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Abstract Background Campylobacter jejuni infection produces a spectrum of clinical presentations in humans – including asymptomatic carriage, watery diarrhea, and bloody diarrhea – and has been epidemiologically associated with subsequent autoimmune neuropathies. This microorganism is genetically variable and possesses genetic mechanisms that may contribute to variability in nature. However, relationships between genetic variation in the pathogen and variation in disease manifestation in the host are not understood. We took a comparative experimental approach to explore differences among different C. jejuni strains and studied the effect of diet on disease manifestation in an interleukin-10 deficient mouse model. Results In the comparative study, C57BL/6 interleukin-10-/- mice were infected with seven genetically distinct C. jejuni strains. Four strains colonized the mice and caused disease; one colonized with no disease; two did not colonize. A DNA:DNA microarray comparison of the strain that colonized mice without disease to C. jejuni 11168 that caused disease revealed that putative virulence determinants, including loci encoding surface structures known to be involved in C. jejuni pathogenesis, differed from or were absent in the strain that did not cause disease. In the experimental study, the five colonizing strains were passaged four times in mice. For three strains, serial passage produced increased incidence and degree of pathology and decreased time to develop pathology; disease shifted from watery to bloody diarrhea. Mice kept on an ~6% fat diet or switched from an ~12% fat diet to an ~6% fat diet just before infection with a non-adapted strain also exhibited increased incidence and severity of disease and decreased time to develop disease, although the effects of diet were only statistically significant in one experiment. Conclusion C. jejuni strain genetic background and adaptation of the strain to the host by serial passage contribute to differences in disease manifestations of C. jejuni infection in C57BL/6 IL-10-/- mice; differences in environmental factors such as diet may also affect disease manifestation. These results in mice reflect the spectrum of clinical presentations of C. jejuni gastroenteritis in humans and contribute to usefulness of the model in studying human disease.

Shortly after promulgation of the Hazardous Waste Combustor MACT rule established regulatory limits for polychlorinated dioxins and furans (dioxins/furans) in incinerator stack gas, the US Environmental Protection Agency (USEPA) announced that facilities could still be required to demonstrate that stack emissions do not present an unacceptable risk to human health and the environment. Guidance for conducting this risk assessment activity, which was to be required under RCRA omnibus authority, was developed by the agency and released in 1998. The guidance represented an increase in complexity over previous documents developed by the agency and contains multiple chemical, fate and transport, and toxicological parameters which are to be used as default deterministic parameters in a complex series of algorithms which ultimately lead to numerical estimates of risk. As these changes were occurring, USEPA was also moving towards completion of its reassessment of dioxin. That series of documents has been the subject of considerable controversy and has, in several of its various drafts, proposed a number of changes, including modification of the existing toxic equivalency factor (TEF) approach and of the cancer potency factor of 2,3,7,8-tetachlorodibenzo-p-dioxin. At this time it is unclear what the impact of these changes will be on facilities progressing through the permitting process, because it is not intuitively obvious how changes in the risk assessment input parameters will impact the magnitude of the dioxinlfuran risk. In this paper, the receptor usually associated with the highest potential risk from dioxins/furans in a combustion risk assessment, the Subsistence Farmer, will be subjected to a sensitivity analysis to determine which of the multiple default input parameters will have the greatest influence on the potential cancer risk.

The fetal uptake of lidocaine was measured continually and quantitatively during and after a constant rate intravenous (iv) maternal infusion into five chronically prepared pregnant ewes. Lidocaine, 6 mg/kg (base), was infused at a constant rate for 1 h and measurements continued to 5 h. Rate of fetal uptake was determined from the product of the umbilical venous (UV) and fetal aortic (FA) concentration difference and umbilical blood flow (Qu). Total fetal uptake was determined by integrating fetal uptake rate with respect to time. Maternal and fetal protein binding was determined, and its effect on fetal blood concentrations was evaluated. Mean total fetal uptake as it related to time and infused dose increased linearly (r = 0.998, P less than 0.001) with a constant, weight-normalized fetal-maternal dose fraction of 0.45 during the infusion. Despite rapidly declining blood concentrations after the infusion, uptake increased an additional 17%. The sevenfold variation in uptake appeared to be inversely related to the biodegradation rate of lidocaine. Fetal-maternal concentration ratios (F/M) increased during declining blood concentrations. Protein binding determinations for maternal and fetal blood were 43.6 +/- 2.48% and 26.9 +/- 1.59%, respectively. These values were used to calculate the F/M in conjunction with the maternal and fetal pH. At maternal-fetal equilibrium the calculated F/M, 1.0 +/- 0.05, closely approximated the observed, 1.0 +/- 0.03. Variations in lidocaine concentrations among the vital organs 4 h after the infusion were small, but high concentrations of metabolites were found in the lungs and kidneys. The results challenge the validity of placental transfer estimates commonly based on the F/M and umbilical cord blood concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

