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V. Alima, M.B. B.CH. B.A.O., Ph.D.

Assistant Professor, Tulane University School of Medicine

Many cytotoxic agents cause both apoptotic and necrotic cell death but the role of apoptosis in diacetyl-induced cell death is unknown. Therefore, we hypothesized that diacetyl causes apoptosis and changes in epithelial adhesion molecules. Lungs were collected from Sprague Dawley rats one day after a 6 h exposure to inhaled air (n=6) or 317 ppm diacetyl vapor (n=6). Clinical studies have demonstrated an association between amiodarone therapy and a variety of pulmonary complications ranging from sub-acute necrotizing pneumonitis to pulmonary fibrosis. In some necrotic foci in the mainstem bronchus epithelium, the normal thin linear staining of -catenin at intercellular junctions was replaced by more focal globular expression. Such alterations may play a role in, or possibly result from, necrosis, apoptosis, and/or epithelial detachment. These findings indicate that both apoptosis and necrosis contribute to diacetyl-induced epithelial injury and suggest that diacetyl may alter intercellular adhesion complexes of respiratory epithelium. Rationale: Recently it was shown in the clinic that inhaled corticosteroids cause rapid bronchial vasoconstriction. Conclusions: the results suggest that corticosteroid-induced airway vasoconstriction is at least partly driven by an 1-adrenoceptor mediated mechanism. The rapid onset of vasoconstriction after inhalation of budesonide suggests that this is a nongenomic effect. This ex-vivo study supports clinical observations of vasoconstriction after inhalation of corticosteroids. This model could serve as a complement to clinical models to uncover effects and mechanisms of pulmonary/bronchial circulatory changes. Ozone (O3) is a common air pollutant that causes a variety of adverse health effects including altered host vulnerability to pathogens. Pulmonary clearance of Staphylococcus aureus is decreased after O3 exposure, but the mechanisms that underlie altered host susceptibility are poorly understood. We determined that this cell line did not release cytokines following exposure to O3. These results indicate that repeated exposures to low level O3 attenuates airway epithelial pro-inflammatory responses to S. We exposed neonatal (7d old) and adult male Sprague Dawley rats to inhaled soot generated by diffusion flame for 6 hrs. We found that exposure to soot stimulated an increase in circulating neutrophils in adult rats and an increase in lavage neutrophils in neonates. There are temporal and spatial differences in neonatal responses compared to adult responses. Ozone (O3), an oxidant air pollutant in photochemical smog, principally targets epithelial cells lining the respiratory tract. However, changes in global gene expression have also been reported in livers of O3-exposed mice. Liver tissue samples were processed for light microscopic examination and morphometric analyses. These results suggest that acute exposure to oxidant air pollution exacerbates drug-induced liver injury and delays hepatic repair. Because of this rapid transformation, extremely limited information is available in terms of potential human exposures and health effects. This may be important in the pathophysiology of lung injury associated with oxidative stress. Ozone, a potent oxidant gas in photochemical smog, poses a threat to the respiratory tract. Its increased ambient levels have been linked to lung injury, inflammation and airway hyper-responsiveness. In children, ozone is known to worsen the asthmatic symptoms even at concentrations below the U. Hypoxic insult to the lung initiates a cascade of events that ultimately results in tissue damage.

