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Carbon monoxide (CO) exposure has been described ever since humans developed products of combustion (e.g. fire, burning charcoal). The Romans realized that CO poisoning leads to death (Penney 2000). Coal fumes were used in ancient times for execution, and the deaths of two Byzantine emperors are attributed to CO poisoning (Lascaratos and Marketos 1998). Admiral Richard E. Byrd developed CO poisoning during the winter he spent alone in a weather station deep in the Antarctic interior (Byrd 1938). Further, CO poisoning took the life of tennis player Vitas Gerulaitis (“Died, Vitas Gerulaitis,” 1994; Lascaratos and Marketos 1998) and may have contributed to Princess Diana’s accidental death in 1997 (Sancton and Macleod 1998). Carbon monoxide is a colorless, tasteless, odorless gas by-product of the combustion of carbon-containing compounds such as natural gas, gasoline, kerosene, propane, and charcoal. The most common sources of CO poisoning are internal combustion engines and faulty gas appliances (Weaver 1999). Carbon monoxide poisoning can also occur from space heaters, methylene chloride in paint removers, and fire (Weaver 1999). The most frequent causes of pediatric CO poisoning are vehicle exhaust, dysfunctional gas appliances and heaters, and charcoal briquettes (Kind 2005; Mendoza and Hampson 2006). Less common sources of CO poisoning include riding in the back of pickup trucks, and while swimming and recreational boating (Hampson and Norkool 1992; Silvers and Hampson 1995). Among pediatric populations, minorities are disproportionately affected by CO poisoning compared to Caucasians, and Latinos and non-Latino blacks were more commonly poisoned by charcoal briquettes used for cooking or heating (Mendoza and Hampson 2006). Carbon monoxide is the leading cause of poisoning injury and death worldwide (Raub et al. 2000) and accidental and intentional poisoning in the United States. In the United States carbon monoxide poisoning results in approximately 40,000 emergency department visits (Hampson 1999) and 800 deaths per year (Piantadosi 2002). Children are particularly venerable to CO poisoning. The Center for Disease Control reports children younger than 4 years have the highest incidence of unintentional CO poisoning but the lowest death rates (2005).

This chapter describes common classes of chemical hazards and some specific chemicals that are important in occupational health: 1) the gases that make up the chemical asphyxiants have in common the characteristic that they interfere with oxygen or energy metabolism in cells. Carbon monoxide is a toxic gas that acts by binding to haemoglobin and preventing haemoglobin from delivering oxygen to tissues in the body. It is the most common cause of chemical poisoning because it is produced by combustion in fires where there is insufficient oxygen and in automobile exhaust. 2) Solvents are substances, usually liquids that readily dissolve other substances. In occupational health the term "solvent" usually refers to organic chemicals that dissolve oils. Their vapours may be inhaled or the main exposure may come from skin contact. Their toxic effects depend on the compound but have in common skin effects and effects on the brain, kidney and liver at varying doses. 3) Exposure to metals and the metalloids usually takes the form of inhaling metal-containing dust, inhaling fumes from molten metal or inhaling or ingesting salts of the element. Their toxicity varies. 4) Pesticides are biologically active chemicals designed to control insect, animal, and plant pests. Their toxicity varies widely and depends on the compound, of which the major functional classes are insecticides, including organochlorines, organophosphates, and carbamates, and herbicides.

The history of the gas chamber is a story of the twentieth century. But an earlier event that would subsequently figure into its evolution occurred one day in 1846, when a French physiologist, Claude Bernard, was in his laboratory studying the properties of carbon monoxide, a colorless, odorless, and tasteless gas suspected of somehow being responsible for many accidental deaths. Bernard and the Swedish chemist and pharmacist Carl Wilhelm Scheele had focused their attention on the effect of gases on the blood—work that later would become central to understanding the lethal power of the gas chamber. As Bernard was conducting his initial experiments with carbon monoxide, others were discovering the properties of carbon dioxide. One significant development in the discussion that would turn into the eugenics movement was set in motion in July 1874, when Richard Louis Dugdale conducted a study of the Jukes clan. Eugenics dovetailed readily with other already established American notions such as manifest destiny, racial segregation, and a reliance on capital punishment.

