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Methods and apparatus for treating anaphylaxis using electrical modulation
Methods and devices for treating anaphylaxis, anaphylactic shock, bronchial constriction, and/or asthma include providing an electrical impulse to a selected region of the vagus nerve of a patient suffering from anaphylaxis to block and/or modulate nerve signals that would regulate the function of, for example, myocardial tissue, vasodilation/constriction and/or pulmonary tissue.
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This application is a continuation of U.S. patent application Ser. No. 11/591,768 filed Nov. 2, 2006, now U.S. Pat. No. 7,711,430 issued May 4, 2010; which claims the benefit of U.S. Provisional Patent Application No. 60/772,361, filed Feb. 10, 2006, the entire disclosure of which is hereby incorporated by reference.BACKGROUND OF THE INVENTION
The present invention relates to the field of delivery of electrical impulses to bodily tissues for therapeutic purposes, and more specifically to devices and methods for treating conditions associated with shock, such as anaphylaxis by blocking and/or modulating signals in the vagus nerve.
There are a number of treatments for various infirmities that require the destruction of otherwise healthy tissue in order to affect a beneficial effect. Malfunctioning tissue is identified, and then lesioned or otherwise compromised in order to affect a beneficial outcome, rather than attempting to repair the tissue to its normal functionality. While there are a variety of different techniques and mechanisms that have been designed to focus lesioning directly onto the target nerve tissue, collateral damage is inevitable.
Still other treatments for malfunctioning tissue can be medicinal in nature, in many cases leaving patients to become dependent upon artificially synthesized chemicals. Examples of this are anti-asthma drugs such as albuterol, proton pump inhibitors such as omeprazole (Prilosec), spastic bladder relievers such as Ditropan, and cholesterol reducing drugs like Lipitor and Zocor. In many cases, these medicinal approaches have side effects that are either unknown or quite significant, for example, at least one popular diet pill of the late 1990's was subsequently found to cause heart attacks and strokes.
Unfortunately, the beneficial outcomes of surgery and medicines are, therefore, often realized at the cost of function of other tissues, or risks of side effects.
The use of electrical stimulation for treatment of medical conditions has been well known in the art for nearly two thousand years. It has been recognized that electrical stimulation of the brain and/or the peripheral nervous system and/or direct stimulation of the malfunctioning tissue, which stimulation is generally a wholly reversible and non-destructive treatment, holds significant promise for the treatment of many ailments.
Electrical stimulation of the brain with implanted electrodes has been approved for use in the treatment of various conditions, including pain and movement disorders including essential tremor and Parkinson's disease. The principle behind these approaches involves disruption and modulation of hyperactive neuronal circuit transmission at specific sites in the brain. As compared with the very dangerous lesioning procedures in which the portions of the brain that are behaving pathologically are physically destroyed, electrical stimulation is achieved by implanting electrodes at these sites to, first sense aberrant electrical signals and then to send electrical pulses to locally disrupt the pathological neuronal transmission, driving it back into the normal range of activity. These electrical stimulation procedures, while invasive, are generally conducted with the patient conscious and a participant in the surgery.
Brain stimulation, and deep brain stimulation in particular, is not without some drawbacks. The procedure requires penetrating the skull, and inserting an electrode into the brain matter using a catheter-shaped lead, or the like. While monitoring the patient's condition (such as tremor activity, etc.), the position of the electrode is adjusted to achieve significant therapeutic potential. Next, adjustments are made to the electrical stimulus signals, such as frequency, periodicity, voltage, current, etc., again to achieve therapeutic results. The electrode is then permanently implanted and wires are directed from the electrode to the site of a surgically implanted pacemaker. The pacemaker provides the electrical stimulus signals to the electrode to maintain the therapeutic effect. While the therapeutic results of deep brain stimulation are promising, there are significant complications that arise from the implantation procedure, including stroke induced by damage to surrounding tissues and the neurovasculature.
One of the most successful modern applications of this basic understanding of the relationship between muscle and nerves is the cardiac pacemaker. Although its roots extend back into the 1800's, it was not until 1950 that the first practical, albeit external and bulky pacemaker was developed. Dr. Rune Elqvist developed the first truly functional, wearable pacemaker in 1957. Shortly thereafter, in 1960, the first fully implanted pacemaker was developed.
Around this time, it was also found that the electrical leads could be connected to the heart through veins, which eliminated the need to open the chest cavity and attach the lead to the heart wall. In 1975 the introduction of the lithium-iodide battery prolonged the battery life of a pacemaker from a few months to more than a decade. The modern pacemaker can treat a variety of different signaling pathologies in the cardiac muscle, and can serve as a defibrillator as well (see U.S. Pat. No. 6,738,667 to Deno, et al., the disclosure of which is incorporated herein by reference).
Anaphylaxis is a severe allergic reaction that occurs when the body is exposed to a substance to which it was previously sensitized. The reaction causes a sudden release of chemicals, including histamines, from cells in the body's tissues. These chemicals dilate the blood vessels, lowering blood pressure, and cause the blood vessels to leak fluid. The chemicals also act on the lungs, causing the airways to constrict which makes breathing very difficult.
In some cases, anaphylaxis is mild, causing only hives and itching; however, anaphylaxis can be deadly. In anaphylactic shock, the most severe form of anaphylaxis, blood pressure drops severely and bronchial tissues swell dramatically. This causes the person to choke and collapse. Anaphylactic shock is fatal if not treated immediately and causes more than eight thousand deaths per year in the United States alone. The triggers for these fatal reactions range from exposure to nuts, insect stings, medication, etc. However, the triggers are mediated by a series of hypersensitivity responses that result in uncontrollable drop in blood pressure and airway occlusion driven by smooth muscle constriction.
Given the common mediators of both asthmatic and anaphylactic bronchoconstriction, it is not surprising that asthma sufferers are at a particular risk for anaphylaxis. Still, estimates place the numbers of people who are susceptible to such responses at more than 40 million in the United States alone. Tragically, many of these patients are fully aware of the severity of their condition, and die while struggling in vain to manage the attack medically. Many of these incidents occur in hospitals or in ambulances, in the presence of highly trained medical personnel who are powerless to break the cycle of hypotension and bronchoconstriction affecting their patient. Typically, the severity and rapid onset of anaphylactic reactions does not render the pathology to chronic treatment, but requires more immediately acting medications. Among the most popular medications for treating anaphylaxis is epinephrine, commonly marketed in so-called "Epi-pen" formulations and administering devices, which potential sufferers carry with them at all times. In addition to serving as an extreme bronchodilator, epinephrine raises the patient's heart rate dramatically, and can result in tachycardia and heart attacks.
The smooth muscles that line the bronchial passages are controlled by a confluence of vagus and sympathetic nerve fiber plexuses. Spasms of the bronchi during asthma attacks and anaphylactic shock can often be directly related to pathological signaling within these plexuses. Anaphylactic shock and asthma are major health concerns.
Asthma, and other airway occluding disorders resulting from inflammatory responses and inflammation-mediated bronchoconstriction, affects an estimated eight to thirteen million adults and children in the United States. A significant subclass of asthmatics suffers from severe asthma. An estimated 5,000 persons die every year in the United States as a result of asthma attacks. Up to twenty percent of the populations of some countries are affected by asthma, estimated at more than a hundred million people worldwide. Asthma's associated morbidity and mortality are rising in most countries despite increasing use of anti-asthma drugs.
Asthma is characterized as a chronic inflammatory condition of the airways. Typical symptoms are coughing, wheezing, tightness of the chest and shortness of breath. Asthma is a result of increased sensitivity to foreign bodies such as pollen, dust mites and cigarette smoke. The body, in effect, overreacts to the presence of these foreign bodies in the airways. As part of the asthmatic reaction, an increase in mucous production is often triggered, exacerbating airway restriction. Smooth muscle surrounding the airways goes into spasm, resulting in constriction of airways. The airways also become inflamed. Over time, this inflammation can lead to scarring of the airways and a further reduction in airflow. This inflammation leads to the airways becoming more irritable, which may cause an increase in coughing and increased susceptibility to asthma episodes.
Two medicinal strategies exist for treating this problem for patients with asthma. The condition is typically managed by means of inhaled medications that are taken after the onset of symptoms, or by injected and/or oral medication that are taken chronically. The medications typically fall into two categories; those that treat the inflammation, and those that treat the smooth muscle constriction. The first is to provide anti-inflammatory medications, like steroids, to treat the airway tissue, reducing its tendency to over-release of the molecules that mediate the inflammatory process. The second strategy is to provide a smooth muscle relaxant (an anti-cholinergic and/or anti-adrenergic medication) to reduce the ability of the muscles to constrict.
It has been highly preferred that patients rely on avoidance of triggers and anti-inflammatory medications, rather than on the bronchodilators as their first line of treatment. For some patients, however, these medications, and even the bronchodilators are insufficient to stop the constriction of their bronchial passages, and more than five thousand people suffocate and die every year as a result of asthma attacks.
Myocardial dysfunction involves a decrease in overall myocardial performance. The determinants of myocardial performance are heart rate, preload, afterload, and contractility. Heart rate is a term used to describe the frequency of the cardiac cycle, usually in number of number of contractions of the heart (heart beats) per minute. The heart contains two natural cardiac pacemakers that spontaneously cause the heart to beat. These can be controlled by the autonomic nervous system and circulating adrenaline.
The body can increase the heart rate in response to a wide variety of conditions in order to increase the cardiac output (the amount of blood ejected by the heart per unit time). Exercise, environmental stressors or psychological stress can cause the heart rate to increase above the resting rate. The pulse is the most straightforward way of measuring the heart rate, but it can be deceptive when some strokes do not lead to much cardiac output. In these cases (as happens in some arrhythmias), the heart rate may be considerably higher than the pulse.
Preload is theoretically most accurately described as the initial stretching of cardiac myocytes prior to contraction. Preload is the volume of blood present in a ventricle of the heart, after passive filling and atrial contraction. Preload is affected by venous blood pressure and the rate of venous return. These are affected by venous tone and volume of circulating blood.
Afterload is the tension produced by a chamber of the heart in order to contract. Afterload can also be described as the pressure that the chamber of the heart has to generate in order to eject blood out of the chamber. In the case of the left ventricle, the afterload is a consequence of the blood pressure, since the pressure in the ventricle must be greater than the blood pressure in order to open the aortic valve. For instance, hypertension (increased blood pressure) increases the left ventricular afterload because the left ventricle has to work harder to eject blood into the aorta. This is because the aortic valve won't open until the pressure generated in the left ventricle is higher than the elevated blood pressure.
