Dietary selenium reduces the formation of aberrant crypts in rats administered 3,2'-dimethyl-4-aminobiphenyl.

Human epidemiologic studies suggest that low selenium status is associated with increased cancer risk and that selenium supplementation is associated with reduction in the incidence of several cancers, including colorectal cancer. Aromatic and heterocyclic amine carcinogens are thought to be important in the etiology of human colorectal cancer, but no information is available on the effects of selenium on aromatic amine-induced colon cancer. In order to investigate this effect, aberrant crypt foci (ACF), the putative preneoplastic lesions of colon cancer in humans and rodents, were used as a biomarker to test the hypothesis that selenium supplementation can reduce aromatic amine-induced colon carcinogenesis. Male weanling F344 inbred rats were fed a basal torula yeast selenium-deficient diet supplemented with 0, 0.1, or 2. 0 mg selenium/kg diet as selenite, selenate, or selenomethionine (SeMet). Animals were fed the diets for 4 weeks and then administered 1 sc injection/week for 2 weeks of 3, 2'-dimethyl-4-aminobiphenyl (DMABP; 100 mg/kg) or vehicle (peanut oil). At 12 weeks, the rats were euthanized and the colon and rectum were removed, opened longitudinally, and fixed in 70% ethanol. Glutathione peroxidase activities in erythrocytes and liver cytosol and selenium concentrations in the colon/rectum and kidney increased significantly (p < 0.05) and in a dose-dependent manner with each of the three selenium diets. No ACF were identified in vehicle-treated rats. In DMABP-treated rats, ACF frequencies decreased significantly (p < 0.05) in groups supplemented with 0.1 or 2.0 mg selenium/kg diet as selenite and selenate but not SeMet. There were no significant differences in ACF and aberrant crypts between rats fed 0.1 vs 2.0 mg selenium/kg diet. These results suggest that dietary selenium, depending on chemical form, can reduce aromatic amine-induced colon carcinogenesis.

Higher frequency of aberrant crypt foci in rapid than slow acetylator inbred rats administered the colon carcinogen 3,2'-dimethyl-4-aminobiphenyl.

Humans and other mammals such as rats exhibit a genetic polymorphism in acetyltransferase (NAT2) capacity, yielding rapid and slow acetylator phenotypes. The rapid acetylator phenotype has been associated with increased incidence of human colorectal cancer in some, but not all, epidemiological studies. In order to investigate this possible association, a rapid (F-344) and slow (WKY) acetylator inbred rat model was utilized to investigate the role of the acetylator genotype (NAT2) in the formation of aberrant crypt foci (ACF) following administration of colon carcinogens. Age-matched (retired breeder) female rapid and slow acetylator inbred rats received two weekly injections (50 or 100 mg/kg, sc) of 3,2'-dimethyl-4-aminobiphenyl (DMABP) or a single 50 mg/kg, sc, injection of 1,2-dimethyl-hydrazine (DMH). The rats were euthanized at 10 weeks and ACF were evaluated in the cecum, ascending, transverse, and descending colon, and rectum. ACF were observed in the colon and rectum, but not the cecum of rapid and slow acetylator inbred rats administered DMABP or DMH. ACF were more concentrated in the descending colon. ACF frequencies were significantly higher in colons of rapid than slow acetylator inbred rats administered DMABP, a colon carcinogen which is activated via O-acetylation catalyzed by polymorphic acetyltransferase (NAT2). At 50 mg/kg, ACF frequency in the distal colon was 2.29 +/- 0.57 in rapid acetylators versus 0.38 +/- 0.18 in slow acetylators. At 100 mg/kg, ACF frequency was 4.11 +/- 1.06 in rapid versus 1.57 +/- 0.48 in slow acetylators. ACF frequency did not differ significantly between rapid and slow acetylator inbred rats administered DMH, a colon carcinogen which is not metabolized by polymorphic acetyltransferase. The two inbred rat strains did not differ in hepatic microsomal phenacetin deethylase activity, which is a marker for CYP1A2 activity important for the activation of aromatic amines. These results support the hypothesis that rapid acetylator (NAT2) genotype is a risk factor in aromatic amine-induced colon carcinogenesis.

