Trypsin and rosmarinic acid reduce the toxicity of Micrurus fulvius venom in mice.

UNLABELLED: CONTEXT. Antivenom is expensive and not always available, so alternative treatments are being investigated. OBJECTIVE. The efficacy of trypsin or rosmarinic acid (RA) in treating Micrurus fulvius in a murine model is determined. MATERIALS AND METHODS. DESIGN: randomized controlled blinded study. SUBJECTS: Fifty mice (20-30 g). Study groups: Intraperitoneal injections of: 1) 2 mg/kg M. fulvius venom (approximately twice the LD50 for mice; n = 10); 2) 2 mg/kg M. fulvius venom incubated in vitro for 1 h prior to injection with RA at a 1:10 ratio (n = 17); 3) 2 mg/kg M. fulvius venom incubated in vitro for 1 h prior to injection with 1 mg of trypsin (n = 17); 4)1 mg trypsin IP without venom (n = 3); and 5) RA IP without venom (n = 3). MAIN OUTCOME: time to toxicity (respiratory distress (< 25 breaths/min.), loss of spontaneous locomotor activity, or inability to upright self). STATISTICAL ANALYSIS: Time to toxicity using Tukey-Kramer HSD; Survival to 4, 6, and 12 h using Chi-square analysis. RESULTS. Onset of toxicity: venom + saline, 120.3 + 64.4 min; venom + rosmarinic acid, 238.1 ± 139.2 min (p = 0.15 relative to venom + saline); venom + trypsin, 319.7 + 201.0 min (p = 0.007 relative to venom + saline). Venom + trypsin but not venom + RA survival to 4 h was significant compared to venom + saline (p = 0.023). Two mice in the venom + trypsin group and one mouse in the venom + RA group survived to 12 h. Mice receiving trypsin without venom or RA without venom survived to 12 h without toxicity. Discussion. This work suggests that trypsin and RA may have efficacy in treatment M. fulvius envenomation. CONCLUSION. In vitro neutralization of M. Fulvius venom by trypsin justifies progressing to an in vivo model in future studies.

A controlled trial of topical nitroglycerin in a New Zealand white rabbit model of brown recluse spider envenomation.

STUDY OBJECTIVES: Topical nitroglycerin has been reported to prevent skin necrosis from brown recluse spider bites, but this has never been scientifically tested. This study attempts to assess the effects of topical nitroglycerin on experimental Loxosceles reclusa envenomations. METHODS: We performed a randomized, blinded, controlled study in an animal care facility. Twenty-four New Zealand white rabbits were experimentally envenomated by means of subcutaneous injection with 20 microg of brown recluse spider venom. Rabbits were randomized to 1 of 2 experimental groups. The treatment group received 1 in of 2% topical nitroglycerin ointment every 6 hours for 3 days applied directly to the envenomation site. The control group received the vehicle without nitroglycerin. Gross examination of the lesions and measurements of the areas of the lesions were made daily. Creatine phosphokinase (CPK), blood urea nitrogen, creatinine, hemoglobin, and hematocrit levels were measured on days 0, 5, and 10. Lesions were excised after 10 days and examined by a blinded pathologist, who measured the area of necrosis and quantified inflammation and edema using a standard wound-healing score. For all values, mean values plus SD were determined. All comparisons made over multiple time points were assessed for significance by using a repeated-measures analysis of variance followed by Fisher least significant difference and Scheffé post hoc comparisons. A P value of.05 or less was used to determine significance. The Student's t test was used to compare the means of single measures. Significance was determined by using 95% confidence intervals. Comparisons of total area of necrosis were made with the nonparametric Mann-Whitney U test because of the heavy positive skew of the data. RESULTS: Skin necrosis developed in all animals. Mean values of the lesion area were not significantly different over time between the 2 groups of animals. At day 10, the median area of necrosis was 22.3 cm2 for the treatment group and 15.4 cm2 for the control group (P =.12). The inflammation score was 3.33+/-0.78 for the treatment group and 2.79+/-1.29 for the control group (P < .01). The edema score was 1.25+/-1.28 for the treatment group and 0.98+/-1.10 for the control group (not significantly different). CPK levels increased dramatically in both groups, with the greatest increase in the treatment group. In both groups hemoglobin and hematocrit levels decreased significantly, whereas WBC counts and platelet counts increased significantly, without significant differences between the 2 groups. CONCLUSION: At the dose used in this experiment, topical nitroglycerin did not prevent skin necrosis, increased inflammation score, and increased serum CPK levels. The results of this study do not support the use of topical nitroglycerin in the treatment of L reclusa envenomation and suggest that systemic toxicity could be increased.

