Debra L. Friedman, MD

• Associate Professor of Pediatrics
• E. Bronson Ingram Chair in Pediatric Oncology
• Department of Pediatrics
• Vanderbilt University School of Medicine
• Cancer Control and Prevention Program Director
• Division of Hematology-Oncology
• Vanderbilt-Ingram Cancer Center
• Nashville, Tennesee

Each branch circuit is protected by a circuit breaker or fuse that limits current to a specific maximum amperage antifungal cream for hands buy generic fulvicin pills. Several higher amperage circuits are also provided for devices such as an electric stove or an electric clothes dryer fungus gnats fox farm buy 250 mg fulvicin with visa. These devices are powered by 240-V circuits fungus gnats report purchase cheapest fulvicin, which can draw from 30 to 50 A of current fungus zucchini plants order fulvicin 250mg. The circuit breaker or fuse will interrupt the flow of current on the hot side of the line in the event of a short circuit or if the demand placed on that circuit is too high antifungal iodine fulvicin 250mg. For example fungus on back order fulvicin 250 mg visa, a 15-A branch circuit will be capable of supporting 1,800 W of power. The neutral wire is connected to ground by the power company and again connected to a service entrance ground when it enters the fuse box. Both the neutral and ground wires are connected together in the fuse box at the neutral bus bar, which is also attached to the service entrance ground. The arrowheads indicate the hot wires energizing the strips where the circuit breakers are located. The arrows point to the neutral bus bar where the neutral and ground wires are connected. This is done to prevent the supply wires in the circuit from melting and starting a fire. The amperage of the circuit breaker on the branch circuit is determined by the thickness of the wire that it supplies. If a 20-A breaker is used with wire rated for only 15 A, the wire could melt and start a fire before the circuit breaker would trip. It is important to note that a 15-A circuit breaker does not protect an individual from lethal shocks. The 15 A of current that would trip the circuit breaker far exceeds the 100 to 200 mA that will produce ventricular fibrillation. The wires that leave the circuit breaker supply the electrical outlets and lighting for the rest of the house. In older homes, the electrical cable consists of two wires, a hot and a neutral, which supply power to the electrical outlets. This third wire is either green or uninsulated (bare) and serves as a ground wire for the power receptacle. It should be realized that in both the old and new situations, the power is grounded. That is, a 120-V potential exists between the hot (black) and the neutral (white) wire and between the hot wire and ground. In modern home construction, there is still a 120-V potential difference between the hot (black) and the neutral (white) wire as well as a 120-V difference between the equipment ground wire (which is the third wire), and between the hot wire and earth. The arrowhead points to the part of the receptacle where the ground wire connects. The arrow points to the ground wire (bare wire), which is attached to the green grounding screw on the power 339 receptacle. Normally, the hot and neutral wires are connected to the two wires of the light bulb socket, and throwing the switch will illuminate the bulb. Similarly, if the hot wire is connected to one side of the bulb socket and the other wire from the light bulb is connected to the equipment ground wire, the bulb will still illuminate. If there is no equipment ground wire, the bulb will still light if the second wire is connected to any grounded metallic object such as a water pipe or a faucet. This illustrates the fact that the 120-V potential difference exists not only between the hot and the neutral wires but also between the hot wire and any grounded object. Thus, in a grounded power system, the current will flow between the hot wire and any conductor with an earth ground. As previously stated, current flow requires a closed loop with a source of voltage. For an individual to receive an electric shock, he or she must contact the loop at two points. Because we may be standing on the ground or be in contact with an object that is referenced to ground, only one additional contact point is necessary to complete the circuit and thus receive an electrical shock. This is an unfortunate and inherently dangerous consequence of grounded power systems. Modern wiring systems have added the third wire, the equipment ground wire, as a safety measure to reduce the severity of a potential electrical shock. This is accomplished by providing an alternate, low-resistance pathway through which the current can flow to ground. A 120-V potential difference exists between the hot and the neutral wires, as well as between the hot wire and the earth. The 120-V potential difference exists between the hot and neutral wires, the hot and the ground wires, and the hot wire and the earth. It is then possible for a bare, hot wire to contact the metal case or frame of an electrical device. The case would then become energized and constitute a shock hazard to someone coming in contact with it. There is no ground wire in the electrical outlet, nor is the electrical apparatus equipped with a ground wire. In this example, the equipment ground wire provides a pathway of low impedance through which the current can travel; therefore, most of the current would travel through the ground wire. A 120-V potential always exists between the hot conductor and the ground or earth. The third or equipment ground wire used in modern electrical wiring systems does not normally have current flowing through it. This provides a significant safety benefit to someone accidentally contacting the defective device. If a large enough fault current exists, the ground wire also will provide a means to complete the short circuit back to the circuit breaker or fuse, and this will either melt the fuse or trip the circuit breaker. Thus, in a grounded power system, it is possible to have either grounded or ungrounded equipment, depending on when the wiring was installed and whether the 342 electrical device is equipped with a three-prong plug containing a ground wire. Obviously, attempts to bypass the safety system of the equipment ground should be avoided. An individual touching the hot case (point A) will receive a shock because he or she is standing on the earth (point B) and completes the circuit. The current (dashed line) will flow from the instrument through the individual touching the hot case. An individual touching the case (point A) while standing on the ground (point B) will still complete the circuit; however, only a small part of the current will go through the individual. In