A positive contrast agent composition containing meglumine diatrizoate, sodium diatrizoate, simethicone, famotidine and aspartame in predetermined amounts that is orally administered to a patient for clinical evaluations of appendicitis wherein a positive contrast effect is achieved. Methods of use include orally administering individual doses of the composition approximately 50 minutes prior to appendix visualization using computerized axial tomography.

This invention relates to a composition and method for direct visualization of the human appendix and method, more particularly, to a composition for use in direct visualization of the human appendix and method for diagnosing appendicitis that provides direct and unambiguous visualization of the human appendix, separate and distinct from the gastrointestinal tract.
The gastrointestinal tract is a long hollow tube, or viscus, extending from the mouth to the anus, and includes the stomach, small intestine, colon, and large intestine. The gastrointestinal tract has an important and necessary physiologic function in the digestion of food into biologically usable form to sustain life.
On the other hand, unlike the gastrointestinal tract, the appendix is not a hollow tube and does not participate in any gastrointestinal function. In fact, the appendix currently has no known biologic function. Instead, the appendix is an organ, distinct from the gastrointestinal tract and not related to digestive function, that is believed to be a vestigial structure, or remnant. In anatomic descriptions, the appendix is a blind-ending pouch, 7 to 8 cm in length, connected to the cecum. The appendix contains lymphoid tissue but it is uncertain whether this serves a physiologic role in lymphoid function.
Based on these distinct anatomic and physiologic differences, the appendix is by definition not considered part of the gastrointestinal tract. These differences make it particularly challenging to visualize and detect pathology of the appendix in humans.
Computed tomography (CT scan) is an imaging technology used to obtain detailed cross-sectional imaging of the human body tissues and organs. Small and insignificant organs, such as the appendix, are amenable to visualization and detection using CT scans. During a CT scan, a rotating x-ray machine and detector assembly rotate around the patient to produce a large number of radiographic images which are in turn stored in a computer for display and archival. Controlled amounts of radiation pass through the body and are attenuated by body tissues and organs, thereby producing radiographic images.
Typical CT examinations can be performed in only a few minutes. The patient lies supine on a table and passes through a narrow tunnel called the gantry, as a rotating x-ray machine and detector assembly capture two dimensional radiographic images of the human body. Because the scan increments can be exceedingly small, on the order of a few millimeters, CT scan can be adapted for organ-specific imaging, such as the appendix. An additional benefit of the CT scan is its speed and non-invasive technology, amenable to the testing of sick, elderly, and pediatric patients, either in a hospitalized or outpatient setting.
In preparing patients for the CT examination, radiopaque materials, also known as radiodense materials, collectively termed contrast agents, can be administered orally and/or intravenously, to produce further attenuation of the x-ray beam, creating optimal image contrast. The net effect of radiopaque contrast agents is that organ and tissue contrast appear white on the radiographic image. Body organs and tissues take up intravenous contrast agents, providing a temporary window of opportunity to study physiologic functions and detailed anatomic information. Oral contrast agents fill hollow tubes, including the esophagus, stomach, and bowel, all of which are considered part of the gastrointestinal or alimentary tract, providing additional information regarding bowel function and pathology.
The speed and accuracy of CT scans are essential in the diagnosis of potentially life threatening medical conditions, including appendicitis, an inflammatory condition of the appendix. During an appendicitis event, the orifice or opening the appendix becomes obstructed due to unknown factors, presumably hypertrophy of lymphoid tissue within the appendix. A build-up of purulent collection builds up within the appendix and can perforate freely into body cavities, resulting in sepsis, which is widespread dissemination of infection throughout the body, and potential death. Purulent concretions can also calcify to form small calculi called appendicoliths.
Thus, appendicitis is a legitimate public health concern. In fact, appendicitis has a lifetime risk of between 1 in 7 and 1 in 9 persons, and over 700,000 cases are evaluated in emergency wards in the United States each year. Delayed or missed appendicitis is among the leading causes of medical liability, which involve principally the morbidity and mortality complications associated with perforation and sepsis, which can occur rapidly, without warning, proving potentially catastrophic to the patient. The perforated appendicitis risk is approximately 65% in the pediatric population, but much less in adults, possibly 1 in 500.
Appendicitis also presents an added diagnostic dilemma, and can evade timely medical diagnosis. A significant number of patients fail to show the classic clinical signs of appendicitis, such as right lower quadrant peritoneal tenderness, fever, and leukocytosis (elevated white blood cell count). In these clinical settings, CT scans can be used to significantly reduce the risk of delayed or missed appendicitis.
One of the difficulties with appendicitis diagnosis is that appendicitis is not part of the gastrointestinal tract and has no known gastrointestinal function. Appendicitis and bowel diseases do not have a common anatomic basis, form, function, or mechanism of disease. In diseases of the bowel, the bowel can become obstructed, leading to abdominal distention and changes in bowel function, such as changes frequency or consistency of bowel movements. Appendicitis produces no such early warning signs. When appendicitis occurs, it often has progressed to the point of frank perforation or peritonitis. In the common practice of performing CT examinations, there also can be a significant time lag between the imaging findings and clinical manifestations of appendicitis.
Further compounding this diagnostic dilemma is the lack of a unified medical consensus regarding the optimal technique for CT scans of the appendix, including the optimal response time between performing a CT scan and obtaining reliable diagnostic results. In actual practice, this response time can lag by as much as 4 to 6 hours or more, an unacceptable standard. Many appendicitis patients are encountered in the outpatient setting in doctor's offices and clinics, but cannot be evaluated in the typical outpatient radiology facility because of significant time limitations and the lack of an available safe diagnostic pharmaceutical agent to facilitate rapid diagnosis.
In descriptions of the prior art, indirect methods of visualizing the appendix must be distinguished from direct methods. Added distinctions also must be made regarding the contrast agent used in the indirect method of evaluation. The choice of contrast agent can be either a positive contrast agent, which appears radiopaque, or radiodense, on the CT scan image, versus a negative contrast agent, which are not radiopaque on the CT scan image. Radiodensity generally appears white on the CT scan image; whereas absence of radiodensity appears black on the CT scan image. Body organs and tissues result in variable attenuation of the x-ray beam, producing a spectrum of image contrast, from white, to gray, to black.
Diatrizoate, a radiopaque contrast agent, is designated chemically as 1-deoxy-1-(methylamino)-D-glucitol-3,5-diacetamido-2,4,6-triiodobenzoate. Gastrografin® and Gastroview® are commercially available forms of diatrizoate, dispensed in a liquid form containing a solution of diatrizoate salts, and are typically used for visualization of the gastrointestinal tract. The potential dosing possibilities of these solutions are infinite but limited by the concentration of diatrizoate salts in solution. However, the most important characteristic of diatrizoate is the high atomic weight of iodine, which allows sufficient radiodensity for visualization of surrounding tissues.
The prescribed adult dosage is 25 mL of Gastrografin® in 1500 mL of water, producing a prepared solution containing 0.6% iodine. Barium suspension is another radiopaque contrast agent and the most commonly used for CT examinations of the gastrointestinal tract. However, barium suspension is contraindicated in clinical evaluations for appendicitis because of the risk of barium-induced peritonitis when barium suspension spills freely into the peritoneal cavity. Barium suspension cannot be used as a practicable alternative contrast media when dealing with bowel perforations or indirect evaluation of the appendix.
Examples of non-radiopaque contrast agents used for CT examinations of the gastrointestinal tract include water, methylcellulose, polyethylene glycol, hydrocolloid, and perfluorocarbons.
During a routine examination of the gastrointestinal tract, the appendix is not directly visualized as it is not part of the gastrointestinal tract. However, the appendix can form an impression or indentation on the bowel during an examination, resulting in an indirect method of visualizing the appendix, which is also known as a negative contrast effect. A positive contrast effect is one in which a radiopaque contrast agent, also known as a positive contrast agent, is concentrated directly within the organ of interest.
Gastrointestinal tract examinations in the prior art can be performed for indirect visualization of the appendix using either radiopaque (positive contrast) or non-radiopaque (negative contrast) agents. However, there are no positive contrast agents available or known commercially that produce an organ-specific positive contrast effect, i.e., concentration within the appendix. An ideal diagnostic pharmaceutical agent for diagnosis of appendicitis is one which is an organ-specific positive contrast agent (radiopaque) and which concentrates within the appendix, producing a positive contrast effect.
The use of negative contrast agents in the prior art has been well studied and lead to the same conclusion: there are significant inherent technical limitations in the evaluation of appendicitis. One of the major drawbacks of negative contrast agents is that they produce a weak bowel opacification that renders the agent useless for direct visualization of the appendix. The considerable bowel distention from air and fluid associated with negative contrast agents often obscures the appendix, which is not part of the gastrointestinal tract. Consequently, the confident diagnosis of appendicitis is rendered ambiguous and not obvious. Significant clinical side effects are also problematic and include diarrhea and patient non-compliance related to bowel distention and discomfort from excessive oral fluid intake, in addition to gaseous distention produced by the addition of mannitol, sorbitol, and sugar-based flavoring agents. The work of Megibow has further shown that a negative contrast effect is not considered sufficient clinically to allow for a confident diagnosis of appendicitis.
Megibow has investigated the extensive use of negative contrast agents available in the prior art, also encompassing those described herein, and concluded that negative contrast agents are not reliable in the diagnosis of appendicitis. Even when sufficient bowel distention has been achieved, the confident diagnosis of appendicitis is not rendered unambiguous or obvious. Particularly when the appendix is surrounded by multiple distended bowel loops, containing air and fluid, the negative contrast effect can further obscure visualization of the appendix.
One of the principal reasons that indirect methods fail to provide direct or organ-specific appendiceal visualization is that the primary goal of negative contrast agents is to visualize the bowel, not the appendix. The indirect visualization of the appendix by forming an impression or indentation on distended bowel loops appears to be an incidental or secondary result or benefit. As noted above, however, the appendix is not part of the gastrointestinal tract. Consequently, appendicitis is not a disease of the gastrointestinal tract, as diseases of the gastrointestinal tract and appendicitis do not have a common origin, causative factor, or mechanism. In order for pharmaceutical agents to work effectively in the appendix, they must target the appendix by considering the distinct and defined differences in anatomy and physiologic function between the appendix and the gastrointestinal tract.
Multiple examples of indirect methods of visualizing the appendix in the prior art reinforce the shortcomings of using gastrointestinal contrast agents to achieve a negative, rather than positive, contrast effect, regardless of whether they are negative contrast agents or positive contrast agents.
In contradistinction to indirect methods of visualizing the appendix, producing a negative contrast effect, a positive contrast agent is one in which there is organ-specific concentration of a pharmaceutical agent, producing a positive contrast effect. Therefore, positive contrast agents producing a positive contrast effect are preferable and represent an ideal pharmaceutical agent.
Neutrospect is an agent in the prior art that can produce a positive contrast effect in the appendix, but the result is not organ-specific. The mechanism of action involves the intravenous administration of radiolabelled murine myoclonal antibodies, which bind to human neutrophils in vivo. The radiolabelled antibodies are sequestered and accumulated in the peri-appendiceal area during an appendicitis event, and an imaging camera detects the radioactivity in the form of a spot on the radiographic film. However, Neutrospect is not site or organ specific for appendicitis and can be associated with any type of infection.
There are a number of inherent technical and therapeutic limitations of using Neutrospect in the clinical setting. First, it is of limited value clinically because it is not organ specific and has limited specificity. Neutospect accumulates not only in the appendix but in any target organ where there is an accumulation of neutrophils, as occurs with other infections, such as inflammatory bowel disease, diverticulitis, and intra-cavitary abscesses or collections. A positive Neutospect scan can produce an accumulation of radioactivity, or a spot on the radiographic film, practically anywhere in the body where there is an infection, confounding the clinician and further rendering a diagnosis of appendicitis as ambiguous and not obvious.
In addition, significant safety issues preclude the safe administration of Neutrospect in human subjects for appendicitis diagnosis. The United States Food and Drug Administration recently suspended clinical use of Neutrospect following documented incidents of fatal anaphylactic reactions leading to cardiopulmonary demise in several hospitalized patients. The long-term implications and future of Neutrospect are presently unclear. However, these significant safety issues, in addition to limited specificity for appendicitis diagnosis, preclude Neutrospect as a practicable diagnostic pharmaceutical for clinical use, particularly in the outpatient setting.
A definite need exists for an organ-specific or purpose-limited diagnostic pharmaceutical agent for appendicitis diagnosis due to the large numbers of subjects with potential lifetime risk for developing appendicitis, estimated at between 1 in 7 and 1 in 9 persons. No such ideal pharmaceutical agent is available commercially for routine clinical application.
Because of the possibilities for large numbers of patients undergoing diagnostic evaluations for appendicitis, particularly in the outpatient setting, a further need exists for a safe diagnostic pharmaceutical agent, in addition to being organ-specific or purpose-limited for appendicitis. Also not provided in the prior art is an ideal diagnostic pharmaceutical that can be easily manufactured in read-to-use packaged individual unit doses adapted for convenient and efficient outpatient usage.
Thus, a need exists for an oral composition of diatrizoate salts which provide a sufficient and faster rate for computerized axial tomographic examinations concentrating in the appendix wherein the contrast media is concentrated in the appendix.
The prior art contains contrast agents but none like the present invention, as follows:
Patent NumberInventorIssue Date5,233,995Yudelson et al.Aug. 10, 19934,735,795Robinson et al.Apr. 05, 19885,360,604Ruddy et al.Nov. 01, 19946,424,857Henrichs et al.Jul. 23, 20026,375,931Ostensen et al.Apr. 23, 20026,409,671B1Eriksen et al.Jun. 25, 20025,716,642Bagchi et al.Feb. 10, 19984,474,747Dimo et al.Oct. 02, 19842004/0241093LauensteinDec. 02, 20045,770,181KirklandJun. 23, 19982005/0180921Taylor et al.Aug. 18, 20056,426,077Grace et al.Jul. 30, 20025,242,683KlavenessSep. 07, 19934,192,859Mackaness et al.Mar. 11, 1980