Acetylator genotype (NAT2)-dependent formation of aberrant crypts in congenic Syrian hamsters administered 3,2'-dimethyl-4-aminobiphenyl.

Some but not all human epidemiological studies suggest a higher incidence of colon cancer in rapid acetylator individuals. Aberrant crypts, the earliest morphologically evident preneoplastic lesions in chemical colon carcinogenesis, were measured in rapid and slow acetylator congenic Syrian hamsters administered 3,2' -dimethyl-4-aminobiphenyl, an aromatic amine colon carcinogen, to investigate the specific role of the acetylator genotype (NAT2) in colon carcinogenesis. Age-matched rapid (Bio. 82.73/H-Patr) and slow (Bio. 82.73/ H-Pat(s) acetylator female Syrian hamsters congenic at the NAT2 locus received a s.c. injection of 3,2' -dimethyl-4-aminobiphenyl (100 mg/kg) at the start of weeks 1 and 2. After 10 and 14 weeks, the hamsters were sacrificed, and each whole cecum, colon, and rectum was stained with 0.2% methylene blue, fixed in 4% paraformaldehyde, and examined under a dissecting microscope for the presence of aberrant crypts. Aberrant crypts were identified in the cecums and colons of both rapid and slow acetylator congenic hamsters treated with 3,2' -dimethyl-4-aminobiphenyl but not in vehicle controls. The size of the aberrant crypt foci was larger in the colon than in the cecum, and the highest frequency of aberrant crypt foci was observed in the cecum. No aberrant crypts were detected in the rectum. The frequency of aberrant crypt foci was significantly higher (2-3-fold) in rapid versus slow acetylator congenic hamsters in both cecum (P = 0.0352) and colon (P = 0.0006). These results support human epidemiological studies that suggest the rapid acetylator genotype is associated with higher risk of colon cancer induced by aromatic amines.

Detrimental hemodynamic effects of nitric oxide synthase inhibition in septic shock.

OBJECTIVE: To investigate the physiologic effects of nitric oxide synthase inhibition with N-nitro-L-arginine methyl ester in an acute resuscitated model of porcine septic shock. DESIGN: Randomized control trial. SETTING: Animal research facility. STUDY SUBJECTS: Domestic Yorkshire swine. INTERVENTIONS: Twenty-four animals were randomly divided into one of four treatment groups as follows: normal saline resuscitation (NSR) (control group); NSR plus 200 micrograms/kg of lipopolysaccharide (LPS) at 1 hour after baseline (LPS group); NSR, LPS, and a continuous infusion of 50 micrograms/kg per minute of N-nitro-L-arginine methyl ester (NAME) at 1 hour after baseline (LPS/NAME group); and NSR and NAME (NAME group). All animals received NSR at 1 mL/kg per minute starting at baseline. MAIN OUTCOME MEASURES: Mean arterial pressure (MAP), systemic vascular resistance index (SVRI), mean pulmonary arterial pressure (MPAP), and pulmonary vascular resistance index (PVRI) were measured at baseline and hourly for 4 hours. Values at baseline and 3 hours are given below as mean (+/- SE). RESULTS: All variables remained unchanged in the control group. The administration of LPS produced a systemic hyperdynamic response characterized by a decrease in MAP and SVRI from 66.0 +/- 3.9 to 55.0 +/- 2.8 mm Hg (P < .05) and from 422.0 +/- 22.0 to 272.0 +/- 29.0 mm Hg.min.kg/L (P < .05), respectively. The administration of LPS produced an increase in MPAP and PVRI from 16.3 +/- 0.8 to 30.0 +/- 1.3 mm Hg (P < .05) and from 37.0 +/- 5.3 to 119.0 +/- 13.0 mm Hg.min.kg/L (P < .05), respectively. In the LPS/NAME group, NAME infusion normalized MAP and increased SVRI from 506.0 +/- 40.0 to 642.0 +/- 72.0 mm Hg.min.kg/L (P < .05). Infusion of NAME potentiated LPS-induced pulmonary hypertension, increasing MPAP and PVRI from 16.8 +/- 0.6 to 36.0 +/- 2.8 mm Hg (P < .05) and from 59.0 +/- 3.5 to 319.0 +/- 64.0 mm Hg.min.kg/L (P < .05), respectively. Infusion of NAME alone increased MAP from 74.0 +/- 1.3 to 100.0 +/- 4.1 mm Hg (P < .05) and had no significant effect on MPAP and PVRI. CONCLUSIONS: The potentiation of LPS-induced pulmonary hypertension following NAME infusion suggests that inhibition of nitric oxide synthase may have a limited role in the treatment of septic shock.