This chapter describes neurologic disorders related primarily to occupational exposures along with presenting signs and symptoms. Acute or subacute occupational exposure to high levels of neurotoxic compounds, which occurred in the past and resulted in unique presentations of neurological disorders, occur infrequently today. Sections include the evaluation of toxic neuropathies and the approach to neurobehavioral impairment along with the cognitive domains commonly affected with exposure to neurointoxicants. A section describes the approach to a patient with exposure to neurointoxicants that includes the need for a temporal association between exposure and effect, a dose-effect relationship, biological plausibility, and other causes eliminated Effects of selected neurotoxins are described, including carbon monoxide, lead, organic solvents, and manganese.

This chapter describes cardiovascular disorders related to occupational and environmental exposures. Sections of the chapter address cardiovascular disease due to carbon monoxide, nitrates, particulate air pollution, and psychosocial factors. The chapter also addresses shift work and sedentary work. A section describes arrhythmias due to various specific chemical exposures. Another section describes hypertension related to lead, excessive noise, and other factors. Finally, a section addresses peripheral vascular disease and Raynaud disease. Cardiovascular disorders are very common and recognition of how occupational and environmental exposures contribute to the occurrence and exacerbation of cardiovascular disorders is important in their prevention, diagnosis, and management.

Building on the principles of toxicology, this chapter describes chemicals by structure, source, use, mechanism of action, environmental properties, and target organ. Major advances in toxic effects include more detailed understanding of the mechanisms by which toxic chemicals damage receptors at the subcellular, cellular, and organ level. The chapter describes properties of various types of inorganic and organic chemicals and their adverse health effects. It discusses asphyxiants, such as carbon monoxide and hydrogen sulfide; heavy metals, such as lead, mercury, and cadmium; organic solvents, such as benzene and trichlorethylene; pesticides, including chlorinated hydrocarbons and organophosphates; and a variety of other toxic chemicals to which people are exposed in the home, community, or workplace environment. Several cases are presented to illustrate various concepts concerning chemical hazards in occupational and environmental health.

In its original meaning, reduction was what was done to a metal ore to obtain the metal itself: the stony ore hacked from the land was reduced to the malleable, ductile, lustrous, useful metal. Ores are commonly oxides or sulfides, so the process of reduction typically involves the removal of oxygen or sulfur. In that sense, reduction is the opposite of oxidation, which I touched on in Reaction 3. In this chapter I shall stick with the metallurgical context and examine that hugely important industrial process, the reduction of iron ore to iron at what can be regarded as the head of the steel chain. However, like oxidation, the concept of reduction has acquired a much broader meaning, as I shall touch on fleetingly in this section and reveal fully in Reaction 5. A typical iron ore is haematite, an iron oxide of composition Fe2O3 and consisting of a stack of Fe3+ and O2– ions (Figure 4.1, over the page; Fe is the symbol for iron, from the Latin ferrum). In the industrial process for the production of iron, the ‘reducing agent’, the substance that brings about reduction, is essentially carbon in the form of coke. Early furnaces used charcoal, but coke is much harder and allows for much taller columns of ore, carbon, and limestone (the last to collect impurities as slag; see Reaction 9). Reduction on this huge scale is carried out in the great blast furnaces that epitomize heavy industry and the industrial revolution, but those furnaces are little more than sophistications of the fires that first led mankind from the Bronze Age to the Iron Age about 3000 years ago. The eponymous blast of a blast furnace is a blast of air. It may seem odd to use oxygen-rich air in a process designed to remove oxygen from an ore, but it is used to oxidize the carbon to carbon monoxide and also to help ensure that the contents of the furnace do not settle to the bottom.

This chapter describes the adverse effects of both outdoor air pollution and indoor air pollution. Various ambient air pollutants are described as well as their adverse health effects, including acute and chronic respiratory disorders, cardiac disorders, cerebrovascular disease, and cancer. A section deals with National Ambient Air Quality Standards of the Environmental Protection Agency for particulate matter, sulfur dioxide, ozone, oxides of nitrogen, and carbon monoxide. Another section describes exposure assessment. The chapter also describes various measures to control hazardous air pollutants and prevent disorders related to air pollution. In addition, a section features indoor air pollution, including pollution due to burning of biomass for cooking and heat.