Composition and method for direct visualization of the human appendix


A method for charging a storage battery includes providing an electric charger having a rapid charge voltage level and a trickle charge voltage level, a total-timer for measuring a total time which has elapsed since initiation of a charging operation, a peak-timer for measuring an amount of time which has elapsed since a peak voltage is reached during rapid charging of the storage battery, and an arithmetic circuit in the peak timer for determining a function of an elapsed time and a value of a charging rate. The arithmetic circuit of the peak-timer determines an elapsed time value of the peak-timer as a function of an elapsed time value of the total-timer and a value of a charging rate. The elapsed time value of the peak-timer is initially set at substantially the same time as an initial setting of a value of the total-timer. The peak-timer is started at a predetermined elapsed time after starting of a rapid charging operation.

1. Field of the Invention
The present invention relates to a method of setting a peak-timer when a storage battery is to be rapidly charged.
2. Description of the Related Art
It is well known to use secondary batteries, especially Ni--Cd types, in various fields as power sources for cordless telephones, video recorders and other home electric appliances. The Ni--Cd type of storage battery is frequently used, and during its use thereof, charging must be performed often, usually by what is commonly referred to as a "rapid charge" or "quick charge" method. In general, the rapid charging is carried out for about 1-2 hours at a charging rate in the range of 0.5.degree. C.-1.5.degree. C., where C represents a current value equal to the normal capacity of the battery in amp-hours. However, charging rates vary with different types of batteries.
Rapid charging subjects the storage battery to severe treatment, and therefore it is necessary to control rapid charging so as to prevent overcharging Regarding systems for detecting rapid charging, a -.DELTA.V system, a voltage detecting system, etc. have been put into practical use. Further, in order to prevent the battery from damage resulting from rapid charging, at least one of a total-timer, a temperature protective device and a voltage protection device is provided and actuated. Here, the total-timer refers to a device that regulates a period of time from a starting time point to an ending time point of the rapid charging, so that the charging operation occurs only for a predetermined period of time. Typically, a total-timer is used together with a peak-timer. The peak-timer starts its charging operation with the detection of a peak value of a charging voltage, and the charging operation is then stopped after a predetermined elapsed time after detection of the peak voltage value by either the total-timer or the peak-timer, whichever expires earlier.
When a total-timer is conventionally operated in a rapid charging operation, the setting and starting of the operation of the peak-timer are carried out without any time-relationship established between the peak-timer and the total-timer. Namely, the setting and starting operations of the total-timer are performed first, and when the peak value of the charging voltage is detected after a lapse of time from the start of rapid charging, the setting and starting operations of the peak-timer are then performed. Accordingly, it is typically necessary to treat the setting and starting operations of the total-timer and those of the peak-timer separately from each other, which can become burdensome to an operator.