At 24 hours post exposure, some strains displayed clear growth inhibition and at 48 hours post exposure, some strains showed lack of survival indicating toxicity. Upon analysis, the sensitive strains had gene deletions involved in various pathways and sensitivity was used to identify ozone toxicity modulating proteins. Two particular gene products, Yap1 and Skn7 were classified as modulating the toxicity of ozone, and these proteins are transcription factors or activators involved in oxidative stress. Another gene product of interest, Pdr17, is a protein involved with lipid synthesis. Also, gene products involved with membrane transport and membrane permeability were identified as being important for modulating the toxicity of ozone. A plausible explanation for the identification of these gene products is that ozone interacts with lipids on the membrane via lipid peroxidation and promotes oxidative stress. Validation assays are being performed with serial dilutions of yeast exposed to varying concentrations of ozone, and mutant complementation experiments will be preformed on a targeted set. Importantly, this is the first high throughput screen to identify proteins that modulate the toxicity of ozone and our results will be projected into human cell systems using homology based approaches. The levels of oxidative stress caused by incubation with the positive controls, potassium bromate (0. Relative fluorescence was measured using a microplate fluorescence spectrophotometer at excitation and emission wavelengths of 485nm and 530nm respectively. Zinc is an essential micronutrient with numerous catalytic and structural cellular functions. Zinc is also a common environmental metallic contaminant that has been implicated in a variety of oxidant-dependent toxicological responses. Lastly, we demonstrate that Zn2+ exposure resulted in rapid swelling of mitochondria isolated from mouse hearts. Taken together, these findings show a disregulation of mitochondrial integrity that leads to H2O2 formation in A431 cells exposed to Zn2+. Similar findings were also observed in primary cultures of human airway epithelial cells. These demonstrate the utility of an imaging approach to the study of the role of oxidant stress in toxicological responses. The products of singleelectron oxidants (such as 8-oxoguanine) have been extensively characterized, however the outcome of two-electron oxidation is less well documented. One of two added oxygen atoms is derived from the oxidant, the other from water; molecular oxygen is not directly required. The 2-Ih lesion thus appears to be a pathway-specific lesion and holds promise as a potential biomarker. These results imply that Na2Cr2O7, CdCl2 and NiCl2 produce cellular oxidative damage through the use of three different mechanisms. As a hemoprotein, Hb can, in the presence of oxidizing equivalents such as H2O2, act as a peroxidase with very high oxidizing potential. In red blood cells, this dangerous activity is strictly regulated by reducing environment and lack of oxidizing equivalents. The ferric form of Hb is short-lived and the hemoprotein is effectively converted into ferro-Hb by metHb reductase. For stroma-free Hb this regulation is lost and a potential for Hb to become a peroxidase is very high. This potential may be markedly increased by inflammatory cells generating oxygen radicals, superoxide. It has been proposed that extra-cellular Hb is controlled by its binding with haptoglobins (Hpt) (types 1-1 or 2-2) resulting in apparent weakening of the peroxidase activity. We demonstrate that: 1) Hb peroxidase activity is not significantly decreased by binding with Hpt; 2) Hb/Hpt peroxidase complexes undergo self-inflicted cross-linking provided H2O2 is available; 3) inflammatory cells generate superoxide->H2O2 at levels sufficient to maintain the peroxidase activity of Hb/Hpt complexes; 4) Hb/Hpt aggregates are taken-up by macrophages at rates comparable or exceeding those for non-covalently-cross linked complexes; 5) the engulfed Hb/Hpt aggregates stimulate oxidative stress and injury to macrophages; 6) plasma of patients with severe sepsis contains Hb/Hpt aggregates.

Several of the genes identified have direct human homologs with conserved biological function, and many more have functional orthologs, supporting the notion that the mechanisms of toxicity identified are relevant to human disease. Due to their unique physical and chemical characteristics, the use of nanoparticles has increased dramatically in recent years leading to a growing need for research examining the potential impact of nanoparticles on the environment and human health. Cerium oxide (CeO2) represents an important nanomaterial with wide ranging applications; however, toxicity data for CeO2 is limited. Mast cells have long been recognized for their prominent role in allergic inflammation, asthma, and cardiovascular disease. These cells reside within tissues including the respiratory tract where they can interface with environmental particles. The aim of this study was to examine the activation of mast cells and the vascular response following exposure to CeO2. Additionally, we assessed vascular reactivity and cytokine profiles in a mouse model instilled with CeO2. Mast cells were exposed in vitro to CeO2 (0-300 g/ml) for 6-48 hrs and both IgE and non-IgE mediated mast cell activation was examined. These findings demonstrate that CeO2 can direct mast cell production of pro-inflammatory mediators which could potentially contribute to impaired vascular relaxation and adverse health effects in vivo. Resveratrol-treated mice showed decreased levels of metastasized tumor leading to increased survival when compared to the controls. Resveratrol administration prevented endothelial cell apoptosis and maintained endothelium integrity. Interestingly, resveratrol did not affect the emigration of lymphocytes across the endothelium and into tumor site. Typically, sickness behavior is the normal manifestation of an inflammatory response to infection or injury and one that resolves with restoration of homeostasis. One answer may relate to a heightened physiological stress response associated with the short-term battlefield environment. Together, these observations are suggestive of a possible unrecognized link between the stressful environment of the Gulf War theater, agent exposures unique to this war, and a resulting adverse and persistent neuroinflammatory outcome. Assessing potential endocrine disrupting effects of human phthalate exposure requires development of appropriate biomarkers. With the long-term goal