this ungrounded power system, the current is isolated from the ground potential. This device uses electromagnetic induction to induce a current in the ungrounded or secondary winding of the transformer from energy supplied to the primary winding. There is no direct electrical connection between the power supplied by the utility company on the primary side and the power induced by the transformer on the ungrounded or secondary side. Since the 120-V potential exists only between the two wires of the isolated circuit, neither wire is hot nor neutral with reference to ground. However, if one connects one of the wires to one side of the isolated power and the other wire to the ground, the light will not illuminate. In comparing the two systems, the standard grounded power has a direct connection to ground, whereas the isolated system imposes a very high impedance to any current flow to ground. Since standing on the ground (point B) does not constitute a part of the isolated circuit, the individual does not complete the loop and will not receive a shock. This is because the ground is part of the primary circuit (solid lines), and the person is contacting only one side of the isolated secondary circuit (cross-hatched lines). Left: the wire attached to the cheater plug is rarely connected to the screw in the middle of the outlet. The arrow points to ground wire connection on the primary side of the transformer. The bottom arrow points to ground (green) wires meeting at the common ground terminal. Arrows 1 and 2 indicate lines 1 and 2 (orange and brown) from the isolated power circuit breaker. An individual contacting one side of the isolated power system (point A) and standing on the ground (point B) will not receive a shock. In this instance, the individual is not contacting the circuit at two points and thus is not completing the circuit. Point A is part of the isolated power system, and point B is part of the primary or grounded side of the circuit. If a faulty electrical appliance with an intact equipment ground wire is plugged into a standard household outlet, and the home wiring has a properly connected ground wire, then the amount of electrical current that will flow through the individual is considerably less than what will flow through the low-resistance ground wire. However, if that ground wire were broken, the individual might receive a lethal shock. This is an important feature because the faulty piece of equipment may be part of a life-support system for a patient. It is important to note that even though the power is isolated from ground, the case or frame of all electrical equipment is still connected to an equipment ground. The third wire (equipment ground wire) is necessary for a total electrical safety program. As previously discussed, electrical power cords, wires, and electrical motors exhibit capacitive coupling to the ground wire and metal conduits and "leak" 347 small amounts of current to the ground. The figure inset illustrates that the isolated power system is now identical to the grounded power system. Therefore, it is essential that a warning system be in place to alert the personnel that the power is no longer ungrounded. As previously discussed, with perfect isolation, impedance would be infinitely high and there would be no current flow in the event of a first fault situation (Z = E/I; if I = 0, then Z =). Once this preset limit is exceeded, visual and audible alarms are triggered to indicate that the isolation from the ground has been degraded beyond a predetermined limit. This does not necessarily mean that there is a hazardous situation, but rather that the system is no longer totally isolated from ground. This faulty piece of equipment should be removed and serviced as soon as possible. However, this piece of equipment could still be used safely if it were essential for the care of the patient. It should be remembered, 349 however, that continuing to use this faulty piece of equipment would create the potential for a serious electrical shock. However, the system is still safe and represents a state significantly different from that in the first situation. Both of these monitors would trigger an alarm at 2 mA, which led to annoying "false" alarms. Also, in the event of a second fault, the equipment ground wire provides a lowresistance path to ground for most of the fault current. If the isolation of the power system is degraded such that more than 2 mA (5 mA in newer systems) of current could flow, the hazard light will illuminate and a warning buzzer will sound. The other possibility is that too many pieces of electrical equipment have been plugged in and the 2 mA limit has been exceeded. If the gauge is between 2 and 5 mA, it is probable that too much electrical equipment has been plugged in. The next step is to identify the faulty equipment, which is done by unplugging each piece of equipment until the alarm ceases. Therefore, if possible, no other electrical equipment should be connected during the remainder of the case, or until the faulty piece of equipment can be safely removed. If it cannot be reset, then the equipment must be removed from service and checked by the biomedical engineering staff. Double Insulation There is one instance in which it is acceptable for a piece of equipment to have only a two-prong and not a three-prong plug. These instruments have two layers of insulation and usually have a plastic exterior. Double insulation is found in many home power tools and is seen in hospital equipment such as infusion pumps. However, if water or saline should get inside the unit, there could be a hazard because the double insulation is bypassed. The equipment ground wire provides a low-impedance path in which the majority of the leakage current (dashed lines) can flow. Microshock As previously discussed, macroshock involves relatively large amounts of current applied to the surface of the body. The current is conducted through all the tissues in proportion to their conductivity and area in a plane perpendicular to the current. Consequently, the "density" of the current (amperes per meter squared) that reaches the heart is considerably less than what is applied to the body surface. Microshock is a particularly difficult problem because of the insidious nature of the hazard. In the electrically susceptible patient, ventricular fibrillation can be produced by a current that is below the threshold of human perception. The exact amount of current necessary to cause ventricular fibrillation in this type of patient is unknown. If an individual simultaneously touches the case of an instrument where this has occurred and the electrically susceptible patient, he or she may unknowingly cause a discharge to the patient that results in ventricular fibrillation.