Method of setting peak-timer of electric charger


A method of detecting hazardous conditions within an underground environment can include obtaining acceleration information at a plurality of communication nodes distributed throughout the underground environment and propagating the acceleration information among selected ones of the plurality of communication nodes to an analysis node. An indication of a hazardous condition within the underground environment can be identified from the acceleration information collected over a period of time. If an indicator is identified, a notification of the hazardous condition can be provided.

Working in underground environments such as tunnels or other underground excavations can be dangerous. Underground environments are associated with a special set of potentially life threatening conditions that include cave-ins, collapsing tunnel structure, exposure to toxic gases, and the like. As such, prevention and detection of these conditions are of paramount concern.
An underground environment, however, poses special challenges that must be addressed to successfully detect and prevent hazardous conditions. Technologies that function well above the ground, such as Global Positioning System (GPS), mobile phones, visual observation, and the like, do not function well below ground. This makes it difficult to assess a potentially dangerous situation in the underground environment.

Detecting hazardous conditions in underground environments

International Business Machines Corporation


A computer system, method, or computer-readable medium corrects a broken portion of an application. A fingerprint indicates classes that comprise the application. The classes indicated in the fingerprint are looked up to determine whether any is broken. For a broken class, a fixed class is substituted when the broken class is loaded at class load time for the application; a fixed class method is substituted into the broken class, when the broken class is loaded at class load time; fixed byte code is substituted for broken byte code corresponding to the broken class, when the broken class is loaded at class load time; the broken class is unloaded and the fixed class is loaded instead, when the application is running; or the broken class is replaced inside the static application with the fixed class; all without replacing classes which are not broken.

Today, there frequently are defects and/or security vulnerabilities or the like in pieces of software that make up an application. Often it takes time to move the fixes for the defects/vulnerabilities through the conventional process before the software application is deemed to be fixed. So, typically now if there is a bug, a developer needs to get an updated version of a piece of the software if using open source software, or a developer must pull up the source code and update the version himself, and then run it through the entire process of creating a version of the application with the update.
In practice, a developer may find out that there is a problem with an open source component that is being used in a software application. The developer will research the fix, go back into the development environment, update the component, re-run the integration test to ensure that all is functional, and then progress through the release process to release a new version. There is no way to do this without manually scouring code to find the vulnerability or bug.
In addition, there are situations where the ability to support a legacy custom application is much more problematic due to tack of understanding of the old application.
Consider Microsoft's Patch Tuesday as an example of a conventional way in which patches are released. Patch Tuesday is normally only once a month. Subsequent patches (and hence updates to pieces of software) will not be released until the next Patch Tuesday. During the time after Microsoft releases the patches, the hackers are reverse engineering the fixes and figuring out where the vulnerabilities are and creating corresponding exploits and then launching those.
Furthermore, Microsoft ships out many binary updates, e.g., to Windows, which can be installed, usually requiring a reboot of the Windows workstation.

Method and system for correcting portion of software application


A base station apparatus, includes: a processor; and a memory that stores a communication controlling program to be executed by the processor, wherein the processor is operable, based on the communication controlling program, to: receive a first call connection request transmitted from a terminal apparatus; compare a pattern including values of a plurality of parameters extracted from the first call connection request with a characteristic pattern of a second call connection request based on application communication; and perform, when the pattern of the first call connection request and the characteristic pattern coincide with each other, a transmission process to a different apparatus in accordance with the first call connection request after a delay time elapses from a reception timing of the first call connection request.

Together with the spread of the smartphone, utilization of an Internet application (for example, a social networking service (SNS), LINE (registered trademark) and so forth) through a mobile network is expanded and a utilization mode of a mobile network is varied significantly.
A related technology is disclosed in Japanese Laid-open Patent Publication No. 2011-155600 and Japanese Laid-open Patent Publication No. 06-28273.

Base station apparatus, communication controlling method and communication system


A resuscitation apparatus includes a fluid pathway in fluid communication with a source of medical fluid, an interface unit for attaching the fluid pathway to the cardiovascular system of a mammal suffering from impaired blood flow in order to establish an artificial circulation in the mammal utilizing the medical fluid, and heat exchange apparatus that provides intense cooling to quickly chill the medical fluid a sufficient amount to slow a metabolic rate of an organ of a mammal into which the medical fluid is introduced. A method of treating anoxic and/or ischemic brain injury in a mammal suffering from impaired blood flow includes utilizing heat exchange apparatus that provides intense cooling to quickly chill a medical fluid a sufficient amount to slow a metabolic rate of a brain of a mammal into which the medical fluid is introduced, and introducing the chilled medical fluid into the cardiovascular system of a mammal suffering from impaired blood flow in order to establish an artificial circulation in the mammal, whereby the mammal remains substantially neurologically intact.

