The micronucleus test and NTP rodent carcinogens: not so many false negatives

In the study by Shelby et al. (1993) on 49 chemicals, the results of the micronucleus (MN) test in mouse bone marrow were compared with the results of the 2 year rodent carcinogenicity assays. Seven of the 25 rodent carcinogens were considered positive in the MN test, 5 following a protocol in which chemicals were given in three daily doses, and a further 2 when the chemical was administered only once. This low rate of positive results has led to disappointment in the MN test as a screen for carcinogens, but a careful examination of the data and of its analysis by Shelby et al. (1993) shows that many of the negative results are appropriate because: of the 18 carcinogens that were negative in the MN test, 1 has been retested and found to be non-carcinogenic, 9 were non-genotoxic and at least 2 were site-of-contact carcinogens not expected to be detected in the bone marrow. Two others were clearly positive in the MN test in other labs. Thus, the MN test 'missed' not 18 carcinogens, but 4 genotoxic carcinogens. The significance of these 4 needs further assessment, since three were liver specific carcinogens and the fourth was a very weak inducer of hemangiosarcomas in female mice only. Overall, the results of Shelby et al. (1993) do not cast such a shadow on the micronucleus test as many feared, and must be examined in the context of all the information available on each chemical. As Ashby and Tinwell emphasize in the accompanying article and in Tinwell and Ashby (1994), the data show that the MN test is capable of identifying human carcinogens and rodent germ cell mutagens, and remains a useful part of genotoxicity evaluation of chemicals.     

Potential anxiolytic properties of R-(+)-8-OSO2CF3-PAT, a 5-HT 1A receptor agonist

The inhibitory effect of 2% ethanol (400 mM) in the incubation medium on several characteristics of the Na(+)-ATPase of basolateral plasma membranes from rat kidney proximal tubular cells was investigated. Ethanol did not change the Km of the enzyme for Mg2+, ATP or Na+; it did not change either the optimal pH or temperature values of the incubation medium for the enzyme to act and finally, it did not affect the apparent energy of activation of the enzyme. It was also found that 2% ethanol produced stronger inhibition of the ATPase when it is in an activated or stimulated state, than when it is working at its lower basal level. The presented results can be explained by assuming that 2% ethanol in the incubation medium inhibits Na(+)-ATPase activity by affecting the enzyme structure as well as its activating mechanism.     

Effect of deoxycholate on immunoglobulin G concentration in bile: studies in humans and pigs

Because an increase in biliary deoxycholate levels seems to be a risk factor for cholesterol gallstone formation, we determined the relationship between deoxycholate levels and levels of the pronucleating protein, immunoglobulin G (Ig) in human gallbladder bile. Patients with cholesterol gallstones had a higher concentration of biliary IgG compared with a pigmented stone group and control patients. This was associated with the simultaneous presence of two conditions in the cholesterol stone group, supersaturated bile and a high deoxycholate/cholate ratio. The other patient groups met only one of the two conditions. Next, animal studies were performed to determine if model biles mimicking the two conditions could affect IgG secretion by the gallbladder. Gallbladders were exposed in vivo and then in an Ussing chamber to model biles. The voltage clamp technique was used to monitor functional integrity of the preparation. Three different model biles were tested: (1) taurodeoxycholate (TDC), 80%; taurocholate (TC), 20%; and cholesterol saturation index (CSI), 1.2; (2) TDC, 20%; TC, 80%; and CSI, 1.2; and (3) TDC, 80%; TC, 20%; and CSI, 0.6. IgG concentrations became significantly higher in group 1 than in the other two groups. The concentration of mucous glycoprotein was also significantly greater in group 1 when compared with group 2. Plasma cells were increased in number in mucosal and submucosal layers in group 1. We conclude that cholesterol supersaturated model bile with high content of TDC induces gallbladder epithelial alterations, which increase the luminal concentration of IgG and mucous glycoprotein.     

