Ultraviolet radiation-induced non-melanoma skin cancer in the Crl:SKH1:hr-BR hairless mouse: augmentation of tumor multiplicity by chlorophyllin and protection by indole-3-carbinol.

Over 1 million new cases of ultraviolet radiation-induced non-melanoma skin cancers (NMSC) per year now occur in the USA and the incidence of these diseases continues to increase. New preventative strategies are required. The hypothesis tested was that dietary administration of the putative cancer chemopreventatives sodium-copper-chlorophyllin (Chlor) or indole-3-carbinol (I3C) would inhibit UV-induced skin carcinogenesis in the Crl:SKH1:hr-BR hairless mouse. Groups of 20 mice were pre-fed isocaloric/isonutritive 20% corn-oil AIN-76a based diets that contained either Chlor (1.52 g%), I3C (5.08 g%) or no chemopreventative (control) for 2 weeks followed by exposure of their dorsal skin to a 10 week incremental, sub-erythemal, carcinogenic simulated solar UV exposure regime. Feeding was continued for the duration of the experiment. Matched non-UV exposed dietary groups were also included in the experimental design. The diets had no significant (p > 0.05) effect on body weight, feed consumption, cutaneous methanol-extractable UV photoprotective substances or on cutaneous UV-reflective characteristics. By day 180, UV-irradiated mice fed the Chlor had a significantly (p < 0.05) higher tumor multiplicity (33.6 +/- 4.72; mean +/- SEM) than UV-irradiated control animals (22.8 +/- 4.25). UV-irradiated mice fed I3C had a significantly (p < 0.001) lower tumor multiplicity (13.0 +/- 2.42) than that of both the UV-irradiated control and UV-irradiated Chlor-fed mice. The Chlor or I3C diets did not significantly (p > 0.05) affect UV-induced systemic suppression of contact hypersensitivity responses. These results demonstrate augmentation of the UV-induced cutaneous carcinogenic process by dietary chlorophyllin and protection from this carcinogenic process by indole-3-carbinol via mechanisms that do not involve changes in skin optical properties, modulation of photoimmunosuppression or caloric/nutrient effects.

A screening study of xylitol binding in vitro to activated charcoal.

Ingestion of foods containing the sweetener xylitol by dogs results in a significant, and often sustained, insulin-mediated hypoglycemic crisis. The efficacy of activated charcoal for gastrointestinal decontamination following xylitol ingestion is unknown. This screening study examined the effect of pH and incubation time on the in vitro binding of xylitol to activated charcoal. The mean percentage activated charcoal binding ranged between 8 and 23%. Mean percentage binding of xylitol at pH 3 was significantly higher (p < 0.05) than the binding of xylitol at pH 1 or pH 5 following 40 or 60 min of incubation with an aQueous 200 g/L activated charcoal slurry. These results suggest binding of xylitol to activated charcoal is relatively low; however, activated charcoal administration may still be beneficial in some canine acute oral xylitol exposures.

Fatal paraquat poisoning in seven Portland, Oregon, dogs.

Paraquat is one of the few broad-spectrum herbicides available in the US; however, it is extremely toxic to companion animals when ingested. Despite its restricted use status, poisoning of dogs and cats remains relatively common. This clinical report documents a series of chronologically and geographically related cases of presumed malicious and fatal sub-acute paraquat poisoning in 7 dogs in Portland, OR. All animals developed acute gastrointestinal disturbance, renal compromise and insidiously progressive respiratory failure. Hyperlipasemia and moderate hypertension were notable featured in 5/7 cases. Trace levels of paraquat were demonstrated in the urine of 4/7 animals by gas-liquid chromatography/mass spectroscopy. Diagnosis in the remaining 3 cases was made through a combination of history or exposure, clinical signs and their progression, and pulmonary and renal histopathology.

Fatal yew (Taxus sp) poisoning in Willamette Valley, Oregon, horses.

Despite the well-founded reputation of plants of the genus Taxus as being amongst the most toxic plants for domestic livestock in the US, there are surprisingly few published case reports of yew poisoning in horses. This report documents 2 acute fatalities in horses in the central Willamette Valley, OR associated with the consumption of Taxus sp. The predominant features of the intoxication were peracute death, with no signs of struggling or convulsions, in otherwise fit and well managed adult horses. The most significant gross necropsy findings were limited to pulmonary congestion and hemorrhage, suggestive of acute circulatory disturbance. A diagnosis of Taxus sp poisoning was confirmed on the basis of a history of potential exposure, by the identification of yew leaves in the gastric contents of the horses, and by the subsequent identification of yew clippings in the pasture. The literature relevant to Taxus sp poisoning in horses is reviewed.

