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PubMed2003

A primer for nuclear terrorism.

Mass exposure to radiologic substances presents a unique challenge to the entire response effort, which includes health care professionals, law enforcement personnel, and other first responders. Recognition of signs and symptoms of exposure, and focus on removal and decontamination are priorities of management. Radiation injuries require specialized equipment and access to experts. Patients can have complex patterns of injury, ranging from trauma and the immediate results of an explosion or exposure, to progressive damage associated with radiation sickness. Both conventional injury and radiation illness may require critical care management. Remembering the essentials of first response, that is, treat the patient, not the poison, by addressing the ABCs of airway, breathing, and circulation, is critical to appropriate treatment of radiation exposure. Understanding the basic science of radiologic agents will aid the provider in managing affected patients and preventing further casualties.

Decontamination↗

PubMed2006

Warfarin and its interactions with foods, herbs and other dietary supplements.

Despite its complex pharmacokinetic and pharmacodynamic profile, warfarin is still one of the most widely used oral anticoagulant agents. Attaining optimal anticoagulation with this agent is clinically challenging in view of its many food and drug interactions. Inappropriate anticoagulation control can expose patients to an increased risk of bleeding or thromboembolic complications, due to over and underanticoagulation, respectively. Fluctuations in dietary vitamin K intake can have a significant effect on the degree of anticoagulation in patients treated with warfarin. In addition, the explosion in use of various dietary supplements and herbal products can lead to undesired outcomes on anticoagulant levels. The aim of this review is to discuss the scope and the potential clinical impact of the most commonly reported food, dietary supplement and herbal interactions with warfarin therapy. Practical steps for patients and providers to minimise these interactions are highlighted.

Administration, Oral↗

PubMed2006

The paradox of histone deacetylase inhibitor-mediated modulation of cellular responses to radiation.

Given the widespread use of radiotherapy in cancer, there has been a longstanding interest in the development of chemical compounds that can modify cellular responses to ionizing radiation. Additionally, recent terrorism threats suggesting attacks with 'dirty bombs' containing combinations of radioactive isotopes with conventional explosives, has increased the interest in compounds that can protect from radiation injury. Histone deacetylase inhibitors represent a new class of compounds that can modulate the effects of radiation. Research with histone deacetylase inhibitors has largely focussed on the consequences of their ability to alter gene transcription via histone acetylation and on their properties as anti-cancer agents. They have been shown to cause cell cycle and growth arrest, differentiation and in certain cases apoptosis in cell cultures and in vivo. In addition to their intrinsic anti-cancer properties, numerous studies have demonstrated that histone deacetylase inhibitors can modulate cellular responses to other toxicity-inducing modalities including ionizing radiation. The consensus is that histone deacetylase inhibitors markedly enhance the sensitivity of cells to radiation by altering numerous molecular pathways. Intriguingly, a report has also shown that histone deacetylase inhibitors can reduce radiation induced acute and late skin damage using a well-established animal model of cutaneous radiation syndrome. Hence, there is an emerging interest in potential use of histone deacetylase inhibitors as radiation sensitizers or protectors. This review focuses on the different mechanisms by which histone deacetylase inhibitors modify cellular responses to ionizing radiation.

Animals↗

PubMed2000

Indirect laser-induced fluorescence detection of explosive compounds using capillary electrochromatography and micellar electrokinetic chromatography.

Mixtures of nitroaromatic and nitramine explosive compounds and their degradation products were analyzed using electrokinetically driven separations with both indirect laser-induced fluorescence (IDLIF) and UV absorption detection. Complete separations of the 14-component mixture (EPA 8330) were achieved using both capillary electrochromatography (CEC) and micellar electrokinetic chromatography (MEKC). IDLIF detection was performed using an epifluorescence system with excitation provided by a 635 nm diode laser and micromolar concentrations of the dye Cy-5 as the visualizing agent. While the sensitivity of the two detection methods was similar for the nitroaromatic compounds, the nitramines could only be detected using UV absorption due to their low fluorescence quenching efficiency of Cy-5. The detection sensitivity using IDLIF was limited by low frequency oscillations in the fluorescence background. The oscillations increased with higher electric field strength and were attributed to thermal fluctuations caused by Joule heating. Due to the more conductive running buffer and higher separation currents used in MEKC, sensitive IDLIF detection could only be achieved using low (approximately 100 V/cm) field strengths, resulting in long analysis times. CEC separations, which are typically run with low conductivity mobile phases to avoid bubble formation, are less sensitive to this effect. In CEC separations with IDLIF detection a stable fluorescence background using Cy-5 could be established using only a nonporous stationary phase. In capillaries packed with porous silica particles, anomalous migration behavior was observed with charged dye molecules and a stable fluorescence background could not be established under electrokinetic flow. This is the first demonstration of IDLIF in packed channel CEC.