Contractility is the intrinsic ability of a cardiac muscle fiber to contract at any given fiber length. If myocardial performance changes while preload, afterload and heart rate are all constant, then the change in performance must be due to the change in contractility. Chemicals that affect contractility are called inotropic agents. For example drugs such as catecholamines (norepinephrine and epinephrine) that enhance contractility are considered to have a positive inotropic effect. All factors that cause an increase in contractility work by causing an increase in intracellular calcium concentration [Ca++] during contraction.
The concept of contractility was necessary to explain why some interventions (e.g. an adrenaline infusion) could cause an increase in myocardial performance even if, as could be shown in experiments, the preload, afterload and heart rate were all held constant. Experimental work controlling the other factors was necessary because a change in contractility is generally not an isolated effect. For example, an increase in sympathetic stimulation to the heart increases contractility and heart rate. An increase in contractility tends to increase stroke volume and thus a secondary decrease in preload.
Blood pressure is the pressure exerted by the blood on the walls of the blood vessels. Unless indicated otherwise, blood pressure refers to systemic arterial blood pressure, i.e., the pressure in the large arteries delivering blood to body parts other than the lungs, such as the brachial artery (in the arm). The pressure of the blood in other vessels is lower than the arterial pressure. Blood pressure values are universally stated in millimeters of mercury (mm Hg), and are always given relative to atmospheric pressure. For example, the absolute pressure of the blood in an artery with mean arterial pressure stated as 100 mm Hg, on a day with atmospheric pressure of 760 mm Hg, is 860 mm Hg.
The systolic pressure is defined as the peak pressure in the arteries during the cardiac cycle; the diastolic pressure is the lowest pressure (at the resting phase of the cardiac cycle). The mean arterial pressure and pulse pressure are other important quantities. Typical values for a resting, healthy adult are approximately 120 mm Hg systolic and 80 mm Hg diastolic (written as 120/80 mm Hg), with large individual variations. These measures of blood pressure are not static, but undergo natural variations from one heartbeat to another or throughout the day (in a circadian rhythm); they also change in response to stress, nutritional factors, drugs, or disease.
An instance of the connection between the vagus nerve and blood pressure regulation may be found in U.S. Pat. No. 5,707,400 ("'400"), to Terry, et al., titled, "Treating refractory hypertension by nerve stimulation," which is incorporated in its entirety by reference. Hypertension (higher than normal blood pressure) and its converse, hypotension (lower than normal blood pressure), largely comprise the two sides of the coin that represents the problems relating to blood pressure. Issuing relating to hypotension, its causes and effects, are discussed also in U.S. Patent Application Number 20050283197 A1, to Daum, et al., titled, "Systems and methods for hypotension," which is incorporated in its entirety by reference.
Blood pressure exceeding normal values is called arterial hypertension. It itself is only rarely an acute problem, with the seldom exception of hypertensive crisis, such as severe hypertension with acute impairment of an organ system (especially the central nervous system, cardiovascular system and/or the renal system) and the possibility of irreversible organ-damage. However, because of its long-term indirect effects (and also as an indicator of other problems) it is a serious worry to physicians diagnosing it. Persistent hypertension is one of the risk factors for strokes, heart attacks, heart failure, arterial aneurysms, and is the second leading cause of chronic renal failure after diabetes mellitus.
All level of blood pressure puts mechanical stress on the arterial walls. Higher pressures increase heart workload and progression of unhealthy tissue growth (atheroma) that develops within the walls of arteries. The higher the pressure, the more stress that is present and the more atheroma tend to progress and the heart muscle tends to thicken, enlarge and become weaker over time.
Blood pressure that is too low is known as hypotension. Low blood pressure may be a sign of severe disease and requires more urgent medical attention. When blood pressure and blood flow is very low, the perfusion of the brain may be critically decreased (i.e., the blood supply is not sufficient), causing lightheadedness, dizziness, weakness and fainting.
Sometimes the blood pressure drops significantly when a patient stands up from sitting. This is known as orthostatic hypotension; gravity reduces the rate of blood return from the body veins below the heart back to the heart, thus reducing stroke volume and cardiac output. When people are healthy, they quickly constrict the veins below the heart and increase their heart rate to minimize and compensate for the gravity effect. This is done at a subconscious level via the autonomic nervous system. The system usually requires a few seconds to fully adjust and if the compensations are too slow or inadequate, the individual will suffer reduced blood flow to the brain, dizziness and potential blackout. Increases in G-loading, such as routinely experienced by supersonic jet pilots "pulling Gs", greatly increases this effect. Repositioning the body perpendicular to gravity largely eliminates the problem.
Hypotension often accompanies and complicates many other systemic health problems, such as anaphylaxis and sepsis, leading to anaphylactic shock and septic shock, making it more difficult to address the underlying health problem. For example, U.S. Patent Application Number 20050065553, Ben Ezra, et al., titled, "Applications of vagal stimulation," which is incorporated in its entirety by reference, proposes to a method to treat a patient's sepsis by applying an appropriately configured current to the vagus nerve. However, when accompanied with refractory arterial hypotension, sepsis becomes septic shock.
Septic shock is a serious medical condition causing such effects as multiple organ failure and death in response to infection and sepsis. Its most common victims are children and the elderly, as their immune systems cannot cope with the infection as well as those of full-grown adults, as well as immunocompromised individuals. The mortality rate from septic shock is approximately 50%. Other various shock conditions include: systemic inflammatory response syndrome, toxic shock syndrome, adrenal insufficiency, and anaphylaxis.
A subclass of distributive shock, shock refers specifically to decreased tissue perfusion resulting in end-organ dysfunction. Cytokines TNFα, IL-1β, IL-6 released in a large scale inflammatory response may result in massive vasodilation, increased capillary permeability, decreased systemic vascular resistance, and hypotension. Hypotension reduces tissue perfusion pressure, and thus tissue hypoxia ensues. Finally, in an attempt to offset decreased blood pressure, ventricular dilatation and myocardial dysfunction will occur.
Accordingly, there is a need in the art for new products and methods for treating the immediate symptoms of anaphylaxis, anaphylactic shock, bronchial constriction, asthma, etc.SUMMARY OF THE INVENTION
The present invention involves products and methods of treatment of anaphylaxis utilizing an electrical signal that may be applied to the vagus nerve to temporarily block and/or modulate the signals in the vagus nerve. The present invention also encompasses treatment of anaphylaxis, anaphylactic shock, bronchial constriction, asthma, etc.
In one or more embodiments, the present invention contemplates methods and apparatus for delivering one or more electrical impulses to at least one selected region of the vagus nerve to block and/or modulate signals to the muscle fibers of the heart facilitating contractility, the fibers surrounding the cardiac tissue facilitating an increase in heart function (thereby raising blood pressure), and/or the muscle fibers surrounding the bronchi (facilitating opening of airways).
It shall be understood that the activation of such impulses may be directed manually by a patient suffering from anaphylaxis.
In one or more embodiments of the present invention, the impulses are applied in a manner that relaxes the myocardium to reduce the baseline level of tonic contraction, effects vasoconstriction (or dilation), and in cases of some shock, relaxes the smooth muscle lining the bronchial passages to relieve the spasms that occur, such as during anaphylactic shock. The impulses may be applied by positioning leads on the nerves that control cardiac activity, and/or bronchial activity respectively, such as the superior and/or inferior cardiac branches, and/or the anterior and/or posterior bronchial branches, of the right and/or left branches of the vagus nerve, which join with fibers from the sympathetic nerve chain to form the anterior and posterior coronary and pulmonary plexuses. Leads may be positioned above one or both of the cardiac and pulmonary branches of the vagus nerve to include a block and/or modulation of both organs. It shall also be understood that leadless impulses as shown in the art may also be utilized for applying impulses to the target regions.
The mechanisms by which the appropriate impulse is applied to the selected region of the vagus nerve can include positioning the distal ends of an electrical lead or leads in the vicinity of the nervous tissue controlling the myocardium, vessels of the heart (e.g., to affect vasoconstriction/dilation) and/or pulmonary muscles, which leads are coupled to an implantable or external electrical impulse generating device. The electric field generated at the distal tip of the lead creates a field of effect that permeates the target nerve fibers and causes the blocking and/or modulating of signals to the subject muscles.
The application of electrical impulses, either to the vagus nerve or the fibers branching off the vagus nerve to the cardiac muscles and/or the bronchial muscles to modulate the parasympathetic tone in order to relax the body's reaction to anaphylaxis is more completely described in the following detailed description of the invention, with reference to the drawings provided herewith, and in claims appended hereto.
Other aspects, features, advantages, etc. will become apparent to one skilled in the art when the description of the invention herein is taken in conjunction with the accompanying drawings.
For the purposes of illustrating the various aspects of the invention, there are shown in the drawings forms that are presently preferred, it being understood, however, that the invention is not limited by or to the precise data, methodologies, arrangements and instrumentalities shown, but rather only by the claims of an issued utility application.
It shall be understood that the embodiments disclosed herein are representative of preferred aspects of the invention and are so provided as examples of the invention. The scope of the invention, however, shall not be limited to the disclosures provided herein, nor by the provisional claims appended hereto.
While the exact physiological causes of anaphylaxis (e.g., inducing bronchial constriction and/or hypotension) have not been determined, the present invention postulates that the direct mediation of the smooth muscle constriction is the result of over-activity in the vagus nerve, which is a response to the flood of pro-inflammatory mediators' interacting with the receptors on the nerve fibers themselves.
It has been observed in the literature that the nervous system maintains a balance of the signals carried by the sympathetic and parasympathetic nerves. The vagus nerve, as the source of the signal to constrict bronchial smooth muscle and/or the cardiac muscle, is thought to provide a baseline level of tonicity in the smooth muscles surrounding the bronchial passages and cardiac muscle, in order to: (i) prevent the tissue lining the airways from collapsing shut; and/or (ii) to prevent tissue from expanding too much and depressing blood pressure.
Specifically, one or more embodiments of the present invention consider the signals carried by the vagus (parasympathetic) nerve to cause: (i) a constriction of the smooth muscle surrounding the bronchial passages, and/or (ii) a slowing of the heart. The sympathetic nerve fibers carry the opposing signals that tend to open the bronchial passages as well as speed up the heart rate. It should be recognized that the signals of the vagus nerve mediate a response similar to that of histamine, while the sympathetic signals generate an effect similar to epinephrine. Given the postulated balance between the parasympathetic and sympathetic signals, removing the parasympathetic signal should create an imbalance emphasizing the sympathetic signal. Along these lines, scientific literature also indicates that severing the vagus nerve in dogs will raise the animals' heart rates, as well as open the bronchial passages, much the same way that epinephrine does.
