6 mm × 150 mm, I.D. 5 μm, Agilent TC-C(18) column was used to perform the chromatographic analysis. The mobile phase consisted of ammonium formate buffer 0.010 M (adjusted to pH 4.3 with 1M formic acid)/acetonitrile (20:80, v/v) The chromatographic run time was 5 min per injection and flow rate was 0.6 mL/min. The retention time was 2.4 and 4.4 min for azatadine and IS, respectively. The tandem mass spectrometric detection mode was achieved with electrospray ionization (ESI) iron source and the multiple reaction monitoring (MRM) (291.3 → 248.2m/z for azatadine, 383.3 → 337.3m/z for IS) was operated in positive ion modes. The low limit of quantitation (LLOQ) was 0.05 ng/mL. The intra-day and inter-day precision of the quality control (QC) samples was 8.93-11.57% relative standard deviation (RSD). The inter-day accuracy of the QC samples was 96.83-105.07% of the nominal values., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality with nearly 700,000 deaths occurring annually. Hepatitis B virus (HBV) is a major contributor to HCC and acquired mutations in the HBV genome may accelerate its pathogenesis. In this study, a matched case-control investigation of 345 men who died of HCC and 625 controls were nested within a cohort of male hepatitis B surface antigen (HBsAg) carriers from Qidong, China. Matched preserving odds ratios (ORs) were used as a measure of association and 95% confidence intervals (CIs) as a measure of precision. Real-time polymerase chain reaction allowed for a quantitative comparison of the levels of the HBV 1762(T)/1764(A) mutation in cases and controls. A total of 278 (81%) of the cases were positive for the HBV 1762(T)/1764(A) mutation compared with 250 (40%) of the controls. The matched preserving OR of 6.72 (95% CI: 4.66 to 9.68) strongly indicated that cases were significantly more probably than controls to have the mutation. Plasma levels of DNA harboring the HBV mutation were on average 15-fold higher in cases compared with controls (P < 0.001). Most strikingly, the level of the mutation in the 20 controls who later developed and died of HCC were on average 274-fold higher than controls who did not develop HCC. Thus, within this cohort of HBsAg carriers at high risk of developing HCC, individuals positive for the HBV 1762(T)/1764(A) mutation at enrollment were substantially more probably to subsequently develop HCC, with a higher concentration of the mutation in plasma enhancing predisposition for cancer development.

Objective: To investigate the effect of mechanical stretch force on the morphologic and apoptotic changes of fibroblasts derived from the OPLL (ossification of posterior longitudinal ligaments) patients., Methods: The third passage cells were collected and subjected to 10% elongations cyclic mechanical stretching for 6 h and 24 h with Flexercell 4000(TM) strain unit. Their morphologic changes were observed and the post-stretching apoptotic rates quantified by flow cytometer. The gene expressions of alkaline phosphatase (ALP), collagen types I (COL I) and osteocalcin (OC) were examined., Results: The treated cells were arranged along the vertical direction of force. Stretch force led to a slight increase of apoptosis rate at 6 h and a significant increase of apoptosis rate at 24 h. No significant difference in cellular senescence was observed between control group and treated group. The mRNA expressions of ALP, COL I and OC were positively up-regulated by cyclic stretch at 24 h., Conclusion: Stretching force can affect the cellular morphology, promote the osteogenic differentiation and enhance the cellular apoptosis.

One of several challenges in design of clinical chemoprevention trials is the selection of the dose, formulation, and dose schedule of the intervention agent. Therefore, a cross-over clinical trial was undertaken to compare the bioavailability and tolerability of sulforaphane from two of broccoli sprout-derived beverages: one glucoraphanin-rich (GRR) and the other sulforaphane-rich (SFR). Sulforaphane was generated from glucoraphanin contained in GRR by gut microflora or formed by treatment of GRR with myrosinase from daikon (Raphanus sativus) sprouts to provide SFR. Fifty healthy, eligible participants were requested to refrain from crucifer consumption and randomized into two treatment arms. The study design was as follows: 5-day run-in period, 7-day administration of beverages, 5-day washout period, and 7-day administration of the opposite intervention. Isotope dilution mass spectrometry was used to measure levels of glucoraphanin, sulforaphane, and sulforaphane thiol conjugates in urine samples collected daily throughout the study. Bioavailability, as measured by urinary excretion of sulforaphane and its metabolites (in approximately 12-hour collections after dosing), was substantially greater with the SFR (mean = 70%) than with GRR (mean = 5%) beverages. Interindividual variability in excretion was considerably lower with SFR than with GRR beverage. Elimination rates were considerably slower with GRR, allowing for achievement of steady-state dosing as opposed to bolus dosing with SFR. Optimal dosing formulations in future studies should consider blends of sulforaphane and glucoraphanin as SFR and GRR mixtures to achieve peak concentrations for activation of some targets and prolonged inhibition of others implicated in the protective actions of sulforaphane. Cancer Prev Res; 4(3); 384-95. ©2011 AACR.

Background: Death with a functioning kidney graft (DWFG) is now a major cause of graft loss after renal transplantation, occurring in up to 40% of cases. Its occurrence provides insight into the medical care of subjects with a functioning kidney transplant. In this study, we used the time to DWFG as an endpoint, to test whether improved medical care has contributed to better kidney transplant outcomes., Methods: We used single-center data from the Milwaukee Regional Medical Center and Froedtert Hospital, on kidney-only transplants from 1969 through 2005. A total of 3,157 kidney transplants were done at our center during this time. There were 714 deaths with functioning kidney. We also recorded the major causes of DWFG over the time period from 1969 through 2005 divided into 3 epochs. The data were analyzed as a serial collection of yearly obituaries., Results: The time to DWFG has increased to 10 years despite a 20-year increase in the mean age of transplant recipients over the same time period., Conclusions: Better pre-transplant evaluation, improved treatments for hypertension and hyperlipidemia, improved management of acute myocardial infarction, superior immunosuppressive protocols and better prophylaxis and treatment of infectious diseases have all likely contributed to this trend.

Objective: To study the relationship between hepatitis B virus (HBV) and primary liver cancer (PLC), and to assess the outcome of PLC in the carriers of HBsAg., Methods: General population over age of 15 from a community in Qidong was screened for HBsAg, anti-HBs, and alanine transaminase (ALT) in 1976, and followed-up thenceforth. From January 1, 1977 through December 31, 2007, 12 351 people were enrolled in the cohort, and their occurrence, outcome of PLC and other cancers, together with all the withdrawals due to death were linked to and checked with database from Qidong Cancer Registry and Qidong Vital Registry programs., Results: The total observed person-years (PYs) were 355 305.0. One hundred and seventy-three PLC cases were identified among the HBsAg carriers, with an incidence of 361.55 per 100 000 PYs, while PLC cases were only 95 for the non-carriers, with an incidence of 30.90 per 100 000 PYs. The overall relative risk (RR) was 11.70 (95%CI: 9.06 - 15.19), with RR 12.30 for men and 10.46 for women. HBsAg carriers had high incidence at each age group, compared with the non-carriers for both men and women. Data from cross-over analysis showed that the incidence rates of PLC for the sub-cohorts of female non-carriers, male non-carriers, female carriers, and male carriers were 1.00, 3.07, 10.46, and 37.76, respectively. The cumulative rates of PLC in the 4 groups were 0.86%, 2.73%, 10.22%, and 34.19%, respectively. Results from non-conditional logistic regression model showed that the gender (male), age, HBsAg(+), and ALT(+) were risk factors for the development of PLC while anti-HBs(+) demonstrated a protective effect. No relationship was found among carriers and non-carriers for cancer sites such as lung, stomach, esophagus, intestine, pancreas, breast, cervix, bladder, and lymphoma, brain tumor, or leukemia., Conclusion: Causation and its strength, together with specificity and persistency of the association were confirmed from this HBsAg-related cohort study in the general population in Qidong. Intervention measures on HBV should be highlighted for the control of PLC among the HBV infected individuals.

Outcome of acute renal failure (ARF) and use of continuous renal replacement therapy (CRRT) have shown a consistently high mortality. (1) Evaluate the short-term patient survival. (2) Evaluate dialysis-free survival. (3) Evaluate risk factors associated with overall survival and the continued need for intermittent dialysis. We identified adults (>/=18 years) needing CRRT, treated in the critical care units of Froedtert Medical and Lutheran Hospital from January 1, 2003 till December 31, 2005. Patients were divided into two major groups needing CRRT, end stage renal disease (ESRD) (chronic dialysis) and non-ESRD with ARF. Continuous renal replacement therapy was performed with an average of 2 L replacement fluid exchanges/h. Sigma stat software was used for analysis. Comparison was done for noncontinuous variables by chi-square and t test for categorical and continuous variables, respectively. A total of 110 (ESRD 24/non-ESRD 86) patients received CRRT during study period. Over all in-hospital mortality among non-ESRD patients was 63% vs. 46% for ESRD. Among non-ESRD patients who survived, 47% needed intermittent hemodialysis on intensive care unit discharge and 28% continued to need hemodialysis at last follow-up. Among non-ESRD patients alive at discharge, those who were dialysis dependent on last follow-up were older (64.5) than those who did not require dialysis on last follow-up (58.4) P=0.347. Non-ESRD patients who died were in the hospital for an average of 17.5 days compared with 29 days for those who were discharged from the hospital. Patients with ARF needing CRRT have high in-hospital mortality. A significant percentage of patients remained dialysis dependant on last follow-up.