of developing surrogate tissue phthalate biomarkers, the aim of this research was to identify phthalate-induced genomic changes in rat placenta. Although preliminary, these data demonstrate that phthalate exposure alters gene expression within rat placenta and suggest similar functional pathways are affected in both the phthalate target tissue (testis) and a potential phthalate surrogate biomarker tissue (placenta). Background: Spermatic development and activity has been reported to be affected by air pollution exposure. The ability to induce acrosome reaction in sperm of mice was compared to their ability to fertilize in vitro oocytes from counterpart females (non-exposed). Testis weight and ratio (testis weight/body weight) showed no significant difference among the three groups. Conclusion: Short-term exposure to diesel air pollution decreases sperm count and motility, and significantly reduced the capacity of the sperms to fertilize females. A traditional Chinese medicinal herb, Radix Astragali, has protective effects on sperm. The mixture combined a dose of iprodione that does not significantly affect androgen-dependent morphological endpoints, with vinclozolin (a 5x2 factorial design). Vinclozolin alone delayed pubertal progression, reduced androgen sensitive organ weights, and increased serum testosterone levels as previously reported. These results demonstrate these fungicides interact when co-administered to delay pubertal development. Hedgehog (Hh) signaling plays an important role in prostate development and prostate cancer. The major goal of our research is to elucidate the molecular mechanisms by which Hh signaling regulates prostate growth. Here, we used both in vivo and in vitro methods to determine the paracrine and autocrine Hh effect on epithelium growth during prostate development. Immunostaining was performed for BrdU, and Pan-cytokeratin on the paraffin sections.

Many people from Christian backgrounds have already made up their mind that this is indeed so, without having actually tried these substances themselves. This is understandable, as I can not imagine any Christian choosing to enter a demonic pact, if that is what they believe they might be doing. It is noteworthy, however, that some Christians who have taken the plunge, in settings appropriate to their beliefs, have had profound spiritual experiences as a result! If such people are not scared away by this, these perceptions can take a long time to come to terms with. Having gone through this painful process myself, I believe that this constituted a valuable lesson in understanding the nature of light and darkness and their fundamental interrelation, as opposed to the immobile human constructs of polarised and mutually exclusive good and evil trying to crush each other, which can promote an unhealthy psychospiritual fear of the unknown. To add to that, things are not always as they seem [see also the quote from Dunham et al. Sometimes a scary facade can be merely a veil behind which truth may be found by those wise enough not to be swayed by gross appearances. However, detailed discussion of this dilemma of good and evil could form a lengthy treatise of its own. Most people in our societies are ruled by subconscious fear and selfloathing, and can not accept themselves for who they are, or communicate with others, without hiding behind masks. At their roots, nearly all difficulties that may be encountered within a bad trip derive from fear. Everyone has fears of some kind, though in many of us they are mostly buried so deeply within our psyches that it can take a traumatic experience such as a bad trip before we even know that they exist, and what they are. It may help to realise that fear only has the power that you give to it by allowing it to take root and grow. Knowing that whatever will happen, will happen, and that we can do nothing more than live moment by moment honourably and humbly, can sometimes help release the grip of fear. How you deal with these fears as they become apparent is a personal and individual matter, which depends very much on the nature of you and your fears. Psychedelic states of consciousness can give us the opportunity to learn how to discard these shackles of destructive thought, in order to move towards our highest aspi- rations, rather than stagnate or dig deeper holes for ourselves. The effects of these psychedelics are the strongest of any yet discovered, and in moderate to large doses are the most likely to precipitate negative reactions in the unprepared. Despite having a similar timecourse, regarding onset and duration, these three substances all have very different effects, and salvinorin A is in a bizarre class of its own. When smoked [or more preferably, vapourised], these substances act very rapidly, and their effects subside slightly less rapidly. The intensity of the peak of the experience, when a fully-active dose has been consumed, is indeed awe-inspiring and overwhelming. No awareness [or only vague awareness] of physical surroundings, body or self remains, but from there the effects can differ widely between the compounds, and between different people at different times. Often extreme time-distortion is experienced [when there is an ego present to experience it], to the point that the peak may seem to last for hours, days, or rarely even weeks, existing in a reality far removed from the familiar. Fortunately, however, many people who have had a terrifying experience during the peak find themselves quite joyful and ecstatic once surroundings begin to return to familiarity, at least in part because of being so happy that the alteration was not permanent! Time-distortion is also a common subjective phenomenon with other psychedelics, though generally to a less-extreme extent. The principal one is the use of laughter, to dispel gloomy thoughts and break negative thought-cycles. The distracting and healing influence of a good laugh can truly work as wondrous medicine, and the most profound realisations may often be found in the midst of such moments. A comforting foot and/or body massage can also be very soothing and calming to a distressed tripper. Of course, the others present would need to be sufficiently well-adjusted and intelligent not to actually agree with the person that they are losing their mind! It certainly helps if at least one other person present is thoroughly familiar with psychedelics, as discussed earlier. A simple change of environment can work wonders in improving mood and outlook, which is largely why the importance of set and setting was emphasised earlier.