Now referring to
In mammals, two vagal components have evolved in the brainstem to regulate peripheral parasympathetic functions. The dorsal vagal complex (DVC), consisting of the dorsal motor nucleus (DMNX) and its connections, controls parasympathetic function below the level of the diaphragm, while the ventral vagal complex (VVC), comprised of nucleus ambiguus and nucleus retrofacial, controls functions above the diaphragm in organs such as the heart, thymus and lungs, as well as other glands and tissues of the neck and upper chest, and specialized muscles such as those of the esophageal complex.
The parasympathetic portion of the vagus innervates ganglionic neurons which are located in or adjacent to each target organ. The VVC appears only in mammals and is associated with positive as well as negative regulation of heart rate, bronchial constriction, vocalization and contraction of the facial muscles in relation to emotional states. Generally speaking, this portion of the vagus nerve regulates parasympathetic tone. The VVC inhibition is released (turned off) in states of alertness. This in turn causes cardiac vagal tone to decrease and airways to open, to support responses to environmental challenges.
The parasympathetic tone is balanced in part by sympathetic innervation, which generally speaking supplies signals tending to expand the myocardium, affect vasoconstriction, and/or to relax the bronchial muscles, so that over-contraction and over-constriction, respectively, do not occur. Overall, myocardium tone, vasodilation, and/or airway smooth muscle tone are dependent on several factors, including parasympathetic input, inhibitory influence of circulating epinephrine, NANC inhibitory nerves and sympathetic innervation of the parasympathetic ganglia. Stimulation of the vagus nerve (up-regulation of tone), such as may occur in shock, results in a heart rate decrease and airway constriction. In this context, up-regulation is the process by which the specific effect is increased, whereas down-regulation involves a decrease of the effect. In general, the pathology of shock appears to be mediated by inflammatory cytokines that overwhelm receptors on the nerve cells and cause the cells to massively up-regulate the parasympathetic tone. On a cellular level, up-regulation is the process by which a cell increases the number of receptors to a given hormone or neurotransmitter to improve its sensitivity to this molecule. A decrease of receptors is called down-regulation.
Anaphylaxis appears to be mediated predominantly by the hypersensitivity to an allergen causing the massive overproduction of cholenergic receptor activating cytokines that overdrive the otherwise normally operating vagus nerve to signal massive constriction of the airways.
In the case of asthma (which may be related to anaphylaxis), it appears that the airway tissue has both (i) a hypersensitivity to the allergen that causes the overproduction of the cytokines that stimulate the cholenergic receptors of the nerves and/or (ii) a baseline high parasympathetic tone or a high ramp up to a strong parasympathetic tone when confronted with any level of cholenergic cytokine. The combination can be lethal.
Sepsis is mediated by severe infection and may result in a large scale inflammatory response that releases cytokines TNFα, IL-1β, IL-6 mediating massive vasodilation, increased capillary permeability, decreased systemic vascular resistance, and hypotension. By comparison, anaphylaxis appears to be mediated predominantly by the hypersensitivity to an allergen causing the massive overproduction of cholenergic receptor activating cytokines that overdrive the otherwise normally operating vagus nerve to signal massive constriction of the airways. Drugs such as epinephrine drive heart rate up while also relaxing the bronchial muscles, effecting temporary relief of symptoms from these conditions.
Drugs such as epinephrine drive heart rate up while also relaxing the bronchial muscles, effecting temporary relief of symptoms from these conditions. As mentioned above, experience has shown that severing the vagus nerve (an extreme version of reducing the parasympathetic tone) has an effect similar to that of epinephrine and adrenaline on heart rate and bronchial diameter in that the heart begins to race (tachycardia) and the bronchial passageways dilate.
In accordance with at least one aspect of the present invention, the delivery, in a patient suffering from anaphylaxis, anaphylactic shock, bronchial constriction, asthma, etc., an electrical impulse sufficient to block and/or modulate transmission of signals along the vagus nerve will result in relaxation of the bronchi smooth muscle, dilating airways, raising the heart function (and thus the blood pressure), and/or counteract the effect of anaphylaxis and/or histamine on the vagus nerve. Depending on the placement of the impulse, the signal blocking and/or modulation can also raise the heart function.
In accordance with at least one aspect of the present invention, blocking and/or modulating the signal in the vagus nerve, and/or blocking and/or affecting the anaphylaxis or histamine response of the vagus nerve, to reduce parasympathetic tone provides an immediate emergency response, much like a defibrillator, in situations of anaphylaxis, anaphylactic shock, bronchial constriction, asthma, etc., providing immediate temporary dilation of the airways and/or an increase of heart function until subsequent measures, such as administration of medication, rescue breathing and intubation can be employed. Moreover, the teachings of the present invention permit immediate airway dilation and/or heart function increase to enable subsequent life saving measures that otherwise would be ineffective or impossible due to severe constriction or other physiological effects. Treatment in accordance with the present invention provides bronchodilation and/or increased heart function for a long enough period of time so that administered medication (such as epinephrine) has time to take effect before the patient suffocates.
The methods described herein of applying an electrical impulse to a selected region of the vagus nerve may further be refined such that the at least one region may comprise at least one nerve fiber emanating from the patient's tenth cranial nerve (the vagus nerve), and in particular, at least one of the anterior bronchial branches thereof, at least one of the posterior bronchial branches thereof, at least one of the superior cardiac branches thereof, and/or at least one of the inferior cardiac branches thereof. Preferably the impulse is provided to at least one of the anterior pulmonary or posterior pulmonary plexuses aligned along the exterior of the lung. As necessary, the impulse may be directed to nerves innervating only the bronchial tree and lung tissue itself. In addition, the impulse may be directed to a region of the vagus nerve to block and/or modulate one or both of the cardiac and bronchial branches. As recognized by those having skill in the art, this embodiment should be carefully evaluated prior to use in patients known to have preexisting cardiac issues.
With respect to the cardiac branches, the cardiac plexus is situated at the base of the heart, and is divided into a superficial part, which lies in the concavity of the aortic arch, and a deep part, between the aortic arch and the trachea. The two parts are, however, closely connected. The superficial part of the cardiac plexus lies beneath the arch of the aorta, in front of the right pulmonary artery. It is formed by the superior cardiac branch of the left sympathetic nerve and the lower superior cervical cardiac branch of the left vagus. The superficial part of the cardiac plexus gives branches (a) to the deep part of the plexus; (b) to the anterior coronary plexus; and (c) to the left anterior pulmonary plexus. The deep part of the cardiac plexus is situated in front of the bifurcation of the trachea, above the point of division of the pulmonary artery, and behind the aortic arch. It is formed by the cardiac nerves derived from the cervical ganglia of the sympathetic, and the cardiac branches of the vagus and recurrent nerves. The only cardiac nerves which do not enter into the formation of the deep part of the cardiac plexus are the superior cardiac nerve of the left sympathetic nerve, and the lower of the two superior cervical cardiac branches from the left vagus, which pass to the superficial part of the plexus.
Further reference is now made to
In accordance with one embodiment, one or more electrical impulses are directed to location A on or near the vagus nerve above the cardiac branch. In this embodiment one or more electrical impulses are introduced at the location A to block and/or modulate and/or inhibit up-regulation of the parasympathetic tone and effect a dilation of airways and increase in heart function.
In accordance with another embodiment, one or more electrical impulses are directed to location B on or near the vagus nerve below the cardiac branch proximal to the pulmonary branch. In this embodiment one or more electrical impulses are introduced at the location B to block and/or modulate and/or inhibit up-regulation of the parasympathetic tone to effect only a dilation of airways.
In patients known to be subject to anaphylactic shock or severe asthma attacks, one or more electrical impulse emitting devices 300 may be implanted in one or more selected regions 200A, 200B of the vagus nerve 200. Device 300 may be percutaneous for emergency applications, wherein device 300 may comprise an electrode 340 powered via an external power source 320.
U.S. Patent Application Publications 2005/0075701 and 2005/0075702, both to Shafer, both of which are incorporated herein by reference, relating to stimulation of neurons of the sympathetic nervous system to attenuate an immune response, contain descriptions of pulse generators that may be applicable to the present invention.
The parameters of the modulation signal 400 are preferably programmable, such as the frequency, amplitude, duty cycle, pulse width, pulse shape, etc. In the case of an implanted pulse generator, programming may take place before or after implantation. For example, an implanted pulse generator may have an external device for communication of settings to the generator. An external communication device may modify the pulse generator programming to improve treatment.
The electrical leads 350 and electrodes 340 are preferably selected to achieve respective impedances permitting a peak pulse voltage in the range from about 0.2 volts to about 20 volts.
The blocking and/or modulating impulse signal 410 preferably has a frequency, an amplitude, a duty cycle, a pulse width, a pulse shape, etc. selected to influence the therapeutic result, namely blocking and/or modulating some or all of the vagus nerve transmissions. For example the frequency may be about 1 Hz or greater, such as between about 25 Hz to 3000 Hz, or between about 1000 Hz to about 2500 Hz. (These are notably higher frequencies than typical nerve stimulation or modulation frequencies.) The modulation signal may have a pulse width selected to influence the therapeutic result, such as about 20 μS or greater, such as about 20 μS to about 1000 μS. The modulation signal may have a peak voltage amplitude selected to influence the therapeutic result, such as about 0.2 volts or greater, such as about 0.2 volts to about 20 volts.
In accordance with a preferred embodiment, VNS devices 300 in accordance with the present invention are provided in the form of a percutaneous or subcutaneous implant that can be reused by an individual.
In accordance with another embodiment, devices in accordance with the present invention are provided in a "pacemaker" type form, in which electrical impulses 410 are generated to a selected region 200A, 200B of the vagus nerve 200 by VNS device 300 on an intermittent basis to create in the patient a lower reactivity of the vagus nerve 200 to up-regulation signals.
In accordance with another embodiment, devices 300 in accordance with the present invention are incorporated in an endotracheal tube device to ameliorate bronchospasm during surgery. In a preferred embodiment one or more devices 300 are located in the distal portion of an endotracheal tube to contact selected regions 200A, 200B of the vagus nerve 200 to impart appropriate electrical impulses to dampen reactivity of the vagus nerve 200 to stimulus. In all cases of permanent implantation, however, the implanting surgeon should vary the signal modulated by the control unit 330 and specific location of the lead 350 until the desired outcome is achieved, and should monitor the long-term maintenance of this effect to ensure that adaptive mechanisms in the patient's body do not nullify the intended effects.