Object: Gamma Knife surgery (GKS) is one of the methods available to treat vestibular schwannomas (VSs), in addition to microsurgical resection; however, clear information regarding balance function outcomes and the impact of treatment on patients' quality of life over time remains an important clinical need. The purpose of this study was to assess the longitudinal balance outcomes and Dizziness Handicap Inventory (DHI) following GKS for VSs., Methods: This was a prospective clinical study of balance outcomes in all patients with VSs treated in the Acoustic Neuroma and Skull Base Surgery Program at a tertiary referral center by the senior author and the Gamma Knife team between June 2000 and May 2008. The main outcome measures included preoperative vestibular testing and postoperative caloric testing performed at 6-month intervals to determine vestibular function. The DHI questionnaires were administered retrospectively to assess the impact of GKS on self-perceived disability., Results: Between June 2000 and May 2008, 55 sporadic VSs were treated. There was a >or= 60-month follow-up available in 27 of these patients, >or= 48 months in 32, >or= 36 months in 38, >or= 24 months in 43, >or= 12 months in 51, and >or= 6 months in 54 (1 patient was excluded from the analysis because the follow-up was < 6 months). Various patterns of changes in vestibular function were observed in either positive or negative directions. A significant difference in total DHI score was seen only in the elderly (> 65 years old) patients pre-GKS compared with post-GKS (t = 1.34, p = 0.05)., Conclusions: Longitudinal changes in vestibular function occur over time, with the largest changes seen in the first 6 months after treatment. Potential for clinical intervention, such as vestibular rehabilitation therapy, exists during this interval; however, larger cohorts must be studied to determine the timing and efficacy of this intervention. The statistically significant improvement in the DHI score in the patient cohort > 65 years old treated with GKS suggests that this group may benefit from this option when considering the symptom of dizziness.

Background: Efficacy and timing of operative intervention in patients with multiple endocrine neoplasia type 1 (MEN-1) syndrome remains controversial. This report utilizes a novel approach to evaluate the influence of evolving operative interventions for patients with MEN-1 syndrome., Methods: Six generations from a large MEN-1 family pedigree were studied. The number of operations for MEN-1 related pathology was recorded according to birth eras over 150 years. Length of life was a primary outcome measurement., Results: Inheritance of the MEN-1 trait was near 50%. There were no instances of a skipped generation. Affected individuals born before 1900 died from gastrointestinal hemorrhage and without any surgical intervention. After 1900, there were increasing numbers of gastric, parathyroid, and pancreatic operations in successive eras. Death occurred >20 years earlier in MEN-1 individuals than unaffected family members in eras 1 and 2. Family members with MEN-1 lived longer in succeeding eras with increasing number of operative and pharmacologic interventions., Conclusion: MEN-1 family members invariably have pathologic changes in pituitary, parathyroid, and pancreatic islets when long lived, the "all-or-none" phenomenon. Patients are not cured with operative interventions, although they may live longer and without symptoms with a good quality of life. This model may allow better comparisons with other MEN-1 patients when evaluating outcomes of new medical and operative management schemes and long-term follow-up.

A series of novel 2-cyanoacrylates containing different aromatic rings were synthesized, and their structures were characterized by (1)H NMR, elemental analysis, and single-crystal X-ray diffraction analysis. Their herbicidal activities against four weeds and inhibition of photosynthetic electron transport against isolated chloroplasts (the Hill reaction) were evaluated. Both in vivo and in vitro data showed that the compounds containing benzene, pyridine, and thiazole moieties gave higher activities than those containing pyrimidine, pyridazine, furan, and tetrahedronfuran moieties. To further explore the comprehensive structure-activity relationship on the basis of in vitro data, comparative molecular field analysis (CoMFA) was performed, and the results showed that a bulky and electronegative group around the para-position of the aromatic rings would have the potential for higher activity, which offered important structural insights into designing highly active compounds prior to the next synthesis.

Objective: To investigate the mortality and predictors of outcome of children with acute respiratory distress syndrome (ARDS) in pediatric intensive care unit (PICU)., Methods: ARDS cases were selected from the 12 018 patients admitted in 25 pediatric intensive care units in China from January 1 to December 31, 2004, aged 29 days to 14 years, using the Chinese Pediatric Critical Index of Severity (PCIS) and American Guidelines for Admission and Discharge Policies for PICU. ARDS was diagnosed according to the 1994 American-European Consensus Conference criteria., Results: 105 of the 12 018 patients (1.44%) were diagnosed as with ARDS. The overall mortality of ARDS was 61.0% (64/105), 9 times as high as that of the 7269 severe cases in PICU. Logistic regression analysis showed that infiltration shadows in 2 - 3 quadrants, pediatric critical illness score (PCIS), and partial pressure of carbon dioxide (PaCO2) at the onset of ARDS were independently associated with the mortality., Conclusion: ARDS has a high risk of death, and the infiltration shadows in 2-3 quadrants, PCIS, and PaCO2 are independently associated with mortality.

Liver cancer is the leading cause of cancer death in many regions of the world. With the goal to discover biomarkers that reflect subsets of high-risk individuals and their prognosis, we nested our study in a male cohort of 5,581 hepatitis B surface antigen carriers in Qidong, People's Republic of China, who were recruited starting in 1989. By December 2003, 667 liver cancer cases were diagnosed in this group and plasma samples collected at the initial screening at enrollment were available in 515 cases who had succumbed to liver cancer. Hepatitis B virus (HBV) DNA could be isolated in 355 (69%) of these samples. In 14%, 15%, 19%, 31%, and 22%, screening took place at < or = 1.5, 1.51 to 3, 3.01 to 5, 5.01 to 9, and > 9 years before death, respectively; and 39% died at age below 45 years. The relation between mutations in HBV and time to death were determined by logistic regression for the odds of mutation and by survival analyses methods with age as the time scale. In 279 (79%) of these individuals, the samples contained a two-nucleotide 1762T/1764A HBV mutation. Sixteen samples lacking the 1762T/1764A mutation had novel mutations elsewhere in the 1761 to 1767 region of the HBV genome. There was a statistically significant difference (P = 0.012) for the high prevalence of the HBV mutations in the men who died from hepatocellular carcinoma under the age of 45 years relative to those who died after 55 years of age and HBV mutations accelerated death (relative hazard, 1.40; 95% confidence interval, 1.06-1.85) and that the effect was attenuated by age from 2.04 for age 35 years to 1.0 for age 65 years with the 90% confidence band being above 1 for ages < 50 years. These findings provide a conceptual framework to explain the acceleration of mortality in individuals infected with HBV.

Objective: To explore the patterns of cancer incidence from 1972 to 2005 in Qidong, Jiangsu province., Methods: A population-based cancer registration system was established in Qidong region with 1.1 millions residents to collect data of cancer incident cases. 70,646 cases were registered during the years from 1972 to 2005, and ICD-10 was administrated for classification and coding, and crude rate (CR) and age-standardized rate (ASR), percent change (PC), annual percent change (APC) were calculated using annual data on population size. Changes within age-groups for different periods of incidence, and for different years of birth (birth cohort) for the leading sites of cancers were analyzed., Results: The average annual incidence for cancers during the years of 1972-2005 was 184.77 per 100,000 (ASR: 109.32 per 100,000), of which, the incidence for male was 239.22 (ASR: 136.08), and 131.58 (ASR: 79.26) per 100,000 for female. The cumulative risk of cancer occurrence was 16.31% (21.62% in males, and 11.11% in females). The most common leading sites in rank in this area were liver (CR: 60.69 per 100,000), stomach (32.97), lung (27.59), oesophagus (9.34), rectum (8.06), breast (6.48), pancreas (5.97), leukaemia (3.84), bran and CNS (3.43), and colon (2.93). Female breast cancer (12.59) and cervix cancer (4.62) were the forth and the eighth in rank among all sites for women. Liver cancer accounted for almost one third (32.84) of the malignancies. Furthermore, the cancers from digestive organs accounted for 65.85% of all sites. CR rates were rising overall, at 87.19% for PC, and at 1.85% for APC. The ASR, however, reduced by 12.14% for PC, and by 0.51% for APC. The rising trends were also observed for the ASR from cancers in lung, female breast, and colon-rectum, while the decreasing trends were observed for stomach and oesophagus cancer. Birth cohort analysis showed that there was a decline in ages under 35 for the incidence of liver cancer, in ages over 40 for stomach cancer, and in those aged over 45 for bladder cancer and over 50 for oesophagus cancer. Rising trends existed for incidence rates from lung cancer in the aged over 30, pancreas cancer in aged 45-59, and female breast cancer in those aged 40 and above., Conclusion: Monitoring of cancer incidence rates through population-based cancer registration in 34 years did help to show the burden and patterns of main cancer sites and time trends, which provides some references to future aetiological study, and policy making on cancer control in Qidong.