The reaction of equine renal metallothionein (MT) with excess K2PtCl4 at pH 2 results in a polymeric adduct containing 17 +/- 2 mol Pt/mol MT. A monomeric adduct containing 7 mol Pt/mol MT is obtained at neutral pH. Rates of reaction of Pt7MT with DTNB and iodoacetic acid are consistent with Pt2+ to cysteine thiolate coordination, and the extent of reaction in both cases is 11 +/- 2 mol cys/mol MT. Adducts from the reaction of K2PtCl4 with apoMT chemically modified at the N-terminal methionine residue, Cd7MT, and native MT are also reported. A structural model of Pt7MT is proposed in which the square planar tetrathiolate Pt(II) unit is incorporated into a three-metal beta cluster. Implications for the metabolism of platinum anticancer drugs are discussed.

Direct continual measurement of placental drug transfer was introduced to evaluate more precisely the fetal uptake of a commonly used local anesthetic in obstetrics. Bupivacaine, 2.7 mg X kg-1 (base), was infused at a constant rate over 1 h into a maternal jugular vein of five chronically prepared pregnant ewes. Blood was sampled simultaneously from the umbilical vein (UV), fetal aorta (FA), and a maternal artery (MA). Fetal uptake rate was determined from the product of the bupivacaine UV-FA blood concentration difference and the umbilical flow rate (Qu). Total fetal accumulation was determined by integrating uptake rate over 5 h. Correlation of total fetal uptake and the infused mean maternal dose (r = 0.993, P less than 0.001) indicated that during the infusion, mean fetal uptake was a constant fraction (0.16) of the maternal infused dose. Total fetal uptake was linear despite wide individual changes in Qu, suggesting that within limits fetal accumulation is not Qu-dependent. Mean ovine protein binding of bupivacaine by maternal and fetal whole blood was 85.49% +/- 2.61 (SD) and by fetal blood, 40.43% +/- 9.60 (SD). Back-transfer of bupivacaine to the mother proceeded against a higher total bupivacaine concentration because unbound unionized drug concentrations in maternal blood were less than in fetal blood. At maternal-fetal equilibrium when UV and FA total blood concentrations were equal, the calculated fetal/maternal concentration ratio (f/m) (0.36) determined from the maternal and fetal protein binding and pH closely approximated the observed (0.35). The f/m increased during both fetal uptake and back-transfer and cannot be considered a good index of placental transfer.(ABSTRACT TRUNCATED AT 250 WORDS)

The concentration of metallothionein (MT) in the liver of the perinatal rat is relatively high at term and 7 days after birth and then decreases to barely detectable levels by day 28. The developmental pattern MT-zinc parallels that of MT. When challenged with a single injection of cadmium chloride, the 26-day-old rat responds with a dose-related increase in hepatic MT which sequesters both cadmium and zinc. When the 5-day-old rat is similarly challenged, induction of MT occurs only at the highest dose tested (6 mg Cd/kg); however, due to the pre-existence of MT in these younger rats, cadmium administered at the lower doses still binds to the MT in a dose-related manner. Despite the induction of MT seen in both age groups following the 6.0 mg/kg dose, exposure to that level of the metal produced death in 30% of the younger animals but in only 4% of the older animals. When cadmium was administered to pregnant rats on day 19 of gestation, it was found to produce a dose-related induction of maternal hepatic MT over the following 48 hr. In contrast, maternal exposure to the metal led to a significant depression of fetal hepatic MT over the same time interval.