Benzene Derivatives↗

PubMed2003

Commitment to apoptosis by ceramides depends on mitochondrial respiratory function, cytochrome c release and caspase-3 activation in Hep-G2 cells.

Apoptosis and necrosis are distinct forms of cell death that occur in response to various agents. We studied the action of N-Acetyl-D-sphingosine (C2-ceramide) or N-hexanoyl-D-sphingosine (C6-ceramide) in human hepatoma HepG2 cell line. The cells were treated in vitro for 1-24 h. Cell toxicity was evaluated by MTT assay. DNA content was estimated by gel electrophoresis and flow cytometry. Measurement of mitochondrial respiration, analysis of cytochrome c release and caspase-3 activation were assessed in order to determine if either of these events in the induction of apoptosis and/or necrosis was predominant. We have demonstrated that C2 and C6-ceramide were cytotoxic in a time and dose-dependent manner. After 24 h of treatment with 100 microM of C2 and C6 the morphology (May-Giemsa staining) of treated cells displayed an apoptotic phenotype in C6-treated cells, confirmed by a high (sub-G1 peak > 20%) proportion by flow cytometry while a necrotic morphology was observed after C2-ceramide treatment, confirmed by DNA smearing in DNA electrophoresis. After C6-ceramide incubation, the respiratory chain was functional only slightly inhibited (20%), there was production of ATP, cytochrome c release without ROS production, activation of caspase-3 and induction of apoptosis. On the contrary, C2-ceramide inhibited the respiratory chain more intensely (80%) increased significantly ROS production, which resulted in an arrest of ATP production, no cytochrome c release and absence of caspase-3 activation. Finally after complete exhaustion of intracellular ATP, mitochondrial explosion induced necrotic cell death. In conclusion, evidence suggest that mitochondrial respiratory chain function is essential for controlling the decision of the cell to enter a apoptotic or necrosis process.

Apoptosis↗

PubMed1993

Retrospective DNA analysis using fixed tissue specimens.

The recent explosion of scientific and technical knowledge in the field of molecular biology has allowed us to make important advances in our understanding of the molecular basis of many human diseases. This technology has now entered the clinical laboratory where identification of specific genetic sequences can aid in the precise diagnosis of hematologic and other malignancies, inherited diseases, specific infectious agents, and inherited predisposition to disease. In addition, it can be applied to prenatal diagnosis, paternity testing, identification of minimal residual disease following treatment, and assessment of drug sensitivity or resistance. In many cases in diagnostic pathology, the need for molecular analysis often is not realized until after a critical tissue specimen has been fixed, embedded, and examined microscopically. Thus, there is a clear need for development of techniques that would allow the retrospective study of archival tissues that have been fixed and embedded in paraffin. This review examines in depth those factors which influence the quality of the DNA available from fixed embedded tissues and discusses the usefulness of polymerase chain reaction amplification in obtaining sufficient diagnostically useful DNA from archival specimens. It is hoped that this review will aid the diagnostic pathologist interested in the application of molecular techniques in the retrospective study of fixed embedded tissues.

DNA↗

PubMed2004

Melanocortin-4 receptor agonists for the treatment of obesity.

The identification of a highly efficacious anti-obesity agent remains an illusive goal. While many avenues of investigation have been pursued, none of the existing compounds claim much more than a 10% reduction in weight in humans (over a one year period with diet and exercise). Nonetheless, the potential reward for fulfilling this unmet medical need has kept interest levels high in the research community. The recent explosion of genetic information has identified numerous potential targets for drug screening. The melanocortin-4 receptor is a promising target and is currently being intensively investigated by many companies and academic research groups.

Amides↗

PubMed1985

Smell of danger: an analysis of LP-gas odorization.