The cDNA of Alocasia macrorrhiza lectin (aml, GenBank accession number: DQ340864) was cloned by RACE-PCR and its characteristics were predicted by various bioinformatics tools. GSPs (Gene Specific Primers) were designed according to the conserved regions of the genes encoded for lectins and similar proteins from the same family Araceae. Total RNAs were extracted from the tubers of A macrorrhiza by Qiagen RNeasy mini kit. The 3'- and 5'-RACE-PCRs were performed with the isolated total RNAs by SMART(TM)RACE cDNA amplification kit from BD Biosciences Clontech Company, respectively. The purified PCR products were ligated with pMD 18-T vector, and the confirmed clones were sequenced. The full-length cDNA of aml was obtained by combination of 3'- and 5'-end sequences, and was then confirmed by full-length 3'-RACE-PCR. The aml cDNA is 1 124 bp long. The deduced amino acid length of AML lectin is 270 aa. Its relative molecular weight is 29.7 kD. The results of homologous analysis showed a high similarity between AML and other mannose-binding lectins and similar proteins from Araceae family. Two typical B-lectin domains and three mannose- binding motifs were found in the sequence of AML. With all these taken together, it can be concluded that this newly cloned aml cDNA encodes for a mannose-binding lectin.

A population-based cancer registry was established in Qidong, Jiangsu Province, China, in 1972, and the trends in incidence rates of the major cancer sites have been analyzed for a 25-year period, 1978-2002. Five-year age-specific rates, crude incidence rates, world age-standardized rates (ASR), percent change (PC) and annual percent change (APC) were calculated using annual data on population size, and estimates of its age structure. The indices of histological verification of diagnosis, death certificate only and proportion of mortality to incidence were employed for assessing the registration quality. A total of 51,933 incident cases of cancer were registered in Qidong from years 1978 to 2002, with a male-to-female sex ratio of 1.9:1. Crude incidence increased markedly over the 25-year period (PC and APC of +55.6% and +2.1%, respectively), but ASR showed a slight decrease (-0.4% in males, and -0.3% in females), indicating that the major part of this is due to population ageing. The leading cancer sites in rank were liver (average ASR = 50.8 per 100,000), stomach (26.7), lung (22.7), colon-rectum (8.9), oesophagus (7.4) and breast (5.4). Cancers of liver, lung, colon-rectum and female breast all showed increases in incidence during the study period, with APCs (ASR) of +0.1%, +1.7% and +1.4% for males, and +0.2%, +0.9%, +1.9% and +1.1% for females, while the cancers of stomach (APC: -3.2% in male, and --2.4% in female) and cervix (APC: -4.7%) showed notable declines. Examination of age-specific rates showed declining trends in the younger generations for liver cancer, but increases for cervix cancer. The results underline the increasing importance of cancer as a cause of mortality and morbidity in a population that is ageing and undergoing profound changes in socioeconomic development and lifestyle. The cancers of high lethality that have been common in the Chinese population (liver, stomach, oesophagus) are showing some evidence of decline, at least in younger generations, but they remain major problems. At the same time, the cancers associated with economically "developed" societies -- lung, colon-rectum and female breast -- are showing increases. The population-based cancer registry is an indispensable tool for providing data for planning and evaluation of programmes for cancer control in all societies.

Background: Interferon-gamma modulates host defense in a number of infectious diseases. Previous studies have shown that systemic administration of interferon-gamma (IFN-gamma) can enhance survival in experimental invasive aspergillosis (IA)., Methods: Using a novel model of murine IA that is characterized by primary pulmonary infection, we investigated the role of IFN-gamma in the phagocytosis and killing of Aspergillus fumigatus by murine neutrophils and pulmonary alveolar macrophages in vitro and the impact of systemic and regional administration of IFN-gamma on the course of IA in glucocorticoid-treated mice., Results: In vitro, IFN-gamma significantly enhanced phagocytosis and killing function of both neutrophils and alveolar macrophages from normal animals, but not cortisone-treated animals. In vivo, intravenous administration of IFN-gamma did not improve phagocyte recruitment, in vivo killing, or mortality from IA. Regional (intranasal) administration of IFN-gamma to the lungs enhanced recruitment of phagocytic cells to the lungs and improved in vivo killing, but did not alter (and actually worsened) mortality from IA., Conclusions: The in vitro and in vivo effects of IFN-gamma in IA are contingent on many variables, including the route of administration and the specific pathogenesis of infection.

Objective: To evaluate the secular trend of liver cancer incidence 1973-2002 in Qidong, a high-prevalent area in Jiangsu province., Methods: The population-based cancer registration data collected during the period of 1973-2002 were used to calculate the crude rate (CR), world age-standardized rate (WASR), five-year age-specific rate, truncated rate of those aged 35-64, cumulative rates of those aged 0-64 and 0-74, percent change (PC), and annual percent change (APC). The incidence rates by age, period/age, and cohort/age were analyzed and compared., Results: The CR was 59.28 per 100,000 on average; and was 91.65 per 100,000 for males and 27.64 per 100,000 for females, with a sex ratio of 3.32:1. The WASR was 58.71 per 100,000 on average; and was 93.32 per 100,000 for males and 26.46 per 100,000 for the females. The truncated rate and cumulative rate of those aged 0-64 and 0-74 were 143.61 per 100,000 and 4.74% and 6.07% respectively. The PC and the APC were +30.90% and +1.58% for the crude incidence rate, and +12.33% and +0.41% for the age-standardized rate. The incidence data demonstrated a rising trend in general and a decreasing pattern for the age-specific rates under age of 35 by comparing the two 15-year periods. Decline trend also existed for the younger age groups when the time was divided into 6 subperiods. Birth cohort analysis showed notable reducing changes for those born after the year 1963., Conclusion: The crude rate of incidence of liver cancer has arisen in general in the past 30 years in Qidong area, which may reflects the increase of middle-aged and elderly populations. Many years' comprehensive prevention measures taken in the area, however, have been and will continue to be effective on the decrease of the incidence of liver cancer among the younger generations.

Residents of Qidong, People's Republic of China, are at high risk for development of hepatocellular carcinoma, in part due to consumption of aflatoxin-contaminated foods, and are exposed to high levels of phenanthrene, a sentinel of hydrocarbon air toxics. Cruciferous vegetables, such as broccoli, contain anticarcinogens. Glucoraphanin, the principal glucosinolate in broccoli sprouts, can be hydrolyzed by gut microflora to sulforaphane, a potent inducer of carcinogen detoxication enzymes. In a randomized, placebo-controlled chemoprevention trial, we tested whether drinking hot water infusions of 3-day-old broccoli sprouts, containing defined concentrations of glucosinolates, could alter the disposition of aflatoxin and phenanthrene. Two hundred healthy adults drank infusions containing either 400 or < 3 micromol glucoraphanin nightly for 2 weeks. Adherence to the study protocol was outstanding; no problems with safety or tolerance were noted. Urinary levels of aflatoxin-N(7)-guanine were not different between the two intervention arms (P = 0.68). However, measurement of urinary levels of dithiocarbamates (sulforaphane metabolites) indicated striking interindividual differences in bioavailability. An inverse association was observed for excretion of dithiocarbamates and aflatoxin-DNA adducts (P = 0.002; R = 0.31) in individuals receiving broccoli sprout glucosinolates. Moreover, trans, anti-phenanthrene tetraol, a metabolite of the combustion product phenanthrene, was detected in urine of all participants and showed a robust inverse association with dithiocarbamate levels (P = 0.0001; R = 0.39), although again no overall difference between intervention arms was observed (P = 0.29). Understanding factors influencing glucosinolate hydrolysis and bioavailability will be required for optimal use of broccoli sprouts in human interventions.

