Polypeptides, compositions, and methods for treating shock are described. A isolated polypeptide, Deltorphin-E, can be administered without concomitant fluid resuscitation, before, concurrently with, or after the onset of shock or the occurrence of an event that creates a risk of shock. Deltorphin-E can be administered in accordance with the method as part of a preconditioning strategy, which reduces the extent of ischemic injury. Deltorphin-E can be used in preparation for planned ischemia or in a prophylactic manner in anticipation of further ischemic events.

Circulatory shock and hypovolemic shock are commonly occurring threatening pathophysiological states, which can occur secondary to trauma, hemorrhage, burns, sepsis, allergic reactions, and heart failure. Shock-like microcirculatory abnormalities are also associated with certain procedures, such as surgical procedures. Such shock, whether systemic or localized, is characterized by a reduction in blood pressure, blood flow, and/or blood volume, and can cause an insufficient supply of blood and oxygen to vital organs and tissues. This insufficient blood and oxygen supply can cause local hypoxia, ischemia, and can lead to loss of cellular and organ function and even death.
Currently-available treatments for circulatory and hypovolemic shock include forms of volume infusion. For example, the standard of care in initial management of hemorrhagic shock is rapid administration of large volumes fluids, several liters in an adult patient. A preferred fluid is Ringer's lactate, although normal saline or other similar isotonic crystalloid solutions are also used. The standard continued treatment is based on an observed response to the initial fluid therapy. Guidelines generally provide that up to 300 ml of electrolyte solution is required for each 100 ml of blood lost ("three for one" rule). For blood losses up to 30% of circulation blood volume, crystalloid alone will often suffice; however, with ongoing blood loss, or a more significant hemorrhage, prompt surgical intervention or blood therapy becomes necessary.
Over the last decade, this standard approach has been reexamined, leading to the conclusion that changes are needed in current resuscitation strategies used by first responders to trauma settings and by medical personnel in emergency rooms (ER) and intensive care units (ICU). There are multiple reasons for this conclusion.
First, the clinical trajectory of patients who develop multiple organ failure is set early in the resuscitation process (i.e., within about 6 hr of an event that creates a risk of shock, such as an injury resulting in hemorrhaging). Many patients at high risk require emergency surgery or interventional radiology, and arrive in an ICU after this time window. Although resuscitation efforts in the ICU can clearly modify the subsequent clinical course for the patient, even highly refined and individually tailored resuscitation cannot reverse the dysfunctional response that has already occurred. As such, currently-used resuscitation strategies do not adequately limit the incidence of multiple organ failure.
Second, although initial crystalloid volume loading is valuable in defining hemodynamic stability, to continue this process in the face of ongoing hemorrhaging promotes further bleeding, hemodilutes the patient, and sets the stage for hypothermia, acidosis, and coagulopathy. This syndrome is particularly problematic in patients with blunt trauma, who often have sources of bleeding that are not amenable to direct control. Failure to resuscitate these patients will, however, ultimately lead to irreversible shock. As such, currently used resuscitation strategies can actually exacerbate ischemic injury.
Third, although crystalloid resuscitation is efficacious in most patients, it produces problematic tissue edema in patients who arrive to an ICU in severe shock. These patients typically need massive fluid resuscitation to maintain intravascular volume and many develop abdominal compartment syndrome, which creates increased risks for multiple organ failure. Patients with severe torso trauma who are admitted with shock and an associated severe closed head injury are in a precarious situation. Under-resuscitation decreases cerebral perfusion pressure, which causes secondary brain injury. Excessive crystalloid administration promotes cerebral edema, which increases intracranial pressure and further decrease cerebral perfusion pressure. As such, currently used resuscitation strategies can exacerbate injury.
Fourth, shock initiates dysfunctional inflammation that causes multiple organ failure. Resuscitation is an obligatory intervention to decrease the severity of the shock insult, but current strategy is not directed at modulating inflammation, in fact, it may worsen it. Laboratory studies show that lactated Ringer's solution activates neutrophils. Even more disturbing is an observation that blood transfusion contains proinflammatory mediators that both prime and activate neutrophils. As such, currently used resuscitation strategies can exacerbate injury.
Prospective randomized controlled trials studying currently-used resuscitation strategies (crystalloid and colloid resuscitation) were conducted in the 1970s and 1980s, before the recognition of abdominal compartment syndrome as an important clinical entity. Additionally, albumin was the principal colloid used, but other types of colloid, such as starches and gelatins, are available and are now being used in resuscitation. Because of their higher molecular weights, colloids such as starches and gelatins are confined to the intravascular space, and their infusion results in more efficient plasma volume expansion. In severe hemorrhagic shock, however, the permeability of capillary membranes increases, allowing colloids to enter the interstitial space, which can then worsen edema and impair tissue oxygenation. Although it has been suggested that these high-molecular-weight agents could plug capillary leaks that occur during neutrophil-mediated organ injury, it has not been established that such a benefit could result from their use.
It has also been proposed that resuscitation with albumin induces renal failure and even impairs pulmonary function. Similarly, hetastarch has been shown to induce renal dysfunction in patients with septic shock and in recipients of kidneys from brain-dead donors. Hetastarch also has a limited role in massive resuscitation because it causes a coagulopathy and hyperchloremic acidosis due to its high chloride content. A new hydroxyethyl starch (HES) preparation (e.g., HEXTEND®) purportedly does not cause these adverse effects, but has not been studied in massive resuscitation. It is now thought that colloids might reduce the incidence of abdominal compartment syndrome, but this possible benefit must be weighed against the potentially detrimental effects of colloids already reported.
Results of numerous studies indicate that HES administration can lead to reduction in circulating factor VII and von Willebrand factor levels, impairment of platelet function, prolongation of partial thromboplastin time and activated partial thromboplastin time, and increase in bleeding complications. Coagulopathy and hemorrhage associated with HES are often encountered in cardiac surgery, a setting in which susceptibility to such complications is heightened by transient acquired platelet dysfunction resulting from the procedure. Thus, in cardiac surgery studies with albumin as the control, HES has resulted in platelet depletion and dysfunction, prothrombin time and activated partial thromboplastin time prolongation, and increased postoperative bleeding. Dextran, as compared with albumin, has been shown to reduce platelets and increase postoperative bleeding in cardiac surgery patients. Postoperative blood loss was early correlated with the volume of gelatin used to prime the extracorporeal circuit. Artificial colloids, including dextran, hetastarch and pentastarch, have been associated with renal impairment, and HES has been demonstrated to increase sensitive markers of renal tubule damage in surgical patients. In a study of sepsis patients, HES exposure was recently shown to be an independent risk factor for acute renal failure. In the renal transplantation setting, HES has been found to reduce urinary output, increase creatinine levels and dopamine requirement, and increase the need for hemodialysis or hemodiafiltration.
Studies have suggested that both over- and under-resuscitation can increase mortality. Early aggressive fluid resuscitation can be deleterious, according to a clinical trail in which mortality was reduced by delaying fluid therapy. Also, there are several practical and logistic limitations to the current methods of prehospital resuscitation, which include limitations on the amount of fluid that can be delivered due to inadequate i.v. bore size and limited availability of fluid in the field, e.g. combat casualty care. Hypotensive resuscitation is one approach that has been advocated as a better means to perform field resuscitation of penetrating trauma. However, early application of aggressive resuscitation has been shown to affect outcomes deleteriously in animal models of uncontrolled hemorrhage, in which aggressive resuscitation using a variety of fluids caused rapid increases in blood pressure, internal bleeding, and higher mortality.
In the early 1980s research interest in hypertonic saline was spurred. Small-volume hypertonic saline was shown to be as effective as large-volume crystalloids in expanding plasma volume and enhancing cardiac output in hemorrhagic shock in animals. Furthermore, hypertonic saline increased perfusion of the microcirculation, presumably by selective arteriolar vasodilation and by decreasing swelling of red blood cells and of the endothelium. This improved microcirculation, however, could lead to increased bleeding. Consequently, hypertonic saline was tested in animal models of uncontrolled hemorrhagic shock and was shown to increase bleeding, but mortality was model-dependent and the best survival was obtained when saline was given with high-volume crystalloids. Additionally, the resuscitative effectiveness of hypertonic saline was found to be enhanced by combination with dextran (hypertonic saline dextran (HSD)). In view of the small volume needed to achieve these effects, there was great interest in the use of these fluids in resuscitation in the field for both military and civilian use.
From the late 1980s through the early 1990s, several trials were done. Individually, these trials found survival outcome to be inconsistently improved, but did document that a bolus of hypertonic saline or HSD was safe. Meta-analysis of these data suggests that hypertonic saline is no better than standard of care isotonic crystalloid fluids, but that HSD might be better. Subgroup analysis showed that patients who presented with shock and concomitant severe closed head injury benefited most from HSD. This observation was consistent with laboratory data showing that, compared with isotonic crystalloid, hypertonic saline or HSD increases cerebral perfusion pressure, decreases intracranial pressure, and decreases brain edema, in combined head injury and hemorrhagic shock. This finding has led some authorities to recommend that hypertonic saline should replace mannitol in the management of intracranial hypertension in patients with severe closed head injury. The argument in favor of hypertonic saline is even more compelling with the recent recognition that hypertonic saline resuscitation decreases the inflammatory response (specifically neutrophil cytotoxicity) in animal models of hemorrhagic shock, ischemia and reperfusion, and sepsis.
More recent studies have compared hypotensive and normotensive resuscitation of hemorrhage using lactated Ringer's (LR) with hypotensive resuscitation using HEXTEND® (Hex) 6% hetastarch in isotonic buffered saline in a multi-hemorrhage sheep model. Hypotensive resuscitation with LR greatly reduced volume requirements as compared with normotensive resuscitation, and Hex achieved additional volume sparing. However, trends toward lower base excess (BE) values and low levels of urinary flow in some animals in both hypotensive treatment protocols and the occurrence of deaths only in the hypotensive treatment protocols suggest that resuscitation to a target MAP of 65 mmHg may be too low for optimal outcomes. Hypotensive resuscitation regimens may reduce bleeding but do not optimally restore metabolic function.
To summarize, currently-available treatments for circulatory and hypovolemic shock focus on various forms of volume infusion. Intravenous fluids appear to improve hemodynamic indices in the short term, but most also have adverse consequences on hemostatic mechanisms. Indeed, it is now becoming clear that resuscitation fluids may actually potentiate cellular injury via severe immune activation and upregulation of cellular injury markers that can result in exacerbation of blood loss. Bleeding can also be enhanced by injudicious fluid administration as a consequence of dilutional coagulopathy and secondary clot disruption from increased blood flow, increased perfusion pressure, and decreased blood viscosity.
Accordingly, there remains a need in the art for a method of treating circulatory and hypovolemic shock, which avoids the above-identified problems.