Kinetics of nitrogen oxide production following experimental thermal injury in rats.

Nitric oxide is biosynthesized from the amino acid L-arginine by the enzyme nitric oxide synthase. Nitric oxide is a vasodilator, a neurotransmitter, and may modulate immune function. The experiments presented here were performed to determine whether the synthesis of nitric oxide is increased following experimental burn injury in rats. After a 30% total body surface area burn in 300-g Lewis rats, the urinary output of nitrate, a stable metabolite of nitric oxide, was significantly increased for 8 days postburn compared with that in sham-burned control rats. The origin of the urinary nitrate from L-arginine was demonstrated by administering the stable isotope 15N2-guanido-arginine to burned and sham-burned rats and observing an immediate enrichment of 15N in nitrate. The amount of administered 15N recovered as 15NO3 was < 1% of the administered arginine isotope in both the burned and unburned rats; the recovery of the isotope increased tenfold over baseline recovery in burned rats. The arginine analog N-monomethyl-arginine, an inhibitor of the enzyme nitric oxide synthase, blocked the postburn rise in urinary NO3 output in burned rats, but did not completely inhibit the output of NO3 in burn wound-infected rats. Experimental burn injury in rats results in an increase in L-arginine-dependent nitric oxide production and urinary nitrate output.

Inaccuracy of nitrogen balance determinations in thermal injury with calculated total urinary nitrogen.

Many burn centers use nitrogen balance studies to estimate the adequacy of nutritional support. Nitrogen loss includes the sum of urinary urea nitrogen, nonurea urinary nitrogen, and losses from skin, wound, and stool. Urinary urea nitrogen is often used to calculate total urinary nitrogen by multiplying the urinary urea nitrogen by a factor of 1.25 to account for nonurea urinary nitrogen. This formula is appropriate when applied to a nonstressed individual who has fasted overnight but is not appropriate for patients who have undergone surgery or experienced trauma. We have undertaken this study to assess the predictability of this formula in patients with thermal injuries. Twenty-seven patients with major thermal injuries had random 24-hour urine collections, which were analyzed for both urinary urea nitrogen and total urinary nitrogen. In these patients with burns we found that urinary urea nitrogen represented approximately 65% of the directly measured total urinary nitrogen rather than 80% as assumed by the formula. This increase in the nonurea nitrogen loss is greater than that found after surgery or trauma. Individual measurements may underestimate losses by 20% to 60%. Directly measured total urinary nitrogen should replace calculated total urinary nitrogen as the index of urine nitrogen losses for nitrogen balance studies in patients with burns.

Fungal burn wound infection. A 10-year experience.