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Genetically engineered mice also show that distinct anesthetic targets mediate different anesthetic endpoints and that not all anesthetics have the same targets fungus gnats allergic reaction 250mg fulvicin for sale. While anesthetic action to produce immobility occurs largely at the spinal cord antifungal group order fulvicin 250mg amex, specific molecular targets for amnesia lie in the hippocampus japanese antifungal cream buy fulvicin 250 mg free shipping. Anesthetic-induced unconsciousness can be viewed as impairment of both arousal and awareness fungi definition and classification cheap 250 mg fulvicin visa. These actions are mediated by targets distributed across the brainstem anti fungal lung infection buy discount fulvicin 250mg on line, hypothalamus anti fungal paint additive b&q purchase fulvicin 250 mg otc, thalamus, and cerebral cortex. Anesthetic ablation of arousal relies on disruption of redundant subcortical systems that regulate sleep and patterns of cortical activity. Anesthetics alter the interaction of cortical networks responsible for cognitive functions and may thereby alter awareness by limiting the capacity to both represent and integrate information. The introduction of general anesthetics into clinical practice over 150 years ago stands as one of the seminal innovations of medicine. This single discovery facilitated the development of modern surgery and spawned the specialty of anesthesiology. Despite the importance of general anesthetics, and despite more than 100 years of active research, the molecular mechanisms responsible for anesthetic action are only partially understood. Anesthetics, as a class of drugs, are challenging to study for three major reasons: 1. Anesthesia, by definition, is a change in the responses of an intact animal to external stimuli. Making a definitive link between anesthetic effects observed in vitro and the anesthetic state observed and defined in vivo has proven difficult. This suggests that there are multiple molecular mechanisms that can produce clinical anesthesia. Anesthetics work at very high concentrations in comparison to drugs, neurotransmitters, and hormones that act at specific receptors. This implies that if anesthetics do act by binding to specific receptor sites, they must bind with very low affinity and probably stay bound to the receptor for very short periods of time. Low-affinity binding is much more difficult to observe and characterize than is high-affinity binding. The aim of this chapter is to provide a conceptual framework for the reader to catalog current knowledge and integrate future developments about mechanisms of anesthesia. How are the molecular and cellular effects of anesthetics linked to the behavioral effects of anesthetics observed in vivo Anesthesia is not simply a deafferented state; amnesia and unconsciousness are important aspects of the anesthetic state. Second, the definition is too broad, as all general anesthetics do not produce equal depression of all sensory modalities. For example, barbiturates are considered to be anesthetics but produce minimal analgesia. Regardless of which definition of anesthesia is used, rapid and reversible drug-induced changes in behavior or perception are essential to anesthesia. Changes in behavior such as unconsciousness or amnesia can be intuitively understood in higher organisms such as mammals, but become increasingly difficult to define as one descends the phylogenetic tree. Thus, while anesthetics have effects on organisms ranging from worms to man, it is difficult to map with certainty the effects of anesthetics observed in lower organisms to any of our behavioral definitions of anesthesia. This contributes to the difficulty of using simple organisms as models in which to study the 594 molecular mechanisms of anesthesia. Similarly, any cellular or molecular effects of anesthetics observed in higher organisms can be extremely difficult to link with the constellation of behaviors that constitute the anesthetic state. The absence of a simple and concise definition of anesthesia has clearly been one of the stumbling blocks to elucidating the mechanisms of anesthesia at a molecular and cellular level. Precise definitions for each of the component behaviors of the anesthetic state will be an important tool in dissecting the molecular and cellular mechanisms of each of the clinically important effects of anesthetic agents. An additional difficulty in defining anesthesia is that our understanding of the mechanisms of consciousness is rather amorphous at present. One cannot easily define anesthesia when the neurobiologic phenomena ablated by anesthesia are not well understood. As discussed later in this chapter, the neural substrates for consciousness are beginning to be unraveled1,2 and new theories3,4 have incorporated this new anatomic knowledge leading to identification of surrogate physiologic markers of consciousness. Finally, it has long been assumed that anesthesia is a state that is achieved when an anesthetic agent reaches a specific concentration at its effect site in the brain and that if tolerance to the anesthetic develops, increasing concentrations of anesthetic might be required to maintain a constant level of anesthesia during prolonged anesthetic administration. The finding that it takes a higher anesthetic brain concentration to induce anesthesia than to maintain anesthesia. This suggestion is supported by the recent finding that the sedative component of anesthesia can be reversed by stimulation of specific arousal pathways in the brain, even in the presence of "anesthetic" concentrations of inhalational agents. In order to study the pharmacology of anesthetic action, quantitative measurements of anesthetic potency are absolutely essential. First, it is an extremely reproducible measurement that is remarkably constant over a wide range of species. To date, these monitors have not been shown to be more effective at preventing awareness during anesthesia than simply maintaining an adequate end-tidal anesthetic concentration13,14 or giving a standard dose of intravenous anesthetic. On the basis of this reasoning, the anesthetic target site was assumed to be hydrophobic in nature. Since olive oil/gas partition coefficients can be determined for gases and volatile liquids, but not for liquid anesthetics, attempts have been made to correlate anesthetic potency with solvent/water partition coefficients. To date, the octanol/water partition coefficient best correlates with anesthetic potency. This correlation holds for a variety of classes of anesthetics and spans a 10,000-fold range of anesthetic potencies. Some characteristics of an exceptionally potent inhaled anesthetic: thiomethoxyflurane. On the basis of olive oil/gas partition coefficients of the halogenated convulsant compounds, anesthesia should have been achieved within the range of concentrations studied. In several homologous series of anesthetics, anesthetic potency increases with increasing chain length until a certain critical chain length is reached. Beyond this critical chain length, compounds are unable to produce anesthesia, even at the highest attainable concentrations. In the series of nalkanols, for example, anesthetic potency increases from methanol through dodecanol; all longer alkanols are unable to produce anesthesia. Cutoff effects have been described for several homologous series of anesthetics including n-alkanes, nalkanols, cycloalkanemethanols,26 