The development of the apparent kinetic parameters K- m and V-max was studied in perinatal Wistar rats for three functionally diverse, hepatic enzymes (p-nitroanisole O-demethylase, carboxylesterase and bromosulphophthalein-glutathione conjugating enzyme), the period studied being from 3 days prepatum to 35 days postpartum. The kinetic parameters underwent marked quantitative changes during development, which appeared to be independent of sex for the first 5 weeks postpartum.

The anticancer drug, cis-diamminedichloroplatinum, was administered to male rats at a dose of 0.5, 1.0, 2.0 or 4.0 mg platinum/kg body weight. After 48 hrs, the animals were killed and platinum, zinc, copper and metallothionein were measured in renal and hepatic tissue and platinum, zinc and copper were measured in the plasma. Administration of this platinum-containing compound did not induce hepatic or renal metallothionein and did not significantly alter the concentrations of copper or zinc in hepatic or renal tissue or in the plasma.

Pregnant rats were injected subcutaneously on day 10 of pregnancy with 0.0, 0.25, 0.50, 1.0 or 3.0 mg cadmium/kg and sacrificed at term (day 21). There were no fetal or maternal deaths following the cadmium exposure with the exception of the e.0 mg/kg level where a 54% fetal mortality rate was observed. At doses of 1.0 mg/kg or less, non-specific parameters of fetal toxicity including body weight, crown-rump length, and liver weight were not significantly different from control values. The same was true of term placental weight as well as maternal weight gain over the 48-h treatment period. Following gel-filtration of hepatic cytosols from control fetuses, over 70% of the endogenous cytosolic zinc was associated with a peak previously described as metallothionein. It was found that cadmium exposure at sub-lethal doses caused a depression in both total cytosolic zinc and metallothionein-bound zinc levels in the fetus, whereas both these parameters increased in the maternal liver. In vitro cadmium saturation prior to gel filtration revealed that the cadmium-binding capacity of the metallothionein peak was significantly reduced at all dosage levels in the fetus but increased in maternal liver. These findings suggest that maternal administration of cadmium can depress fetal metallothionein levels and cytosolic zinc levels at doses which do not produce overt fetal toxicity. This reduction in fetal metallothionein is in sharp contrast with the well established finding of induction of metallothionein seen in the adult following exposure to cadmium.

Samples of tail muscle from 32 American alligators (Alligator mississippiensis) in Florida were analyzed for contaminant concentrations to provide preliminary information on the potential public health hazard of meat consumption. Detectable levels were found for eight metals; copper, zinc, iron, chromium, mercury, lead, cadmium and arsenic. Mean residue was highest for mercury (geometric mean = 0.61 ppm). DDE, DDD, DDT, dieldrin, heptachlor epoxide, lindane, and PCB's were found. Mean residue concentrations were compared by lake. Alligators appeared to be suitable monitors of environmental pollution. Concentrations of contaminants found in these animals probably pose little threat to public health. However, recommendations must await analysis of larger sample sizes and information on amount and frequency of meat consumption. Alligators killed for human consumption should continue to be monitored for contaminant residues.

We describe the electrothermal atomic absorption spectrophotometry of cadmium in rabbit semen collected before and after seven days of subcutaneous administration of 0.5 mg of cadmium per kilogram body weight per day. The analytical technique involves combining an aliquot of an acid-digested semen sample with an equal volume of an (NH4)2HOP4 solution (50 g/L), to allow an increase in charring temperature, which results in more nearly complete destruction of matrix. Cadmium values as determined by this method correlated well with those determined by the method of standard additions. The dosing regimen resulted in a statistically significant (p < 0.01) increase in cadmium concentrations in semen (and whole blood) sampled just after the last day of cadmium administration.