In addition, or as an alternative to the devices to implement the modulation unit for producing the electrical voltage/current profile of the blocking and/or modulating impulse to the electrodes, the device disclosed in U.S. Patent Publication No.: 2005/0216062 (the entire disclosure of which is incorporated herein by reference), may be employed. U.S. Patent Publication No.: 2005/0216062 discloses a multi-functional electrical stimulation (ES) system adapted to yield output signals for effecting faradic, electromagnetic or other forms of electrical stimulation for a broad spectrum of different biological and biomedical applications. The system includes an ES signal stage having a selector coupled to a plurality of different signal generators, each producing a signal having a distinct shape such as a sine, a square or a saw-tooth wave, or simple or complex pulse, the parameters of which are adjustable in regard to amplitude, duration, repetition rate and other variables. The signal from the selected generator in the ES stage is fed to at least one output stage where it is processed to produce a high or low voltage or current output of a desired polarity whereby the output stage is capable of yielding an electrical stimulation signal appropriate for its intended application. Also included in the system is a measuring stage which measures and displays the electrical stimulation signal operating on the substance being treated as well as the outputs of various sensors which sense conditions prevailing in this substance whereby the user of the system can manually adjust it or have it automatically adjusted by feedback to provide an electrical stimulation signal of whatever type he wishes and the user can then observe the effect of this signal on a substance being treated.
Prior to discussing experimental results, a general approach to treating anaphylaxis, anaphylactic shock, bronchial constriction, asthma, hypotension, etc., in accordance with one or more embodiments of the invention may include applying at least one electrical impulse to one or more selected regions of the vagus nerve of a mammal in need of relief from anaphylaxis.
The method may include: implanting one or more electrodes to the selected regions of the vagus nerve; and applying one or more electrical stimulation signals to the electrodes to produce the at least one electrical impulse, wherein the one or more electrical stimulation signals are of a frequency between about 1 Hz to 3000 Hz, and an amplitude of between about 1-6 volts.
The one or more electrical stimulation signals may be of a frequency between about 750 Hz to 1250 Hz; or between about 10 Hz to 35 Hz. The one or more electrical stimulation signals may be of an amplitude of between about 0.75 to 1.5 volts, such as about 1.25 volts. The one or more electrical stimulation signals may be one or more of a full or partial sinusoid, square wave, rectangular wave, and/or triangle wave. The one or more electrical stimulation signals may have a pulsed on-time of between about 50 to 500 microseconds, such as about 100, 200 or 400 microseconds.
The polarity of the pulses may be maintained either positive or negative. Alternatively, the polarity of the pulses may be positive for some periods of the wave and negative for some other periods of the wave. By way of example, the polarity of the pulses may be altered about every second.
While up-regulating the signal provided by the sympathetic nerves may accomplish the desired treatment effect, the present invention suggests that a more direct route to immediately breaking the cycle of anaphylaxis, anaphylactic shock, bronchial constriction, asthma, hypotension, etc., is via the vagus nerve because the mode of action for the hypersensitivity response is at the vagus nerve and not through the sympathetic nerves. Therefore, experiments were performed to identify exemplary methods of how electrical signals can be supplied to the peripheral nerve fibers that innervate and/or control the bronchial smooth muscle to (i) reduce the sensitivity of the muscle to the signals to constrict, and (ii) to blunt the intensity of, or break the constriction once it has been initiated. In addition, experiments were performed to identify exemplary methods of how electrical signals can be supplied to the peripheral nerve fibers that innervate and/or control vasoconstriction/dilation, and/or that innervate and/or control the myocardium to (i) reduce the sensitivity of the muscle to the signals of tonic contraction, and (ii) to blunt the intensity of, or break the tonic over-contraction once it has been initiated.
In particular, specific signals, selected from within a range of known nerve signals, were applied to the vagus nerves and/or the sympathetic nerves in guinea pigs, to produce selective interruption or reduction in the effects of lung vagal nerve activity leading to attenuation of anaphylaxis-induced bronchoconstriction and/or hypotension.EXPERIMENTATION
As opposed to experiments in which hypotension and/or bronchial constriction is induced using i.v. histamine, the testing procedure and test data below were obtained in response to anaphylaxis. Fifteen male guinea pigs (400 g) were sensitized by the intraperitoneal injection of ovalbumin (10 mg/kg i.p. every 48 hrs for three doses). Three weeks later animals were transported to the lab and immediately anesthetized with an i.p. injection of urethane 1.5 g/kg. Skin over the anterior neck was opened and the carotid artery and both jugular veins were cannulated with PE50 tubing to allow for blood pressure/heart rate monitoring and drug administration, respectively. The trachea was cannulated and the animal ventilated by positive pressure, constant volume ventilation followed by paralysis with succinylcholine (10 ug/kg/min) to paralyzed chest wall musculature to remove the contribution of chest wall rigidity from airway pressure measurements. Both vagus nerves were isolated and connected to shielded electrodes to allow selective stimuli of these nerves in the manner disclosed in the one or more embodiments disclosed above. Following fifteen minutes of stabilization, baseline hemodynamic and airway pressure measurements were made before and after the administration of increasing concentrations of ovalbumin (0.001-1.0 mg/kg i.v.). Following the increase in airway pressure and hypotension accompanying the anaphylactic response, vagal nerve modulation was made at variations of frequency, voltage and pulse duration to identity parameters that attenuate the hypotensive and bronchoconstrictive responses. Euthanasia was accomplished with intravenous potassium chloride.
With reference to
With reference to
With reference to
Conclusions that may be drawn from the above experimental data include: (1) That the airway constriction and hypotension caused by anaphylaxis in guinea pigs can be significantly reduced by applying appropriate electrical signals to the vagus nerve. (2) That signals from 15 Hz to 25 Hz, 200 uS to 300 uS, and 1.0V to 1.5V were equally effective. (3) That a 25 Hz, 200 μS, 1.25V signal applied to the vagus nerve, airway constriction due to anaphylaxis was reduced up to 68%. This effect has been repeated on several animals. (4) That the 25 Hz, 200 uS, 1.25V signal applied to the vagus nerve produces up to a 100% increase in blood pressure in an anaphylactic guinea pig experiencing severe hypotension. This effect has been repeated on several animals. This may have applications in the treatment of other low blood pressure conditions such as septic shock. (5) That there is some evidence that the application of the signal to the vagus nerve may have the ability to shorten the duration of an anaphylactic episode.
Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as defined by the appended claims.
1. A method of treating bronchoconstriction in a patient comprising modulating activity in at least one selected nerve in a region of a parasympathetic nervous system of the patient, comprising parasympathetic nerves to stimulate a nervous response to relax bronchial smooth muscle to reduce a magnitude of constriction of the bronchial smooth muscle of the patient.
2. The method set forth in claim 1 wherein the region of the parasympathetic nervous system comprises a region of the vagus nerve proximal to at least one of the cardiac branch and the bronchial branch of the vagus nerve.
3. The method set forth in claim 1 wherein the modulating step is carried out by applying at least one electrical impulse to the at least one selected nerve.
4. The method of claim 3 wherein the electrical impulse does not substantially increase a heart rate of the patient.
5. The method set forth in claim 2 wherein the region of the vagus nerve includes one or more of:
- the superior and/or inferior cardiac branches of the vagus nerve;
- the anterior and/or posterior bronchial branches of the vagus nerve;
- the right branch of the vagus nerve,
- the left branch of the vagus nerve;
- at or near the anterior or posterior coronary plexus; and
- at or near the anterior or posterior pulmonary plexus.
6. The method of claim 3, further comprising:
- implanting one or more electrodes to the one or more regions of the parasympathetic nervous system; and
- applying one or more electrical stimulation signals to the electrodes to produce the at least one electrical impulse.
7. The method of claim 3 further comprising percutaneously introducing one or more electrodes to the one or more regions of the parasympathetic nervous system.
8. The method of claim 3 wherein the electrical impulse has a frequency of between about 1 Hz to 3000 Hz, and an amplitude of between about 1-12 volts.
9. The method of claim 8 wherein the frequency is between about 10 Hz to 50 Hz.
10. The method of claim 8 wherein the electrical impulse has an amplitude of between about 5 to 12 volts.
11. The method of claim 8 wherein the electrical impulse has a pulsed on-time of between about 50 to 500 microseconds.
12. The method of claim 8 wherein the electrical impulse has a frequency of about 25 Hz, a pulsed on-time of about 100-400 microseconds, and an amplitude of about 6 to 12 volts.
13. The method of claim 1 wherein the bronchoconstriction is associated with anaphylaxis, anaphylactic shock, bronchial constriction, and/or asthma.
14. A method of treating bronchoconstriction in a patient comprising applying energy to one or more selected nerve(s) in a parasympathetic nervous system of the patient, the energy being sufficient to increase a blood pressure and relax bronchial smooth muscle and reduce a magnitude of constriction of the bronchial smooth muscle of the patient.
15. The method set forth in claim 14 wherein the one or more selected nerve(s) comprise a region of the vagus nerve proximal to at least one of the cardiac branch and the bronchial branch of the vagus nerve.
16. The method set forth in claim 14 wherein the applying energy step is carried out by applying at least one electrical impulse to the one or more selected nerve(s).
17. The method of claim 14 wherein the energy does not substantially increase a heart rate of the patient.
18. The method set forth in claim 15 wherein the region of the vagus nerve includes one or more of:
- the superior and/or inferior cardiac branches of the vagus nerve;
- the anterior and/or posterior bronchial branches of the vagus nerve;
- the right branch of the vagus nerve,
- the left branch of the vagus nerve;
- at or near the anterior or posterior coronary plexus; and
- at or near the anterior or posterior pulmonary plexus.
19. The method of claim 16 further comprising implanting one or more electrodes adjacent to or near the one or more selected nerve(s) and applying one or more electrical stimulation signals to the electrodes to produce the at least one electrical impulse.
20. The method of claim 16 further comprising percutaneously introducing one or more electrodes adjacent to or near the one or more selected nerve(s).
21. The method of claim 16 wherein the electrical impulse has a frequency of between about 1 Hz to 3000 Hz, and an amplitude of between about 1-12 volts.
22. The method of claim 21 wherein the frequency is between about 10 Hz to 50 Hz.
23. The method of claim 21 wherein the electrical impulse has an amplitude of between about 5 to 12 volts.
24. The method of claim 21 wherein the electrical impulse has a pulsed on-time of between about 50 to 500 microseconds.
25. The method of claim 21 wherein the electrical impulse has a frequency of about 25 Hz, a pulsed on-time of about 100-400 microseconds, and an amplitude of about 6 to 12 volts.
26. The method of claim 14 wherein the bronchoconstriction is associated with anaphylaxis, anaphylactic shock, bronchial constriction, and/or asthma.
|September 29, 2009
|Danek et al.
Type: Grant
Filed: Apr 1, 2010
Date of Patent: Jan 11, 2011
Patent Publication Number: 20100228316
Assignee: ElectroCore LLC (Morris Plains, NJ)
Inventors: Joseph P. Errico (Warren, NJ), Steven Mendez (New York, NY)
Primary Examiner: George Manuel
Assistant Examiner: Robert N Wieland
Attorney: John T. Raffle
Application Number: 12/752,395
International Classification: A61N 1/00 (20060101);


