Bioavailability and toxicity after oral administration of m-iodobenzylguanidine (MIBG)

meta-iodobenzylguanidine (MIBG) radiolabelled with iodine-131 is used for diagnosis and treatment of neuroadrenergic neoplasms such as phaeochromocytoma and neuroblastoma. In addition, non-radiolabelled MIBG, administered i.v., is used in several clinical studies. These include palliation of the carcinoid syndrome, in which MIBG proved to be effective in 60% of the patients. Oral MIBG administration might be convenient to maintain palliation and possibly improve the percentage of responders. We have, therefore, investigated the feasibility of oral administration of MIBG in an animal model. Orally administered MIBG demonstrated a bioavailability of 59%, with a maximal tolerated dose of 60 mg kg−1. The first and only toxicity encountered was a decrease in renal function, measured by a reduced clearance of [51Cr]EDTA and accompanied by histological tubular damage. Repeated MIBG administration of 40 mg kg−1for 5 sequential days or of 20 mg kg−1for two courses of 5 sequential days with a 2-day interval did not affect renal clearance and was not accompanied by histological abnormalities in kidney, stomach, intestines, liver, heart, lungs, thymus, salivary glands and testes. Because of a sufficient bioavailability in absence of gastrointestinal toxicity, MIBG is considered suitable for further clinical investigation of repeated oral administration in patients. 1999 Cancer Research Campaig

Clinical Judgment Versus Biomarker Prostate Cancer Gene 3: Which Is Best When Determining the Need for Repeat Prostate Biopsy?

ObjectiveTo assess the value of best clinical judgment (BCJ) and the prostate cancer gene 3 (PCA3) assay in guiding the decision to perform a repeat prostate biopsy (PBx) after a previous negative PBx.Materials and MethodsUsing the RAND/UCLA Appropriateness Method, 12 European urologists established recommendations (BCJ) for the appropriateness of PBx according to the prostate-specific antigen level, digital rectal examination findings, number of previous negative PBxs, prostate volume, and life expectancy, with and without consideration of the PCA3 scores. These recommendations were applied to 1024 subjects receiving placebo in the Reduction by Dutasteride of Prostate Cancer Events trial, including men with a previous negative PBx, a baseline prostate-specific antigen level of 2.5-10 ng/mL, and a PCA3 test performed before the protocol-mandated 2- and 4-year repeat PBxs. Three scenarios (ie, BCJ alone, BCJ with PCA3, and the PCA3 score alone) were tested for their ability to reduce the repeat PBx rate versus missing Gleason sum ≥7 prostate cancer (PCa).ResultsBCJ with PCA3 would have avoided 64% of repeat PBxs compared with 26% for BCJ alone and 55% for PCA3 alone (cutoff score 20). Of 55 PCa cases (Gleason sum ≥7), 13 would have been missed using BCJ alone compared with 7 using PCA3 (cutoff score 20) alone and 8 using BCJ plus PCA3. The diagnostic accuracy for Gleason sum ≥7 PCa of the BCJ with PCA3 scenario was superior to that of the other scenarios, with a negative predictive value of 99%.ConclusionApplication of the BCJ together with PCA3 testing can reduce the number of repeat PBxs while maintaining the sensitivity to detect Gleason sum ≥7 PCa

CES technology and business cycle fluctuations

We contribute to an emerging literature that brings the constant elasticity of substitution (CES) specification of the production function into the analysis of business cycle fluctuations. Using US data, we estimate by Bayesian-Maximum-Likelihood methods a standard medium-sized DSGE model with a CES rather than Cobb-Douglas (CD) technology. We estimate a elasticity of substitution between capital and labour well below unity at 0.15–0.18. In a marginal likelihood race CES decisively beats the CD production and this is matched by its ability to fit the data better in terms of second moments. We show that this result is mainly driven by the implied fluctuations of factor shares under the CES specification. The CES model performance is further improved when the estimation is carried out under an imperfect information assumption. Hence the main message for DSGE models is that we should dismiss once and for all the use of CD for business cycle analysis

Regional distribution of fatiguing illnesses in the United States: a pilot study

BACKGROUND: Chronic fatigue syndrome (CFS) is a debilitating illness with no known cause or effective therapy. Population-based epidemiologic data on CFS prevalence are critical to put CFS in a realistic context for public health officials and others responsible for allocating resources. METHODS: We conducted a pilot random-digit-dialing survey to estimate the prevalence of fatiguing illnesses in different geographic regions and in urban and rural populations of the United States. This report focuses on 884 of 7,317 respondents 18 to 69 years old. Fatigued (440) and randomly selected non-fatigued (444) respondents completed telephone questionnaires concerning fatigue, other symptoms, and medical history. RESULTS: We estimated 12,186 per 100,000 persons 18 to 69 years of age suffered from fatigue lasting for at least 6 months (chronic fatigue), and 1,197 per 100,000 described an illness that, though lacking clinical evaluation, met criteria for CFS (CFS-like). Chronic fatigue and CFS-like illness were more common in rural than in urban populations, although the differences were not significant. The prevalence of these fatiguing illnesses did not differ meaningfully among the four regions surveyed, and no significant geographic trends were observed. CONCLUSIONS: This investigation estimated that nearly 2.2 million American adults suffer from CFS-like illness. The study also suggested the need to focus future investigations of fatigue on populations with lower incomes and less education. There was no evidence for regional differences in the occurrence of fatiguing illnesses

Intermittent aeration to regulate microbial activities in membrane-aerated biofilm reactors: energy-efficient nitrogen removal and low nitrous oxide emission

autotrophic nitrogen removal, yet control of nitrogen turnover remains challenging in MABR counter-diffusion biofilms. In this study, we regulated microbial activities in two lab-scale MABRs by providing continuous versus intermittent aeration. Nitrogen consumption by different functional microbial groups was estimated from bulk measurements via a mass balance approach. Nitrite-oxidizing bacteria (NOB) proliferated under continuous aeration while they were significantly suppressed under intermittent aeration, and NOB suppression activated anaerobic ammonium oxidation. Nitritation performance in the MABR was studied through long-term bulk measurements and in situ biofilm microprofiles of dissolved oxygen (DO) and pH. During intermittent aeration pH effects rather than DO effects determined nitritation success, especially ammonia speciation, which serves as substrate and inhibitor in nitrification processes. Biofilm transition phases were monitored upon aeration switches. Canonical correspondence analysis suggested that the relative transition after anoxia and aeration intermittency were less decisive for biofilm performance than the relative aeration duration. Heterotrophic bacteria displayed minor denitrification rates with aeration control, but contributed to mitigation of nitrous oxide (N2O) emissions. N2O production hotspots were identified at the top of the anoxic biofilm zone under continuous aeration. Instead, under intermittent aeration an anoxic N2O reduction zone was established. Our observations support intermittent aeration control of MABRs as a simple strategy for energy-efficient nitrogen removal with low N2O emission