Expression and immune response to foreign epitopes in bacteria. Perspectives for live vaccine development

We previously developed a general procedure which allows the genetic coupling of a chosen foreign linear epitope in different regions of a carrier protein. By using as carriers, two bacterial envelope proteins, the LamB and MalE proteins of E. coli K12, we were able to express the same epitope in different sites of the two proteins and in different compartments of the bacteria. This allowed us to analyze the influence of the localization in E. coli cells of a foreign B-cell epitope on the induction of specific antibody responses, and the role of the molecular environment on the immunological properties of foreign B- or T-cell epitopes, using either purified hybrid proteins or live recombinant bacteria. Several LamB and MalE hybrid proteins were expressed in the aroA attenuated strain of S. typhimurium, SL3261. Immunizations of mice with live recombinant bacteria by the intravenous route showed that it was possible to induce humoral responses against inserted foreign sequences. In order to improve the in vivo stability of the plasmids carrying the different contructions, and to increase the amounts of recombinant LamB and MalE hybrid proteins expressed in vivo, the LamB and malE genes were placed under the control of the anaerobically inducible pnirBpromoter control. The genetic factors susceptible of influencing the immune response to recombinant Salmonella in mice were also studied.     

The immunomodulation of enteric neuromuscular function: implications for motility and inflammatory disorders

Gastrointestinal motility and sensory perception are altered in a variety of mucosal inflammatory conditions of the gut, ranging from peptic esophagitis to ulcerative colitis. Studies in animal models now clearly indicate a causal relationship between the presence of mucosal inflammation and altered sensory-motor function. In many instances, these changes occur in the absence of any discernible encroachment of the deeper neuromuscular layers by the inflammatory infiltrate, which remains largely within the lamina propria. Accordingly, attention has focused on local sources of mediators, and recent studies indicate that smooth muscle cells and enteroglia are sources of and targets for cytokines such as interleukin 1 beta and interleukin 6. In several instances, neuromuscular dysfunction persists after mucosal inflammation has subsided; this state may be maintained by locally produced mediators. Studies also show the ability of enteric muscle to modulate lymphocyte function via major histocompatibility complex II-restricted antigen presentation. Clinical observation and experimental data also suggest that nerves modulate intestinal inflammation via local release of proinflammatory neuropeptides (substance P) and via the activation of extensive circuits that may involve the brain. Taken together, these findings provide plausible explanations for a variety of clinical scenarios ranging from inflammatory bowel disease to pseudo-obstruction syndromes and subgroups of functional bowel disorders.     

Prevalence and epidemiology of Schistosoma mansoni and S. haematobium infection in two areas of Egypt recently reclaimed from the desert

Projects are being carried out in many regions of Egypt to reclaim land from the desert for agriculture. This paper presents findings from a baseline epidemiologic study conducted in 1992 in two newly reclaimed areas near Ismailia, Egypt. In the first area, just east of the Suez Canal, 40.0% of the residents tested positive for Schistosoma mansoni and 1.7% tested positive for S. haematobium, while in the second area, 15 km southwest of Ismailia, 49.3% tested positive for S. mansoni and 3.3% tested positive for S. haematobium. The intensities of S. mansoni infection were moderately high, with a geometric mean egg count of 76 eggs/gram of feces among positive individuals in the first area, and 100 eggs/gram of feces in the second area. When compared with a previous study conducted in 1985, the prevalence of S. mansoni infection in the first area has increased from 21.7% to 42.1% among settlers in the last seven years, while that of S. haematobium has decreased from 7.8% to 1.7%. These trends may result from changes in irrigation practices or other alterations in the local environment. There is a risk of schistosomiasis becoming a major public health problem in reclaimed areas if adequate control measures are not taken.     

Evidence that luminant and equiluminant motion signals are integrated by directionally selective mechanisms

Three experiments tested whether motion information for nonequiluminant (luminant) and equiluminant dots affects direction judgments when both types of stimuli are moving simultaneously in the same display. The motion directions for the two sets of dots were manipulated to produce four direction differences (0 degrees, 30 degrees, 60 degrees, and 90 degrees). The equiluminant dots were moved in a perfectly correlated fashion, but the percentage of correlated motion for the luminant dots was varied. When subjects judged whether the directions of the equiluminant and luminant dots were the same or different, performance for the conditions with 0 degrees, 60 degrees, and 90 degrees difference improved as the percentage of correlated luminant motion increased. The same result occurred for a control display that contained two sets of luminant dots. However, for the 30 degrees difference, performance was at chance level for the control display, but dropped below chance for the equiluminant-luminant display. When subjects indicated just the direction of the luminant dots, judgments were not affected by equiluminant motion. Judgments for the equiluminant dots also were accurate, except for the conditions with 30 degrees difference; these responses were biased by the luminant motion, indicating some form of motion capture. The interactive effects are discussed in terms of a directionally selective mechanism that combines equiluminant and luminant motion signals.