Background: BK virus nephritis (BKVN) has emerged as an important cause of renal transplant failure. Quantified analysis of its timing and clinical course is generally lacking. We have thus quantified the timing, risk factors, evolution of renal function, and transplant graft outcome in renal transplant recipients with BKVN from our center., Methods: A total of 41 cases of BKVN were diagnosed in 1001 renal and renal/pancreas transplant recipients. There were 2 groups: group I (N= 16), with diagnosis based on renal biopsy alone from January 1996 to August 2001, and group II (N= 25), with diagnosis based on quantitative blood BKV-PCR and biopsy from September 2001 to December 2003. The demographics, the clinical course, immunosuppressive therapy, renal function, and graft outcome were quantified. Donor, recipient, and transplant risk variables were studied using a univariate analysis. Actuarial graft survival was calculated. An immunosuppressive scale created to evaluate the degree of immunosuppression in these patients and its reduction after the diagnosis of BKVN., Results: The median time from transplant to BKVN diagnosis was 318 days (range 48-1356). The actuarial graft survival in patients with BKVN at 6 months, 1, 3, and 5 years was 97%, 90%, 58%, and 47%. The corresponding values for those without BKVN were 94%, 92%, 83%, and 76%, respectively, P < 0.001. Graft loss occurred in 46% of patients. The rate of decline of renal function in group II (N= 25) patients in the 4 months preceding BKVN was rapid (4.8 mL/min/month) and this declined to 0.7 mL/min/month at 3 months' post-BKVN diagnosis, P= 0.004. In those who recovered, the time to stabilization of renal function was a median of 112 days. The immunosuppressive scale score was 7 units at the time of diagnosis of BKVN and decreased to 3.5 units at 3 months' post-BKVN. Reduction in the dose of calcineurin inhibitors but not the overall reduction in dose of immunosuppression correlated with recovery of renal function in these patients., Conclusion: BKVN is a relatively late complication of renal transplantation. Despite reduction in immunosuppression, graft loss occurred in 46% of patients. There was a steep decline in renal function in months preceding the diagnosis of BKVN, and reduction in calcineurin inhibitor dose, but not overall immunosuppression, correlated with stabilization of renal function.

Hepatocellular carcinoma is one of the most common cancers worldwide. Infection with hepatitis B virus and exposure to aflatoxins in the diet act synergistically to amplify risk. From a public health perspective, hepatitis virus vaccination programs and efforts to both reduce aflatoxin exposures and to attenuate the toxicological consequences of unavoidable exposures should have major impacts on the global incidence of this disease. Experimentally, aflatoxin-induced hepatocarcinogenesis can be inhibited by over a score of different chemopreventive agents with multiple mechanisms of action. One agent, oltipraz, is a potent inducer of phase 2 enzymes involved in the detoxication of carcinogens including aflatoxin. A second agent, chlorophyllin, impedes the bioavailability of carcinogens by forming molecular complexes and enhances their elimination in the fecal stream. This review highlights the findings of recent randomized clinical trials with oltipraz and chlorophyllin conducted in individuals exposed to dietary aflatoxins and at high risk for development of liver cancer. Both chemopreventive agents modulated levels of aflatoxin biomarkers in the study participants in manners consonant with protection. Although pharmacological approaches establish proof of principle and help identify key molecular targets for interventions, food-based approaches that also use these molecular targets may be the most practical for widespread application in high-risk populations.

Objective and Design: To document in vivo immunolocalization and activation of nuclear factor-kappaB (NF-kappaB) and inducible nitric oxide synthase (iNOS) expression in prediabetic stages of diabetes mellitus., Material or Subjects: Genetic, diabetic-prone or diabetic-resistant BB rats (total = 189)., Treatment: Various doses of an oral dithiocarbamate derivative, NOX-700, or cyclosporine (2.5 mg/kg) starting at 30 or 60 days of age., Methods: Immunohistochemistry, electrophoretic mobility shift assays, plasma glucose., Results: NF-kappaB and iNOS was increased in pancreas of hyperglycemic, diabetic-prone rats but not normoglycemic, diabetic-resistant rats. Immunostaining for NF-kappaB and iNOS was largely confined to islets and occurred in diabetic-prone rats prior to overt hyperglycemia. NOX-700 decreased cell infiltration, delayed the onset of disease and decreased the incidence of hyperglycemia to levels achieved by immunosuppressant therapy. NOX-700 also decreased the intensity of immunoreactive NF-kappaB and iNOS within pancreatic islets., Conclusions: These studies support a role of NF-kB and iNOS in diabetogenesis in vivo.

Aim: To investigate whether acute lung injury (ALI) in ventilated piglets with bacterial infection affects NF-kappaB and AP-1 expression in alveolar macrophages (AM) and whether nitric oxide (NO), surfactant (Surf), glucocorticoids (GC) affect NF-kappaB and AP-1 activation in AM in vivo and in vitro., Methods: The animals were intraperitoneally injected Escherichia coli, which caused ALI. Nuclear extracts of AM were analyzed by electrophoretic mobility shift assay (EMSA) for the nuclear factor-kappa B (NF-kappaB) and activation protein-1 (AP-1) expression. Detection of IkappaB-alpha protein was from cytoplasmic extract by Western blotting. Immunocytochemistry staining was used for intracellular location of p65 subunits of NF-kappaB., Results: In ex vivo experiments, strikingly higher expression of NF-kappaB and AP-1 by EMSA was found 6 h after bacterial injection in contrast to the Normal group. In the NO, SNO, and GC groups, markedly attenuated NF-kappaB and AP-1 activation was observed. The NF-kappaB and AP-1 activation in Surf group showed lower levels of the expression. Immunoblotting of AM cytoplasmic extract showed low expression of IkappaB-alphaprotein in the Control and Surf groups. The stronger expression was observed in the NO, GC, and SNO groups. AM of the Control and Surf groups showed intense nuclear staining, with decreased nuclear staining in the NO, GC and SNO groups. In in vitro experiment, it caused a significant increase in NF-kappaB and AP-1 activity in AM 1 h after exposure to lipopolysaccharides (LPS). In AM treated by LPS+SNP and LPS+GC, all showed decrease of DNA binding activity of NF-kappaB and AP-1 compared to those exposed to LPS+Surf. Immunoblotting of AM cytoplasmic extract showed that LPS stimulation of AM resulted in the low expression of IkappaB-alpha protein, which was not observed in the presence of SNP and methylprednisolone. However, the surfactant did not show such effect. LPS+Surf-exposed AM had intense nuclear staining, whereas decreased nuclear staining in the LPS+NO and LPS+GC-treated cultures was found, confirming a decrease in NF-kappaB activity., Conclusion: Activation of NF-kappaB was found in AM of ventilated piglets with bacterial ALI. NO and GS could prevent NF-kappaB and AP-1 activation in vivo and in vitro. Surfactant has limited effects on NF-kappaB and AP-1 activity.

Objective: To evaluate dose response of inhaled nitric oxide (iNO) for surfactant-treated rabbits with meconium aspiration-induced acute lung injury (ALI) and hypoxemic respiratory failure (HRF), and variation of measured iNO by continuous NO delivery in pressure support ventilation (PSV)., Methods: Adult rabbits (2.0 - 3.5 kg, n = 33) were randomized to receive intratracheal meconium instillation for 30 min and subjected to following treatment (n = 6 - 8). There were 4 groups: Control (C); NO, iNO at 1, 10, 20 and 40 x 10(-6) each for 60 min at 30 min interval of disconnection; Surf, intratracheal instillation of porcine lung surfactant phospholipids (100 mg/kg); SNO, both iNO and surfactant as in the NO and Surf groups; and a normal group (N), which did not undergo meconium aspiration but received sham deliveries of normal saline. All the animals were treated with PSV for 6 h. iNO levels at different input and sampling sites in the NO and SNO groups were detected by on-line chemiluminescent technique. The blood gas and lung mechanics were measured during the experiments every 2 h., Results: (1) Meconium aspiration induced ALI and severe HRF (PaO(2)/FiO(2) < 200 mmHg) and depressed dynamic compliance of respiratory system (Cdyn) and airway resistance (Raw). In both Surf and NO groups modestly improved oxygenation was observed. In the SNO, values for PaO(2)/FiO(2) were improved from (185 +/- 39) mmHg at baseline to (301 +/- 123) mmHg at 6 h, while moderate or transient improvement was observed in both Surf and NO groups. Cdyn and Raw were only improved for short time in the Surf, NO and SNO groups. iNO had a mild response at 1 x 10(-6) to good response at 10 and 20 x 10(-6), but no further improvement occurred at 40 x 10(-6). The response of iNO in NO group was relatively transient compared to the SNO group. (2) When iNO was connected to the ventilator circuit, the connected site should be placed before humidifier to minimize fluctuation of iNO concentration, and sampling site for iNO monitoring should be placed adequately to eliminate artifact., Conclusions: iNO synergistically improved surfactant effects on oxygenation and lung mechanics. Continuous supply of iNO with non-continuous flow ventilator provided stable NO within accepted target range with least variation.

