Assessment of salivary cortisol dynamics in an infantry training exercise: a pilot study.

INTRODUCTION: Measuring cortisol during military training offers insights into physiological responses to stress. We attempted precisely timed, cortisol awakening response (CAR) and pre-sleep cortisol (PSC), and diurnal slope (peak morning minus evening cortisol), during a British Army exercise. We aimed to understand cortisol dynamics and evaluate the feasibility of CAR and PSC in this environment. METHOD: Setting: high-intensity, 10-day infantry exercise. Participants: regular infantry soldiers exercising (EX, n=25) or headquarters-based (HQ, n=6). Participants undertook PSC and WAKE and WAKE+30 min samples after 1-2 days, 5-6 days and 9-10 days. Wrist-worn GENEActiv accelerometers were used to assess sleep duration in EX only. Samples taken ±15 min from prespecified time points were deemed adherent. Validated questionnaires were used to measure resilience and perceived stress. Cortisol and cortisone were measured simultaneously by liquid chromatography tandem mass spectrometry. RESULTS: From adherent participants' samples, CAR was positive and tended to decrease as the exercise progressed. From all available data, HQ demonstrated greater diurnal slope than EX (F=7.68, p=0.02), reflecting higher morning cortisol (F=4.72, p=0.038) and lower PSC (p=0.04). No differences were seen in cortisol:cortisone ratio. 26.1% of CAR samples were adherent, with moderately strong associations between adherence and stress (r=0.41, p=0.009) but no association between adherence and day of exercise (χ2=0.27, p=0.8), sleep duration (r=-0.112, p=0.43) or resilience (r=-0.79, p=0.75). Test-retest reliability ratings for CAR were Cronbach's α of 0.48, -11.7 and 0.34 for the beginning, middle and end of the exercise, respectively. CONCLUSIONS: We observed a reduction in morning cortisol and decreased diurnal slope during a high-intensity military exercise, compared with the HQ comparator cohort in whom diurnal slope was preserved. A carefully timed CAR was not feasible in this setting.

New Zealand white rabbit progeny exposed in utero to methanol are resistant to skeletal anomalies reported for rodents, but exhibit a novel vertebral defect.

Rabbits may serve as a useful model for predicting the human risk for methanol (MeOH) teratogenicity, which currently is unknown. New Zealand white (NZW) rabbits are resistant to the MeOH-initiated gross morphological anomalies characteristically observed in several strains of mice and rats, but skeletal development has not been assessed. Pregnant rabbits were administered 2 doses of 2g/kg MeOH on gestational day (GD) 7 or 8, and assessed for skeletal abnormalities on GD 29. Variations between treated and control fetuses were observed only in the number of post-lumbar vertebrae, where MeOH-exposed fetuses had fewer ossified vertebrae, which has not been reported for rodents. Furthermore, rabbits did not exhibit the MeOH-initiated skeletal defects characteristically reported for rodent fetuses. These results expand the morphological breadth of the relative species-dependent resistance of rabbits to MeOH teratogenicity compared to rodents, yet reveal a novel skeletal defect or delay in ossification not reported for rodents.

Naso-enteric Tube Placement: A Review of Methods to Confirm Tip Location, Global Applicability and Requirements.

BACKGROUND: The insertion of a tube through the nose and into the stomach or beyond is a common clinical procedure for feeding and decompression. The safety, accuracy and reliability of tube insertion and methods used to confirm the location of the naso-enteric tube (NET) tip have not been systematically reviewed. The aim of this study is to review and compare these methods and determine their global applicability by end-user engagement. METHODS: A systematic literature review of four major databases was performed to identify all relevant studies. The methods for NET tip localization were then compared for their accuracy with reference to a gold standard method (radiography or endoscopy). The global applicability of the different methods was analysed using a house of quality matrix. RESULTS: After applying the inclusion and exclusion criteria, 76 articles were selected. Limitations were found to be associated with the 20 different methods described for NET tip localization. The method with the best combined sensitivity and specificity (where n > 1) was ultrasound/sonography, followed by external magnetic guidance, electromagnetic methods and then capnography/capnometry. The top three performance criteria that were considered most important for global applicability were cost per tube/disposable, success rate and cost for non-disposable components. CONCLUSION: There is no ideal method for confirming NET tip localisation. While radiography (the gold standard used for comparison) and ultrasound were the most accurate methods, they are costly and not universally available. There remains the need to develop a low-cost, easy-use, accurate and reliable method for NET tip localization.

Methanol exposure does not produce oxidatively damaged DNA in lung, liver or kidney of adult mice, rabbits or primates.

In vitro and in vivo genotoxicity tests indicate methanol (MeOH) is not mutagenic, but carcinogenic potential has been claimed in one controversial long-term rodent cancer bioassay that has not been replicated. To determine whether MeOH could indirectly damage DNA via reactive oxygen species (ROS)-mediated mechanisms, we treated male CD-1 mice, New Zealand white rabbits and cynomolgus monkeys with MeOH (2.0 g/kg ip) and 6h later assessed oxidative damage to DNA, measured as 8-oxo-2'-deoxyguanosine (8-oxodG) by HPLC with electrochemical detection. We found no MeOH-dependent increases in 8-oxodG in lung, liver or kidney of any species. Chronic treatment of CD-1 mice with MeOH (2.0 g/kg ip) daily for 15 days also did not increase 8-oxodG levels in these organs. These results were corroborated in DNA repair-deficient oxoguanine glycosylase 1 (Ogg1) knockout (KO) mice, which accumulated 8-oxodG in lung, kidney and liver with age, but exhibited no increase following MeOH, despite a 2-fold increase in renal 8-oxodG in Ogg1 KO mice following treatment with a ROS-initiating positive control, the renal carcinogen potassium bromate (KBrO3; 100 mg/kg ip). These observations suggest that MeOH exposure does not promote the accumulation of oxidatively damaged DNA in lung, kidney or liver, and that environmental exposure to MeOH is unlikely to initiate carcinogenesis in these organs by DNA oxidation.