1. Field of Invention
The invention relates to a resuscitation apparatus and method for directing a chilled medical fluid to the brain at a sufficient rate to allow a rapid drop in overall brain temperature. The apparatus and method extend the period of time in which life resuscitation methodologies may be performed on a patient suffering from trauma or decreased blood flow to the brain, without permanent brain damage resulting if recovery is achieved.
2. Description of Related Art
When trauma or decreased blood flow to the brain occurs, the brain is deprived of freshly oxygenated blood. For example, this situation typically occurs during cardiac arrest, respiratory arrest, stroke and other cerebrovascular trauma, suffocation, drowning, strangulation, electrocution, toxic poisoning (carbon monoxide, cyanide, etc.), metabolic insults or other similar trauma. Without a steady supply of freshly oxygenated blood, the brain ceases to function. After resuscitation, most patients will suffer some damage to the brain and associated neurologic tissues.
For example, among cardiac arrest victims overall less than 10% survive neurologically intact and without significant brain damage. The other approximately 90% either die or sustain some neurologic injury from ischemia (i.e., lack of blood flow to the brain) or anoxia (i.e., lack of oxygen to the brain). Such frequency of neurologic injury occurs because after a cardiac arrest, basic cardiopulmonary resuscitation and advanced life support techniques, such as CPR, closed heart cardiac chest massage, and electroshock treatments, typically require fifteen to twenty minutes to regain circulation from a failed heart. Reversible neurologic damage begins as early as four minutes and irreversible neurologic damage begins as early as six minutes after circulation stops. To combat this potential neurologic injury, initial resuscitation efforts need to be directed toward reviving and/or preserving the viability of the brain in addition to resuscitating the heart.
Anoxic and ischemic brain injuries from cardiac arrest result in damage to the brain and associated neurologic tissues after about four minutes. In contrast, the heart can survive intact up to four hours after cardiac arrest. The short viability of brain tissue upon deprivation of oxygenated blood is a result of the requirement of high amounts of nutrients for tissue maintenance. Brain tissue uses for maintenance almost all of the nutrients supplied to it by the circulating blood, and stores only a very small amount of nutrients. Absent blood flow to the brain, the small amount of stored nutrients is rapidly exhausted. Once the stored nutrients are exhausted, brain oxygen content rapidly depletes. This oxygen depletion is traumatic and causes a series of reactions in the oxygen starved brain tissue cells. These reactions are believed to produce free radical ions, primarily consisting of the superoxide radical O2xe2x88x92. These free radicals complex with proteins in the brain and associated neurologic tissues, altering respiration, energy transfer and other vital cellular functions, and irreversibly damaging these tissues.
Efforts should be directed toward extending the period of time the brain can function without oxygen while the patient remains neurologically intact.
The medical literature is replete with examples of humans surviving extended periods of time (greater than 5 minutes) without oxygen being delivered to the brain. For example, children revived after hours of submersion in very cold water have fully recovered with little if any neurologic damage.
Hypothermic therapy is one method of keeping the brain alive absent oxygen. It involves cooling the brain to a temperature where its metabolic activity is decreased. When the brain""s metabolic activity is decreased, it uses much less oxygen and more slowly exhausts stored nutrients, while production of irreversibly damaging O2xe2x88x92 free radicals is slowed and almost completely ceased. Thus, upon resuscitating the body from trauma, the patient emerges neurologically intact. The literature has demonstrated that a drop of 3-4 degrees Celsius can be sufficient to protect the brain from irreversible damage in a hypoxic state for at least 10-20 minutes.
Various apparatus and/or methods have previously been disclosed for directing a chilled medical fluid to the brain to prevent anoxic and/or ischemic injury during trauma.
In the article, xe2x80x9cPreservation of Cerebral Function During Circulatory Arrest and Resuscitation: Hypothermic Protective Considerationsxe2x80x9d, Robert M. White teaches delivering chilled fluids to the brain via the carotid arteries. According to the White method, the carotid arteries are punctured with Rochester no. 15 needles connected via plastic tubing to intravenous bottles containing cooled perfusate. The fluids are delivered at an average pressure of 75 mm mercury by an attached standard sphygmomanometer bulb. The fluids taught include saline, dextran and oxygenated blood.
Russian Patent No. 760,972 to Raduschkevi et al. discloses apparatus for cooling the brain during a sudden stoppage of the heart or an ineffective functioning of the heart. The apparatus includes a refrigeration unit that includes a heat-insulated chamber for cooling a blood-mixed fluid; a heat exchanger; a filter/trap; a perfusion pump; cannulae for connecting to blood vessels; and means for control and regulation of temperature and fluid transport. Blood from an artery can also be withdrawn through a tube, circulated through the apparatus, passing through the perfusion pump, the heat exchanger and the filter trap, and returned to the artery via a tube.
In U.S. Pat. No. 4,451,251, Osterholm discloses an apparatus and method for circulating a nutrient emulsion through the cerebrospinal fluid pathway system to satisfy cerebral metabolic needs where the vascular system has been obstructed. Osterholm teaches injecting the nutrient emulsion via cerebral catheter means directly into a cerebral ventricle. Osterholm further teaches that hypothermic temperatures may be selected for the nutrient emulsion in order to establish certain treatment conditions if so desired. The apparatus includes a nutrient emulsion reservoir, a heat exchanger, an oxygenator, a filtration device and the cerebral catheter means.
In U.S. Pat. Nos. 5,149,321, 5,234,405 and 5,395,314 and co-pending U.S. patent application Ser. No. 08/484,601 now U.S. Pat. No. 5,827,222, Ronald M. Klatz and Robert M. Goldman disclose a brain resuscitation device and corresponding method. The device includes a solution reservoir, an oxygenator, a heat exchanger, a fluid pathway and a catheter. The catheter may be a balloon catheter. The solution may include barbiturates, free radical scavengers and/or oxygen carrying agents. Further, the device may be portable.
However, none of these references provide heat exchange apparatus that provides intense cooling to quickly chill a medical fluid a sufficient amount to slow a metabolic rate of a brain of a mammal into which the medical fluid is introduced. Further, none of them provides a convenient portable apparatus. Furthermore, none discloses docking apparatus that allows the portable apparatus to be removably attached to a heat exchange apparatus in order to maintain a medical fluid chilled an amount sufficient to slow a metabolic rate of a brain of a mammal into which the medical fluid is introduced until the portable apparatus is needed. Additionally, none discloses a control unit that controls the introduction of medical fluid into the system to prime the system prior to introducing the medical fluid into a mammal.
The apparatus and method according to the invention extend the period of time in which life resuscitation methodologies may be performed on a patient suffering from trauma or decreased blood flow to the brain, without permanent brain damage resulting if recovery is achieved. Because emergency personnel often must treat patients suffering from trauma or decreased blood flow to the brain without the conveniences of a hospital, sometimes an apparatus is needed that can be carried with emergency personnel to the patient and be ready upon demand.
The apparatus and method according to the invention can utilize heat exchange apparatus that provide intense cooling to quickly chill a medical fluid a sufficient amount to slow a metabolic rate of a brain or other organ of a mammal into which the medical fluid is introduced, or alternatively, the resuscitation apparatus can be provided with docking apparatus that allows the portable apparatus to be removably attached to a heat exchange apparatus in order to maintain the medical fluid chilled an amount sufficient to slow a metabolic rate of an organ of a mammal into which the medical fluid is introduced until the portable apparatus is needed. Accordingly, the apparatus can provide the necessary cooling on demand, and, if optionally configured to be portable, can be carried to the patient. The apparatus is particularly applied to slow the metabolic rate of the brain but can be used to slow the metabolic rate of other organs depending on the location of entry in the cardiovascular system.
Further, medical fluids are expensive, and, away from the conveniences of a hospital, may be in short supply. The apparatus and method according to the invention can withdraw medical fluid from a mammal, degas, oxygenate and/or chill the medical fluid before reintroducing the medical fluid into the mammal. Accordingly, less medical fluid is needed.
Additionally, the apparatus and method can utilize a control unit to prime the system prior to introducing medical fluid into a patient. This allows medical personnel to focus more of their attention on life resuscitation methodologies which they are performing to revive the patient.

Brain resuscitation apparatus and method


There is provided a method and materials for cooling the power train components, such as transformers, rectifiers, chokes, and the like, of an integrated on-board power supply IOP) using a single heatsink. Spacers are positioned between the power train components and a substrate, the substrate for mounting the components. The spacers are individually dimensioned and shaped to raise the heat-removal surfaces of the components to a substantially uniform and minimal height. A heatsink having a substantially planar, heat-acquiring surface is positioned on the heat-removal surfaces of the power train components. Fasteners are used to compress the spacers, urging the components against the heatsink to provide a substantially continuous and coplanar thermal interface between the components and the heatsink. After the components, heat sink and substrate have been fastened to each other, the components are electrically connected to the substrate by soldering.

A very significant limitation on the operation and reliability of electronic components is the efficient extraction of heat. Unless heat generating components are provided with an efficient heat transfer mechanism to maintain them within a predetermined operating temperature range, the power and useful life of the components are severely limited. Excessive over-heating of electronic components may cause their destruction.
The problem of heat removal is increased for power supply modules having components of different heights, and which are densely populated on a substrate. Particularly, with integrated on-board power supplies (IOPs), such as DC-to-DC converters the problem of heat removal is acute, since power supplies generate a substantial amount of heat. An IOP is a module which is self-contained and typically mounted on a circuit board containing the logic components of the computer system. In order to minimize the total size of the system, the spacing or pitch between the various circuit boards of the computer system which are inserted in parallel fashion in the back plane of the computer system is kept to a minimum. Therefore, the height or profile of the IOP, including the heat generating components is kept, for example, less than 0.3 inches, and the height of the IOP including the heat dissipating components, such as a heatsink, must be kept less than the inter-board spacing.
A typical IOP includes heat generating power train components, for example, transformers, field effect transistors (FETs), rectifiers, and chokes. In general, the power train components are of varying surface topologies and of different heights. The components are provided with leads to permit attachment to a substrate. The leads are inserted in plated through holes or vias and electrically connected by solder to conductive circuit traces formed on the substrate.
It is a common approach in the cooling of heat generating components having different heights to provide the components, with poli-directional, or mono-directional heatsinks. Typically, the heatsinks are individually attached to the tops of the components for the purpose of dissipating heat. The drawbacks of such an approach is that the individual heatsinks are of necessity limited in their footprints, must each be sized to conform to the geometry of the components being cooled, must be aligned carefully with the components and are otherwise limited by the overall size of the system into which the module is incorporated. It is tedious and expensive to adapt individually heatsinks to discrete heat generating components 11-14 which are diverse in placement, shape, and height.
Alternatively, the power train components of the IOP are cooled by a single heatsink which is placed in thermal contact with the opposite side of the substrate on which the components are located. Although this scheme is fairly simple to assemble, it is less efficient in drawing heat from the components through the substrate, particularly if the components are surface mounted and lack leads protruding through the substrate for conducting heat, or if the substrate is made of relatively inexpensive material, for example, epoxy-glass, which has poor thermal conduction characteristics. Moreover, because the IOP is usually mounted on a circuit board, an undesirable cut-out may be required in the circuit board to accommodate the heatsink. Furthermore, some power train components generate so much heat that direct thermal contact with a heatsink is required to maintain the components at a desirable temperature.
Another approach is to provide a single heatsink for the group of components. The main drawback of this approach is that it is a complex task to thermally mate the rigid heatsinks with the components. Generally, a thermally conductive epoxy is used to cover the components in order to create a relatively smooth surface to mate with the heatsink. Thermally conductive epoxies require special handling, long curing time, and generally increase the manufacturing cost of the module. Also, the thermal conductivity of epoxies is relatively poor, typically about 10% than that of metals, requiring that the module be operated at substantially reduced power.
Alternatively, the mating surface of the single heatsink is especially machined to conform to the external mating surfaces of the components. This approach requires additional labor and careful alignment of the heatsink and components during assembly.
Accordingly, the known solutions for cooling an IOP increase the cost of assembly, and do not always provide for effective cooling of discrete and variously shaped heat generating components.
Therefore, it is desirable to provide an apparatus and method for reliably cooling an integrated on-board power supply which is simple to assemble, uses readily available inexpensive materials, and is easily adaptable to mass production methods at reduced costs.