Topical exposure to exogenous ultraviolet-irradiated urocanic acid enhances Mycobacterium ulcerans infection in a Crl:IAF(HA)-hrBR hairless guinea-pig model of Buruli ulcer disease.

BACKGROUND: Ultraviolet radiation (UVR) pre-exposure enhances Mycobacterium ulcerans infection in the Crl:IAF(HA)-hrBR hairless guinea-pig, possibly via a photoimmunosuppressive mechanism. The trans-cis photoisomerization of epidermal urocanic acid is an important initiator of the web of events leading to photoimmunosuppression. Thus, the hypothesis tested in this paper was that topical pre-exposure to UVR-irradiated urocanic acid mixture containing cis-urocanic acid (UVR-UCA) enhances the ulcerative form of M. ulcerans infection in the Crl:IAF(HA)-hrBR hairless guinea-pig model of human Buruli ulcer disease. METHODS: Groups of six animals were subjected to daily topical treatment with either 0 (vehicle only), 0.1, 0.5 or 1 mg of trans (tUCA) or UVR-UCA (contained a cis : trans urocanic acid isomer ratio of 1 : 9) for three consecutive days. A sham treatment group was also included in the experiment. Three days following their final treatment, the guinea-pigs were intradermally infected in the right dorsal flank with 1.5 x 107 CFU of M. ulcerans in 0.1 ml of phosphate-buffered saline (PBS) and sham infected with 0.1 ml of PBS in the left dorsal flank. The resultant skin lesions were then measured over the next 21 days. At day 21 postinfection, the animals were tested for delayed-type hypersensitivity (DTH) reactivity to M. ulcerans cell fragment antigens (MCF). RESULTS: Distinct, well-demarcated, dermally situated skin nodules were present at infected, but not sham-infected, skin sites by day 3 postinfection, and the lesions progressed to frank ulcers by day 5. Between days 5 and 21, the mean lesion diameters of the UVR-UCA-treated animals were significantly (P<0.001) greater than those of the sham, vehicle only or tUCA-treated groups. UVR-UCA-treated guinea-pigs also had significantly (P<0.001) suppressed DTH responses to MCF compared with the other treatment groups. There were no significant (P>0.4) differences between the lesion sizes and DTH responses of the tUCA, vehicle only or sham treatment groups. These results demonstrate that topical exposure to UVR-UCA promotes M. ulcerans infection and suppresses DTH responses to M. uclerans antigens in infected animals. These results lend credence to the hypothesis that UVR-mediated enhancement of Buruli ulcer disease in the Crl:IAF(HA)-hrBR hairless guinea-pig model occurs via modulation of cis-urocanic acid-susceptible immune pathways.

Ultraviolet radiation enhances both the nodular and ulcerative forms of Mycobacterium ulcerans infection in a Crl:IAF(HA)-hrBR hairless guinea pig model of Buruli ulcer disease.

BACKGROUND: Ultraviolet radiation (UV) pre-exposure enhances intracellular mycobacterial infections, however, its effect upon the pathogenesis of the extracellular Mycobacterium ulcerans parasite had not been previously examined. The hypothesis tested was that UV pre-exposure enhances both the nodular and ulcerative forms of M. ulcerans infection in the Crl:IAF(HA)-hrBR hairless guinea pig. METHODS: Groups of five animals were exposed to total cumulative UV doses of 0 (control), 3 or 30 kJ/m2 followed 3 days later by subcutaneous infection with 3 x 10(4) CFU of M. ulcerans in order to induce the nodular form of the disease. The resultant nodules were then measured for the next 22 days. The experiment was then repeated using intradermal infection with 2 x 10(6) CFU in order to induce the ulcerative form of the disease. The resultant ulcers were measured for the next 30 days. In both experiments, the animals were tested for delayed-type hypersensitivity (DTH) reactivity to Burulin-S as a marker of the onset of the reactive phase of the disease. RESULTS: Following low inoculum subcutaneous infection, distinct, well-demarcated, subcutaneously situated skin nodules were present at infected skin sites between 7 and 22 days post-infection. Between days 14 and 21, the mean nodule diameters of the UV irradiated groups were significantly (P < 0.03) greater than that of the control group. UV pre-exposure resulted in significant (P < 0.035) suppression of DTH responses to Burulin-S challenge. High inoculum intradermal infection resulted in the development of ulcerative lesions. Between 10 and 30 days post-infection, the mean lesion diameters and mean ulcer development times of UV irradiated groups were significantly (P < 0.05) greater than those of the controls. However, UV irradiation did not affect DTH responses to Burulins in the high inoculum experiment. In both experiments, the lesions were histologically consistent with human Buruli ulcer disease. These results demonstrate that UV pre-exposure results in enhanced M. ulcerans infection in the hairless guinea pig model of Buruli ulcer disease and suggest that UV exposure may be a relevant factor in the pathogenesis of human forms of the disease.