Liver cancer is one of the most common cancers worldwide. Infection with hepatitis B virus and exposure to aflatoxins in the diet act synergistically to amplify risk. From a public health perspective, hepatitis virus vaccination programs and efforts to both reduce aflatoxin exposures and to attenuate the toxicological consequences of unavoidable exposures should have major impacts on the incidence of this disease. Experimentally, aflatoxin-induced hepatocarcinogenesis can be inhibited by over a score of different chemopreventive agents with multiple mechanisms of action. One agent, oltipraz, is a potent inducer of phase 2 enzymes involved in the detoxication of carcinogens including aflatoxin. A second agent, chlorophyllin, impedes the bioavailability of carcinogens by forming molecular complexes and enhances their elimination in the fecal stream. This review highlights the findings of recent randomized clinical trials with oltipraz and chlorophyllin conducted in individuals exposed to dietary aflatoxins and at high risk for development of liver cancer. Both chemopreventive agents modulated levels of aflatoxin biomarkers in the study participants in manners consonant with protection.

Residents of Qidong, People's Republic of China, are at high risk for development of hepatocellular carcinoma, in part from consumption of foods contaminated with aflatoxins. Chlorophyllin, a mixture of semisynthetic, water-soluble derivatives of chlorophyll that is used as a food colorant and over-the-counter medicine, has been shown to be an effective inhibitor of aflatoxin hepatocarcinogenesis in animal models by blocking carcinogen bioavailability. In a randomized, double-blind, placebo-controlled chemoprevention trial, we tested whether chlorophyllin could alter the disposition of aflatoxin. One hundred and eighty healthy adults from Qidong were randomly assigned to ingest 100 mg of chlorophyllin or a placebo three times a day for 4 months. The primary endpoint was modulation of levels of aflatoxin-N(7)-guanine adducts in urine samples collected 3 months into the intervention measured by using sequential immunoaffinity chromatography and liquid chromatography-electrospray mass spectrometry. This aflatoxin-DNA adduct excretion product serves as a biomarker of the biologically effective dose of aflatoxin, and elevated levels are associated with increased risk of liver cancer. Adherence to the study protocol was outstanding, and no adverse events were reported. Aflatoxin-N(7)-guanine could be detected in 105 of 169 available samples. Chlorophyllin consumption at each meal led to an overall 55% reduction (P = 0.036) in median urinary levels of this aflatoxin biomarker compared with those taking placebo. Thus, prophylactic interventions with chlorophyllin or supplementation of diets with foods rich in chlorophylls may represent practical means to prevent the development of hepatocellular carcinoma or other environmentally induced cancers.

A Phase II chemoprevention trial was carried out in Qidong, Jiangsu Province, People's Republic of China. The recruited subjects, all of whom were positive for serum aflatoxin-albumin adducts, were divided into three treatment arms: placebo; oltipraz ([5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione]) given daily at 125 mg p.o.; and oltipraz given once per week at 500 mg p.o. Besides biomarkers related to aflatoxin B(1) exposure, the genotoxicity of blind-coded urine XAD-2 concentrates was evaluated in 201 subjects on the fifth and seventh week of intervention. Genotoxicity was assessed both in the Ames reversion test in strain YG1024 of Salmonella typhimurium, in the presence of an exogenous metabolic system (S9 mix), with or without beta-glucuronidase, and in a DNA repair test in Escherichia coli. Heating of concentrated urine samples or of cigarette smoke condensates was discovered to result in a significant enhancement of their mutagenicity. It was also found that the mutagenicity of condensates from the most extensively used brands of cigarettes in Qidong was much lower than that of Western cigarette brands. Urine mutagenicity was unrelated to treatment with oltipraz, intervention time, gender, and supplement of S9 mix with beta-glucuronidase. Mutagenicity was significantly but variably higher in cigarette smokers than in nonsmokers, which suggests that the urinary excretion of mutagens in the examined population was not exclusively attributable to smoking. Nevertheless, within smokers (28% of the recruited subjects; 67% of all males), the mutagenic potency was significantly correlated with the self-reported number of cigarettes smoked per day and, even more sharply, with the cotinine concentrations in urines. In conclusion, this study demonstrated the validity of urine mutagenicity assays as a biomarker of tobacco smoke exposure that can be investigated on a relatively large scale in chemoprevention trials and provided evidence that oltipraz treatment had no influence on this parameter in the examined population.

There are scant data on the frequency of parathyroidectomy (PTX) for end-stage renal disease (ESRD). Medical therapy for ESRD and secondary hyperparathyroidism has evolved to include better dialytic urea removal and the use of calcitriol. The aim of this study was to determine whether medical therapy has changed the frequency or indications for PTX in the management of renal failure. Hospital and clinic records were analyzed to gather information on all patients undergoing PTX for secondary hyperparathyroidism (2HPT) (n = 48) and tertiary hyperparathyroidism (3HPT) (n = 26) from 1986 through 1998 at our institution. Prospective computer databases were queried for information concerning both chronic dialysis and renal transplant patients at our center. The patients were divided based on date of operation before or after 1991, a divider that separated the patients into groups before or after the widespread adoption of intravenous calcitriol treatment during hemodialysis at our institution. Over the 12 year period, the proportion of our chronic dialysis patients undergoing PTX did not change significantly, ranging from 0% to 2.5% per year. Comparing all patients undergoing PTX for 2HPT during 1986-1991 versus 1992-1998, there was no significant difference in time on dialysis [7.0 +/- 4.2 (n = 11) vs. 7.5 +/- 4.6 (n = 36) years, mean +/- SD]. The later group had higher intact parathyroid hormone (iPTH) levels [765 +/- 415 (n = 6) vs. 1377 +/- 636 (n = 28) pg/ml; p = 0.03], lower serum calcium [11.2 +/- 1.0 (n = 12) vs. 9.9 +/- 1.5 (n = 34) mg/dl; p = 0.006], and higher serum phosphate [5.7 +/- 1.6 (n = 12) vs. 7.2 +/- 2.3 (n = 31) mg/dl; p = 0.042]. Among the population of patients with transplants undergoing PTX for 3HPT, the average percent per year undergoing PTX ranged from 0% to 4.2% and did not change during the study period. Comparing the 1986-1991 group to the 1992-1998 group, the time from transplantation to PTX did not change during the study period (3.3 +/- 2.3 vs. 2.9 +/- 3.0 years; p = 0.391), and there were no significant differences between preoperative calcium levels or iPTH levels. Despite advances in dialysis technique and pharmacologic therapy, there has been no change in the proportion of dialysis patients requiring PTX for 2HPT or 3HPT. There was also no change in the time on dialysis for patients with 2HPT or the time from transplant to PTX for patients with 3HPT. Analysis of preoperative biochemical markers as evidence of disease severity suggests there was no change in indications for PTX during our study. From this information we conclude that parathyroid pathophysiology is incompletely understood and medical therapy is not optimal, resulting in a continuing need for PTX in some patients.

Hepatocellular carcinoma (HCC), a common cause of cancer deaths worldwide, has several major etiological risk factors, including infection with the hepatitis viruses and exposure to aflatoxin B1. A specific missense mutation resulting from a guanine to thymine transversion at the third position of codon 249 in the p53 tumor suppressor gene has been reported in 10-70% of HCCs from areas of high dietary exposure to aflatoxin B1. Short oligonucleotide mass analysis was compared with DNA sequencing in 25 HCC samples for specific p53 mutations. Mutations were detected in 10 samples by short oligonucleotide mass analysis in agreement with DNA sequencing. Analysis of another 20 plasma and tumor pairs showed 11 tumors containing the specific mutation, and this change was detected in six of the paired plasma samples. Four of the plasma samples had detectable levels of the mutation; however, the tumors were negative, suggesting possible multiple independent HCCs. Ten plasma samples from healthy individuals were all negative. This molecular diagnostic technique has implications for prevention trials and for the early diagnosis of HCC.

Background: The effects of intestinal transplantation on gut motility have not been completely defined. In this study we examine the effects of ileal transplantation on ileal smooth muscle contractility, together with gastroduodenal emptying, intestinal flow, and transit rates in a canine model of short-gut syndrome., Methods: Animals (n = 22) were instrumented with strain gauge transducers, collection cannulae, and infusion catheters to assess motility, intestinal flow and transit rates, and gastroduodenal emptying. Ten animals served to define normal parameters. Six animals underwent a 70% resection of the proximal small intestine to serve as short-gut controls. Six animals underwent removal of a 100-cm segment of the ileum, with cold storage, and autotransplantation the following day combined with a 70% resection of proximal bowel., Results: Transplant animals exhibited delayed gastroduodenal emptying, reduced intestinal flow rates, and postprandial phasic contractions that were similar to short-gut controls. However, transplant animals experienced rapid intestinal transit compared with short-gut controls (4.8 +/- 0.4 cm/min vs 2.0 +/- 0.3 cm/min; mean +/- SEM; P <.05)., Conclusions: The transplanted intestine, even with 18 hours of cold storage, exhibits a relatively normal postprandial motor response. However, adaptive responses of the transplanted intestine, such as regulation of intestine transit, may be impaired by neuromuscular injury associated with denervation or ischemia.