Coplanar heatsink and electronics assembly


Embodiments are directed to receiving, by a microphone configured for audio use, an ultrasonic signal, applying an analog-to-digital (A/D) converter to the signal to generate a digital version of the signal, obtaining phase information from the digital version of the signal, and determining a position of an emitter of the ultrasonic signal based on the phase information.

Ultrasonic microphones may be used to detect a position of an ultrasound emitting stylus. The microphones used typically utilize the inherent mechanical resonance of small-sized micro-electro-mechanical system (MEMS) structures in order to make a small and inexpensive receiver. The resonance frequency is on the order of 35 to 55 kilohertz (kHz).
The microphones are typically sampled at least twice the largest frequency used (Nyquist criterion) a frequency larger than the resonance frequency. For example, sampling frequencies of 96 kHz or 192 kHz are common, resulting in a relatively large current consumption and low electromagnetic interference (EMI) immunity. An ultrasonic microphone with digital output would similarly suffer from high current consumption due to a large sample rate and a large bandwidth needed to transfer data.

Phase sensitive low power digital ultrasonic microphone


An inductor, a semiconductor component including the inductor, and a method of manufacture. A leadframe has a plurality of conductive strips and a flag. A ferrite core is mounted on a die attach material disposed on the conductive strips and a semiconductor die is mounted on a die attach material disposed on the flag. Wire bonds are formed from the conductive strips on one side of the ferrite core to corresponding conductive strips on an opposing side of the ferrite core. The wire bonds and the conductive strips cooperate to form the coil of the inductor. Wire bonds electrically couple one end of the inductor to leadframe leads adjacent the semiconductor die. Wire bonds couple bond pads on the semiconductor die to the leadframe leads coupled to the inductor. An encapsulant is formed around the inductor and the semiconductor die. Alternatively, a stand-alone inductor is manufactured.

Semiconductor component manufacturers are constantly striving to increase the functionality and performance of their products while decreasing their cost of manufacture. One approach for increasing functionality and performance has been to integrate passive circuit elements with active circuit elements in a semiconductor substrate. However, a passive circuit element such as an inductor occupies a large region of the semiconductor substrate. Thus, integrating an inductor with an active device increases the cost of semiconductor components composed of passive and active circuit elements. Another approach has been to couple a passive circuit element to an active circuit element on a printed circuit board substrate. This approach uses complex input and output interconnect structures. In both of these approaches, the cost of manufacturing the passive circuit elements increases the cost of the semiconductor component.
Thus, it would be advantageous to have a passive circuit element such as, for example, an inductor and a method for manufacturing the passive circuit element that is cost efficient and suitable for coupling with a semiconductor die.

Circuit component and method of manufacture

Semiconductor Components Industries, L.L.C.


There are provided novel compounds of formula (I), wherein R1, R2, R4, R5, G1, G2, L, Y and n are as defined in the Specification and optical isomers, racemates and tautomers thereof, and pharmaceutically acceptable salts thereof; together with processes for their preparation, compositions containing them and their use in therapy. The compounds are inhibitors of neutrophil elastase.