To evaluate our experience with fungal burn wound infection, we performed a 10-year review for comparison with our experience with bacterial burn wound infection. During the study period, a marked decline occurred in bacterial wound infection but not in fungal wound infection. Patients with either bacterial or fungal burn wound infection had massive injury, with burn size averaging greater than 50% of the total body surface area. Factors that appear to have markedly reduced bacterial burn wound infection, including patient isolation, topical chemotherapeutic agents, and burn wound excision, do not appear to have had a similar effect on fungal wound infection. The mechanism of spread and colonization of fungi, and the lack of effective topical chemotherapeutic antifungal agents, may explain in part our findings.

Effects of granulocyte-macrophage colony-stimulating factor in burn patients.

We studied the effects of granulocyte-macrophage colony-stimulating factor in burn patients. Serial measurements of granulocyte oxidative function were obtained in treated patients and in a group of controls matched for age and total burn size. The administration of granulocyte-macrophage colony-stimulating factor resulted in a 50% increase in mean leukocyte counts. Both groups showed significant baseline increases in granulocytic cytosolic oxidative function. Treated patients showed normal stimulated cytosolic oxidative function, which was significantly depressed compared with that of untreated patients. Myeloperoxidase activity was increased in treated patients during the first postburn week but then declined to normal levels. Untreated patients had a significant increase in myeloperoxidase activity for the first 3 weeks following injury. Untreated patients exhibited a significant decrease in superoxide activity during the second 3 weeks following injury. Treated patients demonstrated normal superoxide activity.

Bashkirian train-gas pipeline disaster: the American military response.

The United States Army Institute of Surgical Research was asked to provide burn care assistance in June 1989 following the explosion of leaking methane/propane gas in the Central Soviet Union, which destroyed two passenger trains and injured 800 passengers. A 17-member burn team flew from San Antonio, Texas, to Ufa, USSR and assisted in the management of 150 burn patients in a general medical-surgical hospital. Early problems included heavily colonized burn wounds, with a microbial flora that demonstrated broad antibiotic resistance. As wound complications were controlled, 28 operative procedures were performed to excise and graft the burn wounds. The recommendations for burn disaster management, based on our experience in Ufa, should be of assistance to other groups that may be asked to provide similar assistance in the future.

Bashkiria train-gas pipeline disaster: a history of the joint USSR/USA collaboration.

In June 1989, a methane/propane pipeline explosion destroyed two passenger trains in the Bashkirian Republic of the Soviet Union. Over 400 passengers died immediately and 806 were injured. Most of those injured suffered thermal injuries. One hundred and fifty patients were treated at Hospital 21 in Ufa, Bashkiria, by a combined Soviet-US team. Twenty-six patients underwent excision and grafting of their burn wounds. Microbiological studies indicated significant resistance to locally available antibiotics. Antibiotics provided by the US team proved useful in treating the resistant organisms. This disaster and the international response to it exemplify the need for a coordinated response to major burn disasters and the positive results of international cooperation.

Ibuprofen inhibits granulocyte responses to inflammatory mediators. A proposed mechanism for reduction of experimental myocardial infarct size.

The use of nonsteroidal antiinflammatory agents to reduce myocardial infarct size has demonstrated a dichotomy between ibuprofen, which reduces myocardial infarct size, and aspirin, which does not. A feline model of coronary ischemia using ligation of the anterior descending artery demonstrated that intravenous ibuprofen (2.5-20 mg/kg) given immediately and 2 h after ligation significantly decreased (by about 40%) myocardial infarct size. In contrast, aspirin did not diminish infarct size at any achieved dose; in fact, at some doses it tended to increase infarct size. In vitro studies with purified granulocytes demonstrated a similar dichotomy between ibuprofen and aspirin. Ibuprofen inhibits granulocyte aggregation, superoxide production, lysosomal enzyme release, and granulocyte-mediated endothelial cytotoxicity, while aspirin is without effect on these modalities. We propose that ibuprofen's beneficial effect in experimental myocardial ischemia is related to its ability to inhibit activated granulocytes and thus to diminish myocardial cell death in experimental myocardial infarction.