Effects of a single IM injection of selenium-vitamin E (Se-E; 5 mg of Se + 68 IU of alpha-tocopherol/60 kg of body weight) as a pretreatment 14 days before an oral dose of aflatoxin B1 (1.0 mg/kg) were studied in 24 dairy calves. Treatment groups were designated as follows: group 1 = no Se-E or aflatoxin B1 (control); group 2 = Se-E supplementation only; group 3 = aflatoxin B1 dose only; and group 4 = Se-E supplementation before aflatoxin B1 dose. Clinical signs of toxicosis in aflatoxin B1-treated calves included anorexia, ataxia, rough haircoats, increased respiration rates, dyspnea, dehydration, and nasal discharge. Packed-cell volume, RBC, WBC, and hemoglobin were increased in aflatoxin-treated calves. Significant increases in serum aspartate aminotransferase (P less than 0.05) and gamma-glutamyl-transferase (P less than 0.001) activities and prothrombin times (P less than 0.001) were observed in aflatoxin-treated calves, indicating that there was hepatic involvement. Although aflatoxin exposure caused a significant decrease in body weight (P less than 0.01) and feed intake (P less than 0.001) in treatment groups 3 and 4, Se was demonstrated to interact significantly (P less than 0.001) with aflatoxin B1 for feed intake, causing an improved feed intake in treatment group 4 calves.

1. Serum samples were collected from ten foals at predetermined times during the first 12 months following birth and zinc and copper concentrations and ceruloplasmin activity were evaluated. 2. Serum zinc concentrations were found to be quite variable with respect to age (range = 67-95 micrograms/dl). 3. Serum copper concentrations increased in a linear fashion from day 0 to day 28 before levelling off at 190-247 micrograms/dl. 4. Ceruloplasmin activity was found to correlate with the concentration of serum copper (r = 0.92) and reached a plateau at an activity of 30-38 IU by day 28.

With the increased use of chemicals in health related sciences, there is a need for a better understanding as to how these chemicals interact with the immune system. The purpose of this review was to bring together published information on the effects chemicals have on antibody-dependent cellular cytotoxicity (ADCC). This immunoeffector mechanism requires the interaction of both the humoral (antibody) and cellular components (expressing Fc receptors on the plasma membrane) with the specificity being determined by the antibody. Most of the chemicals tested and mentioned in this review are those that are currently used in chemotherapy, antibiotic and drug regimes and in the maintenance of anesthesia. The major point that emerges from this review is that while a great deal of information has been obtained, there is also a good deal of conflicting information. Furthermore, the mechanisms of action are not fully understood or are unknown in many cases. Further work, therefore, is needed to ascertain the importance and relevance of these chemicals in interfering with the ADCC phenomenon and the mode of action of these chemicals within the ADCC mechanism.

Ring-necked ducks (Aythya collaris) were administered a single lead shot by gastric intubation. At weekly intervals over a 7-week period, the birds were weighed and blood samples obtained for measurement of hematocrit, free erythrocyte protoporphyrin (FEP), blood lead and delta-aminolevulinic acid dehydratase (delta-ALAD) activity. The birds were fluoroscoped weekly to ensure that the pellets had been retained. Blood lead concentrations peaked 1 week after dosing at a concentration of 7.75 micrograms/ml and then fell to control levels by Week 4. FEP concentrations in the treated ducks also peaked 1 week after dosing at levels which were roughly 1200% of control concentrations. The return of FEP concentrations to normal paralleled blood lead. ALAD activity was inhibited by approximately 85% by Week 1; however, there was a gradual but steady recovery of ALAD activity through Week 7. Four of the treated birds died within 2 to 3 weeks of lead administration. Physical signs of lead toxicity were maximal 7 to 10 days postdosing and included ataxia, loss of body weight, impaction of the upper gastrointestinal tract, and bile green diarrhea. In surviving birds, overt signs of toxicity declined with time and all birds appeared normal by Week 7.

Two inbred strains of mice were used in this study, the C57BL/6J which is reported to be a high interferon producer and the C3H/HeJ which is reported to be a low interferon producer. Each mouse received a single i.p. injection of either Newcastle disease virus (NDV) or the double-stranded nucleotide, polyinosinic acid-polycytidilic acid (poly (rI.rC], both type I interferon inducers, or cadmium chloride, a known inducer of metallothionein (MT), and were killed 24-hr later. Treatment of the C57BL and C3H mice with 1 mg Cd/kg caused a 14- and 16-fold increase in hepatic MT concentrations, respectively. In both strains, this induction was accompanied by an increase in the hepatic concentration of zinc but not copper. There were no observed changes in the circulating levels of interferon. In the C57BL mice, both the administration of poly (rI.rC), at a dose of 10 mg/kg, and NDV, at a dose of 512 hemagglutinating units/mouse, produced a 4-fold increase in the hepatic concentration of MT. Although both treatments caused an increase in levels of interferon, the increase seen with NDV was greater than that seen with poly (rI.rC). In the C3H mice, the results were quite different. Although both treatments induced hepatic MT concentrations 4- to 5-fold, the increase in interferon levels observed following the administration of poly (rI.rC) was higher than that seen with NDV and some 50-fold higher than the increase produced by the polynucleotide in the C57BL mice. The results of this study indicate that two interferon-inducing agents, poly (rI.rC) and NDV, are also capable of inducing hepatic metallothionein.