Trends in emergency department utilization, 1988-1997.

OBJECTIVES: To study changes in ED utilization over a ten-year period; and to try to identify factors that affect utilization. METHODS: This study was conducted in a university-affiliated rural tertiary referral center in a stage 1 managed care market, providing primary emergency services to a county of 120,000 and tertiary services to a 29-county area with 1.2 million people. The year of visit, time of visit, level of care required, length of stay (LOS), and admission status were entered into a computer database for each ED visit. RESULTS: Over the period from 1988 to 1997, the population grew by 18.7%. Over the same time period, the number of ED visits grew 27%. By regression analysis, the number of ED visits was directly related to the size of the service population (correlation coefficient 0.97). During the study period, patient acuity increased, with urgent visits increasing from 45% to 52% while nonurgent visits declined from 55% to 48%. Percentage of patients admitted increased from 14% in 1989 to 20% in 1997. Percentage of patients with LOS exceeding six hours also increased, from 8% in 1989 to 16% in 1997. CONCLUSIONS: For the study hospital there was a direct relationship between the ED utilization and population size as well as a historical trend toward increased patient acuity. These trends quantified at one hospital may reflect trends occurring throughout the United States that would affect ED staffing, space, and resource needs.

Mechanisms of allergy and chemical sensitivity.

Allergy and chemical sensitivity are closely related disorders in which environmental exposures produce inflammatory reactions. For allergy, environmental proteins bind to IgE antibody on mast cells leading to the release of inflammatory mediators. In chemical sensitivity, low molecular weight chemicals bind to chemoreceptors on sensory nerve C-fibers leading to the release of inflammatory mediators. Clinical manifestations are similar in the two conditions. The overlap between the two conditions has a basis in mechanism, so the similarity of clinical manifestations and high percentage of individuals with both conditions may have a biological basis. Chronic exposures can lead to adaptation phenomena. Depression has been associated with both allergy and chemical sensitivity. Both the allergic and chemical irritant responses may be subjected to conditioning so that the response is triggered by other stimuli. Evidence for conditioning is strongest for allergy. Both allergy and chemical sensitivity can be acquired in association with irritant exposures.

Chemical hazards faced by animal handlers.

A number of chemical hazards are associated with the care and handling of animals. A variety of pesticides are used to control fleas, ticks, and other insects. Rodenticides often are used in animal housing facilities. Veterinarians and their helpers may be exposed to anesthetic gases, pharmaceuticals, including antineoplastic agents, disinfectants such as phenol and formaldehyde, and sterilants such as ethylene oxide. Great care must be taken to minimize occupational exposures to chemical hazards.

Emergency department hemodialysis in a case of severe ethylene glycol poisoning.

A 36-year-old man with a history of depression presented to the emergency department after ingesting approximately 3,000 mL of ethylene glycol antifreeze in a suicide attempt. The patient's ethylene glycol concentration, 1,889 mg/dL, was higher than any level previously documented in the medical literature. Although his course was complicated by nausea, emesis, lethargy, metabolic acidosis, and kidney failure, the patient survived without persistent kidney failure or other chronic problems. Sustained hemodialysis and ethanol infusion were instituted in the ED, on the basis of the patient's history, before laboratory confirmation of the ingestion was obtained.

Development of multiple chemical sensitivities in laborers after acute gasoline fume exposure in an underground tunneling operation.

In this article, investigators report on the presence and nature of chemical sensitivities and other indices of illness in a cohort of workers excavating a new subway tunnel located under a former gasoline station. The workers were exposed to gasoline fumes for up to approximately 2 mo when they inadvertently dug into soil contaminated by gasoline. The cohort was unique in several ways: (a) contact with gasoline was made by the workers at a time when no one had complained of multiple chemical sensitivities syndrome; (b) all were males of low socioeconomic status; (c) the exposure was well documented; (d) the cohort could be considered "naive" because, at the time of the study, the men were not members of support groups and were not being seen by clinical ecologists, and they were not labeled, either by self or others, as having multiple chemical sensitivities syndrome or any related diagnosis; and (e) at the time of interview, all workers we contacted appeared to be either gainfully employed or laid off temporarily and seeking gainful employment. We explored the health status of the workers at two different times: (1) soon after the tunnel was closed as a result of high, measured benzene-exposure levels and (2) 10-13 mo after the tunnel was closed. The workers were chronically overexposed to gasoline fumes, after which approximately one-fourth (26.7%) of our random sample of relatively naive, low-socioeconomic-status male laborers-although neither disabled nor generally litigious-reported the new onset of chemical hypersensitivities and other characteristics that fit conservative criteria for multiple chemical sensitivities syndrome.

