Carcinogens in food: priorities for regulatory action

A pragmatic possible approach to the prioritization of chemical carcinogens occurring as food contaminants is described, based on the carcinogenic risk to the population. This should be of value in ensuring that resources for assessment and management of carcinogens in food are directed to the most important areas with regard to carcinogenic risk to the population. Key components of this approach are an assessment of the carcinogenic hazard to humans combined with estimations of intakes per person and of the proportion of the population exposed. These are used to derive an index referred to as the Population Carcinogenic Index. Concerning the hazard assessment expert judgement is used to place the chemical in one of five categories. The highest category is for chemical carcinogens that are believed to act by a genotoxic mechanism. It is recognised that such compounds may vary enormously with respect to their potency and various approaches to ranking carcinogens on the basis of potency are reviewed. The approach adopted is to subdivide the genotoxic carcinogens category into high, medium and low potency based on the TD50 value. Methods of estimating intakes and exposed populations are considered and an approach which groups these into broad categories is developed. The hazard and exposure assessments are then combined to derive the Population Carcinogenicity Index.     

Demonstration of protein tyrosine phosphatase activity in the second of two homologous domains of CD45

It has been reported that alteration of deletion of critical residues within one of the two homologous protein tyrosine phosphatase (PTPase)-like domains of CD45 completely abolishes all activity, suggesting that only the more N-terminal domain is catalytically active. However, we now demonstrate, by two independent techniques, that the second (C-terminal) domain is also a viable phosphatase. Limited proteolysis by endoproteinase Lys-C or trypsin increased the phosphatase activity toward reduced, carboxymethylated, and maleylated lysozyme approximately 8-fold. A 50-kDa fragment, isolated by ion exchange chromatography, was found to be responsible for this activity. N-terminal sequencing revealed that this fragment includes less than half of the first phosphatase domain and most, if not all, of the second. In a second experiment, 109 residues, including the presumed catalytic region, were removed from domain I by site-directed mutagenesis. Expression of this construct in a mammalian cell line resulted in increased PTPase activity over nontransfected control cells. Isolation of the recombinant CD45 by immunoprecipitation and immunoaffinity chromatography revealed that it had phosphatase activity. Both of these experimental approaches demonstrate that the second conserved PTPase domain of CD45 is a functioning PTPase, but that external regulation may be required to express its activity in the context of the native molecule.     

Health-related quality of life in patients served by the Department of Veterans Affairs: results from the Veterans Health Study

In a curative resection for advanced sigmoid or rectal cancer, an extensive dissection of the regional lymph nodes is generally required. This often necessitates the removal of the autonomic nerves around the inferior mesenteric artery. The present study was done in an attempt to clarify the influence of a neurectomy around the inferior mesenteric ganglion and plexus on the motility of the colon. In eight dogs, we resected the ganglion and plexus around the inferior mesenteric artery, together with an implantation of strain gauge force transducers in various parts of the colon, and 7-10 days later, colonic motility was examined. The percentage of contractile states and contractile forces increased at both the distal colon in fasting dogs, as well as at the middle colon in the late postprandial period. At the distal colon, contractile forces were noted in the early and late postprandial periods. These contractile abnormalities at the middle and distal colon may thus explain the frequent bowel movements or diarrhea often observed after extensive surgery in patients with sigmoid or rectal cancer.     

Evaluation of an ultramicroELISA system for the diagnosis of rubella

An indirect Ultramicro ELISA assay, previously standardized in our laboratory, for detecting antibodies IgG to the rubella virus was assessed in comparison to the hemagglutination inhibition technique. This assessment allowed to determine its efficacy in the National System for Epidemiological Surveillance of this entity. One hundred and ninety serum pairs of clinically suspected cases of rubella were studied and a high percent of coincidence (99.4%), specificity (99.4%), and sensitivity (100%) was found between both techniques. In addition, 73 serum samples of blood donors were processed using an indirect microELISA system (Berhing) which was compared to the Ultramicro ELISA technique for rubella and it showed a 100% of sensitivity, specificity, and coincidence.     

Transient alteration in intestinal permeability to technetium Tc99m diethylenetriaminopentaacetate during the prodromal stages of alimentary laminitis in ponies

OBJECTIVES: To determine whether mucosal permeability is altered during the prodromal stages of alimentary laminitis. ANIMALS: 15 healthy adult ponies. PROCEDURES: intestinal permeability was evaluated for control ponies (n = 5) and for ponies 4 to 12 (n = 5) and 20 to 28 (n = 5) hours after administration of carbohydrate overload. Mucosal permeability was determined by measuring the percentage of orally administered technetium Tc99m diethylenetriaminopentaacetate (99mTc-DTPA) excreted in urine during an 8-hour period, then measuring blood radioactivity at hourly intervals. Plasma endotoxin-like activity was measured by use of a chromogenic Limulus amebocyte assay. RESULTS: Urinary excretion of 99mTc-DTPA was 2.45% of administered dose for control ponies, and was 16.67% of administered dose 4 to 12 hours and 3.57% of administered dose 20 to 28 hours after administration of carbohydrate. CONCLUSIONS: A marked but transient increase in intestinal permeability was observed early in the prodromal stages of alimentary laminitis. CLINICAL RELEVANCE: Absorption of substances from the intestine may be an initiating event in alimentary laminitis.     

Modulation of the N-methyl-D-aspartate receptor by haloperidol: NR2B-specific interactions

The dopaminergic antagonist haloperidol has an eight- to 10-fold higher affinity for NMDA receptors containing the NR2B (epsilon2) subunit, showing the same subunit specificity as ifenprodil, polyamines, and magnesium. In the present study, we have compared the effects of mutations altering polyamine and ifenprodil sensitivity on haloperidol sensitivity of NMDA receptors. As seen for spermidine stimulation, high-affinity haloperidol inhibition is governed by the region around amino acid 198, based on results from chimeric murine NR2A/NR2B (epislon1/epsilon2) receptors. Mutation of epsilon2E201 in this region to asparagine or arginine causes a 10-fold decrease in the ability of haloperidol to inhibit 125I-MK-801 binding. Epsilon2E201 does not govern the interactions of ifenprodil, because all of the mutants at epsilon2E201 exhibited wild-type affinity for ifenprodil. Mutation of epsilon2R337 causes a 400-fold loss in apparent affinity for ifenprodil but does not change the effects of haloperidol. The structural determinants of spermidine stimulation do not perfectly match those for haloperidol inhibition, as mutations of E200 remove haloperidol inhibition but do not alter polyamine stimulation. The present results thus demonstrate that although spermidine, haloperidol, and ifenprodil share subunit selectivity and overlapping pharmacology, they also have specific structural determinants.     

Evidence for an X-linked genetic component in familial typical migraine

Although in cord blood (CB) transplantation graft-versus-host disease (GVHD) is reported to be less severe, GVHD may occur even in patients with HLA-identical sibling donors. This result shows that HLA typing can not entirely predict GVHD. The standard MLR with CB cells was either normal or slightly reduced compared with adult peripheral blood (PB) cells. We used two manipulations to increase the responses of CB cells to allo-antigens. The first was to treat the stimulator cells with cytokines, and the second to amplify weak proliferative responses by adding exogenous cytokines to MLR cultures (modified MLR). The stimulator cells were treated with both interferon-gamma (IFN-gamma) and IL-4. The responder cells were treated with both IL-2 and tumour necrosis factor-alpha (TNF-alpha). It is still to be determined whether or not this cytokine-enhanced MLR could be a possible predictor of GVHD. However, using these cytokines, 90% of CB could recognize allo-antigens, even if the standard MLR was negative.