and perfluoroalkanes. Enantiomers (mirror-image compounds) are a class of stereoisomers that have identical physical properties, including identical solubility in solvents such as octanol or olive oil. Animal studies of barbiturate anesthetics,28 ketamine,29 neurosteroids,30 etomidate,31 and isoflurane32 all show enantioselective differences in anesthetic potency. It is argued that a major difference in anesthetic potency between a pair of enantiomers can only be explained by a protein-binding site (see Protein Theories of Anesthesia); this appears to be the case for etomidate and the neurosteroids. Properties such as size and shape must also be important determinants of anesthetic sites 598 of action. Lipid versus Protein Targets Anesthetics might interact with several possible molecular targets to produce their effects on the function of ion channels and other proteins. Anesthetics might dissolve in the lipid bilayer, causing physicochemical changes in membrane structure that alter the ability of embedded membrane proteins to undergo conformational changes important for their function. Alternatively, anesthetics could bind directly to proteins (either ion channel proteins or modulatory proteins), thus either interfering with binding of a ligand. The following section summarizes the arguments for and against lipid theories and protein theories of anesthesia. Lipid Theories of Anesthesia In its simplest incarnation, the lipid theory of anesthesia postulates that anesthetics dissolve in the lipid bilayers of biologic membranes and produce anesthesia when they reach a critical concentration in the membrane. Consistent with this hypothesis, the membrane/gas partition coefficients of anesthetic gases in pure lipid bilayers correlate strongly with anesthetic potency. Thus, most investigators do not consider lipids as the most likely target of general anesthetics. Anesthetics could bind in hydrophobic pockets that are fortuitously present in the protein core. Hydrophobic amino acids also form the lining of binding sites for hydrophobic ligands. Anesthetics could compete with endogenous ligands for binding to such sites on either water-soluble or membrane proteins. Hydrophobic amino acids are major constituents of the -helices, which form the membrane-spanning regions of membrane proteins; hydrophobic amino acid side chains form the protein surface that faces the membrane lipid. Any protein-binding site is likely to be defined by properties such as size and shape in addition to its solvent properties. Limitations in size and shape could reduce the binding affinity of compounds beyond the cutoff, thus explaining their lack of anesthetic effect. Enantioselectivity is also most easily explained by a direct binding of anesthetic molecules to defined sites on proteins; a protein-binding site of defined dimensions could readily distinguish between enantiomers on the basis of their different shapes. Protein-binding sites for anesthetics could also explain the convulsant effects of some polyhalogenated alkanes. Different compounds binding (in slightly different ways) to the same binding pocket can produce different effects on protein conformation and hence on protein function. For example, polyhalogenated alkanes (nonimmobilizers) could be inverse agonists, binding at the same protein sites at which halogenated alkane anesthetics are agonists. The evidence for direct interactions between anesthetics and proteins is briefly reviewed in the following section. Evidence for Anesthetic Binding to Proteins A breakthrough in protein theories of anesthesia was the demonstration that a purified water-soluble protein, firefly luciferase, could be inhibited by general anesthetics. This provided the important proof of principle that anesthetics could bind to proteins in the absence of membranes. To address proteins more relevant to anesthetic effects on the nervous system, numerous studies have employed site-directed mutagenesis of anesthetic-sensitive ion channels to identify amino acid residues that are crucial to anesthetic action. While the residues identified in these studies may contribute to anesthetic-binding sites, they may alternatively be sites that are essential for anesthetic-induced conformational changes in the protein. The literature on site-directed mutagenesis studies to identify putative anestheticbinding sites on ion channels is extensively reviewed in the section Anesthetic Actions on Ion Channels. These data suggest an etomidate-binding pocket in the transmembrane domain at the interface between the 1 and 3 subunits. Photoaffinity-labeling studies with other anesthetic agents including propofol43,47 and barbiturates48 have identified binding pockets for anesthetics, which are currently being tested and validated using site-directed 601 mutagenesis. Although photoaffinity-labeling techniques can provide extensive information about anesthetic-binding sites on proteins, they cannot reveal the details of the three-dimensional structure of these sites. X-ray diffraction crystallography can provide this kind of three-dimensional detail and has been used to study anesthetic interactions with a small number of proteins. While these data provide insight into the structure of anesthetic-binding sites, x-ray crystallographic studies of anesthetic-binding sites on biologically relevant targets such as ion channels have been hampered by difficulties with crystallizing membrane proteins. It is important to recognize that even the x-ray crystal structures of anesthetics bound to target ion channels may not fully elucidate how and where anesthetics act. Ion channels are allosteric proteins that fluctuate between multiple conformations, whereas x-ray structures are static "snapshots" of just one conformation. Anesthetics bind to and stabilize specific conformations of proteins, which may or may not be the same conformation in which the protein is crystallized. Mutagenesis of amino acids within this etomidate-binding pocket eliminates the anesthetic effect of etomidate, providing unequivocal evidence that anesthetic action can be mediated by binding to a specific protein site. Do anesthetics compete with endogenous ligands for binding to hydrophobic pockets on protein targets or do they bind to fortuitous cavities in the protein Do all anesthetics bind to the same pocket on a protein or are there multiple hydrophobic pockets for different anesthetics How many proteins have hydrophobic pockets in which anesthetics can bind at clinically relevant concentrations How Do Anesthetics Interfere with the Electrophysiologic Function of the Nervous System In the simplest terms, anesthetics could accomplish this by altering the intrinsic firing rate of individual neurons, termed neuronal excitability, and/or by altering communication between neurons, generally occurring via synaptic transmission. Neuronal Excitability Neurons transmit information down their axons through action potentials. The propensity of a neuron to generate and propagate action potentials from the cell body to their nerve terminals is called its excitability. Intrinsic neuronal excitability is chiefly determined by three parameters: resting membrane potential, the threshold potential for action-potential generation, and the size/propagation of the action potential. Anesthetics can hyperpolarize (create a more negative resting membrane potential) both spinal motor neurons and cortical neurons,53,54 and this ability to hyperpolarize neurons correlates with anesthetic potency.