Compositions and methods useful for treating circulatory and hypovolemic shock

University of Kentucky Research Foundation


This invention relates resiniferatoxin derivatives useful in a vanilloid receptor binding assay and methods for production thereof.

Noxious chemical, thermal and mechanical stimuli excite peripheral nerve endings of small diameter sensory neurons (nociceptors) in sensory ganglia (e. g., dorsal root, nodose and trigeminal ganglia) and initate signals that are perceived as pain. These neurons are crucial for the detection of harmful or potentially harmful stimuli (heat) and tissue damage (H+ (local tissue acidosis), and/or stretch) which arise from changes in the extracellular space during inflammatory or ischaemic conditions (Wall, P. D., and Melzack, R., Textbook of Pain, 1994, New York: Churchill Livingstone).
Capsaicin, (N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methyl-6-nonenamide), the main pungent Ingredient in "hot" capsicum peppers, interacts with specific membrane recognition sites called vanilloid receptors (VR). These proteins are expressed almost exclusively by primary sensory neurons involved in nociception and neurogenic inflammation (Bevan, S., and Szolcsanyi, J., Sensory neuron-specific actions of capsaicin: mechanisms and applications, Trends Pharmacol. Sci., 1990, 11, 330-3). Capsaicin itself is a selective activator of thinly myelinated or unmyelinated nociceptive afferents (Szolcsanyi, J., Actions of capsaicin on sensory receptors, In Capsaicin Study, Pain, J. N. Wood, ed.: Academic, London, UK, 1993, pp. 1-26; and Szolcsanyi, J., Capsaicin-sensitive sensory nerve terminals with local and systemic efferent functions: facts and scopes of an unorthodox neuroregulatory mechanism, Prog. Brain Res., 1996, 113, 343-359).
Capsaicin and structurally-related derivatives show structure-function relationships and these effects can be blocked by a selective antagonist, capsazepine. The tricyclic diterpene resiniferatoxin (RTX) (Szolcsanyi, J., Szallasi, A., Szallasi, Z., Joo, F., and Blumberg, P. M., Resiniferatoxin: An ultrapotent neurotoxin of capsaicin-sensitive primary afferent neurons. Ann. N. Y. Acad. Sci., 1991, 632, 473-5) binds at the capsaicin binding site and has revealed a very localized distribution of capsaicin receptors at rat somatic and visceral primary sensory neurons (Szallasi, A., Nilsson, S., Farkas-Szallasi, T., Blumberg, P. M., Hoekfelt, T., and Lundberg, J. M., Vanilloid (capsaicin) receptors in the rat: distribution in the brain, regional differences in the spinal cord, axonal transport to the periphery, and depletion by systemic vanilloid treatment. Brain Res., 1995, 703, 175-83). Interestingly, the density of RTX receptor sites in nodose and dorsal root ganglia increased after ligation of the vagal and sciatic nerves (Szallasi et al., 1995).
Multiple effects of capsaicin on sensor neurons have been characterized (Szallasi, A. and Blumberg, P. M., Vanilloid receptor: new insights enhance potential as a therapeutic target, Pain, 1996, 68,195-208). Capsaicin excites the neuron resulting in calcium influx, the release of various neuropeptides such as CGRP and SP (Purkiss, J., Welch, M., Doward, S. and Foster, K, Capsaicin-stimulated release of substance P from culture dorsal root ganglion neurons: involvement of two distinct mechanisms, Biochem. Pharmacol., 2000, 59, 1403-1406) and cytokine release (Veronesi, B., Oortgiesen, M., Carter, J. D. and Devlin, R. B., Particulate matter initiates inflammatory cytokine release by activation of capsaicin and acid receptors in a human bronchial epithelial cell line, Toxicol. Appl. Pharmacol., 1999, 154,106-115). These events are believed to contribute to pain states and inflammation. Additionally, capsaicin and RTX can cause vanilloid receptor desensitization (Acs, G., Biro, T., Ace, P., Modarres, S. and Blumberg, P. M., Differential activation and desensitization of sensory neurons by resiniferatoxin, J. Neurosci., 1997, 17, 6522-5628) which, in animals, manifests as a state of reduced nociception. This phenomenon may constitute a novel approach to the treatment of neuropathic pain (Winter, J., Bevan, S. and Campbell, E. A., Capsaicin and pain mechanism, Br. J. Anaesth., 1995, 75, 157-168) and other pain states. However, under certain conditions, capsaicin and RTX can be neurotoxic (Bevan and Szolcsanyi, 1990).
Recently, one receptor protein for capsaicin was cloned from rat (Caterina, M. J., Schumacher, M. A., Tominaga, M., Rosen, T. A., Levine, J. D., and Julius, D., The capsaicin receptor: a heat-activated ion channel in the pain pathway, Nature (London), 1997, 389, 816-824) and shown to be a coincidence detector for H+ (low pH) and heat (Tominaga, M., Caterina, M. J., Malmberg, A. B., Rosen, T. A., Gilbert, H., Skinner, K., Raumann, B., Basbaum, A. I., and Julius, D., The cloned capsaicin receptor integrates multiple pain-producing stimuli, Neuron, 1998, 21, 531-543). VRI is a ligand-gated non-selective cation channel that shows pronounced outward rectification (Caterina et al., 1997). The vanilloid ("capsaicin") receptor VR1 is activated by capsaicin and RTX, and activation of VRI is blocked by the antagonists capsazepine (CPZ) (Bevan, S., Hothi, S., Hughes, G., James, I. F., Rang, H. P., Shah, K., Walpole, C. S. J., and Yeats, J. C., Capsazepine: a competitive antagonist of the sensory neuron excitant capsaicin, Br. J. Pharmacol., 1992, 107, 544-52) and ruthenium red (RR) (Wood, J. N., Winter, J., James, I. F., Rang, H. P., Yeats, J., and Bevan, S., Capsaicin-induced ion fluxes in dorsal root ganglion cells in culture, J. Neurosci., 1988, 8, 3208-20). VR1 Receptors are sensitive to vanilloids, heat and protons and thus these proteins are believed to be widely involved in the initiation, modulation and modification of pain (Woolf, C. J. and Salter, M. W., Neuronal plasticity: increasing the gain in pain, Science, 2000, 288, 1765-11768). Furthermore, VR1 is expressed in small nociceptive neurons of the dorsal root ganglion, consistent with its role in modulating peripheral pain (Tominaga, et al., 1998; and, Michael, G. J. and Priestley, J. V., Differential expression of the mRNA for the vanilloid receptor subtype 1 in calls of the adult rat dorsal root and nodose ganglia and its downreglulation by axotomy, J. Neurosci., 1999, 19, 1844-1854).
Patent application WO 99/09140 identifies the vanilloid receptor (VR) as a ligand-gated, non-selective cation channel that is expressed in sensory neurons and which is involved in nociceptive processes such as hyperalgesia. Resiniferatoxin, a naturally-occurring terpenoid phorbol derivative, binds to the VR protein with sub-nanomolar affinity and behaves as a functional agonist (stimulates calcium influx). Accordingly, iodinated and labeled RTX derivatives may similarly be potent in binding to the vanilloid receptor and may therefore be useful in identifying compounds that have affinity for vanilloid receptor when utilized in a receptor-binding assay. Indeed, tritiated-RTX is known to display a nanomolar affinity for VR, and can be used to identify or indicate compounds that also bind to this receptor.
Several [3H] RTX-based VR binding assays have been disclosed: a filtration assay (Szallasi, A. and Blumberg, P. M., Specific binding of resiniferatoxin, an ultrapotent capsaicin analog, by dorsal root ganglia membranes, Brain Res., 1990, 524, 106-111; and, Harvey, J. S., Davis, C., James, I. F. and Burgess, G. M., Activation of protein kinase C by the capsaicin analogue resiniferatoxin in sensory neurons, J. Neurochem., 1995, 65, 1309-1317) and a centrifugation assay (Szallasi, A., Goso, C., Blumberg, P. M., and Manzini, S., Competitive inhibition by capsazepine of [3H] resinferatoxin binding to central (spinal cord and dorsal root ganglia) and peripheral (urinary bladder and airways) vanilloid (capsaicin) receptors in the rat, J. Pharmacol. Exp. Ther., 1993, 267, 728-33; Szallasi, A. and Goso, C., Characterization by [3H] resiniferatoxin binding of a human vanilloid (capsaicin) receptor in post-morten spinal cord, Neurosci. Letters, 1994, 165, 101-104; and, Acs, G., Palkovits, M., and Blumberg, P. M., [3H] Resiniferatoxin binding by the human vanilloid (capsaicin) receptor, Mol. Brain Res., 1994, 23, 185-90). Use of filtration assay protocols is hampered by a high non-specific binding. Using the centrifugation assay, VRI receptors were found in several tissues, such as, dorsal root ganglia, spinal cord, dorsal vagal complex, trachea and main bronchi and urinary bladder. The affinities of [3H]RTX to the VR1 receptor were different with different tissues (Szallasi, A. and Blumberg, P. M., Vanilloid (capsaicin) receptors and mechanisms, Pharmacol. Rev., 1999, 51, 159-211). High expression of VR1 receptors was observed in human and rat spinal cord and dorsal root ganglia tissues (Szallasi, et al, 1993; Szallasi and Goso, 1994; and, Acs, et al., 1994). The affinity of [3H]RTX to VR1 receptors in rat spinal cord is higher than that in human spinal cord (Szallasi and Goso, 1994).
U.S. patent application 546,141 A0 to Blumberg, et. al., filed Apr. 15, 1991, describes labeled RTX or labeled congeners thereof, wherein representative radiolabels include tritium, 125iodine [125I] and 131iodine [311] having a preferred formula:
Other representative congeners of RTX include those of the formula: wherein
n is 0 to 10 n is 0 to 10, preferably 2, and R′ is a fluorescent label. In lieu of radiolabeled RTX, the Blumberg application describes that biologically active congeners of RTX can be radiolabeled using the same synthetic route as for tritiated RTX, wherein such congeners have the general structure: wherein R is: R3 is OH, x is 0 or 1, R1, R2, R4 and R5 each are: H, OH, OC(═O)(CH2)nH, O(CH2)nH with n=0 to 10. In labeled compounds of the above congeners, at least of R1, R2, R4 or R5 is labeled, for instance, with 3H, 125I or 131I. In this formula, one of more of R1, R2, R4, and R5 is 3H. R3 should be OH so that the derivative is active. The preparation of 125I or 131I labeled RTX, tinyatoxin and congeners thereof possessing an unsubstituted m-hydrogen on the substituted phenylacetic acid side chain have been described, wherein such compounds can be prepared by iodination using chloramine T or using glucose oxidase or lactoperoxidase and, in the described compounds, one or more of R1, R2, R4 and R5 may be 125I or 131I.
PCT patent application WO 98/20867 to Blumberg, et. al., describes a pharmaceutical composition comprising a capsaicin agonist, a capsaicin antagonist and a pharmaceutically acceptable carrier wherein the capsaicin agonist is of the formula: wherein R1 is: R2 is hydroxy or methoxy; R3 is loweralkylaryl or an aryl group having 1 to 3 rings; and, R4 to R7, which may be the same or different, are independently selected from the group consisting of hydrogen, hydroxy, methoxy, sulfhydryl, nitro, amino, ethoxy, halo and OCOCH3.
No reference has heretofore disclosed a method for preparing an iodinated or labeled resiniferatoxin derivative. The object of the present invention is to provide a method for preparing an iodinated resiniferatoxin derivative and congeners thereof. Another object of the invention is to provide a method for preparing a labeled resiniferatoxin derivative and congeners thereof. Also another object of the invention is to provide a method for iodinating or labelling a specific site of a para-O-acetylated vanilloid receptor intermediate. A further object of the invention is to provide a method for use of an lodinated or labeled resiniferatoxin derivative and congeners thereof in a vanilloid receptor binding assay.