Fatality resulting from intraventricular vincristine administration.

BACKGROUND: Inadvertent intrathecal administration of vincristine has been reported and is uniformly fatal except in two of three cases treated with spinal fluid exchange. We report a case of inadvertent direct intraventricular vincristine administration. CASE REPORT: A 59-year-old woman developed acute lymphocytic leukemia with meningeal involvement and was being treated with intraventricular cytarabine (beta-cytosine arabinoside, Ara-C) injected via an Ommaya reservoir, intravenous (i.v.) vincristine, prednisone, and i.v. daunorubicin. The vincristine (2 mg in 10 mL diluent) was inadvertently injected into her Ommaya reservoir. Within 10 minutes, the error was realized. Despite optimal care, nausea and vomiting developed the first night, followed sequentially by coarse tremor, disorientation, horizontal nystagmus, and stupor. Her mental status waxed and waned until day 9, at which time she became responsive only to noxious stimuli. By day 11, she was deeply comatose and on day 40 she died without regaining any neurological function. CONCLUSION: Despite aggressive and immediate therapy, intraventricular vincristine infusion produced neurologic toxicity, with progressive loss of mental function, followed by coma and death. Systems need to be developed to prevent inadvertent central nervous system administrations.

Biological homing: hypothesis for a quantum effect that leads to the existence of life.

In biological systems, complex molecules interact with specificity and rapidity. The hypothesis is advanced that there are complementary sites on the surfaces of pairs of biological molecules with an enhanced attraction due to quantum mechanics. I postulate that a biological homing effect arises from the quantum mechanical probability that complementary pairs of molecules will join, and that this phenomenon is the force that drives biology and gives rise to the existence of life. To illustrate the approach, a simplified calculation is given for the interaction cross-section between two molecules, each with N surface charges that have an identical spatial distribution but with paired charges having opposite signs. The resulting cross-section is enhanced by a factor of N2 over the coulomb-scattering cross-section for a single pair of charges. We hypothesize that the existence of life is a direct and inevitable consequence of the principles presented here.

Hypothesis for induction and propagation of chemical sensitivity based on biopsy studies.

The reactive airways dysfunction syndrome (RADS), the reactive upper airways dysfunction syndrome (RUDS), the sick building syndrome (SBS), and the multiple chemical sensitivity syndrome (MCS) are overlapping disorders in which there is an intolerance to environmental chemicals. The onset of these illnesses is often associated with an initial acute chemical exposure. To understand the pathophysiology of these conditions, a study of the nasal pathology of individuals experiencing these syndromes was undertaken. Preliminary data indicate that the nasal pathology of these disorders is characterized by defects in tight junctions between cells, desquamation of the respiratory epithelium, glandular hyperplasia, lymphocytic infiltrates, and peripheral nerve fiber proliferation. These findings suggest a model for a relationship between the chronic inflammation seen in these conditions and an individual's sensitivity to chemicals. A positive feedback loop is set up: the inflammatory response to low levels of chemical irritants is enhanced due to the observed changes in the epithelium, and the epithelial changes are propagated by the inflammatory response to the chemicals. This model, combined with the concept of neurogenic switching, has the potential to explain many aspects of RADS, RUDS, SBS, and MCS in a unified way.

Neurogenic inflammation: with additional discussion of central and perceptual integration of nonneurogenic inflammation.