Background: Cell cycle arrest after DNA damage is partly mediated through the transcriptional activation of p21(WAF1) by the p53 tumor suppressor gene. p21(WAF1) and p53 are both critical in maintaining cell cycle control in response to DNA damage from radiation or chemotherapy. Therefore, we examined the role of p21(WAF1) and p53 in the determination of outcome for patients who receive radiation and/or chemotherapy for pancreatic cancer., Methods: p21(WAF1) and p53 protein expression were determined (with the use of immunohistochemistry) in specimens from 90 patients with pancreatic cancer. Forty-four patients underwent surgical resection, and 46 patients had either locally unresectable tumors (n = 9 patients) or distant metastases (n = 37 patients). Seventy-three percent of the patients who underwent resection and 63% of the patients who did not undergo resection received radiation and/or chemotherapy., Results: p21(WAF1) expression was present in 48 of 86 tumors (56%) and was significantly (P<.05) associated with advanced tumor stage. Median survival among patients with resected pancreatic cancer who received adjuvant chemoradiation with p21(WAF1)-positive tumors was significantly longer than in patients with no p21(WAF1) staining (25 vs. 11 months; P = .01). Fifty of 89 tumors (56%) stained positive for p53 protein. p53 overexpression was associated with decreased survival in patients who did not undergo resection., Conclusions: Normal p21(WAF1) expression may be necessary for a beneficial response to current adjuvant chemoradiation protocols for pancreatic cancer. Alternate strategies for adjuvant therapy should be explored for patients with pancreatic cancer who lack functional p21(WAF1).

Molecular biomarkers are becoming increasingly important tools to identify people who are at highest risk of developing cancer. For many years we have been studying residents of Qidong County, People's Republic of China, to examine the combined impact of aflatoxin exposure with other risk factors as contributors to the high liver cancer incidence rates in this region. This study was conducted to determine the effects of aflatoxin exposure, as measured by serum aflatoxin-albumin adduct levels, on somatic mutation frequency in the human hypoxanthine guanine phosphoribosyl transferase gene (HPRT). Subjects were assigned as low or high according to a dichotomization around the population mean of aflatoxin-albumin adducts. HPRT mutant frequency was determined in individuals by a T cell clonal assay and the samples were categorized as low or high according to mean values. Separate analyses were also conducted for the small set of hepatitis B virus surface antigen (HBsAg)-positive and the larger set of HBsAg-negative individuals, known risk factors for liver cancer. An odds ratio of 19.3 (95% confidence interval 2.0, 183) was demonstrated for a high HPRT mutation frequency in individuals with high aflatoxin exposure compared with those with low aflatoxin exposure. This association indicates that aflatoxin-induced DNA damage in T lymphocytes, assessed using the validated surrogate albumin adduct markers, leads to increased mutations reflected as elevated HPRT gene mutations. This cross-sectional study suggests the potential use of mutation frequency of the HPRT gene as a long-term biomarker of aflatoxin exposure in high risk populations.

Background: In the absence of metastases, there are no reliable microscopic features that distinguish malignant from benign pheochromocytomas. Because a common feature of malignancy is the loss of cell cycle regulation and normal growth arrest, the authors hypothesized that analysis of the cell cycle could be used to aid in the diagnosis of malignant pheochromocytoma., Methods: Cell cycle analysis of archival samples of 51 pheochromocytomas (40 sporadic, 11 familial) from 45 patients, including 6 malignant and 45 benign tumors, was conducted. Flow cytometry data and immunohistochemistry for markers of cell proliferation (proliferating cell nuclear antigen [PCNA] and MIB-1 [Ki-67]) were correlated with the authors' clinical data base records, with a mean follow-up of 66 months., Results: No correlation of DNA ploidy, S-phase fraction by flow cytometry, or PCNA with malignancy was observed. Staining for the MIB-1 nuclear proliferation marker was positive in 3 of 6 (50%) of the malignant pheochromocytomas and negative in all 45 benign tumors (P< 0.01)., Conclusions: Contrary to some previous reports, a diploid DNA pattern does not necessarily predict benign behavior of pheochromocytoma. In this study, cell cycle analysis and, in particular, assessment of the MIB-1 nuclear proliferation marker was useful in the histologic evaluation of pheochromocytoma, as MIB-1 was expressed only in malignant tumors., (Copyright 1999 American Cancer Society.)

Background: Residents of Qidong, People's Republic of China, are at high risk for development of hepatocellular carcinoma, in part due to consumption of foods contaminated with aflatoxins, which require metabolic activation to become carcinogenic. In a randomized, placebo-controlled, double-blind phase IIa chemoprevention trial, we tested oltipraz, an antischistosomal drug that has been shown to be a potent and effective inhibitor of aflatoxin-induced hepatocarcinogenesis in animal models., Methods: In 1995, 234 adults from Qidong were enrolled. Healthy eligible individuals were randomly assigned to receive by mouth 125 mg oltipraz daily, 500 mg oltipraz weekly, or a placebo. Sequential immunoaffinity chromatography and liquid chromatography coupled to mass spectrometry or to fluorescence detection were used to identify and quantify phase 1 and phase 2 metabolites of aflatoxin B1 in the urine of study participants. Reported P values are two-sided., Results: One month of weekly administration of 500 mg oltipraz led to a 51% decrease in median levels of the phase 1 metabolite aflatoxin M1 excreted in urine compared with administration of a placebo (P = .030), but it had no effect on levels of a phase 2 metabolite, aflatoxin-mercapturic acid (P = .871). By contrast, daily intervention with 125 mg oltipraz led to a 2.6-fold increase in median aflatoxin-mercapturic acid excretion (P = .017) but had no effect on excreted aflatoxin M1 levels (P = .682)., Conclusions: Intermittent, high-dose oltipraz inhibited phase 1 activation of aflatoxins, and sustained low-dose oltipraz increased phase 2 conjugation of aflatoxin, yielding higher levels of aflatoxin-mercapturic acid. While both mechanisms can contribute to protection, this study highlights the feasibility of inducing phase 2 enzymes as a chemopreventive strategy in humans.

Background: Reports of improved survival rates for patients with resected adenocarcinoma of the pancreas coincide with the adoption of adjuvant chemoradiation protocols. The impact of nodal micrometastases demonstrated by molecular assays and adjuvant therapy on survival of patients with stage I pancreatic cancer has not been adequately assessed., Methods: A retrospective analysis of postoperative chemoradiation on survival in 61 patients undergoing resection of pancreatic adenocarcinomas from 1984 to 1997 was performed. Archival tumors and regional nodes from 25 patients with stage I cancers were tested for a Kiras oncogene mutation using polymerase chain reaction and analysis for restriction fragment length polymorphisms (PCR/RFLP)., Results: Adjuvant chemoradiation was associated with improved survival for stage I (P < .01), but not stage III, disease. Seventeen (68%) of 25 patients with stage I disease tested had evidence of mutant Kiras in one or more regional nodes. Survival did not differ for patients with molecular micrometastases. Six of 17 (35%) patients with micrometastases received adjuvant chemoradiation and had improved survival (P < .05)., Conclusions: The majority of patients with stage I pancreatic cancer have PCR/RFLP evidence of lymph node micrometastases. Adjuvant chemoradiation improves survival in these patients by treating micrometastases not detected by histology. Adjuvant chemoradiation should be used for patients with stage I pancreatic cancers.

Background: The purpose of this study was to correlate intraoperative blood flow measurements with outcome in vascular access surgery., Methods: In 303 patients, 389 vascular access operations were performed. Intraoperative blood flow measurements were made immediately following construction of 227 autogenous and 162 prosthetic arteriovenous fistulas (AVFs) using a handheld flowprobe. Blood flow measurements were stratified by demographic variables such as age, race, sex, and presence of diabetes and were correlated with primary and secondary (assisted) patency. Statistical methods included life-table analysis and Cox proportional hazards model., Results: Blood flow increased progressively from distal to proximal access sites and was not significantly affected by age, race, sex, or presence of diabetes. Autogenous AVFs with flow rates at or below 320 mL/min and polytetrafluoroethylene (PTFE) grafts with flow rates at or below 400 mL/min had significantly worse primary and secondary patency rates compared to their higher flow counterparts at all sites. Using hazard analysis flow rate was the single most important determinant of primary and secondary patency. PTFE grafts with flow rates at or below 400 mL/min also required more interventions (1.58 per patient-year) and failed sooner (median time, 0.5 +/- 4.7 months) than grafts with flow rates above 400 mL/min (1.08 interventions per patient-year; P = .03; median time, 1.6 +/- 5.0 months; P = .003)., Conclusions: Intraoperative measurements of access blood flow provide objective, reliable data that correlate with outcome. Routine use of this technology might lead to more efficient management of patients undergoing hemodialysis access surgery.