text:
The North West Rail Campaign is a partnership of organisations across the North West, working to improve rail in the region in order to generate economic growth and to assist Government in delivering an effective railway network.
To register your support for investment into the Northern Hub please click here.
There have been a number of successes for the railway where the Campaign has been actively involved in lobbying. Over the years these have included the 3rd platform at Manchester Airport, the Olive Mount Chord Liverpool, and improvements to stations including Warrington Bank Quay and Warrington Central. More recently this has involved a Network Rail report into the Northern Hub, and a decision to proceed with electrification of the "Lancashire Triangle" (Manc - Liverpool - Preston).
The North West Rail Campaign was set up in 2004 to focus on the issue of rail investment in the North West Region.
Its primary function is to highlight where investment is required to sustain the railway network, make it fit for purpose, and to ensure that the railway contributes to economic, social and environmental sustainability.
Born out of a desire to deliver the region's railway needs, particularly in regard to the Northern rail hub, the campaign has not only highlighted pressing need in its priorities, but has been very active in lobbying Government, the EU and the railway industry, emphasising the need for investment.
This lobbying has been done not in a negative or over-demanding way, but by arguing on a case-by-case basis, helping to provide an evidence base as well as pointing out the positives that our priority schemes would bring, not only to the railway but to the region and country as a whole.