Health-care workers and children with spina bifida antifungal for nails order 250mg fulvicin otc, urogenital abnormalities fungus contagious buy 250mg fulvicin amex, or certain food allergies have also been recognized as people at increased risk for anaphylaxis to latex antifungal lip order cheap fulvicin. Brown and colleagues reported a 24% incidence of irritant or contact dermatitis and a 12 fungus link diet buy fulvicin cheap online. Brown and colleagues suggested that these people are in their early stages of sensitization and perhaps fungus gnats bite effective 250mg fulvicin, by avoiding latex exposure antifungal spray for jock itch purchase discount fulvicin on-line, their progression to symptomatic disease can be prevented. If latex allergy occurs, then strict avoidance of latex from gloves and other sources needs to be considered, following recommendations as reported by Holzman. More importantly, anesthesiologists must be prepared to treat the lifethreatening cardiopulmonary collapse that occurs after anaphylaxis, as previously discussed. The most important preventive therapy is to avoid antigen exposure; although clinicians have used pretreatment with 583 antihistamine (diphenhydramine and cimetidine) and corticosteroids, there are no data in the literature to suggest that pretreatment prevents anaphylaxis or decreases its severity. When this is not possible, patients should be treated as if they were latex allergic, and the antigen avoided. Patients with a documented history of latex allergy should wear Medic Alert bracelets. If prick and intradermal tests are negative, the procedure of subcutaneous provocation testing is applied in a placebocontrolled manner. Only seven skin tests per five patients met the criteria for a positive skin test, and one patient had a skin reaction without systemic effects, three patients had a 584 negative subcutaneous challenge, and one patient did not undergo a challenge. Although suggestions have been made that this is because of underreporting, the severity of anaphylaxis and its sequelae to produce adverse outcomes clearly make this unlikely based on the current medicolegal climate that exists in the United States. One of the only ways to explain this widely divergent perspective is to understand how the diagnosis is made, because the recommended threshold test concentrations have not been defined, resulting in unreliable results. We have previously reported that steroid-derived agents can induce positive weal and flare responses independent of mast cell degranulation, even at low concentrations, following intradermal injection. A positive cutaneous reaction without evidence of mast cell degranulation was noted at low concentrations (100 g/mL) of rocuronium in almost all the volunteers. We have used intradermal injections to compare cutaneous effects of anesthetic and other agents. They noted 50% and 40% of the subjects had a positive skin reaction to undiluted rocuronium and vecuronium, respectively. To avoid false-positive results, they suggested that prick testing with rocuronium and vecuronium should be performed in subjects who have experienced a hypersensitivity reaction during anesthesia, with concentrations below that commonly inducing positive reactions in anesthesia-naive, healthy subjects. In female subjects, positive skin reactions were reported with dilutions of 1/100 of both relaxants. In male subjects, positive skin reactions were noted with the undiluted concentration, except for one volunteer who reacted to rocuronium (1/10 dilution). A spectrum of life-threatening allergic reactions to any drug or agent can occur in the perioperative period. Certain patients undergoing high-risk procedures with multiple blood product exposures are also at higher risk. However, a high index of suspicion, prompt recognition, and appropriate and aggressive therapy can help avoid a disastrous outcome. Advances in the management of sepsis and the understanding of key immunologic defects. The effect of histamine and serotonin on vascular permeability: an electron microscopic study. The site of action of histamine and serotonin along the vascular tree: a topographic study. Roles of cysteinyl leukotrienes in airway inflammation, smooth muscle function, and remodeling. Mechanisms of nonimmunological histamine and tryptase release from human cutaneous mast cells. Determination of the hemodynamics and histamine release of rocuronium (Org 9426) when administered in increased doses under N2 O/O2-sufentanil anesthesia. The effects of rapacuronium on histamine release and hemodynamics in adult patients undergoing general anesthesia. Predisposing factors in anaphylactoid reactions to anaesthetic drugs in an Australian population: the role of allergy, atopy and previous anaesthesia. Drugs and other agents involved in anaphylactic shock occurring during anaesthesia: a French multicenter epidemiological inquiry. Anaphylactic reactions during anaesthesia: let us treat the problem rather than debating its existence. Anaphylaxis during induction of general anesthesia: subsequent evaluation and management. Anaphylactic reactions to neuromuscular blocking drugs: are we making the correct diagnosis Nature and extent of penicillin side-reactions, with particular reference to fatalities from anaphylactic shock. A review of evidence supporting the American Academy of Pediatrics recommendation for prescribing cephalosporin antibiotics for penicillinallergic patients. Prevalence of latex allergy among anesthesiologists: Identification of sensitized but asymptomatic individuals. Allergy to latex, avocado pear, and banana: Evidence for a 30 kd antigen in immunoblotting. The predictive value of skin testing in the diagnosis of local anesthetic allergy. Skin sensitivity to rocuronium and vecuronium: a randomized controlled prick-testing study in healthy volunteers. Furthermore, the effects of anesthetics on synaptic function differ among various anesthetic agents, neurotransmitters, and neuronal preparations. However, some sodium channel subtypes are inhibited by volatile anesthetics and this effect may be responsible in part for a reduction in neurotransmitter release at some synapses. In general, the hyperpolarization produced by anesthetics is small in magnitude and is unlikely to alter propagation of an action potential down an axon. Small changes in resting potential may, however, inhibit the initiation of an action potential generated in response to synaptic excitation or 603 in a spontaneously firing neuron. Indeed, isoflurane has been shown to hyperpolarize thalamic neurons, leading to an inhibition of tonic firing of action potentials. However, the data are conflicting on whether the size of the action potential, once initiated, is diminished by general anesthetics. A classic article by Larrabee and Posternak56 demonstrated that concentrations of ether and chloroform that completely block synaptic transmission in mammalian sympathetic ganglia have no effect on presynaptic action-potential amplitude. Similar results have been obtained with fluorinated volatile anesthetics in mammalian brain preparations. Synaptic Transmission Synaptic transmission is widely considered to be the most likely subcellular site of general anesthetic action. Neurotransmission across both excitatory and