A method for titrating a drug to provide a medical therapy to a patient. The method includes the steps of providing an implantable medical device having a controller, providing one or more implantable sensors configured to sense physical parameters of the patient and configured to transmit signals to the controller. The method further includes the step of receiving signals from the one or more sensors at the controller. The method additionally includes processing the received signals to determine at least two cardiopulmonary characteristics of the patient. The method also includes determining a composite index based on the at least two cardiopulmonary characteristics. In addition, the method includes generating a signal based on the composite index. Medical device systems are also disclosed.

Congestive heart failure (CHF), also called just heart failure, is a condition that can result from any structural or functional cardiac disorder that impairs the ability of the heart to fill with blood or to pump a sufficient amount of blood throughout the body. Heart failure is a common syndrome. By one estimate, heart failure affects 5 million people in the U.S. and 550,000 new cases are diagnosed each year.
One characteristic of heart failure, among others, is autonomic imbalance. Continuously high sympathetic tone can cause increased heart rate, cardiac oxygen consumption, and risks of arrhythmias. Therefore, a common medical therapy for the treatment of heart failure is the administration of beta blockers. Examples of beta-blockers that are indicated for the treatment of heart failure include bisoprolol, carvedilol, and extended-release metoprolol. Beta blockers block the action of certain central nervous system neurotransmitters, such as epinephrine (adrenaline) and norepinephrine (noradrenaline), on the receptors of the sympathetic nervous system that mediate the "fight or flight" response. For example, stimulation of certain receptors by epinephrine induces a positive chronotropic and inotropic effect on the heart and increases cardiac conduction velocity and automaticity. Beta blockers also have an antiarrhythmic effect, which arises from the depression of sinus node function and atrioventricular node conduction, and prolonged atrial refractory periods. Beta blockers inhibit normal epinephrine-mediated sympathetic actions, but have minimal effect on resting patients. That is, they reduce the effect of excitement/physical exertion on heart rate and force of contraction, dilation of blood vessels, opening of bronchi, reduce tremor, and breakdown of glycogen.
However, the use of beta blockers can also result in side effects. The administration of beta blockers is a balance between the effectiveness of the drug in treating the heart disease or other medical condition and the side effects. Because beta blockers tend to depress cardiac activity, a primary side effect is bradycardia or low heart rate. In many cases, the ideal balance point is defined as the dosage of beta blockers that results in a desired resting heart rate, where further increases in dosage would result in a heart rate that is undesirably low. Other side effects of beta blockers include atrioventricular block, which is a delay or interruption in the conduction of electrical signals from the atria to the ventricles, resulting in arrhythmias or bradycardia. Furthermore, beta blockers may also cause hypotension, where the patient's blood pressure is too low, because of the depressive effects of the beta blockers on the patient's cardiac system. Certain other drugs, such as certain antiarrhythmics, can create similar side effects.
The balance between therapy and side effects generally requires that a patient undergoing drug therapy go through a drug titration procedure. Basically, drug titration normally involves first administering a relatively small dosage of a drug, then monitoring the patient's side effects, and subsequently increasing the dosage of the drug until the targeted benefits are achieved or until the patient's side effects meet or exceed a desired threshold. The dosage is increased until the patient's side effects increase to the point that they are judged to warrant no further increase in dosage or that the patient reaches a maximum recommended dosage.
However, improved techniques are needed for drug titration. Current techniques do not necessarily yield optimum results. Furthermore, current drug titration techniques require face-to-face interaction with medical personnel, which consumes resources and is inconvenient for the patient.

Drug titration utilizing an implantable medical device


A NFC communicator or NFC communications enabled device has a data store to store data, a coupler to couple inductively with the magnetic field of a radio frequency signal and a signal generator to supply a radio frequency signal to the coupler. A modulator is provided to modulate a radio frequency signal in accordance with data and a demodulator is provided to extract data from a modulated radio frequency signal inductively coupled to the coupler. A controller enables the NFC communicator or NFC communications enabled device both to initiate near field radio frequency communication with another near field RF communicator and to respond to near field radio frequency communication initiated by another near field RF communicator. The NFC communicator or NFC communications enabled device also has a power deriver that derives power from a radio frequency signal inductively coupled to the coupler to charge a chargeable power supply.

Near field RF (radio frequency) communication requires an antenna of one near field RF communicator to be present within the alternating magnetic field (H field) generated by the antenna of another near field RF communicator by transmission of an RF signal (for example a 13.56 Mega Hertz signal) to enable the magnetic field (H field) of the RF signal to be inductively coupled between the communicators. The RF signal may be modulated to enable communication of control and/or other data. Ranges of up to several centimeters (generally a maximum of 1 meter) are common for near field RF communicators.
Near field communication may be referred to as near-field RFID (Radio Frequency Identification) or near-field communication. NFC communicators are a type of near field RF communicator that is capable of both initiating a near field RF communication (through transmission or generation of an alternating magnetic field) with another near field RF communicator and of responding to initiation of a near field RF communicator" includes not only NFC communicators but also initiating near field RF communicators such as RFID transceivers or readers that are capable of initiating a near field RF communication but not responding to initiation of a near field RF communication by another near field RF communicator and responding near field RF communicators such as RFID transponders or tags that are capable of responding to initiation of a near field RF communication by another near field RF communicator but not of initiating a near field RF communication with another near field RF communicator. Hence NFC communicators can act as both RFID transceivers and RFID transponders and are able to communicate with other NFC communicators, RFID transceivers and RFID transponders.
Examples of near field RF communicators are defined in various standards for example ISO/TEC 18092, ISO/IEC 14443, ISO/IEC 15693 ISO/IEC 21481.
NFC communicators may be provided as standalone or discrete devices or may be incorporated within or coupled to larger electrical devices or host devices (referred to below as NFC communications enabled devices) to enable those devices to communicate by the near field with other near field RF communicators or devices incorporating or coupled to such near field RF communicators. When incorporated within a larger device or host, a NFC communicator may be a discrete entity or may be provided by functionality within the larger device or host. Examples of such larger devices or host devices are, for example, mobile telephones, portable computing devices (such as personal digital assistants, notebooks, lap-tops), other computing devices such as personal or desk top computers, computer peripherals such as printers, or other electrical devices such as portable audio and/or video players such as MP3 players, IPODs®, CD players, DVD players.
NFC communicators and host devices of course require a power supply to function. Where an NFC communicator or host device incorporating or coupled to an NFC communicator is powered by a chargeable power supply such as a rechargeable battery, then maintenance of a sufficient power supply is of prime importance to the functioning of both the host device and the NFC communicator, particularly where the NFC communicator or host device is being used in circumstances in which charging of the battery using a mains charging unit is not possible, for example because the user of the NFC communicator or host device does not have the mains recharging unit with them or is in a location without access to a mains power supply point. These power supply issues may be exacerbated for a host device because the NFC communicator may place an additional drain on the chargeable power supply of the host device. Additionally absence of suitable power supply may prevent or interrupt near field RF communication between one NFC communicator and another near field RF communicator. Depending on the application of such communication this could result in a failure to complete a required function or action, for example, a failure to obtain access to a location, refusal of a ticket to travel, inability to purchase goods or transfer data or information between electrical devices.

This patent is subject to a terminal disclaimer.