subset: commoncrawl


text:
One True Pairing
You may be looking for the zine publisher OTP Press (aka One True Pairing Press) or the zine publisher OTP Press (aka Other Times and Places Press).
|See also:
|OTC, Shipping, Multishipping
|Click here for related articles on Fanlore.
One True Pairing, or OTP, is a fan's favorite pairing in a given fandom. The term implies extreme devotion, and some fans have no interest in creating or consuming fanworks for anything but their OTP. However, other fans with OTPs are also interested in fanworks for other pairings or fanworks with no pairings at all (gen).
Only shippers can have an OTP, and not all shippers have one. Having an OTP does not preclude a shipper from enjoying gen fanworks.
The opposite of an OTP is a NOTP.
Contemporary Usage
The term and its derivatives are largely synonymous with shipping. For example, "I ship Harry/Hermione" can mean "My OTP is Harry/Hermione". However, some fans ship more than one pairing in a given fandom; these fans are called multishippers, and they may use the term OTP to identify their favorite pairing in that fandom.
Original Understanding of the Concept
Back in the days of Mono-Fandom fans, the term OTP meant the only pairing that the fan was interested in, period. There wasn't even a second fandom, let alone a second pairing within the fandom, that was included as part of the definition.
One of the first uses of the term was in 1984 from a summary from the publisher of zine Alternaties #2, "This zine has something for everybody...The stories are mostly Spock-centric, so if you love a certain Vulcan, this one's for you!...And boy, does he get around -- we have Kirk/Spock, Spock/McCoy, Spock/Chapel, Spock/and various others, including T'Pring...And of course, more Kirk/Spock, because we all know that's our one true pairing!!!...Variety is the spice of life -- and this zine is extremely spicy."
Another early mention was in 2002 in Discovered in a Letterbox #23 in which a fan commented on whether Daniel (in Stargate SG-1) could be slashed with anyone other than Jack: "... I guess that could be applied to any fandom and the idea of OTP (one true pairing)."
OT3 is a play on OTP, and means "one true threesome". The term was in widespread use by the early 2000s. Its use is generally looser than OTP; OT3 tends to mean "the threesome I really like" more than "I'm only interested in this threesome and no other pairings or combinations." 3TP is a synonym. In some contexts, "trio" or "trinity" is a synonym for OT3.
Popular OT3s include:
- Harry/Ron/Hermione in Harry Potter
- Jack/Will/Elizabeth in Pirates of the Caribbean
- Frodo/Sam/Rosie in Lord of the Rings
- Fraser/Vecchio/Kowalski in due South
- Alec Hardison/Parker/Eliot Spencer in Leverage
- Peter/Elizabeth/Neal in White Collar
- Doctor/Jack/Rose in Doctor Who
- Dean/Sam/Castiel in Supernatural
- Santana/Brittany/Quinn in Glee
- Poe Dameron/Finn/Rey in Star Wars
- Rukia/Ichigo/Orihime in Bleach
- Eren/Mikasa/Armin in Attack on Titan
- Shawn/Cory/Topanga in Boy Meets World
- N/Hilda/Hilbert in Pokemon
- Mai/Ty Lee/Azula in Avatar: The Last Airbender
- Phoenix/Maya/Edgeworth in Ace Attorney
- Widowmaker/Tracer/Emily in Overwatch
- Frisk/Chara/Asriel in Undertale
OT4 means "one true foursome", and is a riff off OTP and OT3. When used on a story it generally means an actual sexual foursome, but it's also sometimes used by readers to describe a warm gen "team" story that made them feel like the four people are (or could be) "together" -- a sort of team smarm. It is fairly popular in SGA and Merlin, although marginal compared to the common OTPs John/Rodney and Arthur/Merlin; for details on SGA, see OT4 (Stargate Atlantis pairing); for Merlin, see OT4/5 (Merlin pairing). The popular Lord of the Rings hobbit foursome Frodo/Sam/Merry/Pippin is occasionally referred to as an OT4.
The term has since become common in a number of fandoms and is also used as a general term for a foursome.
Popular OT4s include:
- Ronon/Teyla/Rodney/John in Stargate Atlantis
- Arthur/Gwen/Merlin/Morgana in Merlin
- Frodo/Sam/Merry/Pippin in Lord of the Rings
- Brendon/Spencer/Ryan/Jon in Panic! at the Disco (also called GSF)
- Lyn-Z/Gerard/Frank/Jamia in MCR
- Sam/Jack/Daniel/Tealc in Stargate SG-1
- Colbert/Cooper/Olbermann/Stewart in Pundit RPF (usually called PRT, but also referred to as an OT4)
- Dan/Phil/PJ/Chris in The Youtube RPF (usually known as the Fantastic Foursome, a pun on The Fantastic Four)
- Luke/Calum/Ashton/Michael(5SOS OT4 aka C.A.L.M])
Though many OT4 fans identify as polyshippers and prefer moresomes in general, one common joke is that OT4 shipping happens when a fan can't choose a pairing to ship[1]. Despite the obvious intended humor, there are cases where OT4s are made from two popular pairings in a fandom, such as the hobbit OT4 listed above, which is constructed from the popular Frodo/Sam and Merry/Pippin pairings.
OT5, aka "one true fivesome", is a riff off OT3 and OT4 and refers to a sexual or romantic relationship between five people, though sometimes aromantic and nonsexual made for each other or found family works are also labelled this way. Some OT5 includes all five characters in a single relationship, while others involve a complex collection of relationships of various types between them.
OT5 was first used in Merlin fandom to refer to works in which Merlin, Arthur, Guinevere, Morgana, and Lancelot were all involved in a single relationship or pattern of intertwining relationships.[2] Later, other characters were substituted, or completely different groups were sometimes labelled as OT5.
In Prince of Tennis fandom OT5 usually refers to Fuji/Tezuka/Echizen/Atobe/Sanada stories. OT6 occasionally shows up too, adding Yukimura to the group. However it sometimes refers to a slightly different group of five or six characters, PoT having a large surplus of attractive boys.
The term appears frequently in Arashi fandom, where it refers to Sho/Jun/Aiba/Ohno/Nino.[3]
In Gundam Wing fandom, stories in which the five main characters are together are generally not referred to as OT5, but as a 'pilot pile'.
The term appears in One Direction fandom, and generally refers to all five members of the band. See Zianourry.
OT5 also exists in The Raven Boys fandom to refer to Adam/Ronan/Gansey/Noah/Blue (ie, all of the novel's main characters) and is, to some extent, supported by canon.
OT6 ("one true sixsome"), like OT5, can involve a sexual or nonsexual relationship between six people, and the relationship may be a single one or a collection of interwoven ones.
OT6 is commonly used in the Avengers Movieverse to refer to the Avengers themselves: Bruce/Clint/Steve/Natasha/Tony/Thor.[4] It may describe both sexual works and team works. Other characters are often added to this collection to form an OT7 or OT8, but who is added varies widely by creator.
OT8 ("one true eightsome") is commonly used in the Sense8 fandom due to the eight main characters that are part of a psychically reborn "cluster" (Will/Riley/Capheus/Sun/Lito/Kala/Wolfgang/Nomi, the relationship is also named Cluster Ship), and can involve a sexual or nonsexual relationship between eight people, with the possibility of another individual being interwoven within the group.
It's also used in the Avengers Movieverse and other fandoms.
OTE is commonly used in the Avengers Movieverse fandom to refer to the six Avengers + multiple other characters, often girlfriends like Pepper Potts and Jane Foster or SHIELD characters like Phil Coulson, Nick Fury, and Maria Hill. The "E" stands for "Everyone."
Further Reading/Meta
- 'It's Stars AND Stripes': Shipping Bisexual Characters in The Marvel Cinematic Universe; WebCite, In Media Res (2015)
- I found another OTP (One True Poll)!, a fan survey by gabrielleabelle
- Fan Speak! What's An OT3?
- ↑ Shipping Squirrel. Image text: "Can't decide which ship to ship. OT4". Posted July 12, 2011. Accessed July 17, 2013.
- ↑ merlin_ot4's profile includes, as part of Rule #2: "This flexible rule also applies to any wandering Lancelots that happen to pop up and decide to make the ol' reliable OT4 a cozy OT5 instead." Rules posted Feb. 23, 2009. Accessed July 17, 2013.
- ↑ OT5 Recs, posted Jan. 22, 2012. Accessed July 17, 2013.
- ↑ Bruce Banner/Clint Barton/Steve Rogers/Natasha Romanov/Tony Stark/Thor tag on AO3, with 8 uses of the term "OT6" on each page as of the date of access, July 17, 2013.


text:
Prevue Pet Products Birdie Basic 3/8 Inch X 16 Inch Perches
- Birdie Basics is a complete line of products designed to meet the everyday needs of birds and their humans.
- Birdie Basics contains everything even a novice bird owner could ask for to keep their fine feathered friend(s) feeling fabulous.
- All items have a full-color header card and are packaged in heavy-duty clear vinyl bags.


text:
Electric Picnic sells out in record time
Announcements, News, etc from the good people of the Electric Picnic - Lineup announcements, festival details etc
Post Reply
1 post • Page 1 of 1
- Posts: 102
- Joined: Mon Jun 09, 2008 11:07 pm
Proving yet again that Electric Picnic is festival-goers' first preference!
The final tally is in and we have reached a full quota! We can now confirm that public tickets are now officially SOLD OUT apart from a limited number of tickets available to Three customers just 9 days after announcing its first line-up. Electric Picnic takes place in the heavenly grounds of Stradbally Hall on the weekend of September 2nd - 4th 2016
Since its inception 13 years ago, tickets have never, ever sold out so far in advance, a testament to the popularity and future longevity of Ireland's favourite music and arts festival – Electric Picnic.
With only 27 acts announced to date we still have a veritable feast of music and activity to announce and tantalise you with over the coming five months.
For those of you who have bought your tickets, get ready to be entertained by a veritable feast of fun with Body &Soul, Other Voices, Trailer Park, Salty Dog, Comedy Stage, Trenchtown, Casa Bacardi, Mindfield and not forgetting…
LCD Soundsystem | Lana Del Rey | The Chemical Brothers | New Order
HAIM | Super Furry Animals | Years & Years | Todd Terje
Nathaniel Rateliff & The Night Sweats | Animal Collective | Gavin James | Wolf Alice
The Avett Brothers | Wild Beasts | Glass Animals | Jack Garratt | Savages
Pantha Du Prince presents The Triad | Phosphorescent | Broken Social Scene | Ezra Furman
Mount Kimbie DJ Set | Daniel Avery | Blossoms | Aurora
NAO | Girls Names | Meilyr Jones
Three will return to Electric Picnic for the second year in a row to give festival-goers even more great live music experiences. As an official partner of Electric Picnic Festival, Three has announced that its customers will once again have the chance to purchase the last available tickets to the festival through its dedicated customer rewards programme, 3Plus. Stay tuned to facebook.com/3Ireland or @ThreeIreland for more details coming soon…
Weekend Camping Tickets: SOLD OUT
Family Weekend Camping Tickets: SOLD OUT
Sunday day tickets: SOLD OUT
Campervan/Caravan + Car passes: SOLD OUT
Family Campervan/Caravan + Car passes: SOLD OUT
Post Reply
1 post • Page 1 of 1