Scorpion venom itself can be dried to a greyish powder, which remains potent for years if stored in refrigeration. Scorpions were often represented on monuments of the ancient Egyptians, and were also prominently depicted on monuments relating to the mystery cult of Mithras in n. It is considered pungent, neutral and slightly poisonous, acting on the liver meridian. It has a weaker antispasmodic effect than the centipede, and is antifungal, nervine and strongly sedative, also causing vasodilation and inhibiting epinephrine release. The haemolytic activity of its venom is in contrast to most other scorpions, stings of which do not cause haemolysis (Balozet 1971). Scorpion venom consists mostly of proteins, and generally loses toxicity when treated with ammonia or iodine. Scorpion venoms are generally neurotoxic, with stings causing severe local pain [followed by a prickling sensation and then desensitisation], agitation, increased muscle tone with contractions, suppressed reflexes, crying, salivation, perspiration, mydriasis, impaired vision, arrhythmia, impaired respiration, hyperglycaemia, feelings of anguish, and sometimes fainting, vomiting and diarrhoea. Even handling scorpions or inhaling the air over their enclosures can result in spasmodic sneezing. Venoms of many scorpion species, such as Buthotus minax, Centruroides gracilis, Leiurus quinquestriatus, Opisthocanthus cavaporum, Parabuthus hunteri, Tityus bahiensis, T. One person noted marked stimulation and moodenhancement after being stung by a scorpion of the genus Centruroides the night before (C. Symptoms include great mental anxiety, dizziness, vomiting, irregular pulse, headache, local pain and inflammation. This symptomology is similar to that induced by cholinergic neurotoxins found in spider and cobra venoms [see above, and Naja]. Madagascan brown lemurs [Eulemur fulvus] have been observed using unspecified millipede species as a probable psychotrope and medicament. The lemurs will take a single millipede, place it in the mouth, and bite it gently, prior to rolling it across the skin and fur for apparent antiparasitic and insect-repelling properties. Presumably from absorption of millipede toxins through the mouth, the lemurs display "an expression of blissful pleasure" for c. In this latter case, the millipedes were identified as Anadenobolus monilicornis, possibly accidentally imported on plants or fruit from the West Indies or S. These ants are actually regarded as being more powerful than Datura as a shamanic ally, and consuming them is a matter of individual choice, rather than an enforced initiation procedure. Different groups differ in the details of their procedures, though there are also many common elements. In winter [though some do it in summer], fasting and nightly vomiting are practiced for at least 3 days before the quest, particularly excluding salt, grease, meat and blood. Up to 90 or more such balls may be swallowed in a single session, each holding 5 or so ants. Bloodshot eyes and lassitude indicate a sufficient dose, upon which ingestion ceases. Shortly after, the ant doctor sneaks up on the novice and shakes him, to agitate the ants into biting, causing him to fall into a stupor for about 8-10hrs. After awakening, hot water is drunk to induce vomiting, the balls of down being regurgitated with the ants still alive [when ingested for curing, it may be taken as a bad sign if the ants are dead]. Occasionally, after awakening, more ants may be consumed, continuing the process for several days if required. Following the ritual, further dietary restrictions may be adhered to for some time, as well as behavioural restrictions including isolation and not speaking. Various red ants have also been used in smaller doses medicinally [internally and/ or externally] to treat rheumatism, paralysis, body pain, stomach aches, heavy colds and some gynaecological disorders, in ways that reflect some facets of the ritual ingestions, though visions are usually not sought or received. All tribal groups who use ants ritually also use them medicinally, but not all who use them medicinally use them ritually. Interestingly, ants have been used as an aphrodisiac stimulant in wine, said to have been consumed by soldiers to give courage for battle. One consisted of macerating 2 handfuls of ants in a gallon of wine for a month, before distilling and repeating the procedure 3 times with fresh batches of ants.