Charging a chargeable power supply of a near field communication (NFC) enabled device from a radio frequency (RF) signal inductively coupled onto a magnetic field


A mobile working machine includes a working arm which is mounted in an articulated manner, by a first end, on a revolving superstructure of the working machine, and a tool which is mounted in a displaceable manner on a second end of the working arm. The mobile working machine includes a position control device of a working arm. At least one inclination sensor is arranged on the revolving superstructure and at least one inclination sensor is arranged on the working arm. Also, at least one rotation rate sensor is arranged on the working arm. The working machine further includes a calculation unit for processing the signals of the at least one inclination sensor, of at least one additional inclination sensor, and of at least one rotational rate sensor.

The disclosure relates to a mobile working machine, for example an excavator, a truck with a superstructure, or an agricultural and forestry device comprising at least one working arm. Working arms of such working machines usually have a plurality of segments interconnected in an articulated fashion, a tool such as a bucket, a gripper or a hammer being fitted on a segment, also called a shank.
The current position and attitude of the working arm and, in particular, also of the tool is frequently indicated to the operator of such a working machine on a display, the operator thereby being enabled to carry out work according to accurately prescribed plans, and receives direct feedback relating to achieved levels, lengths, depths or inclinations, for example of a bulk material or soil which has been moved, or of the underlying ground which is to be shaped or has already been shaped.
Such operator displays are known, for example, from DE 201 16 666 U1 and U.S. Pat. No. 5,854,988 A.
In this case, the position and the attitude of the tool are frequently determined, partly because of the good retrofitting possibility, by inclination sensors that are fitted on the individual segments of the working arm. The position and attitude of the tool can then be calculated from the inclinations of the individual arm segments via the known geometric relationships of the kinematic chain comprising, for example, adjustable boom, boom, shank and tool.
Since, however, sensors based on the measurement principle of inertia such as, for example, gravitation-sensitive pendulums, are used as inclination sensors, they are frequently also sensitive to accelerations due to shocks and vibrations such as occur unavoidably when such work machines are used. Such motion-induced accelerations can substantially disturb or temporarily disable the measurement of the position and attitude of the tool. A known measure for suppressing these disturbances consists of a lowpass filtering of the sensor signals such that motion-induced accelerations outside the useful frequency band are suppressed.
However, this is attended by a number of disadvantages: firstly, accelerations within the useful frequency band cannot be suppressed in this way, while secondly the lowpass filtering causes a temporal delay of up to a few hundred milliseconds which is, however, accepted, because it still enables an adequately accurate position display and does not hinder the manual operation of the working arm.
It is known from other technical fields to make use of a combination of acceleration-based inclination and rotation rate sensors to control the position of, for example, a robot, an aerodynamic vehicle or a vehicle. WO 01/57474 A1 discloses such a method, in which a quaternion representation is used to calculate a position.

Mobile working machine comprising a position control device of a working arm, and method for controlling the position of a working arm of a mobile working machine


A display unit includes a first substrate and a second substrate opposed to each other, a display element having a first electrode and a second electrode on the first substrate, an auxiliary electrode provided on a surface facing the first substrate of the second substrate, and including a plurality of films stacked in a direction from the second substrate to the first substrate, and a plurality of pillars configured to electrically connect the auxiliary electrode to the second electrode.

The present disclosure relates to a display unit and an electronic apparatus having a display element such as an organic light emitting element or the like.
Recently, an organic EL display, in which a self-luminous organic light emitting element including an organic layer is used as a display element, has been practically used. The organic EL display is a self-luminous display, and therefore has a wide viewing angle compared with, for example, a liquid crystal display, etc., and has sufficient response even to a high definition, high-speed video signal.
Previously, the organic light emitting element has been tried to be improved in display performance by controlling light generated by a light emitting layer, such as improving color purity of an emission color and/or luminous efficiency through introducing a resonator structure. For example, the organic light emitting element may adopt a structure where a first electrode, an organic layer, and a second electrode are stacked in order on a first substrate via a drive circuit including a drive transistor and the like. In an organic light emitting element of a top emission type, the second electrode is configured of a transparent conductive material, light from the organic layer is multiply reflected between the first and second electrodes, and the light is extracted through a second substrate opposed to the first substrate. The transparent conductive material used for the second electrode in general has a resistance value higher than a metal material. In a relatively large organic light emitting display unit, therefore, display performance may be gradually degraded along a direction from an end region to a central region of a display section due to an effect of voltage drop. If thickness of the second electrode is increased, a resistance value is lowered and voltage drop is reduced in a display plane, but visible light transmittance of the second electrode is lowered, resulting in lowering of light extraction efficiency of the light emitting element.
To overcome such a difficulty, there has been proposed a technique where an auxiliary electrode is provided on the second substrate, and the auxiliary electrode is electrically connected to the second electrode of the organic light emitting element, thereby voltage drop of the second electrode is reduced (for example, see Japanese Unexamined Patent Application Publication No. 2002-33198). For example, the auxiliary electrode may be electrically connected to the second electrode of the organic light emitting element via conductive pillars.


A carbon dioxide containing fluid is flowed through a membrane in an open position. The membrane encapsulates an adsorbent bed operating at a first temperature. The adsorbent bed adsorbs at least a portion of the carbon dioxide of the carbon dioxide containing fluid. The membrane is adjusted to a closed position, thereby isolating the adsorbent bed and preventing fluid flow into and out of the membrane. The adsorbent bed is heated to a second temperature, thereby desorbing the carbon dioxide captured from the carbon dioxide containing fluid. The membrane is adjusted to the open position. The adsorbent bed is cooled to the first temperature.

With rising concerns of climate change and greenhouse gas emissions, carbon dioxide capturing processes can be an avenue for mitigating emissions. Typically, carbon dioxide captured from large point sources, such as cement factories and biomass power plants, is transported and sequestered in an underground geological formation, so that it does not enter the atmosphere. In some cases, carbon dioxide can be captured from air. In some cases, the carbon dioxide captured in such processes can be used as part of a feedstock for creating synthetic fuels.


A liquid, radiation curable composition is disclosed that includes a reactive diluent to lower initial application viscosity without substantial reduction of cure rate. The composition of the present invention comprises: (a) an unsaturated polyester polymer; (b) a non-polymerized, cocurable polyfunctional vinyl ether component; and (c) a reactive diluent which is an unsaturated dioic acid ester having the following structural formula: ##STR1## wherein at least one of R.sup.1 and R.sup.2 is a group that includes an oxygen with a carbon adlacent thereto and an abstractable hydrogen attached to the carbon.

The present invention relates to liquid, radiation curable compositions, particularly coating compositions, containing an unsaturated polyester component in combination with a vinyl ether component. Such compositions have rapid cure rates initiated by exposure to ultraviolet light or electron beam.
Radiation curable coating compositions based on unsaturated polyester polymers and vinyl ether compounds are the subject of commonly owned, co-pending U.S. Pat. No. 5,536,760 to Charles B. Friedlander and David A. Diehl, which corresponds to European Patent Publication 0 322 808. The use of unsaturated polyester polymers in such compositions, particularly polyesters having relatively high molecular weight, is desirable in that they can produce very good final film properties. However, some unsaturated polyesters that are preferred for their desirable final film properties tend to render the viscosity of the coating formulations unacceptably high for conventional coating application processes.
These coatings also contain vinyl ether compounds of the general formula R--(O--CH.dbd.CH.sub.2).sub.n (where R may be selected from a wide variety of alkyl (groups, and n is at least 1, preferably greater than 1.0). The vinyl ethers are used to produce a three dimensional crosslinked network, and they may also serve to reduce the initial application viscosity of the formulation during coating application. However, the use of the vinyl ether component to reduce viscosity of the coating composition has limits. When formulating such compositions, the stoichiometric ratio of unsaturated bonds in the polyester polymer component to the unsaturated bonds in the vinyl ether component is typically about 1:1. Increasing the vinyl ether component content above the 1:1 stoichiometry in order to reduce viscosity is not an attractive alternative due to the relatively high cost of vinyl ethers and because the excess vinyl ether component may remain uncrosslinked under typical free radical initiated radiation curing conditions. Residual uncrosslinked vinyl ether component remaining after curing may result in a degradation of the final cured film properties.
It is also known to employ reactive diluents (i.e., those that react into the cured film molecular network) such as styrene to reduce the initial viscosity of coating compositions without substantially sacrificing final film properties. Styrene is not desirable as a reactive diluent for radiation curable compositions of the type involved here because styrene slows the cure rate, which is one of the attractive features of these coating compositions.
Solvents are commonly used to reduce the viscosity of coating compositions during application, but the use of solvents is not desirable with the radiation curable coatings of the type involved here. These coatings may be made extremely low in volatile organic content, whereby they are attractive from an environmental standpoint. Using solvents to reduce the viscosity would detract from this desirable feature.
It would be desirable to utilize the advantages of cured film properties yielded by unsaturated polyester polymers in coating compositions having suitable viscosities for application without the disadvantages of substantially higher cost, substantially slower radiation cure rate, or addition of volatile organic components.

Polyester and vinyl ether radiation curable compositions with reactive diluent


Method for routing mobile phone signaling messages between different collaborating networks (20,30) including an STP (25,35) and at least two home networks (10,40) including an STP (16,36). A collaborating ITP (29,39) is connected to a collaborating STP (25,35), a home ITP (17,47) is connected to a home STP (16,46), and a central ITP (51) is connected to each ITP via a wide area network (6) which is not a PSTN. A visited country IMSI identifies a mobile subscriber as a subscriber to a collaborating network. A visited IMSI is associated with a home network in the central ITP. A signaling message, including the visited IMSI, is sent from a collaborating STP to the collaborating ITP, and is forwarded to the central ITP. The message is forwarded from the central ITP to a home ITP with which the visited IMSI is associated, and sent to the corresponding home STP.