inhibitory synapses is markedly altered by general anesthetics. General anesthetics inhibit excitatory synaptic transmission in a variety of preparations, including sympathetic ganglia,56 olfactory cortex,57 hippocampus,58 and spinal cord. Enhancement of inhibitory transmission has also been observed with many other general anesthetics including etomidate,65 propofol,66 inhalational anesthetics,67 and neurosteroids. Presynaptic Effects Neurotransmitter release at glutamatergic synapses has consistently been found to be inhibited by clinical concentrations of volatile anesthetics. Reduction of glutamate release by intravenous anesthetics has also been demonstrated, but the evidence is more limited and the effects potentially indirect. More recently the same group has shown that release from norepinephrine, dopamine, and acetylcholine-containing synaptosomes is also inhibited by isoflurane, although again less potently compared to glutamatergic synaptosomes. The mechanism does not appear to involve reduced neurotransmitter synthesis or storage, but rather is a direct effect on neurosecretion. A variety of evidence argues that at some synapses a substantial portion of the anesthetic effect is upstream of the transmitter release machinery,78 perhaps on presynaptic sodium channels or potassium leak channels (see later discussion). However, genetic data in Caenorhabditis elegans show that mutations in the transmitter release machinery strongly influence volatile anesthetic sensitivity. Anesthetic modulation of excitatory neurotransmitter receptor function varies depending on the receptor type, anesthetic agent, and preparation. They found that while pentobarbital, diethyl ether, methoxyflurane, and alphaxalone depressed the electrical response to glutamate, halothane did not. In contrast, when acetylcholine was applied to the same olfactory cortical preparation, halothane and methoxyflurane stimulated the electrical response, whereas pentobarbital had no effect; only alphaxalone depressed the electrical response to acetylcholine. Enflurane increases both the amplitude of the current (B) and the time (1/2) it takes for the current to decay (C). Enhancement of -aminobutyric acidactivated Cl- currents in cultured rat hippocampal neurones by three volatile anaesthetics. Anesthetics have powerful and widespread effects on synaptic transmission that would logically contribute to general anesthesia. Thus, the synapse is generally thought to be the more relevant site of anesthetic action. Existing evidence indicates that even at the synapse, anesthetics have diverse actions, including presynaptic inhibition of neurotransmitter release, inhibition of excitatory neurotransmitter effect, and enhancement of inhibitory neurotransmitter effect. Furthermore, the synaptic effects of anesthetics differ among various anesthetic agents, neurotransmitters, and neuronal preparations. Anesthetic Actions on Ion Channels Ion channels are a likely target of anesthetic action. The advent of patch clamp techniques in the early 1980s made it possible to measure directly the currents from single ion channel proteins. Accordingly, during the 1980s and 1990s a major effort was directed at describing the effects of anesthetics on the various kinds of ion channels. For the purposes of this discussion, ion channels are cataloged according to the stimuli to which they respond by opening or closing. Anesthetic Effects on Voltage-dependent Ion Channels A variety of ion channels can sense a change in membrane potential and respond by either opening or closing their pores. These channels include voltage-dependent sodium, potassium, and calcium channels, all of which share significant structural homologies. Voltage-dependent sodium and potassium channels are largely involved in generating and shaping action potentials. The effects of anesthetics on these channels have been extensively studied by Haydon and Urban87 in the squid giant axon. These studies show that these invertebrate sodium and potassium channels are remarkably insensitive to volatile anesthetics. For example, the halothane concentration required to inhibit 50% of the peak sodium channel current is eight times the halothane concentration required to produce anesthesia. The delayed rectifier potassium channel was even less sensitive, requiring halothane concentrations more than 20 times those required to produce anesthesia. Ratnakumari and Hemmings91 showed that sodium flux mediated by rat brain sodium channels was significantly inhibited by clinical concentrations of halothane. Shiraishi and Harris92 documented the effects of isoflurane on a variety of sodium channel subtypes and found that several but not all subtypes are sensitive to clinical concentrations. Thus, sodium channel activity not only appears to be inhibited by volatile anesthetics, but this inhibition results in a significant reduction in synaptic function, at least at some mammalian synapses. Intravenous anesthetics have also been shown to inhibit sodium channels, but the concentrations for this effect are supraclinical. This allows calcium to enter the cell, activating calcium-dependent secretion of neurotransmitter into the synaptic cleft. At least six types of calcium channels (designated L, N, P, Q, R, and T) have been identified on the basis of electrophysiologic properties, and a larger number based on amino acid sequence similarities. N-, P-, Q-, and R-type channels, as well as some of the untitled channels, are preferentially expressed in the nervous system and are thought to play a major role in synaptic transmission. L-type calcium channels, although expressed in brain, have been best studied in their role in excitation-contraction coupling in cardiac, skeletal, and smooth muscle and are thought to be less important in synaptic transmission. Takenoshita and Steinbach100 reported a T-type calcium current in dorsal root ganglion neurons that was inhibited by subanesthetic concentrations of halothane. Potassium channels are the most diverse of the ion channel types and include voltage-gated, background, or leak channels that open over a wide range of voltages, including the resting membrane potential of neurons, second messenger and ligand-activated, and so-called inward rectifying channels; some channels fall into more than one category. High concentrations of both volatile anesthetics and intravenous anesthetics are required to significantly affect the function of voltage-gated K+ channels. Background or leak K+ channels are activated by both volatile and gaseous anesthetics. Anesthetic activation of a leak channel was first observed in a ganglion of the pond snail, Lymnea stagnalis. A similar anesthetic-activated background potassium channel was subsequently found by Winegar and Yost110 in the marine mollusk Aplysia. The importance of volatile anesthetic activation of these invertebrate potassium channels has now become apparent with the discovery of a large family of background potassium channels in mammals. Indeed, genetic evidence argues for a role 609 of these channels in producing anesthesia (see later discussion). C: Predicted structure of a typical subunit of the mammalian background K+ channels. Note the four transmembrane spanning segments (orange rectangles) and the two pore-forming domains (P1 and P2).