The effects of high pressure up to 1500 bar on the recombination kinetics of oxygen and carbon monoxide (CO) binding to human hemoglobin (intact and isolated chain forms), human myoglobin (and its mutants), and cytochrome P-450 were studied by the use of millisecond and nanosecond laser photolysis. The activation volumes for the binding of CO to the R- and T-quaternary states of hemoglobin (Hbs) were determined to be –9.0 and –31.7 ml, respectively. The characteristic pressure dependence of the activation volume was observed for the R-state Hb but not for the T-state Hb. More detailed studies were made with isolated α- and β-chains of human Hb. The kinetic data were analyzed on the basis of a simple three-species model, which assumes two elementary reaction processes of bond formation and steps of ligand migration. A pressure-dependent activation volume change from negative lo positive values in the bimolecular CO association reaction was observed for both chains. This is attributed to a change of the rate-limiting step from the bond-formation step to the ligandmigration step. High-pressure ligand-binding kinetics were also examined for site-specific mutants of human myoglobin in which some amino acid residues at the heme distal sites, such as Leu 29, Lys 45, Ala 66, and Thr 67, are substituted by others. The pressure dependence of the CO binding rate for the L29 mutants was unusual: a positive value was obtained unexpectedly for overall CO binding. Corresponding to this anomaly was an unusual geometry of the iron-bound CO, which was determined by IR and NMR spectroscopies. The effects of camphor and camphor analogues as substrates on the CO-binding kinetics for P-450cam were also studied under pressure. The positive activation volumes for CO binding were obtained for substrate-free and norcamphor- and adamantane-bound P-450, whereas other substrate analogue-bound P-450 complexes exhibited the negative activation volumes. All of the present high-pressure results are discussed in relation to (1) the dynamic aspects of the protein conformation, and (2) the specific participation of amino acid residues in the heme distal site in each elementary step of the ligand-binding reaction process.

Propagation within the atmosphere is an important consideration concerning the performance of many electro-optical systems. An electro-optical system can be described as containing three basic components: source, detector, and propagation medium. Because of the quality of source and detection systems today, often the limiting factor in overall system performance is the propagation medium. Thus a thorough discussion of the atmosphere and various mechanisms of attenuation is required. Absorption, scattering, and turbulence are the dominant mechanisms of signal loss and distortion. This chapter covers gaseous absorption and scattering in the atmosphere of the earth. Turbulence is not covered, and the reader is referred to other texts (see Chapter 1, Refs. 1.10 and 1.11). The atmosphere surrounds and protects the earth in the form of a gaseous blanket that acts as the transition between the solid surface of the earth and the near-vacuum of the outer solar atmosphere. It acts as a shield against harmful particle radiation, meteors, and high-energy photons. The dynamics of the atmosphere drive the weather on the surface. It provides for life itself as part of the earth’s biosphere. Thus optical propagation in this medium has many important characteristics and consequences. These include meteorological optics, infrared and visible astronomy, remote sensing, and electro-optical systems performance in general. Therefore, it is appropriate to begin this chapter with an introduction to the nature of the atmosphere. The atmosphere is composed of gases and suspended particles or aerosols at various temperatures and concentrations as a function of altitude and azimuth. The variations in altitude show a marked structure. Six main horizontal layers form the stratified structure of the atmosphere, as shown in Fig. 7.1. The lowest is the troposphere, which extends from ground level to approximately 11 km (36,000 ft or 7 mi.). The temperature in this layer generally decreases with increasing altitude at the rate of 6.5 K/km. However, variations can exist on this rate, which creates interesting refractive effects. The pressure varies from one atmosphere at sea level to a few tenths of an atmosphere at the top of this layer.