Simulated solar UVB exposure inhibits transcutaneous immunization to cholera toxin via an irradiated skin site in cattle.

Transcutaneous immunization (TCI) is a new needle-free vaccination technology with the potential to reduce the risk of needle-borne disease transmission and carcass damage within the livestock industries. The principal antigen-presenting cell involved in TCI is thought to be the epidermal Langerhans cell. Langerhans cell function is inhibited by cutaneous ultraviolet-B radiation (UVB) exposure. Such exposure may inhibit TCI through sun exposed skin sites due to the phenomenon of local low dose photoimmunosuppression. TCI of cattle to cholera toxin (CT) resulted in the generation of a serum anti-CT-specific IgG(2) response. However, exposure of cattle to a sub-inflammatory dose of simulated solar UVB (2.43 x 10(3)J/m(2)) significantly (P<0.05) inhibited TCI to CT via irradiated skin sites.

Resistance of a lizard (the green anole, Anolis carolinensis; Polychridae) to ultraviolet radiation-induced immunosuppression.

The green anole (Anolis carolinensis) is the most northerly distributed of its Neotropical genus. This lizard avoids a winter hibernation phase by the use of sun basking behaviors. Inevitably, this species is exposed to high doses of ambient solar ultraviolet radiation (UVR). Increases in terrestrial ultraviolet-B (UV-B) radiation secondary to stratospheric ozone depletion and habitat perturbation potentially place this species at risk of UVR-induced immunosuppression. Daily exposure to subinflammatory UVR (8 kJ/m2/day UV-B, 85 kJ/m2/day ultraviolet A [UV-A]), 6 days per week for 4 weeks (total cumulative doses of 192 kJ/m2 UV-B, 2.04 x 10(3) kJ/m2 UV-A) did not suppress the anole's acute or delayed type hypersensitivity (DTH) response to horseshoe crab hemocyanin. In comparison with the available literature UV-B doses as low as 0.1 and 15.9 kJ/m2 induced suppression of DTH responses in mice and humans, respectively. Exposure of anoles to UVR did not result in the inhibition of ex vivo splenocyte phagocytosis of fluorescein labeled Escherichia coli or ex vivo splenocyte nitric oxide production. Doses of UV-B ranging from 0.35 to 45 kJ/m2 have been reported to suppress murine splenic/peritoneal macrophage phagocytosis and nitric oxide production. These preliminary studies demonstrate the resistance of green anoles to UVR-induced immunosuppression. Methanol extracts of anole skin contained two peaks in the ultraviolet wavelength range that could be indicative of photoprotective substances. However, the resistance of green anoles to UVR is probably not completely attributable to absorption by UVR photoprotective substances in the skin but more likely results from a combination of other factors including absorption by the cutis and absorption and reflectance by various components of the dermis.

Effect on systemic antibody concentrations of topical application of choleratoxin to skin of sheep.

OBJECTIVE: To examine the ability of a vaccine formulation combining choleratoxin with an experimental antigen to induce a systemic antibody response when applied topically on unbroken skin of sheep. DESIGN: Seven treatment groups of five adult sheep received systemic or topical priming followed 4 weeks later by systemic or topical boosting with choleratoxin and/or bovine serum albumin. Topical vaccines were administered to clipped skin on the ventral abdomen for 2 h. Booster immunisations were repeated 8 weeks after initial boosting. Serum antibody titres to choleratoxin and bovine serum albumin were determined by ELISA. RESULTS: An antibody response to choleratoxin was observed in serum, but no antibody response to bovine serum albumin was detected. CONCLUSION: Transdermal delivery may be feasible for livestock vaccines, however, further work is necessary to develop formulations that induce protective immunity by this route.