However fungus link diet buy 250mg fulvicin overnight delivery, this repeated use of the same injection areas can lead to the formation of fatty lumps (lipo-hypertrophies or lipos) or atrophy of the site antifungal moisturiser buy cheap fulvicin 250 mg on line. The absorption of insulin from lipos is known to be slow and erratic and this can lead to poor glycaemic control fungus gnats get rid order fulvicin 250 mg on-line. Thus the user increases their insulin requirements in response to higher blood glucose measurements antifungal pregnancy buy generic fulvicin 250mg on line. Should the patient then choose to inject into a fresh site (with normal blood flow) the increased insulin injected may lead to a hypoglycaemic attack antifungal uses buy fulvicin online pills. It is therefore important that patients are educated to rotate injection sites on a daily basis to reduce the formation of lipos antifungal for nails purchase fulvicin 250mg with mastercard. The endocrine system and associated disorders Chapter 13 Type 2 diabetes this is the most common form of diabetes and is traditionally thought to be a disease of people over the age of 40 years. Overall the number of patients developing type 2 diabetes is increasing and this increase is occurring across all age ranges, including in adolescents and young adults (Royal College of Paediatrics and Child Health, 2009). The reasons for this increase are probably related to lifestyle factors, including the increase in the rates of obesity, overeating (particularly sugary foods) and a lack of exercise (Hossain et al. Type 2 diabetes is normally characterised by the development of resistance to the effects of insulin in the tissues, and a reduction in the ability of the beta cells to increase the production of insulin in response to this increased insulin resistance in the body. The resulting high blood levels of glucose lead to damage of the beta cells, thus further reducing the production of insulin. The treatment of type 2 diabetes varies depending on the severity of the condition. In some patients, weight reduction, increased exercise and reduced food intake can resolve the raised blood sugar levels. However, once the beta cell damage has occurred, the need for medications is increased. Current drug therapies for type 2 diabetes (oral hypoglycaemics) target several aspects of the disease, including reducing glucose production by the liver, enhancing insulin output from the pancreas or increasing the sensitivity of the muscle, fat and liver cells to the effects of insulin and thus reducing insulin resistance. Increasingly, a role is being seen for the use of insulin in type 2 diabetes (Inzucchi et al. Patients with both type 1 and type 2 diabetes will have similar educational needs in terms of their personal control of the diabetes. The aim of disease management is to alleviate the symptoms of diabetes and optimise the control of blood glucose levels, thus preventing long-term complications. However, strenuous exercise can reduce blood glucose levels and exercise regimens should be agreed with appropriate healthcare professionals. Weight loss in overweight patients improves the control of diabetes as inactivity and obesity are strongly linked to insulin resistance (Hossain et al. Patients with diabetes have an increased risk of vascular diseases (including heart disease and stroke), and smoking further increases this risk. Education on how to monitor blood glucose levels using capillary blood glucose monitoring or urinalysis (as appropriate). The use and administration of medications, such as insulin injection techniques and adjusting insulin doses. Poor control of diabetes often leads to hyperglycaemia and is associated with a range of long-term complications, including blindness or reduced vision, peripheral neuropathy, renal failure, cardiovascular disease, peripheral artery disease and foot ulcers (Box 13. Red Flag Patients under your care who suffer from diabetes must not be mobilized without appropriate footwear to protect the feet from damage. The poor sensation and blood flow in the feet of many diabetic patients mean that any damage to the foot through trauma (such as stubbing a toe, stepping on a sharp item) can lead to the development of foot ulcers. The treatment of diabetic foot ulcers may require surgical debridement of the wound to remove dead tissue which is a host for bacteria; appropriate wound dressings and antibiotics may also be necessary (Yazdanpanah et al. Relief of pressure on the ulcer is critical to the success of treatment and referral to a podiatrist will be required for continued foot care and assessment for pressure-relieving devices (Bus et al. Conclusion this chapter has introduced the physiology of both normal and disordered endocrine functioning and the treatment of the related disorders. The endocrine system has a wide and varied role in the maintenance of normal bodily functioning. Disorders of any of the endocrine organs can produce a variety of signs and symptoms and may even lead to a life-threatening crisis. The healthcare professional has a crucial role in the detection of endocrine conditions, the monitoring of disease progression and treatment effects, and the prevention and treatment of endocrine emergencies. Most patients with an endocrine disorder will take responsibility for the management of their own condition and it is essential that they are given appropriate advice and support. In order to carry out these roles, the healthcare professional must have a good understanding of the physiology and treatment of the endocrine disorders. The aspect of the adrenal gland is functionally separated into three different zones 7. A sensory receptor primarily found in the hypothalamus that detects changes in osmotic pressure 10. This gland is said to be a butterfly-shaped gland located in the front of the neck 14. These are organs whose sole function is the production and release of harmones 16. The inability of the pituitary gland to produce enough hormones for normal bodily functioning is known as this 18. These gland are tiny glands normally located on the back of the thyroid gland Down 1. This hormone stimulates the cortex of the adrenal glands to release corticosteroid hormones 5. A part of the brain that has a vital role in controlling many bodily functions including the release of hormones from the pituitary gland 9. It is interesting to note that this website is often highly recommended by other websites. There is a comprehensive list of web links, reviews of pituitary-related disorders and proceedings from conferences (which are often hard to find). The endocrine system and associated