LP-gas derives warning properties from the odorants ethyl mercaptan or thiophane. Laboratory tests have implied that the average person has the ability to smell the odors before leaking LP-gas reaches one-fifth its lower limit of flammability. Generally, however, laboratory tests ignore or discard persons with a poor sense of smell, especially the elderly and persons with certain types of hyposmia. Some persons who apparently can smell the warning agents when directed may otherwise fail to notice or identify them. Elderly men seem particularly vulnerable to instances of incidental anosmia and olfactory agnosia. Psychophysical testing of the warning agents has been rather unsophisticated. There exists neither a standard protocol for testing nor adequate specification of the perceptual properties that might make one warning agent better than another. Without such developments, improvement in warning agents will fail to occur. Possible improvements include increases in concentration, the use of blends to insure more uniform delivery of agent and, to decrease the perceptual vulnerability of relatively insensitive people, use of agents with favorable psychophysical (stimulus-response) functions and use of agents with favorable adaptation characteristics. Even without a change in existing products, it seems advisable to learn more about the vulnerability of LP-gas users and to employ educational means to reduce risks.

Diffusion↗

PubMed1986

Pulmonary edema of environmental origin--newer concepts.

Pulmonary edema of non-cardiac origin is usually an urgent clinical problem, which has recently increased in frequency throughout the world in the past few years. This is partly due to sociological factors and to pre-eminent advances in industrial technology. Recent severe massive toxic gas explosions have had national and worldwide implications. Therefore, urgent and appropriate therapy is of utmost importance in most of these patients. The use of high flow oxygen with Constant Positive Pressure Breathing are the main inhalational therapeutic approaches. Newer modalities of treatment include: (1) earlier Fiberoptic bronchoscopy in those individuals afflicted with aspiration problems and (2) certain specific chemical blocking agents for the management of phosgene intoxication and hydrogen sulfide toxicity. Preventive environmental measures are also important.

Adult↗

PubMed1998

Complementary and alternative medicines for Alzheimer's disease.

The recent successes of large, multicenter clinical trials of acetylcholinesterase inhibitors for symptomatic treatment of Alzheimer's disease have spawned enthusiasm that this common and fatal neurologic disease is "treatable." A parallel explosion has occurred in the consumption of alternative medicines by the public seeking more effective, natural, or safer methods for treatment of dementia. Some of these medicines may, in fact, be biologically active in modulating the disease as well as producing side effects and interactions with accepted pharmaceuticals. This review brings to focus the scientific evidence presently available regarding such agents.

Aged↗

PubMed1996

Different effects of azole-antifungal agents on the regulation of intracellular calcium concentration of Trichophyton rubrum.

Prior studies have indicated that intracellular calcium concentration ([Ca2+]i) is involved in fungal cell growth. However, it has not been known whether antifungal drugs affect signal transduction via calcium in fungal cells. In this context, we examined the effects of antifungal drugs, itraconazole, bifonazole and ketoconazole, on [Ca2+]i in Trichophyton rubrum. Itraconazole (1-5 ng/ml) induced a rapid and transient [Ca2+]i increase, peaking at 15-20s in hyphal cells of T. rubrum, but not in spores. The slow descending phase of the [Ca2+]i increase induced by itraconazole was depleted by chelating extracellular calcium with ethylene glycol bis (beta-aminoethyl ether)-N, N,N',N'-tetraacetic acid (EGTA), suggesting that the increase in [Ca2+]i is biphasic: Ca2+ mobilization from the internal pool and influx from the outside of the cell. At 10 ng/ml and 100 ng/ml, however, itraconazole induced an explosive and sustained calcium increase in both spores and hyphae. At less than 1 ng/ml, no [Ca2+]i increase was caused in both hyphae and spores. On the other hand, although some hyphal cells showed a transient [Ca2+]i increase, most of the cells did not show any changes of [Ca2+]i after the addition of ketoconazole at 10 ng/ml. Both spores and hyphal cells incubated with 100 ng/ml of bifonazole or ketoconazole showed a gradual increase of intracellular calcium concentration until 5 min, when the measurement was ceased. These findings suggest that signal transduction via calcium might be involved in some biological effects of itraconazole on T. rubrum, and that bifonazole and ketoconazole could differently affect [Ca2+]i in T. rubrum from itraconazole. In addition, the determination of [Ca2+]i changes induced by antifungal agents may contribute to clarification of the biological effects on fungal membranes.

Antifungal Agents↗

PubMed2004

Lessons from curbing the coronary artery disease epidemic for confronting the impending epidemic of heart failure.

This article describes five decades of epidemiologic research that has contributed to an explosive expansion of knowledge about the causes and evolution of cardiovascular disease. Cardiovascular epidemiology has become a basic science of preventive cardiology and has provided vital information about predisposing but modifiable risk factors to public health workers, physicians, scientists, and basic researchers. This research also has stimulated national public health initiatives, global attention to cardiovascular disease prevention,and pharmacologic development of agents to control hypertension and dyslipidemia and controlled trials that demonstrate their efficacy.