Seven American alligators, Alligator mississippiensis, were each administered a single, intracardiac injection of cadmium chloride, at a dose of 1.0 mg Cd/kg body wt. At sacrifice, the highest concentration of Cd was found in the liver, bound to a cytosolic protein with characteristics similar to mammalian metallothionein (MT). Gel filtration (Sephadex G-75) of the cytosol revealed a peak containing Cd and to a lesser extent, zinc (Zn), having the same relative elution volume (Ve/Vo) as rat hepatic Cd, Zn-MT. Anion-exchange chromatography (DEAE-Sephacel) of material having a Ve/Vo of 1.7-1.9 revealed a major Cd-peak corresponding to rat Cd, Zn-MT(I) and a minor peak corresponding to Cd, Zn-MT(II). Neither peak contained significant amounts of Zn. Heat treatment of alligator hepatic cytosol, followed by selective acetone precipitation, yielded material having a molar Cd:Zn ratio of 9.15:1 compared to 0.67:1 in material purified from Cd-pretreated rat liver. Spectral analysis of the material purified from both sources showed an absorbance peak between 250 and 260 nm and no absorbance peak at 280 nm, characteristic of mammalian MT.

A programme consisting of 14 daily injections of progesterone (10 mg) followed by single injection of PMSG (500 i.u.) and oestradiol- 17 beta (30 micrograms), along with controlled temperature (18-20 degrees C) and lighting (10 h light/24 h), was applied to 60 anoestrous ewes between late May and early August to induce reproductive activity. Breeding started within 24 h of the oestradiol injection and 80.0% of the ewes conceived at the induced oestrus. Dorset ewes had higher conception (95.2 versus 71.8%) and prolificacy (1.74 versus 1.52 fetuses/ewe) rates than did crossbred Suffolk ewes. Plasma progesterone concentrations during progesterone administration were significantly higher than those found during anoestrus and were generally lower in ewes which did not conceive than in those which did. The plasma progesterone data indicated that ovulation had occurred in most of the ewes which were not pregnant at 90-100 days and that many may have been pregnant initially but then lost the conceptus.

Phenobarbitone (PB) (75 mg/kg) was administered orally for three consecutive days to pregnant or lactating rats at different pre- and postnatal stages in order that the perinatal animals would receive the agent either by transplacental passage or via the milk. Control animals received equivalent volumes of saline. The dams, fetuses, and pups were killed 24 h after the last dose. Hepatic p-nitroanisole O-demetnylase (OD), carboxylesterase (CE), and bromosulfophthalein-glutathione (BSP-GSH) conjugating enzyme activities in a 12 100 g - 20 min supernatant of a 20% w/v homogenate were measured. The morphology of the developing rat liver in the absence and presence of PB was examined by electron microscopy. The results demonstrated that the transplacental passage of PB to rat fetuses at term or 3 days prepartum had no effect on either the hepatic drug-metabolizing enzyme activities or on the ultrastructural appearance of the liver. Increased hepatic OD activity was observed in the pregnant animal but no effect was observed in the lactating dam. Phenobarbitone received by the suckling rat had two distinct effects. Compared to control activities, twofold increases in hepatic OD activity were observed in rat pups as early as 4 days after birth, associated with a marked proliferation in hepatic smooth endoplasmic reticulum. In contrast, PB-related significant increases in neonatal hepatic CE and BSP-GSH conjugating enzyme activities were not observed until 21 days of age. In the 4-day-old treated pups, characteristic morphological changes included numerous small membrane whorls in addition to increased smooth endoplasmic reticulum and microbodies in the liver.