Alteration in methyl-methanesulfonate-induced poly(ADP-ribosyl)ation by 2-butoxyethanol in Syrian hamster embryo cells

The effects of 2-butoxyethanol (2-BE) on poly(ADP-ribosyl)ation were studied in Syrian hamster embryo (SHE) cells by measuring the cellular concentrations of the polymer poly(ADP-ribose) (pADPr) and of NAD+, the substrate of poly(ADP-ribose) polymerase (PARP). As biotransformation pathways of ethylene glycol ethers involve NAD+-dehydrogenases, it was hypothesized that 2-BE could reduce poly(ADP-ribosyl)ation by consuming NAD+. As a result DNA repair could be altered, which would explain that 2-BE had been shown to potentiate the effects of clastogenic substances such as methyl-methanesulfonate (MMS). In this study, the effects of 2- BE on MMS-induced pADPr metabolism were analyzed. The results indicated that: (i) 2-BE (5 mM) by itself did not influence significantly pADPr or NAD+ levels. (ii) 2-BE inhibited pADPr synthesis in MMS (0.2 mM)- pretreated cells, without any change in NAD+ concentrations. (iii) MMS treatment, which rapidly increased pADPr levels, also affected the poly(ADP-ribosyl)ation system as a secondary effect by damaging cell structures. Membrane permeabilization, which occurred at concentrations >1 mM MMS, led to a dramatic leakage of cellular NAD+ resulting in a strong reduction in pADPr levels. (iv) A bleomycin pulse (100 microM) applied after MMS and/or 2-BE treatment confirmed that 2-BE reduced poly(ADP-ribosyl)ation capacities of MMS-treated cells, though the glycol ether had no effect alone. This study confirmed that the inhibition of pADPr synthesis could be responsible for the synergistic effects of 2-BE with genotoxic substances. The mechanism of this inhibition cannot be explained by a lack of NAD+ at the concentrations of 2-BE tested.      

Local metabolism in lung airways increases the uncertainty of pyrene as a biomarker of polycyclic aromatic hydrocarbon exposure

While inhaled polycyclic aromatic hydrocarbons have long been suspected to induce lung cancer in humans, their dosimetry has not been fully elucidated. A key question is whether the critical exposure occurs during absorption in the lungs, or if toxicants in the systemic circulation contribute significantly to lung cancer risk. In particular, data are needed to determine how the physical properties of inhalants affect local dosimetry in the respiratory tract. Pyrene, a tobacco smoke component, was selected for study because it has physical properties between those of highly lipophilic benzo[a]pyrene and water- soluble nitrosamines. Aliquots of 5 ng of pyrene dissolved in a phospholipid/ saline suspension were instilled as a single-spray bolus in the posterior trachea of the dog just anterior to the carina. For 3 h after instillation, blood was repeatedly sampled from the azygous vein, which drains the mucosa around the point of instillation, and from both sides of the systemic circulation. At 3 h post-instillation, tissue samples were taken. Autoradiography was used to determine the depth distribution of pyrene in the tracheal mucosa. The concentration of pyrene-equivalent radioactivity in the azygous vein peaked 9 min after the instillation. At approximately 30 min after instillation, a rapid early clearance phase shifted into a distinctly slower second clearance phase. Rates of rapid clearance were, however, sufficiently slow to indicate diffusion-limited absorption of pyrene in the trachea. This finding was corroborated by high concentrations of pyrene in the epithelium as determined by autoradiography. High epithelial concentration of pyrene combined with a slow penetration into the circulating blood allowed substantial first-pass metabolic conversion of pyrene in the tracheal mucosa. A total of 13% of the instilled pyrene was retained in the tracheal mucosa 3.2 h after instillation; of this, 29% was parent compound, 52% was organic-extractable metabolites, 14% was water-soluble metabolites and 6% (approximately 1% of the instilled amount) was covalently bound to tracheal tissues. Results support the inference that lipophilic protoxicants, because of slow, diffusion-limited absorption, are more likely than water-soluble protoxicants to be bioactivated in the lining epithelium and, in turn, induce first-pass toxicity at the site of entry. In addition, limitations were identified in the use of systemically distributed biomarkers of PAHs, such as urinary hydroxypyrene levels, as indicators of the biologically effective dose in airway target cells.      