text:
Former President Jimmy Carter Joins in Growing Chorus of Support for Legal Weed
During a recent CNN panel event in Georgia, the 39th President delivered this rousing endorsement of the Pro-Pot movement,
I'm in favor of it. I think it's OK, I don't think it's going to happen in Georgia yet, but I think we can watch and see what happens in the state of Washington, for instance around Seattle, and let the American government and let the American people see does it cause a serious problem or not. So I think a few places around the world is good to experiment with and also just a few states in America are good to take the initiative and try something out. That's the way our country has developed over the last 200 years. It's about a few states being kind of experiment states. So on that basis I am in favor of it.
[iMarijuana - Image: the AP]
Colors, How the Fuck Do They Work?
TedX instructor, Colm Kelleher walks us through how the human mind translates varying wavelengths of electromagnetic radiation into the myriad of colors we see daily. [Explore]
Cannabis: What's the Harm?
As in the US, Cannabis is the number one, most-used illegal drug in Britain as well. Former East-Enders star James Alexandrou takes a look at toking in the UK in the first episode of this binary miniseries. Check out episode 2 here.
How To Clone Your Cannabis
Got a prized plant and want to expand your grow op? Good news! This handy, step-by-step guide shows exactly how to Xerox weed.
How To Clone Your Cannabis Using a Modded Igloo
If you're looking for a more self-contained method for nurturing your plant copies as they take root, Mr. Wilson's Workshop has a suggestion.


text:
INDIANAPOLIS — This time, Ryan Tannehill was the one celebrating in Indianapolis. And Miami's defense had Andrew Luck fuming.
The Dolphins' second-year quarterback matched his counterpart virtually throw-for-throw Sunday. Tannehill did a better job managing his team's offense in the second half and cheered his defense after it thwarted yet another Colts' comeback bid to hold on for a 24-20 victory.
"It's nice to win and that's the important thing no matter who we are going against. It's nice to win," Tannehill said. "I think he (Luck) did a good job, I don't really know what his numbers were, but from what I saw, he did a great job of moving around the pocket, but the defense really stepped up and made a play when it counted."
Tannehill was just better Sunday. It was a stark contrast from a year ago, when the two first-round draft picks met as rookies. Luck stole the show that day by throwing for an NFL rookie record 433 yards and two scores as he delivered a three-point win. In Sunday's meeting, with a chance to show everyone how much he and the Dolphins (2-0) had progressed, Tannehill was the winner.
While the two quarterbacks finished with similar numbers — Tannehill was 23 of 34 for 319 yards and one touchdown, while Luck was 25 of 43 for 321 yards and one TD — the difference came down to managing mistakes. Tannehill lost a third down fumble at his 39 in the third quarter, but all the Colts could get was a go-ahead field goal.
Luck, however, stopped one fourth-quarter scoring chance by forcing a deep throw to Reggie Wayne that was picked off by Brent Grimes in the end zone.
Luck had a chance to make amends after driving the Colts (1-1) to the Miami 23-yard line with 1:45 left in the game. Miami, however, forced three straight incompletions and refused to allow the suddenly elusive Luck to escape the pass rush on fourth down.
All Tannehill had to do then was pick up one first down, kneel down once and shake hands with the guy he's been following since they were Texas high school stars. Luck, who has engineered eight fourth-quarter comebacks in 18 games, blamed himself for the loss.
"I guess I'm a little angry at myself," Luck said. "Again, credit to them, they put us in all these situations, but I feel like we are a better team than what we showed out there."
The Dolphins, meanwhile, couldn't have been happier. They started fast, jumping to a 14-3 lead after two possessions, rallied twice and shut down the Colts when they needed, too.
High-priced free-agent Mike Wallace was a little happier with his performance Sunday, finishing with nine receptions for 115 yards and one touchdown a week after making only one catch in his Miami debut. Lamar Miller averaged nearly 5 yards per carry, running 14 times for 69 yards and a touchdown. Charles Clay had five catches for 109 yards and only one carry — a 1-yard TD run with 4:40 left in the third quarter, which turned out to be the game's decisive score and stood up to a replay review.
That, and a staunch defense late was enough for the Dolphins to hold on.
"You have to be balanced to win football games. You can't really win a football game by just throwing the whole game," Wallace said. "You have to mix it up."
The Dolphins didn't shy away from trading jabs, especially after Indy piled up 315 yards of offense in the first half, their highest first-half total in seven years. The Colts finished with 438 yards, but couldn't put Miami away after taking a 17-14 lead in the first half and a 20-17 lead early in the third quarter after Tannehill's fumble.
But Miami made all the big plays after that — the 34-yard completion from Tannehill to Wallace that set up Clay's rushing score, the third down conversions to keep Luck & Co. off the field and the two big fourth-quarter stops.
"Our guys wanted to play them, we wanted to compete," Miami coach Joe Philbin said. "They were ready for a 60-minute game and we knew we would have to make some plays to win."
Notes: Indy lost left guard Donald Thomas in the first quarter with a torn quad tendon that is likely to end his season. The Colts also played the second half without Darius Heyward-Bey, who injured his ribs. ... The Dolphins snapped a four-game losing streak in this series. ... Luck had the NFL's longest active streak with 165 straight passes without an interception before Grimes picked him off. ... Miami scored 14 points in the first quarter for the first time since 2011, a span of 25 games. ... T.Y. Hilton had a career-high 124 yards receiving on six catches for Indy.


text:
Get ready for a night all about Bob Ross!
KLRU will be hosting NEXT Nights focusing on the work of Ross on August 24 from 6:30 pm – 8:30 pm at 800 Congress Avenue.
Enjoy live painting, themed cocktails from Banner Distilling, locally brewed beers from Austin Speciality and treats from Skull & Cakebones. Also, let's not forget our 'Fro'to booth (happy little trees photobooth) and much more!
Make sure and purchase your tickets today!


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Lance Armstrong finally grilled under oath
Lance Armstrong had tried to avoid this day for years. But on Thursday, it finally happened – deposition day.
The disgraced former cyclist was forced to provide sworn videotaped testimony about his doping history as part of a fraud case filed against him by SCA Promotions, a sports insurance company in Dallas.
The deposition testimony, which was not open to the public, had been a long time in the making. It also came after months of fighting from Armstrong, who asked a Texas appeals court and the Texas Supreme Court to stop the deposition from taking place.
Both courts rejected his request, forcing him to sit for questions under SCA Promotions attorney Jeffrey Tillotson, who recently said he is the only opposing attorney to interview Armstrong under oath about doping. In a previous case involving SCA Promotions, Tillotson also questioned Armstrong under oath when he lied and denied doping in 2005-06.
Tillotson declined comment to USA TODAY Sports after the deposition Thursday afternoon in Austin, Texas. Armstrong's attorney, Tim Herman, also declined comment.
The current case stems from a lawsuit the company filed against Armstrong in February 2013, seeking the return of $12 million in costs and bonuses it paid him for winning the Tour de France in 2002-04. The case later moved to arbitration, where a panel is scheduled to hear the case later this summer. Armstrong was subpoenaed for Thursday's deposition as part the evidence-gathering process before the hearing.
In a separate fraud lawsuit filed by the federal government, Armstrong was scheduled for another deposition on June 23. But the government recently said it would postpone that deposition and others it had scheduled for this month.
OTHER CASE:Feds also want Armstrong under oath
NAMING NAMES:Armstrong provided written answers about doping
After years of denials, Armstrong, 42, confessed to doping last year in a televised interview with Oprah Winfrey. He avoided giving details in that interview and since then, he has not been placed under oath to answer doping questions from a hostile attorney, besides some written answers he was compelled to give late last year in a different case.
His attorneys have fought attempts to place him under oath in order to protect him from risk. Because most of the events in question happened more than nine years ago, memories could be faulty, possibly leading to inconsistent testimony that could weaken his defense with two fraud cases pending against him.
Then there's the issue of his false testimony with SCA Promotions in 2005-06. In 2004, Armstrong sued SCA Promotions, claiming breach of contract after the company refused to pay his bonus for winning the Tour de France. The company withheld the payment because it suspected he cheated to win the race, leading to his deposition with Tillotson in 2005.
In that 2005 testimony, Armstrong said he "never" took performance-enhancing drugs. "How many times do I have to say it?" Armstrong asked Tillotson then. He also testified, "I race the bike straight up fair and square."
That false testimony helped Armstrong win a $7.5 million settlement from the company in 2006. The settlement agreement stipulated that the case could not be reopened, a point his attorneys have stressed in trying to block the current case from proceeding.
Tillotson previously said Armstrong's false testimony is too old for him to face perjury charges under the statute of limitations. But he said SCA Promotions wants Armstrong sanctioned for his lies by the same arbitration panel that handled the previous case.
"Our position is simple," Tillotson told USA TODAY Sports May 30. "No one should be able to relentlessly perjure themselves and get away with it."
Follow sports reporter Brent Schrotenboer on Twitter @Schrotenboer. E-mail: firstname.lastname@example.com


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Transfer news: Santos reveal opening bid from Barcelona for Neymar
Santos chief Odilio Rodrigues has confirmed that the club have already rejected an offer from Barcelona for Neymar.
By Paulo Freitas
Last Updated: 18/05/13 12:27pm
Rodrigues has revealed that talks will continue with Barca, but he also admitted that they are expecting to hold discussions with Real Madrid, too.
"There is no agreement for Neymar, there are talks, I met [Barcelona's president Sandro] Rosell and [Barcelona's sporting director] Raul Sanllehi last week," he told Radio A Xarxa.
"We had a very frank conversation. Talks need to continue because the offer was not good enough."
He confirmed that Santos are expecting Real to lodge a bid shortly, adding: "We know Real Madrid will make an offer too."
Rodrigues also insisted that the player will make the final choice, adding: "Neymar will choose the team he wants, it's Neymar's opinion that is important."