Species- and strain-dependent teratogenicity of methanol in rabbits and mice.

Estimates of human risk for developmental toxicity of methanol (MeOH) are based on studies in rodents, which unlike humans use catalase to metabolize MeOH. Rabbits, like humans, may largely use alcohol dehydrogenase (ADH), and more accurately than rodents reflect primate MeOH and formic acid (FA) pharmacokinetic profiles. Here we show that New Zealand white rabbits and one strain of mouse (C3H) are resistant to MeOH teratogenicity, whereas C57BL/6J mice are susceptible. Neither rabbits nor mice were susceptible to the acute MeOH toxicity observed in humans. The strain-dependent teratological susceptibility in mice could not be explained by differences in MeOH or FA disposition, nor could the resistance of rabbits, which exhibited more prolonged FA accumulation, suggesting that different mechanisms underlie MeOH teratogenesis and the FA-mediated acute toxicity in humans. It is not clear if the human risk for MeOH developmental toxicity can be accurately estimated using sensitive rodent strains.

Methanol exposure does not lead to accumulation of oxidative DNA damage in bone marrow and spleen of mice, rabbits or primates.

Genotoxicity tests indicate methanol (MeOH) is not mutagenic, but a rodent study has suggested carcinogenic potential, which could result from free radical-initiated oxidative DNA damage. To investigate this possibility we treated male CD-1 mice, New Zealand white rabbits, and cynomolgus monkeys with MeOH (2.0 g/kg ip) and assessed tissue oxidative DNA damage 6 h post-dose, measured as 8-hydroxy-2'-deoxyguanosine (8-oxodG). We found no MeOH-dependent increases in 8-oxodG in bone marrow or spleen of any species. Chronic treatment of CD-1 mice with MeOH (2.0 g/kg ip) daily for 15 d also did not increase 8-oxodG levels in these organs. Further studies in the DNA repair deficient oxoguanine glycosylase 1 (Ogg1) knockout (KO) mice supported these findings. Fibroblasts from Ogg1 KO mice accumulated 8-oxodG following acute exposure to the renal carcinogen potassium bromate (KBrO(3) ; 2.0 mM) but did not accumulate 8-oxodG following exposure to 125 mM MeOH 6 h post-treatment. Ogg1 KO mice accumulated 8-oxodG in bone marrow and spleen with age but not following exposure to MeOH. In addition, free radical-mediated hydroxynonenal-histidine protein adducts were not enhanced by MeOH in primate bone marrow or spleen, or in rabbit bone marrow or mouse spleen, although modest increases were observed in rabbit spleen and mouse bone marrow. Taken together these observations suggest that MeOH exposure does not promote the accumulation of oxidative DNA damage in bone marrow and spleen, and it is unlikely that human environmental exposure to MeOH would lead to lymphomas via this mechanism.

Species differences in methanol and formic acid pharmacokinetics in mice, rabbits and primates.

Methanol (MeOH) is metabolized primarily by alcohol dehydrogenase in humans, but by catalase in rodents, with species variations in the pharmacokinetics of its formic acid (FA) metabolite. The teratogenic potential of MeOH in humans is unknown, and its teratogenicity in rodents may not accurately reflect human developmental risk due to differential species metabolism, as for some other teratogens. To determine if human MeOH metabolism might be better reflected in rabbits than rodents, the plasma pharmacokinetics of MeOH and FA were compared in male CD-1 mice, New Zealand white rabbits and cynomolgus monkeys over time (24, 48 and 6h, respectively) following a single intraperitoneal injection of 0.5 or 2g/kg MeOH or its saline vehicle. Following the high dose, MeOH exhibited saturated elimination kinetics in all 3 species, with similar peak concentrations and a 2.5-fold higher clearance in mice than rabbits. FA accumulation within 6h in primates was 5-fold and 43-fold higher than in rabbits and mice respectively, with accumulation being 10-fold higher in rabbits than mice. Over 48 h, FA accumulation was nearly 5-fold higher in rabbits than mice. Low-dose MeOH in mice and rabbits resulted in similarly saturated MeOH elimination in both species, but with approximately 2-fold higher clearance rates in mice. FA accumulation was 3.8-fold higher in rabbits than mice. Rabbits more closely than mice reflected primates for in vivo MeOH metabolism, and particularly FA accumulation, suggesting that developmental studies in rabbits may be useful for assessing potential human teratological risk.

Iron-rich foci in chronic viral hepatitis.

Stainable iron in the liver (hemosiderosis) is most commonly seen in individuals with homozygous genetic hemochromatosis, prior transfusion, hemolysis, porphyria cutanea tarda, and chronic alcohol-induced liver disease. In chronic viral hepatitis, however, significant hepatocellular hemosiderosis is uncommon. This report describes unusual foci of hepatocellular hemosiderosis ("iron-rich foci" or IRF) in liver biopsy specimens from three patients with chronic hepatitis with or without cirrhosis (two hepatitis C-related, one hepatitis B-related). IRF present within the lobular parenchyma or cirrhotic nodules contrasted sharply with the immediately adjacent hemosiderin-negative liver tissue. Serum iron indices were abnormal in all three patients, but homozygous hemochromatosis was ruled out based on the hepatic iron concentration and hepatic iron index for each case. These cases highlight the potential for irregular iron storage in chronic viral liver disease and possible confusion with genetic hemochromatosis. The possible pathogenesis of IRF and the relationship of iron storage to the outcome of interferon therapy in chronic viral hepatitis are discussed.