Field of the Invention
The present invention relates to a method and a system for roaming of a mobile communications unit between mobile communication networks in different countries.
Description of the Related Art
Presently, it is common for mobile operators to have national mobile communication networks, such as networks for mobile data and/or voice communication, for example GSM, GPRS, 3G, LTE, etc. When a mobile communication unit is brought outside of the coverage area of a certain network and into the coverage area of the network of another operator, conventional roaming gives rise to problems with high and unpredictable costs for data and/or voice communication.
These problems are especially common when it comes to mobile data traffic, where costs during roaming with variable tariffs can amount to more than 1000 times higher per data unit as compared to mobile data traffic in the home network. Many times there are no efficient ways of keeping track of the costs during a stay abroad or the like. As a consequence, a user risks unpleasant surprises regarding mobile data costs when returning from a stay within the coverage area of the network of a foreign operator.
EP2144458 describes a method using an interface means to provide a SIM card with information regarding available networks for data traffic as well as connection costs for said networks.
WO2007132233 describes a method for remotely configuring a mobile communications device, and for registering and authenticating users of such a device. Configuration data is received and converted by the device, and a configuration database is updated using the data. In one example, different Subscriber Identity Module (SIM) cards with different International Mobile Subscriber Identities (IMSI) can be tied to the same user account for roaming.
WO2005081962 describes a method for keeping costs down for voice communication when roaming, by establishing a corresponding Voice over IP (VoIP) call when requesting a voice call from a mobile unit over a cellular network.
WO2008103446 describes a method in which the IMSI of a SIM is associated with a local telephone number (MSISDN) when roaming, in order to enjoy local tariffs.
WO2001076188 describes a method in which a care of address is used with a mobile device when performing IP-based communication.
The international patent application PCT/SE2011/050886, which has not been published on the filing date of the present application, describes a method according to which a local IMSI is automatically distributed to a SIM card in a mobile device roaming into a visited country.
A drawback of this method is that it exposes the home operator to the risk of misconfiguration in partner networks. Such misconfiguration will lead to malfunction of the roaming function. Namely, the method relies upon that a location update request message from a roaming device is correctly routed from the local roaming partner, via a local PSTN operator and a home PSTN operator, to the home network. This in turn involves processing of the IMSI, for instance using a routine involving translating the IMSI into a so called Global Title number format, which can be understood correctly by the PSTN operators. In the case of a network with many roaming partners, different IMSI number ranges for different purposes, customer agreements and so forth, the risk for misconfiguration of the IMSI number conversion at one or several of the local roaming partners is non-negligible.

Method and system for roaming of a mobile communications unit


A loading apparatus for use in electroplating processes includes a container designed to sealingly receive a plurality of airfoil blades fitted with gaskets. Each fitted airfoil blade is disposed in contact with a plurality of electrical contact assemblies having a spring-like design which ensures an adequate connection is made and complete plating of the airfoil blades occurs.

Generally, electroplating processes involve lowering a workpiece or part into a plating bath containing a plating solution. The workpiece or part may be mounted within a loading apparatus, which is configured to be lowered or inserted into the plating bath(s). The part is typically dipped several times in the same bath or several different plating baths. Each time the part is removed from one bath; the part is dipped in a rinsing bath, or a "tack tank" as commonly referred to by one of ordinary skill in the art, to remove excess plating material, prevent oxidation of the part and prepare the part for the next plating bath.
One example of a loading apparatus of the prior art for electroplating processes, and utilized by Pratt & Whitney in East Hartford, Conn., a division of the United Technologies Corporation, is depicted in FIGS. 1-3. The loading apparatus 10 of the prior art is designed to receive a plurality of turbine airfoil blades (not shown).
Loading apparatus 10 has a substantially rectangular container 12 having an inwardly sloping front wall 14, an inwardly sloping back wall 16, a pair of sidewalls 18, 19, a base 20. A bus bar attachment composed of a pair of plastisol stainless steel bus bars 22, 24 is mounted to base 20 underneath each respective receptacle area 30, 31 and between base 20 and another plastisol coated stainless steel bus bar 26. Bus bars 22, 24 are both threadingly secured to bus bar 26 and base 20 by four bolts 28. A round dowel 29, threadingly secured to bus bar 26 by a bolt 27, is designed to connect to a shaft (not shown) of a conveyor apparatus for use in a line for the intended electroplating process. Container 12 includes a pair of receptacles 30, 31, each designed to receive a turbine airfoil blade (not shown). Once the airfoil blades are pneumatically inserted within receptacles 30, 31, a cover 32 is threadingly secured to container 12 by fourteen threaded bolts 34 and two pairs of threaded bolts 42. Each threaded bolt 34 is fitted between a first o-ring 35 and cover 32 within a plurality of first threaded apertures 40 of cover 32, and proximate to both front wall 14 and backwall 16, and sealed with a second o-ring 37. Each threaded-bolt 42 is fitted between a plate 43 and cover 32 within a plurality of second threaded apertures 45 of cover 32, proximate to both first sidewall 18 and second sidewall 19. Each receptacle 30, 31 includes four sidewalls 44, 46, 48 and 50 and a base 52 having an aperture 54. Sidewalls 44, 46 are formed in part by a center portion 33 of cover 32 and a center portion 39 of base 20.
As known to one of ordinary skill in the art, each airfoil blade contains a hollow cavity. In order to prevent plating solutions of one bath from entering the interior cavity of a blade and then contaminating another subsequent bath, the hollow cavities are typically filled with wax. As a result, an operator of the electroplating process must manually fill each airfoil blade's interior cavity. Each turbine airfoil blade is then inserted platform end first into each receptacle 30, 31 using a pneumatic ram or other similar device capable of generating 110 pounds per square inch (psi) to force each airfoil blade into each receptacle 30, 31. Each receptacle 30, 31 requires an airfoil blade in order to prevent transporting electroplating solutions from one bath to another and thus contaminate the baths.
Each airfoil blade must touch the interior base portion within each receptacle 30, 31 in order to receive electrical current from bus bars 22, 24 and 26. When the airfoil blade did not connect in part or completely with the receptacle's interior base portion, the plating would not evenly and/or completely adhere to the blade tip. The resulting unevenly plated airfoil blade would require a quality inspection to determine whether the blade would be scrapped or could be salvaged. In order to salvage an unevenly coated blade tip, the entire cover of the blade must be stripped, the surface cleaned and the airfoil blade reinstalled into loading apparatus 10. This process involves numerous steps which could prevent that particular airfoil blade from being re-plated for over a day or longer. Moreover, if another airfoil blade was not readily available for insertion into the empty receptacle, loading apparatus 10 would be taken off-line in order to prevent the potential contamination of the electroplating baths.
Once the operator has loaded the airfoil blades into receptacles 30, 31, the operator manually aligns cover 32 with the airfoil blades and secures it to container 12. Cover 32 weighs over approximately thirty pounds (30 lbs.) so the operator must be physically capable of lifting, placing and securing cover 32 onto container 12. Once cover 32 is in place, the operator manually inserts and tightens each bolt 34, 42 using a rachet, torque wrench, or other similar tool. Since an air tight seal must be achieved, it was not uncommon for the operator to apply the tool too strongly and accidentally strip a bolt.
At this time, the operator would attach loading apparatus 10 to a mechanized conveyor apparatus (not shown). Upon completion of the process, loading container 12 is detached from the conveyor apparatus and cover 32 is removed. As described earlier, one or more bolts 34, 42 were typically stripped while installing cover 32. In order to remove stripped bolts 34, 42, a maintenance person equipped with a cutting wheel, saw or similar device would cut away each stripped bolt thus requiring additional time and manpower and increasing the cost of plating the airfoil blades. Once bolts 34, 42 were removed, cover 32 was again manually removed by the operator and each blade tip was visually inspected to determine whether or not an acceptable plating was achieved.
The process for coating airfoil blade tips proved to be time consuming, inefficient and cost prohibitive. The tooling costs and additional manpower contributed both time and costs to each run of the production line. The contamination of plating baths also contributed additional time and even temporarily shut down the process to replace a bath and/or tack tank solution. If the operator discovered loading apparatus 10 was carrying excess bath or tack tank solution, then the operator was required to dismantle loading apparatus 10 in order to clean and remove the contaminants. Likewise, if the operator discovered an airfoil became contaminated, then the airfoil blade had to be removed and replaced, if possible, in order to prevent future contamination. Again, the production line would be halted to remove the airfoil blade, and either replace the blade or halt the line if a replacement blade was not available.
In addition to line problems, operators required a pneumatic ram or other device to insert each airfoil blade into receptacles 30, 31. Operators also had to be physically capable of manually lifting, aligning and placing a 30+ lbs. cover 32 onto container 12, and then securing cover 32 to container 12 using a torque wrench, rachet and the like, to tighten eighteen bolts. Inevitably, one or more bolts would be stripped and require a technician or maintenance personnel to cut or saw off the stripped bolt from loading apparatus 10 in order to remove cover 32. Moreover, and even if the production line operated smoothly, there was always a question as to whether all of the airfoil blade tips would be coated properly.
Consequently, there exists a need for an improved loading apparatus designed to receive airfoil blades without the use of a pneumatic tool and capable of maintaining the integrity of its seal to prevent contamination of the airfoils as well as baths and tack tanks.

Ergonomic loading apparatus for electroplating processes


The invention relates to a method for operating an x-ray diagnostics device having an x-ray source and an x-ray image detector, between which the distance can be adjusted, with an image sequence of low resolution images being provided with a different distance, an adjustment of the coordinates systems of the images being carried out and a high resolution image being calculated from the images. A method for generating high resolution x-ray recordings is achieved here by means of a C-arm system, a so-called C-arm superresolution image.

An x-ray diagnostics device of this type known from DE 100 37 735 A1 is shown for instance in FIG. 1, which comprises a C-arm 2 which is mounted in a rotatable manner on a stand 1, an x-ray emitter 3 and an x-ray image detector 4 being disposed on the ends of said C-arm.
Floor and/ceiling tripods can also be used instead of the stand 1 shown. The C-arm 2 can also be replaced by a so-called electronic C-arm 2, which effects an electronic coupling of the x-ray emitter 3 and the x-ray image detector 4.
The x-ray image detector 4 can be rectangular or square flat semiconductor detector, which is preferably made of amorphous silicon (aSi).
A patient support table 5 for accommodating a patient to be examined is located in the radiation path of the x-ray emitter 3.