Rural Massachusetts is delightful at the end of summer. The classic New England architecture blends with the lawns, gardens, and green forests into a picture of perfect harmony. It is sunny, and the right time in the afternoon for a stroll around the college town of Amherst. However, after a few blocks a distinct crack appears in this idyll: a traditional white wooden house is being renovated and a skull and crossbones sign on the lawn is telling us to keep out due to danger of lead poisoning. It turns out that the customary white colour of the houses around here was oft en due to lead-based pigments. The use of lead in paints was phased out in 1978, but it is still an issue judging from the 16-page pamphlet available in six languages from the US Environmental Protection Agency, and the criminal cases brought against real estate companies and landlords failing to inform tenants and buyers of the lead status of their homes. Marcus Vitruvius Pollio would probably have agreed with this pamphlet and legislation, and so most certainly would Alice Hamilton. Although almost two millennia separate the Roman engineer from the first woman on the faculty of Harvard Medical School, they are united in the fight against the dangers of lead to the workforce and to the public. We do not know much about the life of the first century BC architect and engineer Marcus Vitruvius Pollio, otherwise known as Vitruvius, except what can be inferred from his famous work The Ten Books on Architecture. This magnum opus, written in the days of the Emperor Augustus, probably represents the summary of the professional experience of an old man. The title is slightly misleading, as architecture in Roman times would cover a much broader area than today. So Vitruvius tells us a great deal about engineering in general, about the chemistry of pigments and, to the benefit of this story, about aqueducts and the proper treatment of water. He is also clearly a conservative man, lashing out against ‘decadent frescos’ and ‘these days of bad taste’.

For many years the idea that the activity of integral membrane proteins is regulated by the fluidity of the lipid matrix was popular and appeared to be quite rational. However, as information about the effect of viscosity on the function of different membrane proteins became available, the correlation between the two became increasingly unclear. The purpose of this article is to readdress this issue in light of our recent pressure and temperature studies. This chapter is divided into seven parts: (1) the effect of viscosity on enzyme activity; (2) the effect of viscosity on the local motions of proteins; (3) characterization of membrane viscosity; (4) demonstration of changes in protein-lipid contacts brought about by changes in viscosity; (5) an example of a protein in which the viscosity appears to stabilize a particular conformational state: (6) relations between membrane viscosity and protein function; and (7) conclusions. The effect of viscosity (η) on the rate (k) of a chemical reaction was first given by Kramers (1940): . . . k=A/ηe−Ea/RT (1) . . . In this expression, viscosity will affect the rate of a reaction by limiting the rate of diffusion of reactants. Viscosity will thus modify the frequency factor (A) and should not affect the activation energy. This expression has been applied to aqueous soluble enzymes (for example, Gavish, 1979; Gavish & Werber, 1979; Somogyi et al., 1984), and it appears that, in general, enzymes obey Kramers’s relation, although in some cases the exponent of η is less than one. Viscosity can affect enzymatic rates not only by limiting the diffusion of substrates but also by damping internal motions of the protein chains. It seems reasonable that a high enough viscosities, the protein would be damped sufficiently so that large activation energies will be required for the backbone motions that allow substrates and products to diffuse into and out of the active site. This viscosity-induced increase in activation energy was shown by studies of the reassociation of carbon monoxide and dioxygen to the heme site of myoglobin after flash photodissociation (Austin et al., 1975; Beece et al., 1980).

The question of molecular recognition is a central paradigm of molecular biology, playing central roles in most, if not all, cellular processes. Failed recognition events have been implicated in numerous disease states, ranging from flawed control of gene regulation and cellular proliferation to defects in specific metabolic activities. Historically, questions of molecular recognition have been approached through organic synthesis and through actual structural studies of biomolecular complexes. Fundamental insight into the mechanisms of molecular recognition can be realized through the use of broad interdisciplinary tools and techniques. In particular, the use of recombinant DNA technology in concert with hydrostatic and osmotic pressure methodologies have proven to be ideal for understanding the fundamental mechanisms of recognition. In our presentation, we will focus on recent results from our laboratory that examine three major classes of recognition events in biological systems: 1. Protein-protein recognition: here we seek to define the role of specific surface interactions; electrostatic, hydrogen bonding, and hydrophobic free energies provided through surface complimentarity, which define the specificity and affinity in the formation of complexes between the metalloproteins involved in electron transfer events in cytochrome P-450-dependent oxygenase catalysis and in the assembly of tetrameric hemoglobin. 2. Protein–small molecule recognition: here we seek to ascertain how the same fundamental forces of electrostatics, hydrogen bonding, and the hand-glove fit of a substrate into the active site of an enzyme can give rise to the observed high degree of control of regio- and stereo-specificity in catalysis and in the interfadal interactions of proteins at electrode interfaces. 3. Protein nucleic acid recognition: here again the same fundamental forces control recognition processes, but in this case we will focus on our exciting, recent discovery of a role for solvent water in mediating recognition between protein and nucleic acid components. Representative systems in the binding/ catalytic class of restriction endonucleases and recombinases will be discussed. In all cases, the use of pressure as a variable has provided unique understanding for the molecular details of these processes. Pressure, both hydrostatic and osmotic, has proven to be an enabling experimental technique in understanding the mechanistic origins of molecular recognition events.