Coronary Artery Disease↗

PubMed1975

The neurologic effects of noxious marine creatures.

The concept of the sea as a source of noxious agents is perhaps not a familiar one to clinical neurologists, judging by the lack of reference to these agents in standard textbooks. Chemical, physiologic, and pharmacologic laboratories are increasingly investigating the properties of marine toxins, finding in them compounds with interesting and novel structures or unusual physiologic effects. Such substances are seen as possible agents for biologic and, more particularly, physiologic research, and as possible sources of new pharmaceuticals. These include hormone-like substances and antiviral or antitumor agents. Despite these specialized developments, which are in large measure a consequence of the technological advances of the present century, the clinician is at times directly concerned with the effects of marine toxic substances. For example, in Japan, puffer fish or tetrodotoxic poisoning is one of the major causes of deaths from food poisoning. Another marine toxin that has caused many explosive outbreaks of food poisoning. with many deaths in various parts of the world, comes from clams or mussels. This toxin, saxitoxin, is produced by species of marine protozoa including Gonyaulax, and is concentrated in filter-feeding molluscs. These two examples were of significant interest in medicine long before the technologic developments of the twentieth century. In the last few decades, entirely new problems of marine intoxication have arisen as a result of marine pollution from the disposal of industrial wastes in the sea. The most striking example of a man-made marine intoxication has been the outbreak of Minamata disease. In Minamata, Japan, the disposal of mercury-contaminated industrial wastes from a plastics factory into an enclosed bay, followed by human consumption of the contaminated fishes, crabs, or shellfish, led to many instances of acute cerebral degeneration. With the increasing exploration of the sea for both pleasure and economic exploitation, which is a feature of the second half of the twentieth century, it may be expected that the frequency and variety of human intoxications by marine creatures will be increased. This chapter reviews the neurologic effects of noxious substances of marine biologic origin. The subject is now developing so rapidly that overall surveys, such as this, of the general animal life of theocens will soon be beyond the scope of a single review. Nevertheless, it is hoped that the references given will enable the interested reader to pursue particular aspects further.

Adult↗

PubMed1999

Prevalence of primary HIV drug resistance among seroconverters during an explosive outbreak of HIV infection among injecting drug users.

OBJECTIVES: This study examined the frequency of transmission of drug resistant HIV in the population of injecting drug users (IDU) in Vancouver, Canada during a period of particularly high virus transmission. DESIGN: All subjects enrolled in the Vancouver Injection Drug Users Study who seroconverted from HIV negative to positive status (n = 61) between December 1996 and February 1998 were eligible for analysis. The first seropositive sample from 57 individuals with plasma samples available was analyzed for resistance to antiretroviral agents by population based sequencing of the HIV protease and reverse transcriptase genes. METHODS: Plasma viral RNA was extracted and the viral reverse transcriptase and protease regions were amplified by nested reverse transcription-PCR. The presence of mutations associated with antiretroviral drug resistance was assessed by automated sequence analysis. RESULTS: Protease and reverse transcriptase sequences were successfully obtained from the 57 recent seroconverters. No cases of transmission of variants associated with significant resistance to protease inhibitors or nucleoside and non-nucleosides reverse transcriptase inhibitors were detected. CONCLUSION: The frequency of transmission of drug resistant HIV amongst these recently infected IDU is extremely low, with no protease or reverse transcriptase inhibitor resistant strains detected soon after seroconversion. The data provide no rationale for withholding treatment from this already marginalized population.

Anti-HIV Agents↗

PubMedDate not supplied

Symptom-based, algorithmic approach for handling the initial encounter with victims of a potential terrorist attack.