The Working Group on Neurogenic Inflammation proposed 11 testable hypotheses in the three domains of neurogenic inflammation, perceptual and central integration, and nonneurogenic inflammation. The working group selected the term people reporting chemical sensitivity (PRCS) to identify the primary subject group. In the domain of neurogenic inflammation, testable hypotheses included: PRCS have an increased density of c-fiber neurons in symptomatic tissues; PRCS produce greater quantities of neuropeptides and prostanoids than nonsensitive subjects in response to exposure to low-level capsaicin or irritant chemicals; PRCS have an increased and prolonged response to exogenously administered c-fiber activators such as capsaicin; PRCS demonstrate augmentation of central autonomic reflexes following exposure to agents that produce c-fiber stimulation; PRCS have decreased quantities of neutral endopeptidase in their mucosa; exogenous neuropeptide challenge reproduces symptoms of PRCS. In the domain of perceptual and central integration, testable hypotheses included: PRCS have alterations in adaptation, habituation, cortical representation, perception, cognition, and hedonics compared to controls; the qualitative and quantitative interactions between trigeminal and olfactory systems are altered in PRCS; higher integration of sensory inputs is altered in PRCS. In the domain of nonneurogenic inflammation, testable hypotheses included: increased inflammation is present in PRCS in symptomatic tissues and is associated with a heightened neurosensory response; PRCS show an augmented inflammatory response to chemical exposure. The working group recommended that studies be initiated in these areas.

Effects of Prussian blue and N-acetylcysteine on thallium toxicity in mice.

BACKGROUND: Thallium poisoning is now rare but still occurs as a result of homicide attempts. Prussian blue's efficacy in the treatment of experimental thallium poisoning has been demonstrated in animal models, and its use in humans is supported by anecdotal data. Since thallium binds sulfhydryl groups, the use of N-acetylcysteine is also considered as a potential antidote. STUDY OBJECTIVE: To compare the efficacy of Prussian blue and N-acetylcysteine in a murine model of thallium poisoning. METHODS: Female Swiss albino mice with free access to food and water were used. Two study doses of thallium, given as a subcutaneous injection of thallium acetate dissolved in sterile water, were chosen: 70 mg/kg (LD90) and 85 mg/kg (> LD100). A randomized, placebo controlled study was conducted with survival at 120 h chosen as the outcome measure. Four treatment groups were studied: control, Prussian blue, N-acetylcysteine, and the combination of Prussian blue and N-acetylcysteine. Prussian blue was dissolved in water and given by oral gavage at a dose of 50 mg/kg. N-acetylcysteine was diluted in normal saline and given as intraperitoneal injections of 200 mg/kg. Sterile water by gavage and normal saline by peritoneal injection were given as control treatments whenever an active agent was not given. Survival was recorded over a 120 h study period and compared at 120 h by a Fisher's exact test. RESULTS: At 120 h following subcutaneous injection of thallium 70 mg/kg, only 10% of the control animals survived. Treatment with N-acetylcysteine or Prussian blue increased survival to 35% (p = 0.13) and 50% (p = 0.014), respectively. The addition of N-acetylcysteine to Prussian blue offered no benefit over Prussian blue therapy alone. CONCLUSIONS: Prussian blue was found to decrease mortality from thallium poisoning at a dose equal to the LD90 in this model, but not a dose greater than the LD100. No role for N-acetylcysteine in the treatment of thallium poisoning was demonstrated by this study.

Prevalence and nature of allergy and chemical sensitivity in a general population.

The objectives of this study were (a) to determine the self-reported prevalence of allergy and chemical sensitivity in a rural population of eastern North Carolina, (b) to determine the type and frequency of symptoms for each condition, and (c) to determine the demographic groups affected. A random general telephone survey was conducted during the period May 14, 1993, to September 10, 1993, and questions about allergy and chemical sensitivity were asked. Of the 1 446 households contacted, 1 027 (71%) individuals agreed to participate. Allergies were reported by 365 (35%) individuals. Thirty percent of allergic individuals reported that symptoms occurred once or more each week, whereas 61% reported that symptoms occurred, at most, once each month. Allergic symptoms that occurred daily were reported by 5.3% of the total population. Chemical sensitivity was reported by 336 (33%) individuals. Thirty-five per cent of chemically sensitive individuals reported symptoms at least once each week, whereas 53% reported that symptoms occurred once (or less) each month. Symptoms of chemical sensitivity that occurred daily were reported by 3.9% of the total population. Both allergy and chemical sensitivity were distributed widely across age, income, race, and educational groups. Simultaneous allergy and chemical sensitivity were reported by 16.9% of the population, allergy without chemical sensitivity by 16.0%, chemical sensitivity without allergy by 18.2%, and neither condition by 48.9%. If the prevalence of sensitivity to chemical irritants is, in fact, equivalent to that of allergy, as was found in this study, then support for the scientific investigation of chemical sensitivity is justified.

Nasal pathology and ultrastructure in patients with chronic airway inflammation (RADS and RUDS) following an irritant exposure.