Questions

A 9-year-old male presents to the paediatric A&E department with a history of increasing drowsiness over the last 24 hours. Neurological assessment reveals that there is absence of upward gaze. A CT brain is requested which reveals hydrocephalus, with marked dilatation of the...

As discussed in the introduction to this book, any (bio)physical mechanism that transforms some physical variable, such as the electrical potential across the membrane, in such a way that it can be mapped onto a meaningful formal mathematical operation, such as delayand- correlate or convolution, can be treated as a computation. Traditionally only Vm, spike trains, and the firing rate f(t) have been thought to play this role in the computations performed by the nervous system. Due to the recent and widespread usage of high-resolution calcium-dependent fluorescent dyes, the concentration of free intracellular calcium [Ca2+]i in presynaptic terminals, dendrites, and cell bodies has been promoted into the exalted rank of a variable that can act as a short-term memory and that can be manipulated using buffers, calcium-dependent enzymes, and diffusion in ways that can be said to instantiate specific computations. But why stop here? Why not consider the vast number of signaling molecules that are localized to specific intra- or extracellular compartments to instantiate specific computations that can act over particular spatial and temporal time scales? And what about the peptides and hormones that are released into large areas of the brain or that circulate in the bloodstream? In this penultimate chapter, we will acquaint the reader with several examples of computations that use such unconventional means. The computation in question constitutes a molecular switch that stores a few bits of information at each of the thousands of synapses on a typical cortical cell. In order to describe its principle of operation, it will be necessary to introduce the reader to some basic concepts in biochemistry. The ability of individual synapses to potentially store analog variables is important enough that this modest intellectual investment will pay off. (For an introduction to biochemistry, consult Stryer, 1995).

EDs in the UK see a significant number of patients (347 per 100 000/year and ever-increasing) with acute overdose of drugs. Most of them are ingested orally, but other modes of intake can be used, such as IV and nasal. Sometimes it is not uncommon to see a patient presenting themselves to the ED feeling unwell after having ingested packets of Class I drugs to transport across continents. Another group of patients include those who present themselves after self-harming with a knife or blade on their wrists, arms, abdomen, or other parts of the body. These patients may have a previous history of drug overdose. Management of situations such as those described above requires both a generalized approach and specific actions against each drug involved. The common antidotes are covered in this chapter and advice is available in all EDs through the NPIS (<WEB>www.toxbase.org) to deal with such emergencies, particularly with the treatments of unusual poisons. I encourage all the junior doctors to use the website for all the poison cases presenting to the ED to help build up confidence while treating them. Readers should note though that the URLs provided in this chapter can be accessed only by foundation and more senior doctors as the NPIS does not provide usernames and passwords to medical students. The priorities in the management of poisoned patients are similar to other ED presentations (ABCDE). Most of these patients require supportive therapy for recovery. Some poisons have specific antidotes which could be life-saving and are to be administered straightway. The initial assessment should be able to indicate whether or not the patient has been exposed to a specific poison for which an antidote is available. Hypoglycaemia must be excluded in every patient who presents with a low GCS score or convulsions by performing a capillary blood glucose by the bedside. A patient with respiratory depression, low GCS, and constricted pupils should be given naloxone while preparations are made to secure the airway. The recognition of such a pattern sometimes may direct the treating clinician towards a specific poison immediately, so that treatment with a definitive antidote can be given without delay.