OBJECTIVES: This study intended to create symptom-based triage algorithms for the initial encounter with terror-attack victims. The goals of the triage algorithms include: (1) early recognition; (2) avoiding contamination; (3) early use of antidotes; (4) appropriate handling of unstable, contaminated victims; and (5) provisions of force protection. The algorithms also address industrial accidents and emerging infections, which have similar clinical presentations and risks for contamination as weapons of mass destruction (WMD). METHODS: The algorithms were developed using references from military and civilian sources. They were tested and adjusted using a series of theoretical patients from a CD-ROM chemical, biological, radiological/nuclear, and explosive victim simulator. Then, the algorithms were placed into a card format and sent to experts in relevant fields for academic review. RESULTS: Six inter-connected algorithms were created, described, and presented in figure form. The "attack" algorithm, for example, begins by differentiating between overt and covert attack victims (A covert attack is defined by epidemiological criteria adapted from the Centers for Disease Control and Prevention (CDC) recommendations). The attack algorithm then categorizes patients either as stable or unstable. Unstable patients flow to the "Dirty Resuscitation" algorithm, whereas, stable patients flow to the "Chemical Agent" and "Biological Agent" algorithms. The two remaining algorithms include the "Suicide Bomb/Blast/Explosion" and the "Radiation Dispersal Device" algorithms, which are inter-connected through the overt pathway in the "Attack" algorithm. CONCLUSION: A civilian, symptom-based, algorithmic approach to the initial encounter with victims of terrorist attacks, industrial accidents, or emerging infections was created. Future studies will address the usability of the algorithms with theoretical cases and utility in prospective, announced and unannounced, field drills. Additionally, future studies will assess the effectiveness of teaching modalities used to reinforce the algorithmic approach.

Algorithms↗

PubMed2005

Environmental risk assessment of hydrofluoroethers (HFEs).

Hydrofluoroethers (HFEs) are being used as third generation replacements to chlorofluorocarbons (CFCs), hydrochlorofluorocarbons (HCFCs) and perfluorocarbons (PFCs) because of their nearly zero stratospheric ozone depletion and relatively low global warming potential. HFEs have been developed under commercial uses as cleaning solvents (incl., HFE-7500, C7F15OC2H5; HFE-7200, C4F9OC2H5; HFE-7100, C4F9CH3; HFE-7000, n-C3F7OCH3), blowing agents (incl., HFE-245mc, CF3CF2OCH3; HFC-356mec, CF3CHFCF2OCH3), refrigerants (incl., HFE-143a, CF3OCH3; HFE-134, CHF2OCHF2; HFE-245mc, CF3CF2OCH3), and dry etching agents in semiconductor manufacturing, (incl., HFE-227me, CF3OCHFCF3). From the environmental, ecological, and health points of view, it is important to understand their environmental risks for these HFEs from a diversity of commercial applications and industrial processes. This paper aims to introduce these HFEs with respect to physiochemical properties, commercial uses, and environmental hazards (i.e. global warming, photochemical potential, fire and explosion hazard, and environmental partition). Further, it addresses the updated data on the human toxicity, occupational exposure and potential health risk of commercial HFEs. It is concluded that there are few HFEs that still possess some environmental hazards, including global warming, flammability hazard and adverse effect of exposure. The partition coefficient for these HFEs has been estimated using the group contribution method; the values of logKow for commercial HFEs have been estimated to be below 3.5.

Chlorofluorocarbons↗

PubMedDate not supplied

Morphine, opioid peptides, and pancreatic islet function.

Since the isolation of enkephalins 7 yr ago, there has been an explosive increase in knowledge and an enormous interest in the action of both exogenous and endogenous opiates. This review deals with the interaction of opiates with the endocrine pancreas. The results of animal studies performed in vitro do not allow any conclusion to be drawn, because the effects of opioid peptides on pancreatic hormone release seem dependent on many variables, including the agent investigated, dose administered, concentration of glucose in the medium, and experimental procedure used. The results of in vivo animal studies suggest that central administration of opiates and opioid peptides acts indirectly via the sympathetic nervous system to cause hyperglycemia and impaired insulin secretion, while peripheral administration tends to stimulate insulin and glucagon secretion. This last statement seems also to be true for studies performed in human beings. The narcotic addict offers a model to evaluate the hormonal and metabolic effects of a chronically administered agent that binds and activates endogenous receptors. In these subjects, it is possible to find increased concentrations of glycosylated hemoglobin A1 and a marked reduction of the acute insulin response to intravenous glucose, but not to arginine, which suggests a state of defective glucose recognition by pancreatic beta-cells during narcotic addiction. Thus, the heroin addict, like patients with non-insulin-dependent diabetes, does not respond appropriately to glucose signals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1981

Industrial microbiology.

Industrial microbiology has served humanity since prebiblical times, providing fermented beverages and foods to enhance the quality of life. The antibiotic era featured an explosion in the number of microbial products for medicine, nutrition, industry, and research. Revolutionary developments in molecular genetics are propelling the field into a new growth phase with promise of solutions to major world problems.

Animals↗