Elastases are possibly the most destructive enzymes in the body, having the ability to degrade virtually all connective tissue components. The uncontrolled proteolytic degradation by elastases has been implicated in a number of pathological conditions. Human neutrophil elastase (hNE), a member of the chymotrypsin superfamily of serine proteases is a 33-KDa enzyme stored in the azurophilic granules of the neutrophils. In neutrophils the concentration of NE exceeded 5 mM and its total cellular amount has been estimated to be up to 3 pg. Upon activation, NE is rapidly released from the granules into the extracellular space with some portion remaining bound to neutrophil plasma membrane (See Kawabat et al. 2002, Eur. J. Pharmacol. 451, 1-10). The main intracellular physiological function of NE is degradation of foreign organic molecules phagocytosed by neutrophils, whereas the main target for extracellular elastase is elastin (Janoff and Scherer, 1968, J. Exp. Med. 128, 1137-1155). NE is unique, as compared to other proteases (for example, proteinase 3) in that it has the ability to degrade almost all extracellular matrix and key plasma proteins (See Kawabat et al., 2002, Eur. J. Pharmacol. 451, 1-10). It degrades a wide range of extracellular matrix proteins such as elastin, Type 3 and type 4 collagens, laminin, fibronectin, cytokines, etc. (Ohbayashi, H., 2002, Expert Opin. Investig. Drugs, 11, 965-980). NE is a major common mediator of many pathological changes seen in chronic lung disease including epithelial damage (Stockley, R.A. 1994, Am. J. Resp. Crit. Care Med. 150, 109-113).
The destructive role of NE was solidified almost 40 years ago when Laurell and Eriksson reported an association of chronic airflow obstruction and emphysema with deficiency of serum α1-antitrypsin (Laurell and Eriksson, 1963, Scand. J. Clin. Invest. 15, 132-140). Subsequently it was determined that α1-antitrypsin is the most important endogenous inhibitor of human NE. The imbalance between human NE and endogenous antiprotease is believed to cause excess human NE in pulmonary tissues which is considered as a major pathogenic factor in chronic obstructive pulmonary disease (COPD). The excessive human NE shows a prominent destructive profile and actively takes part in destroying the normal pulmonary structures, followed by the irreversible enlargement of the respiratory airspaces, as seen mainly in emphysema. There is an increase in neutrophil recruitment into the lungs which is associated with increased lung elastase burden and emphysema in α1-proteinase inhibitor-deficient mice (Cavarra et al., 1996, Lab. Invest. 75, 273-280). Individuals with higher levels of the NE-α1 protease inhibitor complex in bronchoalveolar lavage fluid show significantly accelerated decline in lung functions compared to those with lower levels (Betsuyaku et al. 2000, Respiration, 67, 261-267). Instillation of human NE via the trachea in rats causes lung haemorrhage, neutrophil accumulation during acute phase and emphysematous changes during chronic phase (Karaki et al., 2002, Am. J. Resp. Crit. Care Med., 166, 496-500). Studies have shown that the acute phase of pulmonary emphysema and pulmonary haemorrhage caused by NE in hamsters can be inhibited by pre-treatment with inhibitors of NE (Fujie et al.,1999, Inflamm. Res. 48, 160-167).
Neutrophil-predominant airway inflammation and mucus obstruction of the airways are major pathologic features of COPD, including cystic fibrosis and chronic bronchitis. NE impairs mucin production, leading to mucus obstruction of the airways. NE is reported to increase the expression of major respiratory mucin gene, MUC5AC (Fischer, B. M & Voynow, 2002, Am. J. Respir. Cell Biol., 26,447-452). Aerosol administration of NE to guinea pigs produces extensive epithelial damage within 20 minutes of contact (Suzuki et al., 1996, Am. J. Resp. Crit. Care Med., 153, 1405-1411). Furthermore NE reduces the ciliary beat frequency of human respiratory epithelium in vitro (Smallman et al., 1984, Thorax, 39, 663-667) which is consistent with the reduced mucociliary clearance that is seen in COPD patients (Currie et al., 1984, Thorax, 42, 126-130). The instillation of NE into the airways leads to mucus gland hyperplasia in hamsters (Lucey et al., 1985, Am. Resp. Crit. Care Med., 132, 362-366). A role for NE is also implicated in mucus hypersecretion in asthma. In an allergen sensitised guinea pig acute asthma model an inhibitor of NE prevented goblet cell degranulation and mucus hypersecretion (Nadel et al., 1999, Eur. Resp. J., 13, 190-196).
NE has been also shown to play a role in the pathogenesis of pulmonary fibrosis. NE: α1-protenase inhibitor complex is increased in serum of patients with pulmonary fibrosis, which correlates with the clinical parameters in these patients (Yamanouchi et al., 1998, Eur. Resp. J. 11, 120-125). In a murine model of human pulmonary fibrosis, a NE inhibitor reduced bleomycin-induced pulmonary fibrosis (Taooka et al., 1997, Am. J. Resp. Crit. Care Med., 156, 260-265). Furthermore investigators have shown that NE deficient mice are resistant to bleomycin-induced pulmonary fibrosis (Dunsmore et al., 2001, Chest, 120, 35S-36S). Plasma NE level was found to be elevated in patients who progressed to ARDS implicating the importance of NE in early ARDS disease pathogenesis. Donnelly et al., 1995, Am. J. Res. Crit. Care Med., 151, 428-1433). The antiproteases and NE complexed with antiprotease are increased in lung cancer area (Marchandise et al., 1989, Eur. Resp. J. 2, 623-629). Recent studies have shown that polymorphism in the promoter region of the NE gene are associated with lung cancer development (Taniguchi et al., 2002, Clin. Cancer Res., 8, 1115-1120.
Acute lung injury caused by endotoxin in experimental animals is associated with elevated levels of NE (Kawabata, et al., 1999, Am. J. Resp. Crit. Care, 161, 2013-2018). Acute lung inflammation caused by intratracheal injection of lipopolysaccharide in mice has been shown to elevate the NE activity in bronchoalveolar lavage fluid which is significantly inhibited by a NE inhibitor (Fujie et al., 1999, Eur. J. Pharmacol., 374, 117-125; Yasui, et al., 1995, Eur. Resp. J., 8, 1293-1299). NE also plays an important role in the neutrophil-induced increase of pulmonary microvascular permeability observed in a model of acute lung injury caused by tumour necrosis factor α (TNFα) and phorbol myristate acetate (PMA) in isolated perfused rabbit lungs (Miyazaki et al., 1998, Am. J. Respir. Crit. Care Med., 157, 89-94).
A role for NE has also been suggested in monocrotoline-induced pulmonary vascular wall thickening and cardiac hypertrophy (Molteni et al., 1989, Biochemical Pharmacol. 38, 2411-2419). Serine elastase inhibitor reverses the monocrotaline-induced pulmonary hypertension and remodelling in rat pulmonary arteries (Cowan et al., 2000, Nature Medicine, 6, 698-702). Recent studies have shown that serine elastase, that is, NE or vascular elastase are important in cigarette smoke-induced muscularisation of small pulmonary arteries in guinea pigs (Wright et al., 2002, Am. J. Respir. Crit. Care Med., 166, 954-960).
NE plays a key role in experimental cerebral ischemic damage (Shimakura et al., 2000, Brain Research, 858, 55-60), ischemia-reperfusion lung injury (Kishima et al., 1998, Ann. Thorac. Surg. 65, 913-918) and myocardial ischemia in rat heart (Tiefenbacher et al., 1997, Eur. J. Physiol., 433, 563-570). Human NE levels in plasma are significantly increased above normal in inflammatory bowel diseases, for example, Crohn's disease and ulcerative colitis (Adeyemi et al., 1985, Gut, 26, 1306-1311). In addition NE has also been assumed to be involved in the pathogenesis of rheumatoid arthritis (Adeyemi et al., 1986, Rheumatol. Int., 6, 57). The development of collagen induced arthritis in mice is suppressed by a NE inhibitor (akimoto et al., 1995, Cellular Immunol. 165, 26-32).
Thus, human NE is known as one of the most destructive serine proteases and has been implicated in a variety of inflammatory diseases. The important endogenous inhibitor of human NE is α1-antitrypsin. The imbalance between human NE and antiprotease is believed to give rise to an excess of human NE resulting in uncontrolled tissue destruction. The protease/antiprotease balance may be upset by a decreased availability of α1-antitrypsin either through inactivation by oxidants such as cigarette smoke, or as a result of genetic inability to produce sufficient serum levels. Human NE has been implicated in the promotion or exacerbation of a number of diseases such as pulmonary emphysema, pulmonary fibrosis, adult respiratory distress syndrome (ARDS), ischemia reperfusion injury, rheumatoid arthritis and pulmonary hypertension.
WO 02/053543 discloses pyridone derivatives having affinity for cannabinoid 2-type receptor.
The present invention discloses novel 2-pyridione derivatives that are inhibitors of human neutrophil elastase and homologous serine proteases such as proteinase 3 and pancreatic elastase, and are thereby useful in therapy.

2-pyridone derivatives as neutrophil elastase inhibitors and their use


A nozzle plate for ink jet cartridges which are manufactured from a relatively thin film of material, such as, for example, polyimide, polyarylene ether, or composite of a number of materials deposited on a rigid substrate, such as a silicon wafer, and photolithographically processed from the rigid substrate to produce a large quantity of interconnected nozzle plates which may be removed as a sheet of interconnected nozzle plates for ease of handling. The nozzle plates are aligned and bonded to the nozzle bearing front faces of the cartridges.

This invention relates to ink jet printheads and more particularly to nozzle plates for ink jet printheads and method of fabrication thereof.
As the ink jet industry moves to ink jet printheads having higher printing resolution, such as 600 dots per inch or more, a primary limit on image quality will come from errors in the direction that the droplets take when they leave the printhead nozzles. The droplet direction and error therein is referred to as directionality. Directionality problems may be incurred from several sources, such as the nozzle shapes, surface energy of the nozzle face, and ink that collects on a nozzle face near a nozzle to name a few examples. One solution to this problem is to use a nozzle plate. Other advantages of nozzle plates are that the maintenance station has a uniform surface to seal against and to clean.
Because of the small area of a printhead nozzle, especially for high resolution printheads where the sizes are in the range of 0.0332 cm.sup.2 per nozzle, nozzle openings in a typical polymeric nozzle plate are so small that they are generally produced by laser ablation. Such laser ablation processes can not only be time consuming and expensive, but also produce debris or artifacts which must be collected and/or controlled to prevent entry into the printhead, for example.


A protecting group for use in separating oligodeoxyribonucleotide compounds having the formula Ar--L--Y, wherein Ar represents a substantially planar, fused ring system containing at least fused rings; L represents a linker group containing at least one carbon atom which is capable of bonding to Ar and Y; and Y represents a specifically acid labile group.