Method for operating an x-ray diagnostics device


A method and apparatus for optical performance monitoring that provides for multi-rate and multi-protocol monitoring includes, identifying a protocol associated with each of a plurality of communication signals using respective data rates extracted therefrom, determining, for each of the plurality of communication signals, a respective bit-error rate (BER), and generating an alarm indicative of BER excursions beyond a protocol appropriate BER threshold level.

There is a growing trend toward all-optical re-configurable networks promising higher levels of data-rate and protocol transparency. However, in order to maintain these higher performance levels, signal quality monitoring must be provided at the optical layer. In such systems measurement of optical parameters is critical as it provides vital information regarding the performance of the system. Such information can then be used for diagnosis and repair of an optical network or for performance of optimization actions. One standard measurement of signal quality in optical systems has been the bit error rate (BER) of a system. The BER of a system is affected by two forms of signal degradation, noise and distortion. The measurement of such parameters must be accurate, have a wide range, and be performed in a timely manner so as to provide the necessary information in the shortest amount of time for the appropriate actions.
Some techniques used for monitoring optical signal quality include spectral analyzing and sampling. The conventional approach to analyzing the optical parameters of a spectrally dependent system is to use an optical spectrum analyzer. These systems are generally based on an optical tool known as a monochromater. Monochromater-based optical spectrum analyzers are typically slow, large in size for most embedded and field applications, and tend to drift with time, giving poor absolute accuracy. The sampling method on the other hand, is the only method that accounts for both noise and distortion and thus comes closest to BER measurement. Unfortunately, previous implementations of sampling methods have been very complicated, slow, and are limited to a single data rate and a single protocol.

Method and apparatus for multi-protocol and multi-rate optical channel performance monitoring


A chemical composition of matter comprising a wax plasticizing agent (plasticizer) tributoxyethyl phosphate, a mixture of selected long chain fatty acids (preferably C10 to C22), and a mixture of selected low-surface tension surfactants, which when added in solution to crude oil or refined products has been shown to lower both the B.S. & W. (rag layer) and the coefficient of friction of crude oils and refined products. This chemical composition of matter is particularly useful as a wax liquefaction, dispersant, and solubilization agent for asphaltene and paraffins in crude oil and refined products. The reduction in the co-efficient of friction resulting from the addition of this product to crude oil will allow crude oil to pump through pipelines with a minimum amount of resistance due to friction (drag).

1. Field of the Invention
The present invention relates to more efficient use of petroleum. More particularly, the present invention relates to a chemical composition of matter for the liquefaction and dissolution of paraffin waxes and asphaltenes into petroleum crude oil and distillate products at ambient temperatures.
The present invention relates generally to converting crystalline wax, as for example, exists in slop oil, crude oil and refined distillate products, into an amorphous form of wax, causing it to be dissolvable in for example, crude oil at ambient temperature and maintained in a dissolved state for a prolonged period of time at ambient temperature, and more particularly, in its preferred, exemplary embodiment, to the use preferably of a chemical composition of surfactants, leveling or plasticizing agents (plasticizers) and blends of fatty acids that can, for example, recover waste hydrocarbon products (paraffin waxes and asphaltenes) from both naturally occurring and synthetic sources, and more particularly to recover these waste hydrocarbon products for use as energy sources and to reduce environmental pollution. A number of other applications are also disclosed and claimed.
2. General Background of the Invention
Waxy materials present in crude oils and in the high boiling fractions of distillates are considered to be crystalline throughout but under certain conditions may behave like a colloid. Certain wax solutions of refined products such as petrolatum, when agitated or mixed for long periods near or at the crystallizing temperature, will form a completely transparent jelly. But the same solution, when chilled rapidly with moderate agitation will precipitate a wax that can be centrifuged.
It was observed many years ago in the sweating of solid paraffins at the petroleum refinery that three crystalline forms (manifestations) of wax are involved. These are known as "plate", "malcrystal", and "needle" (note, for example, The Chemistry and Technology of Waxes by Albin H. Warth, published by Reinhold Publishing Corp. (New York, 1947) p. 239). It was recognized that the relative proportion of these types of crystals not only has a relationship to the source of the crude but also to the process of handling the wax.
The members of each series crystallize similarly as either plates, malcrystals, or needles. If one type is present (plate, mal, or needle), the crystal form remains the same regardless of such factors as the amount and kind of solvent.
When crude oil is pumped from the ground and transported through pipelines, transported by ocean tankers, or stored in storage tanks on land or offshore, a large amount of heavy material separates and comes out of solution. The main component of this residue is high molecular weight (high melting point) paraffin waxes. In some cases the wax represents as much as 90 percent of the deposited residues.
The amounts of wax present in crude oil are to a large extent an indicator of its origin, whether the crude originated in Venezuela, Mexico, or Malaysia.
The mixture of wax, oil, sand, and water is referred to as "slop oil", or "slop" (sludge), in the petroleum industry. The percentage of slop oil varies according to the type of crude and the conditions under which it has been transported. Usually the amount of slop oil ranges from a low of 0.5% to a high of 10%; normally, it is in the range of 2% to 5%.
For the last century and until today the only way to keep slop oil from separating from crude oil is to heat the slop oil while it is being transferred into mixing tanks with crude oil. The cost of keeping slop oil from separating from crude oil is a function of many variables such as temperature, solvent diluents (cutter stocks), and residence time of the crude in a tank or pipeline.
The petroleum industry is plagued with the problem of having to deliver crude oil to refineries in a timely and economic manner with a minimum amount of slop oil separation. If a pipeline becomes plugged up or clogged because of paraffin wax precipitating out during the pumping operation, a crisis can arise. Numerous pipelines worldwide are clogged daily or monthly due to wax precipitating out of the crude oil. Daily, 80,000,000 barrels of crude oil are pumped from the ground worldwide (as of May, 2004). If 5% of the heavy residues separated out of the crude oil being transported, whether by pipeline or tanker, the amount of slop oil or crude residue formed would be 4,000,000 barrels per day. This amounts to 1.5 billion barrels per year. If 70% of this slop oil is useable crude which can be processed to refine production, then the amount of recoverable hydrocarbon equals over 1.0 billion barrels per year. At a cost of $10.00/barrel for crude oil this amounts to the recovery of $10 billion per year of useable hydrocarbon as either energy or petrochemical feedstock.
In storage tanks the problems associated with wax settling out are tremendous and present an extremely challenging task for petroleum production companies, refiners and terminal operators.
When crude oil remains idle and cold in a storage tank, a heavy residue forms that, over time, accumulates at the bottom of the tank and reduces the tank's useable volume. This residue, known as slop oil (or slop, or sludge) consists of heavy paraffinic waxes and asphaltenes which solidify in crystalline form. Slop oil is extremely difficult to remove from tanks and presents a very costly disposal problem for the refinery and terminal operator.
Traditional tank cleaning methods use a combination of heat (e.g., 60 to 70 degrees C. or greater) and mechanical agitation to force the slop oil back into solution with crude oil, so the mixture can be pumped out of the tank. In order to keep the waxes and asphaltenes in solution in the crude oil, the mixture must be kept at high temperature, for example, 75 degrees C. or greater and, in most cases, continuously circulated. The tremendous amounts of energy required to heat and circulate large volumes of dense crude oil at these elevated temperatures over long periods of time increases handling costs dramatically.
After pumping out the slop oil containing paraffin waxes and asphaltenes, the slop oil mixture must be kept hot or the wax will separate from solution, and the problems associated with slop oil will recur. This need to use heat results in high energy costs and large losses.
For general background, "prior art" information pertinent to the invention, reference is made to (all incorporated herein by reference):
The Chemistry and Technology of Waxes by Albin H. Warth, published by Reinhold Publishing Corp. (New York, 1947), p. 239 et al;
Petroleum Refinery Engineering by W. L. Nelson, published by McGraw-Hill Book Co. (New York, 4th Ed. 1958), particularly Chapter 12 "DeWaxing" (pp 374-75 et seq.);
Physical Chemistry by Walter J. Moore, published by Prentice-Hall, Inc. (New York, 1955), particularly Chapter 16 "Surface Chemistry" (p. 498 et seq.); and chemical and process technology encyclopedia edited by Douglas M. Considine, published by McGraw-Hill Co. (New York, 1974), particularly its sub-section on "Waxes" (p. 1167 et seq.);
Composition and crystal form of the petroleum waxes, S. W. Ferris, H. C. Cowles, Jr., and L. M. Henderson (The Atlantic Refining Company) Industrial and Engineering Chemistry, June 1931, (pp 681 to 688); all references included in this article;
Crystal behavior of paraffin wax, S. W. Ferris and H. C. Cowles (The Atlantic Refining Company), Industrial and Engineering Chemistry, Nov., 1945 (pp 1054 to 1062); all references included in this article.
The following US Patent Documents are incorporated herein by reference: U.S. Pat. Nos. 6,783,582; 6,322,621; 3,554,913; Published US Patent Application Pub. No. US 2002/0066391 A1; and all references cited in these patent documents.

Chemical composition of matter for the liquefaction and dissolution of asphaltene and paraffin sludges into petroleum crude oils and refined products at ambient temperatures and method of use


The present invention provides serological and genetic methods of diagnosing a medically resistant clinical subtype of ulcerative colitis UC. The present invention provides a method of diagnosing a medically resistant clinical subtype of UC by determining the presence or absence of anti-Saccharomyces cerevisiae antibodies (ASCA) in a patient with UC, where the presence of ASCA indicates the medically resistant clinical subtype of UC. The present invention also provides a method of diagnosing a medically resistant clinical subtype of UC by determining the presence or absence of a TNFa2b1c2d4e1 haplotype in a patient with UC, where the presence of said TNFa2b1c2d4e1 haplotype indicates the medically resistant clinical subtype of UC. In addition, the invention provides a method of diagnosing a medically resistant clinical subtype of UC by determining the presence or absence of a TNFa2b1c2d4e1 haplotype in a patient with UC and determining the presence or absence of ASCA in the patient with UC, where the presence of said TNFa2b1c2d4e1 haplotype indicates the medically resistant clinical subtype of UC and the presence of ASCA independently indicates the medically resistant clinical subtype of UC. The invention further provides kits for diagnosing a medically resistant clinical subtype of UC containing antigen specific for ASCA and one or more oligonucleotide primers complementary to a nucleotide sequence flanking TNF microsatellite locus TNFa, TNFb, TNFc, TNFd or TNFe.