In 1995, 234 adults from Qidong, People's Republic of China, were enrolled and followed in a Phase IIa 4-methyl-5-(N-2-pyrazinyl)-1,2-dithiole-3-thione (oltipraz) chemoprevention trial. Residents of this area are at high risk for development of hepatocellular carcinoma, in part due to consumption of aflatoxin-contaminated foods. The intervention was a randomized, placebo-controlled, double-blind study. Elements of the study design and clinical outcomes have been recently published (Jacobson et al, Cancer Epidemiol. Biomark. Prev., 6: 257-265, 1997). The primary objective was to conduct a preliminary assessment of the ability of oltipraz to modulate levels of a validated biomarker of aflatoxin exposure and of the risk of hepatocellular carcinoma by determining levels of aflatoxin-albumin adducts in sera. Healthy eligible individuals were randomized into three arms to receive p.o. 125 mg of oltipraz daily, 500 mg of oltipraz weekly, or placebo for 8 weeks. There were no consistent changes in biomarker levels in the placebo arm over the 16-week observation period, nor was any apparent effect observed in the arm receiving 125 mg of oltipraz each day. However, individuals receiving 500 mg of oltipraz once a week for 8 weeks showed a triphasic response to oltipraz. No effect was observed during the 1st month of the intervention, whereas a significant (P = 0.001) diminution in adduct levels was observed during the 2nd month of active intervention and during the lst month of follow-up. A partial rebound in adduct levels toward baseline values was observed during the 2nd month postintervention. Linear regression models up to week 13 confirmed a significant (P = 0.008) weekly decline of biomarker levels in the group receiving 500 mg of oltipraz once a week. However, despite these effects relative to baseline values within the 500-mg weekly arm, there were no statistically significant differences in biomarker trajectories between treatment arms. The genotype for glutathione S-transferase M1, an oltipraz-inducible isoform involved in the detoxification of aflatoxin B1, did not appear to affect either baseline levels or rates of decline in the biomarker. A follow-up Phase IIb trial with a longer intervention period will be necessary to determine the full extent to which aflatoxin biomarker burden can be reduced and whether diminution of biomarkers can be sustained over the long term.

In 1995, 234 adults from Qidong, Jiangsu Province, People's Republic of China, where hepatocellular carcinoma is the leading cause of cancer deaths and exposure to dietary aflatoxins is widespread, were enrolled and followed in a Phase II chemoprevention trial. The goals of the study were to define a dose and schedule of oltipraz for reducing levels of validated aflatoxin biomarkers and to characterize dose-limiting toxicities. Healthy eligible individuals, including those infected with hepatitis B virus, were randomized to receive either 125 mg of oltipraz daily, 500 mg of oltipraz weekly, or placebo. Blood and urine specimens were collected to monitor toxicities and evaluate biomarkers over the 8-week intervention period and subsequent 8-week follow-up period. Unique trial aspects included a synchronous follow-up schedule, daily observed administration of all medications, timely international data transference, and use of biomarkers as outcomes. One hundred thirty-two participants took their medications without interruptions, approximately 77% contributed all nine urine samples, and 78% contributed all seven blood samples. Fifty-one participants (21.8%) reported clinical adverse events. An extremity syndrome, developing soon after the start of treatment, was the only event that occurred more frequently (P = 0.002) among the active groups (18.4 and 14.1% of the daily 125 and weekly 500 mg arms, respectively) compared with placebo (2.5%). The oltipraz arms did not differ in symptom type or severity, and there were no indications of exacerbated drug intolerance among the few participants infected with hepatitis B virus. The good compliance with an intense follow-up schedule shows that chemoprevention trials with biomarker end points may be conducted in such populations.

Background: The purpose of this study was to elucidate the mechanism of reduced intestinal transit rate in the ileum as compared with the jejunum., Methods: Twenty-one dogs were each instrumented with 12 strain gauge transducers, 2 collection cannulas, and an infusion catheter defining a 100 cm study in the midjejunum (n = 11) and midileum (n = 10). Postprandial motor activity and intestinal transit were measured 1 hour after ingestion of a 650 kcal solid meal. Contractile activity was analyzed by means of computer programs that determine frequency, amplitude, and propagation behavior of circular smooth muscle contractions., Results: Postprandial ileal contractions occurred with greater frequency (13.7 +/- 2.5 versus 11.5 +/- 0.4; p = 0.04) and displayed a higher incidence of propagation (61% +/- 2% versus 44% +/- 3%; p = 0.0001) than jejunal contractions, but traveled at significantly slower rates (1.0 +/- 0.7 cm/sec vs 3.7 +/- 0.9 cm/sec; p = 0.0001). The net result was significantly slower transit in the ileum compared with the jejunum (4.7 +/- 0.7 cm/min versus 13.1 +/- 1.5 cm/min; p = 0.0006). Within each region, transit correlated with parameters of propagating contractions. Stepwise regression of the combined data revealed that contraction velocity was the most important variable determining intestinal transit rate (r = 0.64; p < 0.001)., Conclusions: Contrary to previous thinking, postprandial ileal contractions display a high degree of temporal and spatial organization. Slow ileal transit is mainly due to reduced propagation velocity, which is intrinsic to the circular smooth muscle.

Oltipraz has been used clinically in many regions of the world as an antischistosomal agent and is an effective inhibitor of aflatoxin hepatocarcinogenesis in rats. This chemopreventive action of oltipraz results primarily from an altered balance in aflatoxin metabolic activation and detoxication. In 1995, a randomized, placebo-controlled, double-blind intervention was conducted in residents of Qidong, People's Republic of China, who are at high risk for exposure to aflatoxin and development of hepatocellular carcinoma. The major study objectives were to define a dose and schedule for oltipraz that would reduce levels of aflatoxin biomarkers in biofluids of the participants, and to further characterize dose-limiting side effects. Two hundred thirty-four healthy eligible individuals, including those infected with HBV, were randomized to receive either 125 mg oltipraz daily, 500 mg oltipraz weekly, or placebo. Blood and urine specimens were collected to monitor potential toxicities and evaluate biomarkers over the 8-week intervention and subsequent 8-week follow-up periods. Overall, compliance in the intervention was excellent; approximately 85% of the participants completed the study. Objective evaluation of adverse events was greatly facilitated by inclusion of a placebo arm in the study design. A syndrome involving numbness, tingling, and pain in the fingertips was the only event that occurred more frequently among the active groups (18 and 14% of the daily 125 mg and weekly 500 mg arms, respectively) compared to placebo (3%). These symptoms were reversible and could be relieved with non-steroidal antiinflammatory agents. A more complete understanding of the chemopreventive utility of oltipraz awaits completion of an assessment of the efficacy of oltipraz in modulating levels of aflatoxin biomarkers.

Molecular epidemiological studies of populations at high risk for liver cancer have shown that hepatitis B virus (HBV) and aflatoxin B1 (AFB1) exposure are two major risk factors for this disease. These etiological agents, combined with nutritional deficiencies, are important for the initiation and promotion of liver cancer in various parts of the world. In Qidong, People's Republic of China, liver cancer accounts for 10% of all adult deaths, and both HBV and AFB1 exposures are common. To study temporal and possible chemical-viral interactions in people, serum samples were collected during a longitudinal study designed to measure aflatoxin molecular biomarkers in residents of Daxin Township, Qidong City, People's Republic of China. In this study, the temporal modulation of aflatoxin adduct formation with albumin over multiple lifetimes of serum albumin was examined in both HBV-positive and HBV-negative people in two periods: September-December 1993 (wave 1) and June-September 1994 (wave 2). During the 12-week monitoring period of wave 1, 120 individuals (balanced by gender and HBV status) provided a total of 792 blood samples. AFB1-albumin adducts were detected in all but one of the serum samples. The range of binding detected by RIA in the Daxin population was 0.17-4.39 pmol AFB11/mg albumin with an overall mean +/- SD of 1.51 +/- 0.21 pmol AFB11/mg albumin. The mean +/- SD for weeks 0, 2, 4, 6, 8, 10 and 12 of wave 1 were 1.21 +/- 0.41, 1.58 +/- 0.70, 1.36 +/- 0.52, 1.71 +/- 0.44, 1.18 +/- 0.60, 2.00 +/- 0.59, and 1.68 +/- 0.34 pmol AFB1/mg albumin, respectively. During wave 2, 103 individuals from wave 1 provided a total of 396 blood samples collected monthly over wave 2, with mean +/- SD aflatoxin-albumin adduct levels of 1.19 +/- 0.37, 0.85 +/- 0.45, 0.89 +/- 0.28, and 0.61 +/- 0.15 pmol AFB1/mg albumin. Using linear regression models, the mean aflatoxin-albumin adduct levels increased (P < 0.05) during the 12 weeks of wave 1 and decreased (P < 0.05) over the 4 months of wave 2. Neither HBV surface antigen status nor gender modified either the baseline mean or the temporal trend. High-performance liquid chromatography confirmation was done on a subset of serum samples, and the results show an excellent association between the immunoassay data and high-performance liquid chromatography. Taken together, these data demonstrate that AFB1-albumin is a sensitive and specific biomarker for assessing exposure to this carcinogen in the population in Qidong.