Oligonucleotides are part of the sequence of a molecule of DNA. DNA is a polynucleotide; a polymer built of nucleotide units, each comprising a phosphate group, a sugar (deoxyribose), and a base (adenine, guanine, cytosine or thymine). DNA molecules form a double helix with the two strands held together by hydrogen bonds between specific base pairs: adenine always pairs with thymine and guanine with cytosine. Thus the sequence of one strand of the helix determines the sequence of the other:
.sup.5 '. . . ATGAAATCTGTACATGGT . . . .sup.3 ' PA1 .sup.5 '. . . TACTTTAGACATGTACCA . . . .sup.5 ' PA1 L represents a linker group containing at least one carbon atom which is capable of bonding to Ar and Y; and PA1 Y represents a specifically acid labile group. PA1 a) a chamber, for example a column, filled with a suitable substrate, such as reverse phase silica gel or polystyrene, and PA1 b) a kit for grafting a protective group as defined above on a molecule. PA1 protecting at least one group in at least one compound in a mixture of compounds to be separated with a group as defined above, and PA1 passing the mixture of compounds through a chamber filled with a reverse phase silica or polystyrene material.
The sequence of a particular piece of DNA might represent part of a gene which `encodes`, and thus directs the production of, a particular protein. Protein production is mediated via an RNA copy of this DNA (with uracil in place of thymine), where the order of these bases defines the order in which the amino acids are joined together to form proteins. Because there are 20 amino acids but only four bases, it follows that a group of bases is needed to code for one amino acid. These groups are comprised of three bases called `codons`. Thus methionine is coded for by ATG, histidine by CAT, lysine by AAA, proline by CCT etc, and the DNA sequence .sup.5 'ATGAAACCTCATAAA .sup.3 ' codes for the amino-acid sequence Met-Lys-Pro-His-Lys. Altering the DNA sequence by substituting one base for another can alter the encoded amino acid sequence. For example, if the CCT codon in the DNA sequence .sup.5 'ATGAAACCTCATAAA .sup.3 ' is changed to CAT (a single nucleotide C to A substitution) the resulting amino acid sequence changes from Met-Lys-Pro-His-Lys to Met-Lys-His-His-Lys. This ability to change, or `mutate`, the nucleotide sequence of a gene or DNA fragment is the basis behind the technique known as site-directed mutagenesis. A known DNA sequence is usually mutated with the aid of a synthetic oligonucleotide and is therefore often called oligonucleotide-directed mutagenesis.
The critical feature of site-directed mutagenesis is that it allows pre-designed mutations to be specifically introduced into a target gene. With the structures of many important proteins having been determined at atomic resolution, particularly by X-ray crystallography but also by NMR spectroscopy, it is possible to analyze the structure and function of enzymes in great detail. The importance of one or more amino acid residue can be assessed by engineering specific modifications into the protein structure. Most commonly the mutations involve single base substitutions but it is also possible to construct deletions and insertions in the DNA sequence, resulting in shorter or longer polypeptides.
It can therefore be seen that there is a need to be able to synthesise oligonucleotide sequences of a high purity. Further information regarding site directed mutagenesis is to be found in an article by Chapman and Reid in Chemistry in Britain, March 1993, p 202-204.
In organic synthesis, in particular multi-step, organic synthesis, the purification of the products obtained can present more problems than the synthesis itself. This is particularly true in the case of oligonucleotide synthesis, a synthesis which systematically uses protective groups which can also play supplementary roles. One solution to this problem would be to modify the oligonucleotide, or any other molecule requiring protection, by binding it to a solid in a manner which is physically reversible, in the course of working up and purification. To date no protective group has been disclosed as being capable of exercising such a property.
GB-A-2251242 (Ramage et al) describes a protecting group for use in peptide synthesis. The protecting group is of formula Ar--L-- where Ar represents a substantially plane, fused ring system containing at least 4 aromatic rings and L represents a group containing at least one carbon atom which is capable of bonding to a group to be protected, which may be an N-terminal amino group of an .alpha.-amino acid in the synthesis of peptides. The protecting groups improve the purification of crude peptides by affinity chromatography on porous graphitised carbon (PGC) HPLC columns.
The protecting groups disclosed in GB-A-2251242 are based on tetrabenzo (a,c,g,i) fluorene (Tbf). However this is a base labile group. In oligonucleotide synthesis several basic treatments are carried out, e.g. phosphate deprotection, and therefore this base labile protecting group is unstable in oligonucleotide synthesis. It is also important that the protecting group for oligonucleotide synthesis can be removed under mild acidic conditions. The protecting group should also only require simple reaction conditions for its introduction onto a nucleotide. The molecule should be regioselective as it is important that the 3'-hydroxyl of the nucleotides remains unprotected. It is also preferable that the molecule should enable monitoring of reactions and purifications.

Method and means for oligonucleotide separation


A new and distinct hybrid of Sedum plant substantially as shown and described, with creamy yellow flowers, dark red brown to green leaves, strong, dark red stems, multiple crowns, a dense, low, arching habit, and excellent vigor.

The present invention relates to a new and distinct cultivar of Sedum telephium and given the cultivar name of 'Touchdown Flame'. Sedum is in the family Crassulaceae. The new cultivar is part of a planned breeding program to make short, compact, multicrown plants. The new cultivar originated from a cross of between Sedum 158-2, a proprietary, unselected seedling as the seed parent and Sedum 235-2, a proprietary, unselected seedling as the pollen parent.
Compared to the seed parent, Sedum 158-2, the new cultivar, has a much better habit and creamy yellow flowers rather than light pink.
Compared to the pollen parent, Sedum 235-2, the new cultivar has larger, greener leaves and a lower habit.
Compared to Sedum 'Desert Blonde', U.S. Plant Pat. No. 24,901, the new cultivar has foliage that is dark red brown to green rather than gray green and flowers that are more yellow.
This new and unique Sedum is distinguished by:                1. creamy yellow flowers,        2. dark red brown to green leaves,        3. strong, dark red stems,        4. multiple crowns,        5. a dense, low, arching habit, and        6. excellent vigor.
This new cultivar has been reproduced only by asexual propagation (division and tissue culture). Each of the progeny exhibits identical characteristics to the original plant. Asexual propagation by division and tissue culture using standard micropropagation techniques with terminal and lateral shoots, as done in Canby, Oreg., shows that the foregoing characteristics and distinctions come true to form and are established and transmitted through succeeding propagations. The present invention has not been evaluated under all possible environmental conditions. The phenotype may vary with variations in environment without a change in the genotype of the plant.


An interpersonal towing system deploys two or more harnesses each worn by an individual, each harness connected to opposing sides of a highly elastic towline that is protected by a durable fabric cover. The harnesses are configured for detachable connection to the towline via a pair of loops or rings fixed at upper pelvis level at both the front and rear of each harness. The system is suitable for either person assisting the other to traverse difficult terrain with great efficiency yet without damaging the highly elastic towline.

The present invention relates to sporting goods and in particular to an interpersonal towing system.
In various group sports or outdoor endeavors it is desirable to attach one person to another with a rope or cord such that one participant can assist the other in movement by urging the connecting rope or cord forward, such as by advancing forward.
However, such towing ropes or cords can be a hindrance, exerting an excessive and immediately restoring force when any slack in the cord is removed.
It is desirable and known in the art to use linear elastic members to connect two or more people together.
However, the previously deployed methods of using or attaching a linear elastic member as an interpersonal towing system can be tedious, cumbersome, uncomfortable and unreliable.
Accordingly, it is an object of the invention to provide an improved inter-personal towing system that includes various components to overcome the deficiencies known in the art.


Provided is a method and system for increasing etch rate and etch selectivity of a masking layer on a substrate in an etch treatment system, the etch treatment system configured for single substrate processing. The method comprises obtaining a supply of steam water vapor mixture at elevated pressure, obtaining a supply of treatment liquid for selectively etching the masking layer over the silicon or silicon oxide at a set etch selectivity ratio, placing the substrate into the etch processing chamber, combining the treatment liquid and the steam water vapor mixture, and injecting the combined treatment liquid and the steam water vapor mixture into the etch processing chamber, wherein the flow of the combined treatment liquid and the steam water vapor mixture is controlled to maintain a set etch rate and a set etch selectivity ratio of the masking layer to silicon or silicon oxide.