1. Field of the Invention
The invention relates generally to the fields of autoimmunity and inflammatory bowel disease and more specifically to serological and genetic methods for diagnosing clinical subtypes of ulcerative colitis.
2. Background Information
Inflammatory bowel disease (IBD) is the collective term used to describe two gastrointestinal disorders of unknown etiology: Crohn's disease (CD) and ulcerative colitis (UC). The course and prognosis of IBD, which occurs world-wide and is reported to afflict as many as two million people, varies widely. Onset of IBD is predominantly in young adulthood with diarrhea, abdominal pain, and fever the three most common presenting symptoms. The diarrhea may range from mild to severe, and anemia and weight loss are additional common signs of IBD. Ten percent to fifteen percent of all patients with IBD will require surgery over a ten year period. In addition, patients with IBD are at increased risk for the development of intestinal cancer. Reports of an increasing occurrence of psychological problems, including anxiety and depression, are perhaps not surprising symptoms of what is often a debilitating disease that strikes people in the prime of life.
Unfortunately, the available therapies for ulcerative colitis are limited in effectiveness, and both diagnosis and treatment have been hampered by a lack of knowledge regarding the etiology of the disease. What is clear, however, is that ulcerative colitis is a classification representing a number of distinct disease subtypes that affect the gastrointestinal tract and produce similar symptoms. The heterogeneity underlying UC is reflected in variable responses of UC patients to particular treatment strategies: available anti-inflammatory and steroid therapies are effective in treating some patients with UC, while other patients have disease that is resistant to medical treatment. Methods of diagnosing this medically resistant clinical subtype would be useful since these patients can benefit from early, aggressive treatment prior to full progression of their disease.
Methods for diagnosing the medically resistant clinical subtype of UC would represent a major clinical advance that would aid in the therapeutic management of UC. These diagnostic methods, combined with earlier medical treatment, would provide a patient having medically resistant disease with an alternative to surgical colectomy. Such methods also would advance medical management of UC by identifying a subgroup of patients for whom alternative treatment modalities must be sought. Unfortunately, methods of stratifying UC into medically resistant and medically responsive clinical subtypes are currently not available. Thus, there is a need for such methods. The present invention satisfies this need and provides related advantages as well.

Methods of diagnosing a medically resistant clinical subtype of ulcerative colitis


A method of dividing an optical device wafer includes: a laser beam processing step of performing laser beam processing on the face side of an optical device wafer so as to form breakage starting points along streets; a protective plate bonding step of bonding the face side of the optical device wafer to a surface of a highly rigid protective plate with a bonding agent permitting peeling; a back side grinding step of grinding the back side of the optical device wafer so as to form the optical device wafer to a finished thickness of optical devices; a dicing tape adhering step of adhering the back-side surface of the optical device wafer to a dicing tape; a cut groove forming step of cutting the protective plate bonded to the optical device wafer along the streets so as to form cut grooves; and a wafer dividing step of exerting an external force on the optical device wafer through the protective plate, so as to break up the optical device wafer along the breakage starting points formed along the streets, thereby dividing the optical device wafer into the individual optical devices.

1. Field of the Invention
The present invention relates to a method of processing an optical device wafer by which an optical device wafer having optical devices composed of a gallium nitride compound semiconductor or the like layered in a plurality of regions demarcated by streets formed in a grid pattern on the face-side surface of a substrate such as a sapphire substrate is divided along the streets into the individual optical devices.
2. Description of the Related Art
An optical device wafer in which a plurality of regions are demarcated by planned dividing lines called streets formed in a grid pattern on the face-side surface of a sapphire substrate and optical devices composed of a gallium nitride compound semiconductor or the like are layered in the demarcated regions is divided along the streets into the individual optical devices such as light emitting diodes, which are widely utilized for electric apparatuses. As a method for dividing the optical device wafer along the streets, a method of cutting the optical device wafer by a cutting blade rotated at high speed has been attempted, but it is difficult to cut the sapphire substrate by a cutter, since the sapphire substrate has a high Mohs hardness and is a difficult-to-cut material.
In recent years, as a method for dividing a wafer such as an optical device wafer along streets, there has been proposed a method in which the wafer is irradiated with a pulsed laser beam having such a wavelength as to be absorbed in the wafer along the streets to form laser beam-machined grooves, and an external force is applied along the laser beam-machined grooves so as to break up the wafer along the streets (see, for example, Japanese Patent Laid-open No. Hei 10-305420).
In addition, as a method for dividing a wafer such as an optical device wafer along streets, there has also been proposed a method in which the wafer is irradiated with a pulsed laser beam having such a wavelength as to be transmitted through the wafer along the streets while adjusting the focal point position of the pulsed laser beam to the inside of the wafer, thereby continuously forming an altered layer inside the wafer along the streets, and an external force is exerted along the streets along which the wafer strength has been lowered due to the formation of the altered layer, to break up the wafer along the streets (see, for example, Japanese Patent Laid-open No. 2008-6492).
The optical device wafer as above-mentioned is formed to a predetermined thickness by grinding the back side thereof, prior to division into the individual devices. Besides, in recent years, a reduction of the thickness of optical devices to 50 μm or below is demanded for realizing electric apparatuses reduced in weight and size. When an optical device wafer is ground to a small thickness of 50 μm or below, however, the optical device wafer would be cracked.

Method of processing optical device wafer


An alignment jig for a liquid-jet head, which is used when positioning and joining a nozzle plate and a fixing member, the nozzle plate having nozzle orifices for jetting a liquid of the liquid-jet head and an alignment mark for alignment, the fixing member being adapted to hold a plurality of the liquid-jet heads, the alignment jig comprising a mask which is a transparent member provided with a reference mark for alignment with the alignment mark, the reference mark being formed within the mask.

1. Technical Field
The present invention relates to an alignment jig and an alignment apparatus for a liquid-jet head, which are useful, particularly, when used in high accuracy alignment of the liquid-jet head with an alignment mark printed on a mask as a transparent member; and also relates to a method for producing the liquid-jet head.
2. Related Art
An ink-jet recording apparatus, such as an ink-jet printer or an ink-jet plotter, is equipped with an ink-jet recording head unit (may be hereinafter referred to as a head unit) including an ink-jet recording head which ejects, as ink droplets, ink accommodated in a liquid accommodation portion such as an ink cartridge or an ink tank. The ink-jet recording head has nozzle rows comprising rows of nozzle orifices arranged in parallel, and has its ink ejection surface side covered with a cover head. The cover head has a window frame portion having an opening window portion provided on the ink droplet ejection surface side of the ink-jet recording head for exposing a nozzle opening, and has a side wall portion formed by being bent from the window frame portion beside the side surface of the ink-jet recording head. The cover head is fixed by having the side wall portion joined to the side surface of the ink-jet recording head (see, for example, JP-A-2002-160376 (page 4, FIG. 3)).
When the cover head and a fixing member, such as a fixing plate, are to be joined to a plurality of the ink-jet recording heads, the ink-jet recording heads are moved with respect to the fixing member for predetermined positioning so that an alignment mark provided in a nozzle plate aligns with a reference mark provided in a flat plate-shaped glass mask. The reference mark is generally formed on the surface of the glass mask by chrome printing or the like (see, for example, JP-A-2004-345281 (page 10, FIG. 3)).
However, when the reference mark is formed on the surface of the glass mask, as mentioned above, the problem arises that the reference mark is damaged by chipping or scarring, for example, due to the contact of the surface of the glass mask with the liquid-jet head. To achieve high accuracy positioning, the distance between the reference mark and the alignment mark needs to be minimized. Nevertheless, it has been difficult to support the nozzle plate directly on the surface of the glass mask via the fixing member.
To raise the accuracy of alignment, it is necessary to increase the magnification of an optical system in an optical means for observing the reference mark and the alignment mark. When the magnification is increased, however, the reference mark needs to be rendered smaller and to be formed from thinner lines, in accordance with the increase in the magnification. The smaller and the thinner the reference mark becomes, the higher the risk of the aforementioned chipping or scarring becomes.
Such a problem occurs not only with alignment associated with the production of an ink-jet recording head unit, but also with alignment associated with the production of other liquid-jet head units.

Alignment jig and alignment apparatus for liquid-jet head and method for producing liquid-jet head


A touch screen system is provided herein for use with a commanded system requiring high integrity. The touch screen system includes, but is not limited to, a display screen configured to present information to an operator. A sensor array is arranged proximate the display screen to detect a touch on the display screen and to generate a set of touch position coordinates corresponding to a location of the touch. A processor is operatively coupled to the display screen and is configured to command the display screen to arrange a plurality of touch target images such one of the touch target images is a high integrity touch target image. The high integrity touch target image has a unique X-coordinate that is not shared by any other touch target image and a unique Y-coordinate that is not shared by any other touch target image.