BACKGROUND: Reactive airways dysfunction syndrome is a chronic asthma-like condition developing after an acute irritant exposure, and chronic inflammation has been seen on endobronchial biopsy. Reactive upper-airways dysfunction syndrome is chronic rhinitis developing in temporal association with a toxic inhalation exposure, but the pathophysiology is unknown. OBJECTIVES: To study biopsies of the nasal mucosa in patients with reactive upper-airways dysfunction syndrome and in some cases reactive airways dysfunction syndrome developing in temporal association with a chlorine dioxide exposure, to see if a histologic basis for the persistent rhinitis and sensitivity to chemical irritants could be determined. METHODS: Specimens were stained with hematoxylin-eosin and immunoperoxidase stains for substance P, vasointestinal peptide, and S-100 (nerve fibers), and fixed in glutaraldehyde for electron microscopy. Biopsies of three nonexposed subjects were performed for comparison. A pathologist blinded to clinical data interpreted the specimens. RESULTS: Inflammation ratings of exposed individuals were higher than for the nonexposed individuals. The number of nerve fibers stained was greater for patients vs controls. Substance P and vasointestinal peptide staining was nonspecific. Electron microscopy showed desquamation of the epithelium and permeability of epithelial cell junctions. CONCLUSION: This study suggests a mechanism by which ongoing low level exposures perpetuate airway inflammation after an inducing toxic inhalation. A possible overlap between reactive airways dysfunction syndrome, reactive upper-airway dysfunction syndrome and the multiple chemical sensitivity syndrome is suggested.

Anticholinergic poisoning associated with herbal tea.

An outbreak of cholinergic poisoning occurred in New York City during a 3-day period. Seven individuals from three families of South American origin were affected. Signs and symptoms of illness included dry skin, hyperthermia, tachycardia, dilated pupils, agitation, and hallucinations. Onset of illness in all cases was temporally associated with consumption of a tea that was labeled "Paraguay Tea" and was purchased from a grocery store specializing in South American foods. Paraguay tea, made from the leaves of the holly, Ilex paraguariensis, contains caffeine and theophylline and is a popular beverage in South America. Samples of the tea analyzed with gas chromatography contained belladonna alkaloids but neither caffeine nor theophylline. An investigation by the New York City Department of Health personnel determined that the tea was from a single lot, imported by one distributor, and sold at one grocery store. Unsold inventories of the tea were quarantined, and no further cases of anticholinergic poisoning were reported.

Neurogenic switching: a hypothesis for a mechanism for shifting the site of inflammation in allergy and chemical sensitivity.

Neurogenic switching is proposed as a hypothesis for a mechanism by which a stimulus at one site can lead to inflammation at a distant site. Neurogenic inflammation occurs when substance P and other neuropeptides released from sensory neurons produce an inflammatory response, whereas immunogenic inflammation results from the binding of antigen to antibody or leukocyte receptors. There is a crossover mechanism between these two forms of inflammation. Neurogenic switching is proposed to result when a sensory impulse from a site of activation is rerouted via the central nervous system to a distant location to produce neurogenic inflammation at the second location. Neurogenic switching is a possible explanation for systemic anaphylaxis, in which inoculation of the skin or gut with antigen produces systemic symptoms involving the respiratory and circulatory systems, and an experimental model of anaphylaxis is consistent with this hypothesis. Food-allergy-iducing asthma, urticaria, arthritis, and fibromyalgia are other possible examples of neurogenic switching. Neurogenic switching provides a mechanism to explain how allergens, infectious agents, irritants, and possibly emotional stress can exacerbate conditions such as migraine, asthma, and arthritis. Because neurogenic inflammation is known to be triggered by chemical exposures, it may play a role in the sick building syndrome and the multiple chemical sensitivity syndrome. Thus neurogenic switching would explain how the respiratory irritants lead to symptoms at other sites in these disorders.

Multiple chemical sensitivities--chemical sensitivity as a symptom of airway inflammation.

The term multiple chemical sensitivity confuses etiology with diagnosis. Chemical sensitivity is a symptom expressed by patients. The symptoms complex is also expressed by the majority of patients with asthma reactive airway dysfunction syndrome or rhinitis following a single acute exposure, called reactive upper airway dysfunction syndrome. The chemically sensitivity patient merits evaluation for upper airway and bronchial reactivity that may cause extra-airway symptomatology.