In the UK, trauma is currently the commonest cause of death in people <40 years and its incidence is predicted to rise over the next 20 years. So you have an important role in the assessment and management of this group of patients. Doctors of the ED perform a vital role in the early stages of management of trauma patients. In patients with multiple injuries, the care is delivered by a trauma team constituted by middle-grade doctors from various specialties. A senior doctor, usually from the ED and with training in dealing with trauma, leads the team. The trauma team is often requested by the prehospital ambulance personnel, but this is not always the case. Although in your first few days you would not be expected to manage such situations on your own, you may come across a patient with serious trauma behind the curtains in a cubicle. Recognizing the seriousness of the situation and calling for help in the form of a trauma team may make all the difference to that patient in terms of recovery. The principles of assessment and management of trauma patients are discussed in the first answer of this chapter. The ATLS course introduces you to the principles of early management of trauma victims and this can be applied to any trauma patient whom you will see in the ED. The skills you learn on the ATLS course are applicable in many situations. It is advisable to attend this training course while you are working in the ED. You should suspect major trauma in the following situations: • Related to vehicles: high-speed collisions, victim’s ejection from the vehicle (partial or total), rollover, prolonged extrication, etc. • Death of a co-passenger • Pedestrians run over or thrown away to a distance, or with a significant impact (>20mph/32kph) • Falls from a height of >6m in adults and >3m in children or two to three times the height of the child. Resuscitation in the first hour in the resuscitation room has been proved to reduce mortality and morbidity among trauma patients, and so it might be you who will have saved the life of an individual.

All doctors have to deal with emergencies— this can be a daunting pro­spect, particularly when first on the scene. The fear may be that one wrong decision could be crucial and that the recovery of the patient de­pends entirely on what is done at this moment. The truth is that doctors are rarely— if ever— alone for long and that senior help is, for the most part, just a few seconds away. It should also serve as some consolation that the approach to any clinical emergency should be much the same and depends heavily on the basic and advanced life support algorithms. This chapter is written in the spirit that any clinical encounter should be approached as if it is an emergency— this means resorting to the ABCDE (airway, breathing, circulation, disability, exposure) approach. Clearly, if the patient to whom we are called is sitting up in bed talking and drinking a cup of tea, then expectations can be tailored accordingly. As it is so hard to categorize what constitutes a clinical emergency, it is better that we go into every encounter expecting one. It is easier to taper down one’s level of urgency than it is to suddenly escalate treatment in the light of sudden surprising findings. In this way, the idiosyncratic situations— such as the call regarding the post- op thyroid patient— should be considered just as urgent as the seemingly clear car­diac arrest calls. Having performed the systematic ABCDE assessment of each situ­ation, the next stage is to develop the knowledge and confidence to go on and diagnose which specific emergency is unfolding and to apply appro­priate management plans. Questions in this chapter aim to reinforce the ability to perform this assessment, as well as outlining some of the spe­cific therapies that are required to manage individual emergencies.

Animals live in an ever-changing environment to which they must continuously adapt. Adaptation in the nervous system occurs at every level, from ion channels and synapses to single neurons and whole networks. It operates in many different forms and on many time scales. Retinal adaptation, for example, permits us to adjust within minutes to changes of over eight orders of magnitude of brightness, from the dark of a moonless night to high noon. High-level memory—the storage and recognition of a person's face, for example—can also be seen as a specialized form of adaptation (see Squire, 1987). The ubiquity of adaptation in the nervous system is a radical but often underappreciated difference between brains and computers. With few exceptions, all modern computers are patterned according to the architecture laid out by von Neumann (1956). Here the adaptive elements—the random access memory (RAM)—are both physically and conceptually distinct from the processing elements, the central processing unit (CPU). Even proposals to incorporate massive amounts of so-called intelligent RAM (IRAM) directly onto any future processor chip fall well short of the degree of intermixing present in nervous systems (Kozyrakis et al., 1997). It is only within the last few years that a few pioneers have begun to demonstrate the advantages of incorporating adaptive elements at all stages of the computation into electronic circuits (Mead, 1990; Koch and Mathur, 1996; Diorio et al.,1996). For over a century (Tanzi, 1893; Ramón y Cajal, 1909, 1991), the leading hypothesis among both theoreticians and experimentalists has been that synoptic plasticity underlies most long-term behavioral plasticity. It has nevertheless been extremely difficult to establish a direct link between behavioral plasticity and its biophysical substrate, in part because most biophysical research is conducted with in vitro preparations in which a slice of the brain is removed from the organism, while behavior is best studied in the intact animal. In mammalian systems the problem is particularly acute, but combined pharmacological, behavioral, and genetic approaches are yielding promising if as yet incomplete results (Saucier and Cain, 1995; Cain, 1997; Davis, Butcher, and Morris, 1992; Tonegawa, 1995; McHugh et al., 1996; Rogan, Stäubli, LeDoux, 1997).