Touch screen systems are control systems that are commonly used to control electrical, mechanical and computer systems (hereinafter, "commanded systems"). Touch screen systems present information to an operator with a display screen that is adapted to detect a touch (e.g., physical contact or near physical contact made using a body part, a stylus, a light projector or by some other means of contact). The operator provides an input into a touch screen system by touching the touch sensitive screen. For example, the operator may be presented with images on the display screen that include both text and collocated or associated graphics (e.g., a textual question and closely located "yes" and "no" boxes) and the operator may input a selection into the touch screen system by touching the graphics that corresponds with the operator's choice.
Multiple technologies are available to detect the occurrence and location of the operator's touch on the display screen. Some of the more common technologies include resistive, surface capacitive, projected capacitive, infrared, surface acoustic wave, acoustic pulse recognition, and camera based technologies. Each technology, while generally reliable, experiences occasional errors. It is postulated that each touch screen system employing any one of these technologies may occasionally incorrectly determine the location of the operator's touch or may detect a touch at a time when the operator did not touch the touch sensitive screen.
For some uses, such as selecting a radio station on a stereo, an occasional error may be inconsequential, especially as the operator soon recognizes the error, and thus the use of a touch screen system to control a commanded system in such instances may be acceptable. For other applications, however, an error, especially one undetected by the operator, could potentially have very serious consequences. This may be for safety reasons (as in avionics or industrial control), customer satisfaction reasons (e.g., in an automobile selecting high and low beams), or even financial reasons (in an automatic teller machine transferring money). For example, the avionics system of an aircraft in flight would require a control system that has an exceedingly low error rate, especially if undetectable by the operator, because the commanded system on the aircraft may directly control the aircraft's flight performance and could therefore have a direct impact on passengers and flight crew.
The Federal Aviation Administration (hereinafter, "FAA") has ranked various aircraft functions for safety needs on a sliding scale that ranges from minor to catastrophic events. If an aircraft function failure creates a failure condition whose severity is deemed to be "minor", then that function may be controlled by a control system having a postulated failure probability that exceeds 1/100,000 per flight hour. If an aircraft function failure creates a failure condition whose severity is deemed to be "major", then that function must be controlled by a control system having a postulated failure probability that is less than 1/100,000 per flight hour. If the function failure creates a failure condition whose severity is deemed to be "hazardous", then that function must be controlled by a control system having a postulated failure probability that is less than 1/10,000,000 per flight hour. And if the function creates a failure condition whose severity deemed to be "catastrophic", then that function must be controlled by a control system having a postulated failure probability that is less than 1/1,000,000,000 per flight hour. A minor failure condition has a slight reduction in aircraft safety margins; a major failure condition has a significant reduction in safety margins and may result in some occupant discomfort; a hazardous failure condition has a large reduction in safety margins and may have adverse effects upon occupants; a catastrophic failure condition can result in conditions which prevent safe landing and loss of aircraft. Similar definitions and categories are used in other industries such as industrial control, and by other safety authorities.
The concept of "failure" has several aspects which include detection and permanence. "Failure" denotes the inability to operate in situations where the pilot either knows that the equipment is nonoperational and takes appropriate action, or the system is designed such that a failure of one element results in another part of the system compensating with or without the pilot's knowledge thus averting a failure condition. An example of this is an automatic cabin temperature controller. If this equipment fails, the pilot may feel uncomfortable and can switch to manual control or activate a secondary temperature controller. Alternatively, several controllers can operate in parallel and one may be designed to automatically takes over when another fails without pilot interference and possibly without the pilot knowledge.
In another aspect, "failure" means an uncorrected equipment failure that the pilot is not aware of. This undetected failure can result in a condition typically called an "undetected hazard" or "undetected misleading data". This has the possibility of providing misleading data or control information to the pilot. An example of this is an altimeter malfunction. If the altimeter is showing the wrong altitude and if there is no indication to the pilot that the altimeter is operating improperly and if there are no other means to detect the malfunctioning altimeter, the consequences could be quite serious. For this reason, there are typically several independent sources of altitude and altimeters in the flight deck which the pilot can scan to verify that all are registering the same altitudes, within appropriate limits.
As used herein, the term "failure" refers to failures which are both permanent and transitory in nature. For example, a permanent failure can be the breaking of a wire or the cracking of a resistor. A transitory failure may include radiation or radio interference changing a bit in a register, components drifting in and out of specification due to environmental conditions, or other similar short term variations.
The term "integrity" is an attribute of an item indicating that it can be relied upon to work correctly on demand. Therefore an item having "high integrity" can be relied upon to perform the most critical functions such as an autopilot and items having "low integrity" can be relegated to non-critical functions such as lighting control. In the avionics industry, "integrity" has several aspects. One aspect is the probability at which undetected failures occur. Another aspect is the probability at which undetected failures caused by errors (as opposed to equipment failures) occur.
In the current state of the art, the use of touch screens in avionics is predominately for actions where failures of integrity will result only in minor failure conditions or, at most, in a limited number of major failure conditions. In the current state of the art, if a failure condition supported by a touch screen requires a higher level of integrity, then one mitigating technique is for the pilot to observe that the command from the touch screen has reached the commanded system, and to allow the control action to take place only after the pilot confirms that the system being commanded has received the proper request from the touch screen. For example, to lower the aircraft's landing gear, the pilot selects a gear down graphic on the touch screen. The touch screen then displays a query initiated by the landing gear system asking the pilot to confirm the "gear down" command is the intended command. If the pilot agrees that a "gear down" request was made via the touch screen system, then the pilot selects a confirming graphic (i.e., a "yes" button) to actuate the mechanism for lowering the landing gear. Once the confirming graphic has been selected, the landing gear will be lowered. In this manner, a higher integrity is provided by the touch screen because the touch screen's buttons and sensors, the touch screen's display, and the landing gear system must all fail in order to have the incorrect data transferred. The landing gear is only taken as an example and the description is not intended to imply the actual failure condition severity.
While this approach is adequate, it requires multiple pilot actions to execute a single command and this may be awkward or time consuming in certain flight situations such as in an emergency condition or upon takeoff or landing. At these times, the pilot will want to take a single rapid action, not multiple actions.

Touch screen system for use with a commanded system requiring high integrity


A flash memory cell formed in a semiconductor substrate. The memory cell comprises: (a) a gate oxide formed atop said semiconductor substrate, said gate oxide including a thin region and a thick region; (b) a floating gate formed atop said thin region; (c) a control gate formed atop said thick region; (d) a drain region formed under said thin region and within said floating gate; (e) a source region formed under said thick region and outside said control gate; and (f) an insulating dielectric layer between said control gate and said floating gate.

Flash memory is classified as non-volatile memory because a memory cell in the flash memory can retain the data stored in the memory cell without periodic refreshing. Most prior art flash memory can store a single bit in a memory cell. In other words, the memory cell can either store a "one" or a "zero".
Further, typical prior art flash memory cells are "two poly" processes, i.e., two distinct polysilicon deposition steps are required to form the cell. The most common structure for a flash memory cell is shown in FIG. 1. Further, typical prior art flash memory cells are "two poly" processes, i.e., two distinct polysilicon deposition steps are required to form the cell. In the most common structure for a flash memory cell shown in FIG. 1, a floating gate 101 comprised of polysilicon is formed atop of a thin gate oxide layer 103. A composite dielectric layer 111, such as oxide-nitride-oxide, is located atop the floating gate 101. The floating gate 101 and the composite dielectric layer 111 are in turn deposited and simultaneously patterned atop a semiconductor substrate 105. Finally, a control gate 113 comprised of polysilicon is formed atop the insulating oxide layer 111 and atop the floating gate 101. Adjacent the floating gate 101 are implanted source 107 and drain 109 regions.
In operation, the floating gate 101 can be in one of two states: (1) storing charge or (2) not storing charge. When the floating gate 101 is storing charge, the threshold voltage of the transistor will be shifted in the positive direction and a predetermined applied voltage applied to control gate 113 will not cause current to flow from the source 107 to the drain 109. When the floating gate 101 is not storing charge, the threshold voltage of the transistor will be shifted in the negative direction and the predetermined applied voltage applied to the control gate 113 will cause current to flow from the source 107 to the drain 109. In this manner, by using a "select transistor" (not shown) to measure the current from the source 107 to the drain 109 when a predetermined applied voltage is applied to the control gate 113, a determination can be made as to whether or not the floating gate 101 is carrying a charge, i.e., whether a "one" or a "zero" is being stored in the flash memory cell.
The process of placing a charge into the floating gate 101 ("writing") or removing a charge from the floating gate 101 ("erasing") is well known in the art and is simply the appropriate combination of applying voltages to the control gate 113, the source 107, and the drain 109. Further details of the flash memory cell of FIG. 1 may be found in Prince, "Semiconductor Memories: A Handbook of Design, Manufacture, and Application, 2nd Ed.," J. Wiley, 1991.
As seen in FIG. 1, the floating gate 101 requires the deposition of a first polysilicon layer and the control gate 113 requires the deposition of a second polysilicon layer. Additionally, the gate coupling ratio of the flash memory cell of FIG. 1 is relatively low. What is needed is a flash memory cell that may be manufactured using a single polysilicon layer and that provides a high coupling ratio.

Single polycylindrical flash memory cell having high coupling ratio

Worldwide Semiconductor Manufacturing Corporation


According to an aspect of the present invention, the foregoing needs are addressed by a splicing tool for joining a first tube and a second tube, including a first member and a second member which are moveably coupled. The first member has a first handle section and a first mold section. The first mold section has a first groove. The second member has a second handle section and a second mold section. The second mold section has a second groove. The first groove sized to receive at least a portion of a first tube, at least a portion of a second tube and a bonding material. The bonding material attaches the first tube to the second tube when the first and second grooves are substantially aligned and heat is applied to the bonding material.

Known line splicing tools and methods, including solvent or sealing type systems, soldering-type systems, quick disconnect systems and threading systems have notable drawbacks. For example, solvent or sealing type splicing systems may require the use of plastic or elastomeric tubing and require handling of liquid chemicals. In addition, solvent or sealing type splicing systems do not have built-in process controls to ensure a consistent seal.
The solder approach for splicing metal tubing may be limited to metals such as copper and also lacks built-in process controls.
Splicing via the use of quick disconnect fittings is costly and does not provide a leakproof connection and splicing via threaded fittings in conjunction with teflon tape or other joint compounds may be costly and not applicable to all types of tubing materials. Additionally, the aformentioned line splicing techniques when used in a field environment are cumbersome.
Thus, a need exists for a fluid line splicing tool which is compact, forms consistent seals, does not require the use of liquid chemicals and which includes a built-in process controller.

Splicing tool and method for joining a first tube and a second tube