Cold stress, near drowning and accidental hypothermia: a review

This paper reviews literature on the topic of cold stress, near-drowning and hypothermia, written mainly since the last review of this type in this journal. The main effects of cold stress, especially in cold water immersion, include the "cold shock" response, local cooling causing decrements in physical and mental performance, and ultimately core cooling as hypothermia occurs. The section on cold-water submersion (near-drowning) includes discussion regarding the various mechanisms for brain and body cooling during submersion. The mechanisms for cold-induced protection of the anoxic brain are discussed with attention given to decreased brain temperature and the Q10 principle, the mammalian dive reflex and a newly considered mechanism; cold-induced changes in neurotransmitter release (i.e., glutamate and dopamine). The section on the post-cooling period includes the post-rescue collapse and subsequent rewarming strategies used in the field, during emergency transport or in medical facilities. Recent research on topics such as inhalation warming, body-to-body warming, radio wave therapy, warm water immersion, exercise, body cavity lavage, and cardiopulmonary bypass is reviewed. Information on new methods of warming, including arteriovenous anastomoses (AVA) warming (by application of heat- with or without negative pressure application-to distal extremities in an effort to increase AVA blood flow), forced-air warming, and peripheral vascular extracorporeal warming, are discussed.     

Differential depression at excitatory and inhibitory synapses in visual cortex

The function of cortical circuits depends critically on the balance between excitation and inhibition. This balance reflects not only the relative numbers of excitatory and inhibitory synapses but also their relative strengths. Recent studies of excitatory synapses in visual and somatosensory cortices have emphasized that synaptic strength is not a fixed quantity but is a dynamic variable that reflects recent presynaptic activity. Here, we compare the dynamics of synaptic transmission at excitatory and inhibitory synapses onto visual cortical pyramidal neurons. We find that inhibitory synapses show less overall depression than excitatory synapses and that the kinetics of recovery from depression also differ between the two classes of synapse. When excitatory and inhibitory synapses are stimulated concurrently, this differential depression produces a time- and frequency-dependent shift in the reversal potential of the composite postsynaptic current. These results indicate that the balance between excitation and inhibition can change dynamically as a function of activity.     

PNEUMOPERITONEUM DUE TO PCI IN A PATIENT WITH A STRANGULATED FEMORAL HERNIA

SUMMARY Although pneumatosis cystoides intestinalis (PCI) is a well-recognised condition, an individual surgeon is unlikely to encounter it often. The collected experience of two surgical units in Glasgow teaching hospitals over a 15-year period consisted of five patients.¹ Surgical and radiological trainees may therefore have little or no exposure to the diagnostic difficulties this condition can cause. We report an illustrative case.     

Alcohol and injury: a comparison of emergency room populations in two Canadian provinces.

The few comparative emergency room (ER) studies reported have found alcohol's role in injury occurrence to vary and suggest that regional and cultural differences in drinking patterns may account, in part, for this variation. To further this research, a probability sample of 1708 ER patients was interviewed regarding the role of alcohol in the event, usual drinking patterns, and alcohol-related problems and a urine sample was obtained to estimate blood alcohol concentration (BAC). The sample was from ERs in two Canadian provinces with distinctly different cultures: primarily English-speaking Alberta and French-speaking Quebec. While differences in demographic and drinking characteristics between injured and noninjured in both the Alberta and Quebec ERs were similar to those in other ER studies, the injured in the Alberta ER were more likely to be positive for estimated BAC; to have higher BAC levels; to report drinking prior to the event; and, among those reporting drinking, to have consumed a larger number of drinks and to report feeling drunk at the time of injury compared to those in Quebec. These differences may be associated with cultural differences in typical drinking patterns, with higher rates of abstinence reported in the Alberta ER, but also with higher rates of heavy drinking and alcohol-related problems, while those in the Quebec ER were more likely to report consuming smaller quantities with greater frequency (typical of wine-drinking cultures). Additional research is needed to explicate further alcohol's role in injury occurrence for planning effective prevention strategies that are both culturally relevant and specific.     

Thermoregulatory model for prediction of long-term cold exposure

A multi-segmental mathematical model has been developed for predicting shivering and thermoregulatory responses during long-term cold exposure. The present model incorporates new knowledge on shivering thermogenesis, including the control and maximal limits of its intensity, inhibition due to a low core temperature, and prediction of endurance time. The model also takes into account individual characteristics of age, height, weight, % body fat, and maximum aerobic capacity. The model was validated against three different cold conditions i.e. water immersion up to 38 h and air exposure. The predictions were found to be in good agreement with the observations.