disorders Chapter 13 Eclampsia a condition presenting in pregnancy that is characterised by high blood pressure, seizures and even coma. Electrolyte a chemical element compound that includes sodium, potassium, calcium, chloride and bicarbonate. Gland any organ in the body that secretes substances not related to its own internal functioning. Hormone a chemical substance that is released into the blood by the endocrine system, and that has a physiological control over the function of cells or organs other than those that created it. Insulin resistance a condition where the usual body reaction to insulin is reduced. Ischaemic heart disease a condition of the heart related to a lack of oxygen reaching the heart muscle. Opportunistic screening testing a person for particular diseases or conditions at a point in time they are accessing healthcare for other reasons. Oral hypoglycaemic a drugs used in the treatment of diabetes that is taken by mouth and reduces the blood sugar level. Osteoclast a type of cell that breaks down bone tissue and thus releases the calcium used to create bones. Osteoporosis a condition characterised by reduced bone density and an increased risk of fractures. Parasthaesia abnormal nerve sensations such as pins-and-needles, tingling or burning. Podiatrist a healthcare professional who specialises in the diagnosis and treatment of disorders of the feet (also known as a chiropodist). Postural hypotension inability of the body to maintain an adequate blood pressure when the person rises from sitting or lying to standing too rapidly. Usually characterised by dizziness or fainting if the person rises too quickly to a standing position. Thyroid nodule the growth of thyroid tissue or fluid-filled cyst of the thyroid tissue. London: British Medical Association/Royal Pharmaceutical Society of Great Britain. Supporting People with Long-term Conditions to Self Care: A Guide to Developing Local Strategies and Good Practice. Evidence-based Nutrition Guidelines for the Prevention and Management of Diabetes. Annals of Clinical Biochemistry: An international journal of biochemistry and laboratory medicine. Clinical, immunological, and genetic features of autoimmune primary adrenal insufficiency: Observations from a Norwegian registry. Clinical practice guidelines for hypothyroidism in adults: co-sponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association Taskforce on Hypothyroidism in Adults. Epidemiology of adrenal crisis in chronic adrenal insufficiency and the need for new prevention strategies. Highlights of the guidelines on the management of hyperthyroidism and other causes of thyrotoxicosis. Describe the role of the healthcare professional when providing care to a person who has undergone surgery of the reproductive tract. Discuss the normal and abnormal pathophysiological changes that may occur in the male and female reproductive tracts. Introduction Reproduction is a complex activity requiring a series of integrated anatomical and physiological events. The physiological and anatomical aspects of the reproductive tract are primarily associated with procreation; the psychological and social aspects of reproduction are also important, so too is the pleasure that is usually provided by the reproductive organs. Reproductive illness can result in loss of life, and acute and chronic illness combined with physical and emotional distress. A number of reproductive-related conditions and their associated care are discussed. Reproductive health Reproductive health is a complex term and it should be a right for all men and women. It is a component of overall health throughout the life span regardless of the way the person the reproductive systems and associated disorders Chapter 14 chooses to express their sexuality; it is also an essential feature of human development. Reproductive health is defined by the United Nations (1994) as: A state of physical, mental, and social well-being in all matters relating to the reproductive system at all stages of life. Reproductive health implies that people are able to have a satisfying and safe sex life and that they have the capability to reproduce and the freedom to decide if, when, and how often to do so. People have the right under the Human Rights Act 1998 (article 8) to respect for private and family life. Reproductive health also includes the reproductive processes and functions necessary to reproduce. As such, reproductive health implies that people should have a responsible, satisfying and safe sex life and that they have the ability to reproduce and the option to decide if, when and how often to do so. There have been a number of pioneering developments and the introduction of new technologies over the years that are associated with reproduction; it could be suggested that these innovations have been in response to the national and global incidence of subfertility. For some people, having children and bringing up a family are important aspects of their lives and for those who experience problems with their fertility, this can be devastating, denying them their opportunity to realise their aspirations and hopes. Reproductive health also takes into account issues associated with sexual health and personal relationships. The role of the healthcare professional is multifaceted and one aspect of this role is to act as a health educator, promoting good reproductive health, preventing ill health and supporting people who may experience problems. In order to care for those who have reproductive health issues, and to be able to assess and plan care in a safe and effective manner, the healthcare professional must be familiar with the anatomy and physiology of the reproductive tract. Generally, the pelvis is a ring of bone that supports the weight of the upper body. There are two innominate bones and both are made up of: the ilium the pubic bone the ischium. Towards the front of the pelvis (anteriorly), the bones join at the symphysis pubis. Strong connective tissues (ligaments) join the pelvis to the sacrum at the base of the spine. Large nerves and muscle pass through the pelvis, and there are a number of digestive and reproductive organs within it. The female reproductive tract Female external genitalia the external genitalia, i. The outer surface of the labia majora is covered by a thin layer of skin containing hair follicles, sweat and sebaceous glands, and the inner surface is smoother, without pubic hair and contains a larger number of sebaceous follicles. Both the labia majora and minora are protective structures, protecting the inner structures of the vulva.

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