Urinary genotoxicity assays measure the internal dose of genotoxic carcinogens, thereby providing a particularly sensitive endpoint for selecting cohorts of individuals exposed to cigarette smoke or other mutagens excreted with urines, as well as for evaluating the modulation of this parameter after administration of chemopreventive agents. Mutagenicity of urines was investigated in smoking Italian volunteers, who received oral N-acetylcysteine (NAC) at the same doses which are usually prescribed for the long-term treatment of chronic bronchitis. The daily excretion of mutagens, concentrated on XAD-2 columns and tested in Salmonella typhimurium YG1024 with S9 mix, was significantly and remarkably decreased by NAC in the majority of the subjects examined so far. Time-course experiments showed that this effect starts since the first day of drug administration and reverses when treatment is withdrawn. In addition, NAC administration almost totally prevented urinary genotoxicity in one subject whose concentrated urines induced a differential lethality in Escherichia coli strains having distinctive DNA repair capacities. The decrease of urinary genotoxicity produced by NAC in the majority of smokers correlates with the ability of this thiol to prevent tumors and to affect a variety of intermediate biomarkers in animal models. Modulation of the urinary excretion of mutagens is one of the biomarkers evaluated in two ongoing Phase II chemoprevention trials. One study involves the oral administration of NAC in Dutch smokers. The pretreatment urine samples of all the subjects so far recruited are clearly mutagenic. The other study involves the oral administration of the dithiolethione oltipraz to individuals living in the Qidong County of the People's Republic of China, an area of high endemy for HBV infection and of high exposure to aflatoxins. Additionally, a large proportion of the recruited male subjects are smokers. A total of 500 urine specimens will be assayed from 240 subjects according to a complex protocol arranged in three consecutive phases.

Purpose: To understand the relative importance of changes in ileal smooth muscle contractility versus alteration of intestinal flow rate as control mechanisms for regulating intestinal transit in a surgical model of short-gut syndrome., Methods: A model of short-gut syndrome was created by performing a 70% proximal small-bowel resection in dogs. Ten control and 6 animals with short-gut syndrome were instrumented with strain gauge transducers, steel collection cannulas, and a Silastic intraluminal infusion catheter in the midileum. Motor activity was analyzed by computer programs that determine frequency, amplitude, and propagation behavior of postprandial contractions. Perfusions of 14C-polyethylene glycol and bolus injection of 3H-polyethylene glycol were used to determine intestinal flow and transit rates. Total gastroduodenal emptying was determined using a 14C-polyethylene glycol-labelled meal., Results: Postprandial contraction frequency was decreased in animals with short-gut syndrome, but other significant changes in amplitude, mean area, and propagation behavior of postprandial ileal contractions were not seen. Gastroduodenal emptying and mean intestinal flow rates were markedly slower in animals with short-gut syndrome, as were intestinal transit rates., Conclusions: In this model of short-gut syndrome, the major adaptive change is decreased intestinal flow rate, related to delayed gastroduodenal emptying. The spatial organization of ileal contractions does not change substantially aside from a change in frequency which can be accounted for by transection of the intestinal wall.

Background: The purpose of this study was to determine how transection and reanastomosis of the intestinal wall influences postprandial motor activity and transit in the small intestine., Methods: Six dogs were each instrumented with 12 strain gauge transducers, two collection cannulas, and an infusion catheter defining a 100 cm study segment in the midjejunum. The animals underwent baseline measurements of postprandial motor activity and transit rate after 650 kcal solid and liquid meals. Postprandial motor activity was analyzed by computer methods that identify frequency, duration, amplitude, and propagation behavior of smooth muscle contractions. After the baseline measurements were performed, each animal underwent transection and reanastomosis of the intestinal wall at sites marked during the initial laparotomy. Measurements of postprandial motor activity and transit were repeated and compared with control values., Results: Transection decreased frequency, amplitude, and percent propagation for postprandial contractions. Total propagating area per minute significantly decreased from 382 +/- 20 gram-seconds/minute to 190 +/- 66 gram-seconds/minute after transection (p < 0.05). Intestinal transit decreased from 13.5 +/- 1.5 cm/min to 8.5 +/- 2.4 cm/min (p < 0.05). The change in transit was related primarily to a change in frequency of propagating contractions (r = 0.767; p = 0.004)., Conclusions: Transection and reanastomosis of the intestinal wall changes the temporal and spatial organization of contractions distal to the transection site. The net result is fewer distally propagating contractions and slower intestinal transit.

The role of extrinsic (autonomic) innervation in postprandial contractile activity of the small intestine is unknown. Using a canine model, we investigated the effects of complete extrinsic denervation on the parameters of fasting and postprandial jejunal contractions and their relationship to intestinal transit. Individual contractions were recorded using strain gauge transducers. Spatial and temporal parameters of contractions were analyzed by computer methods. Bolus injection of 14C-polyethylene glycol was used to calculate intestinal transit rates. Statistical comparisons of control and denervated animals were made by nonparametric tests. Extrinsic denervation did not abolish fasting or fed motor activity, but the following effects were observed: (1) the frequency of migrating motor complexes (MMCs) increased; (2) the onset of fed motor activity was delayed, and the duration of fed activity was shortened; (3) frequency, mean amplitude, and mean area of postprandial contractions were decreased; (4) fewer contractions propagated distally, and mean propagation distance was shortened; and (5) intestinal transit was slower for solids, but not for liquids. In the small intestine, extrinsic nerves modulate motor activity, which is under primary control of the intrinsic (enteric) nervous system.

In January 1988, we initiated a prospective, randomized comparison of prophylactic antilymphoblast globulin (ALG; quadruple therapy) versus no prophylactic ALG (triple therapy) in the setting of immediate graft function (defined by a brisk diuresis and a 20% decline in serum creatinine within 24 hr). Recipients were stratified according to presence of diabetes and age greater or less than 50 years. Recipients on quadruple therapy (n = 61) received 7 days of prophylactic Minnesota ALG (5 mg/kg on day 1, 10 mg/kg on day 2, 20 mg/kg on days 3-7). CsA, 10 mg/kg/day, began on day 6. AZA began at 2.5 mg/kg/day and was adjusted according to white blood cell count. Recipients on triple therapy (n = 60) began immediate CsA, 10 mg/kg/day orally and AZA, 5 mg/kg/day, tapering to 2.5 mg/kg/day by day 8. Both groups received identical prednisone tapers beginning at 1 mg/kg/day, decreasing to 0.5 mg/kg/day by 2 weeks and to 0.15 mg/kg/day by 6 months. Demographic characteristics between groups were not different with respect to diabetes, age, sex, race, per cent panel-reactive antibodies (PRA), or HLA matching. Follow-up ranged from 2 to 4.5 years. Patient survival was 93% for the quadruple therapy group and 90% for triple therapy. Actuarial graft survival was 79% in the quadruple group and 72% in the triple group (P = 0.18). Graft loss due to rejection occurred in 6/61 receiving ALG versus 7/60 in the immediate CsA group. Three of 4 high PRA recipients in the immediate CsA group lost their grafts within 30 days compared with none in the ALG group. The mean time to graft loss was significantly longer for the quadruple therapy group (17 +/- 8 months) compared with the triple therapy group (4 +/- 5 months), P = 0.006. The total number of rejection episodes was similar for both groups (29/61 vs. 31/60), as was the number who were rejection free (51% vs. 47%). The use of OKT3 was also similar between groups (28% vs. 30%). The quadruple therapy group had a higher incidence of CMV infection: 20% vs. 7% (P < 0.05), but no grafts or patients were lost as a result. Serum Cr was not different at 1 and 12 months (1.5 and 1.6 vs. 1.6 and 1.7, respectively), nor were Cr clearances (63 and 68 vs. 60 and 63). Conclusion. Early initiation of oral CsA in the setting of immediate graft function is not associated with significant nephrotoxicity.(ABSTRACT TRUNCATED AT 400 WORDS)