Dietary butter protects against ultraviolet radiation-induced suppression of contact hypersensitivity in Skh:HR-1 hairless mice.

Dietary fats modulate a wide variety of T cell functions in mice and humans. This study examined the effects of four different dietary fats, predominantly polyunsaturated sunflower oil, margarine, and predominantly saturated butter, clarified butter, on the T cell-mediated, systemic suppression of contact hypersensitivity by ultraviolet radiation in the Skh:HR-1 hairless mouse. Diets containing either 200 g/kg or 50 g/kg butter or clarified butter as the sole fat source protected against systemic photoimmunosuppression, whether the radiation source was unfiltered ultraviolet B (280-320 nm) or filtered solar simulated ultraviolet radiation (290-400 nm), in comparison with diets containing either 200 or 50 g/kg margarine or sunflower oil. There was a linear relationship (r > 0.9) between protection against photoimmunosuppression and the proportion of clarified butter in mice fed a series of 200 g/kg mixed fat diets that provided varying proportions of clarified butter and sunflower oil. The dietary fats did not modulate the contact hypersensitivity reaction in unirradiated animals. The observed phenomena were not primary due to the carotene, tocopherol, cholecalciferol, retinol, lipid hydroperoxide or the nonfat solid content of the dietary fats used and appeared to be a result of the different fatty acid composition of the fats.

Pyridoxine supplementation protects mice from suppression of contact hypersensitivity induced by 2-acetyl-4-tetrahydroxybutylimidazole (THI), ultraviolet B radiation (280-320 nm), or cis-urocanic acid.

Evidence exists implicating the epidermal ultraviolet B (UVB) photoproduct cis-urocanic acid as an immunogenic mediator of the systemic suppression of T cell-mediated immunity by UVB exposure. Cis-urocanic acid appears to act via histamine receptor pathways, and histamine receptor antagonists and other imidazole ring compounds may modify its immune suppressing action. A component of the food coloring substance ammonia caramel, 2-acetyl-4-tetrahydroxybutylimidazole (THI), which is known to cause lymphopenia in rats, appears to suppress immunity by a similar pathway when the contact hypersensitivity reaction has been the immune function assay in mice. The induction of lymphopenia in rats by THI is inhibited by the vitamin pyridoxine. This study demonstrates that the suppression of contact hypersensitivity in mice by UVB radiation, cis-urocanic acid, or THI is strongly inhibited by supplemental pyridoxine, fed at 30 mg/kg diet, in comparison with the normal diet, which supplies 7 mg pyridoxine/kg diet. These results suggest that pyridoxine competes with cis-urocanic acid and THI for the same binding site or receptor, which we postulate to be a histamine-like T lymphocyte receptor, and that a role may exist for the control of photoimmunosuppression by this vitamin.

Feline immunodeficiency virus infection: plasma, but not peripheral blood mononuclear cell virus titer is influenced by zidovudine and cyclosporine.

The plasma and peripheral blood mononuclear cell (PBMC) titer of feline immunodeficiency virus (FIV) in experimentally infected cats was assessed following administration of either zidovudine or cyclosporine. Treatments were begun 24 h post infection (p.i.) and continued for 4 weeks. Zidovudine treatment did not prevent establishment of infection with FIV, but plasma virus titers were significantly lower than controls at 2 weeks p.i. This reduction of plasma virus titer by zidovudine was not maintained at subsequent sampling times. Similarly, cyclosporine treatment initially lowered plasma virus titers at 2 weeks p.i., but at 4 weeks p.i. the plasma virus titers in cyclosporine-treated cats were significantly higher than in the untreated group. In the untreated group, plasma virus titers declined rapidly to an undetectable level by 14 weeks p.i. Neither zidovudine or cyclosporine treatment significantly influenced the titer of FIV in PBMCs. In all groups (untreated, zidovudine and cyclosporine) the titers in PBMC were high for the duration of the experiment. The decline in plasma virus titers in immunocompetent cats combined with the effect of cyclosporine on plasma titers strongly suggest that the immune system plays a major role in clearing FIV from plasma. In contrast, it appears that the immune response has little impact on PBMC virus titers. This shows that for complete assessment of antiviral agents, both cell-free and cell-associated virus titers must be examined. We also suggest that the limitation of viral titers in PBMC may be of critical importance in the control of lentiviral infection.