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ST. AUGUSTINE, Fla. – The Georgia College volleyball team (3-7, 1-2 PBC) took on a 2012 NCAA Tournament Qualifier in Flagler College (5-4, 2-1 PBC), battling to a straight-set loss on the road, 25-17, 25-10 and 25-19.
Rachel Reynolds (Marietta, Ga.) finished with eight kills to lead the squad, hitting just .080 however, as the Bobcats hit .023 as a team. Haley Ashworth (Cumming, Ga.) added five kills to the effort.
Leading the team in digs was Caroline Ham (Marietta, Ga.) with eight, while setter Micayla Patterson (Tyrone, Ga.) had 18 assists running the offense.
The Flagler squad hit .261 on the match, despite the Bobcats' best defensive effort in the third set of a .175 attack percentage. The Saints had a big advantage on the front line, getting a 9-1 advantage in blocks.
Emilee Taylor led the Saints with 10 kills; the Preseason All-Peach Belt Conference (PBC) pick was the lone player on either team with double-digit kills. Preseason All-PBC setter Amelia Morgan had 16 assists with seven digs.
The Bobcats are back in action tomorrow, Sept. 21 at 2 p.m. traveling to defending PBC Champion Armstrong Atlantic State University.
The Georgia College Department of Athletics, two-time winners of the PBC Commissioner's Cup, sponsors 11 varsity athletic programs at the NCAA Division II level. As a Division II program, Bobcat Athletics prides itself on balancing the life of the student-athlete, evidenced by the teams' multiple appearances in post-season competition as well as documented academic success and community-service involvement. Sign up at @GCBobcats on Twitter and Facebook for up-to-the-minute reports, and visit www.GCBobcats.com for more information, and to nominate your favorite former Bobcats and Colonials to the GC Athletics Hall of Fame.


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A medical history is the most important part of the examination for
urinary incontinence. During the medical history, your
doctor will ask you to describe:
It may be easier for you to answer these questions if you use a bladder diary(What is a PDF document?) for 3 to 4 days before your appointment.
The doctor will ask questions about your general
health. To find out the cause of your incontinence, he or she will ask
specific questions about your urinary and reproductive tracts, your intestines,
and your nervous system.
Symptoms and conditions that are often related to incontinence will
also be investigated, such as:
A physical exam involves abdominal,
rectal, and
pelvic examinations. These exams include:
A medical history and physical exam are done for everyone
who sees a doctor about urinary incontinence.
The medical history is important and can determine some causes of
Be sure to tell the doctor about all prescription
and nonprescription medicines you are taking.
The physical exam can find structural abnormalities of the
urinary tract that may be causing or contributing to incontinence. Findings
from the physical exam help your doctor know whether further testing is
Complete the medical test information form (PDF)(What is a PDF document?) to help you prepare for this test.
Last Revised:
September 11, 2012
Healthwise Staff
Medical Review:
E. Gregory Thompson, MD - Internal Medicine & Avery L. Seifert, MD - Urology
This information does not replace the advice of a doctor. Healthwise, Incorporated disclaims any warranty or liability for your use of this information. Your use of this information means that you agree to the Terms of Use. How this information was developed to help you make better health decisions.
To learn more visit Healthwise.org
© 1995-2012 Healthwise, Incorporated. Healthwise, Healthwise for every health decision, and the Healthwise logo are trademarks of Healthwise, Incorporated.


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Teacher resources and professional development across the curriculum
Teacher professional development and classroom resources across the curriculum
Video Summary
The video for this session examines how to teach writing as a process. Dr. Jeanne R. Paratore begins her lecture by distinguishing between the different forms of writing and the various purposes for writing. She reviews the stages of the writing process and outlines the classroom practices that develop students' writing. The workshop participants then watch and discuss two sets of classroom excerpts showing writing instruction in grades K-2. Following their discussion, they analyze their own instructional practices for teaching and managing their writing programs.
© 2003 WGBH Educational Foundation. All rights reserved.
© Annenberg Foundation 2017. All rights reserved. Legal Policy


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Patiala Satin Glaze Dress Material
Vastrangam Manufacturer and Supplier of Dress Material. Patiala Satin Glaze Dress Material, Satin Glaze with embroidery work Dress Material women use to wear at regular, Festival and Party Wear.
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Click Here to check order proceeding, product details & return and replacement policy.
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Celebrity Chef Rachael Ray pumped up the crowd of kids and parents at Jungle Island's "Fun and Fit as a Family Day."
She started the hour-long cooking demonstration by making turkey tacos with lean ground meat.
"That's a great rule as a family, if you all like to cook together to try and add as much color as you can to every meal and then you know you're getting great nutrition," said Ray.
A lucky audience member joined the bubbly talk show host on stage to cook healthy versions of comfort food, like mac and cheese.
The two-day festival event promotes a healthy lifestyle. Even those so-called bad foods can be good for you.
Barilla served up whole wheat pasta tossed in olive oil. Domino's rolled out a 70-calorie pizza slice.
Kids got active by taking on obstacle courses, enjoyed arts and crafts and got to know the animals on Jungle Island.
Parents hoped just a sample of healthy foods from a dozen vendors would help kids pick up good eating habits.
Ray even dished out career advice to a 13-year-old fan.
"You will always be employed because people need to eat," she said.


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The Red Fox
You've probably read stories about the cunning fox trying to outwit his animal brothers and sisters. Foxes no doubt got their crafty reputation from the way they look, with their long thin faces and yellow eyes that have narrow slits for pupils. But in real life, foxes are more concerned with finding food than with playing tricks on anyone.
The red fox is a lean mean hunting machine that's built for speed. About 3-3 ½ feet in length, slinky and long-legged, they only weigh 9-12 pounds full grown. But red foxes look a lot bigger because of their thick fur, which can range from deep brownish red to sandy blonde with black legs, feet and backs of the ears and white underparts. Sometimes, red foxes can even be all black or black with white tips (called "silver"), or have a dark brown "cross" across their backs.
Out-"Foxing" Their Prey
When hunting, they will slowly approach their prey, creeping low to the ground and stretching their head high to spot the prey. Then, BAM!, they pounce on the mouse, rabbit, or other prey with their forefeet.
Mice, especially meadow voles, are a popular food for red foxes, but their favorite dish is cottontail rabbit. They aren't picky eaters though, and will eat berries and insects in the spring and summer, along with squirrels, songbirds, ducks, and pheasants. In the northern part of the state they'll also eat snowshoe hares. They'll even clean up after us humans and eat garbage.
Nighttime is the right time for red foxes to be active. They do most of their hunting from 2 hours before sunset to about 4 hours after sunrise and travel up to 9 miles a night. When they aren't hunting, foxes like to rest in forests, ravines or woodlots, curling their long bushy tails around themselves to keep warm.
Fox Family Facts
Red foxes don't live in dens most of the year, but do set up nurseries in abandoned badger or woodchuck burrows when it's time to have babies. Male and female foxes breed in mid-January and have 5 or 6 pups in mid-March. Young foxes are called kits. They start hunting with their parents when they're 3 months old, and are ready to strike out on their own after only 7-8 months.
If you look along fence rows, gravel roads, paths or treelines after a light snowfall, you might be able to find some fox tracks. The tracks are the size of a small dog's, about 1 ½ - 2 inches long, but narrower and with smaller toe pads and more fur marks. If you're really lucky, you might even be able to see red fox pups playing outside their den! On spring or summer evenings, search along hillsides with binoculars; if you see a mound of fresh dirt in front of a dark hole, it could be a den entrance. But remember, be careful never to get too close and disturb the family, or they might have to pack up and move. Treat red foxes with respect and you'll be able to watch and enjoy them a lot longer.


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Help the Calabash Bros defeat hordes of monsters!
Mini-golf with marbles - get a hole in one!
Defend the city from the invading zombies!
Commando is back! Rank up to unlock awesome weapons and all new quick fire missions.
Don't let the zombies breach your defenses!
Bring home the Bacon, Hambo!
Our hero is on the defensive, take control of Commando's towers!
Defend against the Zombies migrating into your town!
You must defend your village with advanced war equipment!
Commando joins forces with his Allies to hold off the waves of enemies!
Serve all the customers in the Sushi Restaurant
Master the bow in this medieval archery game
Knock knights from their horses in a jousting tournament.
Starjack.io, multiplayer space strategy game, let's you build your planetary empire and destroy the opposition!
MiniRoyale.io is a browser FPS with battle royale gameplay!