1. Field
The present application generally relates to the design of an etch treatment system and method for increasing etch rate and selectivity of etching a masking layer using a single substrate etch process.
2. Related Art
Current methods in the production of complementary metal oxide semiconductor (CMOS) transistors require masking layers to separate and protect active device regions such as dielectric, metal interconnect, strain, source/drain, and the like. Silicon nitride (Si3N4) or silicon oxide (SiOx, wherein x is greater than 0) is often used as a masking layer due to its electrical and morphological similarity to silicon dioxide (SiO2), as well as because silicon nitride is easily bonded to SiO2. Generally, silicon nitride is used as an etch-stop layer but in certain cases, such as in a "dual damascene" process, the silicon nitride must be etched away without altering the carefully-controlled thickness of the silicon dioxide underlayer. In such instances, the etch selectivity of silicon nitride to silicon oxide, calculated as the etch rate of silicon nitride divided by the etch rate of silicon oxide, ideally is as high as possible to improve the process margin. As devices continue to shrink, the thickness of masking layers and underlayers shrink in tandem. Etch selectivity for ultra-thin layers will become more of a challenge in the future.
Current techniques for selectively etching silicon nitride may use differing chemistries and approaches. Both dry-plasma etching as well as aqueous-chemistry etch are used in the removal of silicon nitride. Aqueous chemistry materials can include dilute hydrofluoric Acid (dHF), hydrofluoric acid/ethylene glycol as well as phosphoric acid. The decision for using the different chemistries is governed by the requirement for silicon nitride etch rate and selectivity to oxide. Aqueous chemistry methods are preferable because of the reduced cost of ownership compared to dry techniques. It is well understood the silicon nitride etch rate in phosphoric acid is strongly influenced by temperature, where the etch rate rises in response to a rise in temperature. In a wet-bench configuration such as immersing substrates into a bath of aqueous phosphoric acid solution, the process temperature is limited by the boiling point of the aqueous phosphoric acid solution. The boiling point of the solution is a function of the concentration of water in aqueous phosphoric acid solution as well as the atmospheric pressure. One current method for maintaining temperature is by a feedback-loop-controller that measures the existence of a boiling state, while adjusting the addition of water volume and heater power timing interval to the bath so as to maintain this boiling state at a target temperature, (typical range of target temperatures is from 140 degrees Centigrade to 160 degrees Centigrade). When the aqueous phosphoric acid solution is heated without addition of water, the boiling point of the aqueous phosphoric acid solution rises as the water is evaporated from the solution.
Increasing the temperature of the phosphoric acid is favorable for increasing the silicon nitride etch rate for production and lower the cost of manufacturing at the expense of lower selectivity because with current phosphoric acid recirculation tanks, the consequence of allowing a high boiling point is to reduce the concentration of water. Water is critical in controlling the selectivity of silicon nitride to silicon oxide or silicon etching. Experimental evidence shows that a non-boiling state (i.e., low water content) at elevated temperature does not result in a favorable etch selectivity. Conversely, to improve selectivity, it would be preferable to have a high concentration of water, (i.e., dilute the acid further), however this is not practical. Increasing the concentration of water in the bath reduces the boiling point of the acid mixture. At lower temperature, the etch rate of the silicon nitride falls significantly due to the strong Arrhenius relationship of the silicon nitride etch rate with temperature.
In the current art, for example, Morris, in U.S. Pat. No. 4,092,211, discloses a method for controlling within a boiling aqueous phosphoric acid solution the etch rate of a silicon oxide insulator layer which is employed in masking a silicon nitride insulator layer. The method employs the deliberate addition of a silicate material to the boiling aqueous phosphoric acid solution. In addition, Bell et al., in U.S. Pat. No. 5,332,145, disclose a method for continuously monitoring and controlling the compositions of low-solids soldering fluxes that employ a solvent with a specific gravity closely matched to the specific gravity of the flux composition. Desirable in the art are methods and systems that can maintain a high etch rate for a masking layer and also maintain a high selectivity of etching the masking layer over the silicon or silicon oxide. There is a need for batch etch treatment systems and methods and single substrate systems and methods that can meet the goals of etch rate, etch selectivity, etch time, and/or cost of ownership.

Etch system and method for single substrate processing


An exhaust timing valve control for an exhaust timing valve of an engine powering a watercraft is disclosed. The engine has an exhaust port leading from a combustion chamber for routing exhaust products therefrom and an exhaust timing valve cooperable with the exhaust port and movable between a first position for delaying the closing of the exhaust port and a second position for advancing the closing of the exhaust port. The engine includes a coil member providing a pulsed output when the engine is running. The exhaust timing valve control controls the position of the exhaust timing valve, the exhaust timing valve control including an engine speed detector which detects the speed of the engine based upon the output of the coil member.

Internal combustion engines include exhaust control mechanisms for controlling the flow of exhaust from each combustion chamber of the engine. In most instances, these mechanisms comprise valves.
In those instances where the engine operates on a two-stroke or two-cycle principal, the valve is often of the sliding or rotating type. Generally, this type of valve does not serve to ever completely close the opening or port in the combustion chamber wall or the exhaust passage. Instead, the valve moves between a first position in which the valve does not obstruct or obstructs very little of the exhaust port, and a second position in which the valve partly obstructs the port. Because the sliding or rotating type valve can partially obstruct the exhaust passage, it can be used to control the timing of the exhaust flow, and thus the performance or running conditions of the engine.
Generally, the position of the valve is arranged to be dependent upon engine speed. Thus, a crankshaft rotation sensor or crankcase pressure sensor is typically associated with the engine for providing engine speed data to an electronic control unit. The position of the valve is then controlled in accordance with the speed of the engine. These sensors, however, may suffer from accuracy and reliability problems. In addition, they increase the cost of the engine and render it more complex.
In accordance with the present invention, there is desired an improved control arrangement for controlling an exhaust timing valve.

Exhaust timing valve control for watercraft engine


This invention is directed to a method for inhibiting the occurrence of a major vascular event in a subject whereby a subject is administered beta-carotene and/or vitamin E, either alone or in combination. Beta-carotene and/or vitamin E is administered such that the subject's risk of experiencing a major vascular event is thereby reduced. In another preferred embodiment, beta-carotene in combination with aspirin is particularly effective.. The invention further includes pharmaceutical compositions comprising beta-carotene in combination with vitamin E.

1. Field of the Invention
The invention generally relates to the field of medicinal chemistry. More specifically, the invention relates to the administration of beta-carotene and/or vitamin E to inhibit the occurrence of a major vascular event. The invention is further directed to pharmaceutical compositions comprising beta-carotene in combination with vitamin E. In one embodiment, beta-carotene is administered in combination with aspirin.
2. Brief Description of the Background Art
Despite a recent decline in cardiovascular disease-related mortality, cardiovascular disease remains the leading cause of morbidity and mortality in men and women in the United States, accounting for 47% of all deaths in 1986 (Dept. of Health and Human Services, Mortality Part B 88-1114:170-95 (1988).
Recent evidence suggests that antioxidant therapy may prevent or impede atherogenesis. Free radical oxidation has been postulated to play a role in the pathogenesis of atherosclerotic disease (Steinberg et al., N. Engl. J. Med. 320(14):915-24 (1989)). Serum lipoproteins can become oxidized in vivo (Warso et al., J. Clin. Invest. 75:667-71 (1985)) and these may be more atherogenic than their unoxidized counterparts. Oxidized low density lipoprotein (LDL) can potentially promote atherogenesis by several mechanisms. First, these modified lipoproteins may be toxic to or alter function of arterial endothelium. Oxidized LDL is cytotoxic to cultured endothelial cells as well as fibroblasts in vitro (Hessler et al., Arteriosclerosis 3(3):215-22 (1983); Yagi, K., Bioessays 1:58-60 (1984)). This altered endothelium may permit diffusion of serum lipids into the subendothelium and/or alter the ability of the endothelium to prevent thrombosis. Second, oxidized LDL chemotactically attracts and immobilizes monocyte/macrophages (Quinn et al., Proc. Natl. Acad. Sci. 82:5949-53 (1985)), some of which are destined to become lipid-laden foam cells within atheromatous plaque (Schaffner et al., Am. J. Pathol. 100:57-73 (1980); Gerrity, R. G., Am. J. Pathol. 103:181-90 (1981)). Finally, oxidized LDL is taken up into foam cells via a scavenger receptor more readily than unoxidized LDL (Fogelman et al., Proc. Natl. Acad. Sci. 77:2214-18 (1980); Goldstein et al., Proc. Natl. Acad. Sci. 76:333-37 (1979)). Thus oxidation of LDL may play an important role in the initiation and propagation of atherosclerosis.
Recent attention has focused on agents that may prevent the oxidation of LDL and thus impede or retard the progression of atherosclerosis. When incubated in various cell preparations, LDL will become oxidized (Morel et al., Artheriosclerosis 4:357-64 (1984); Cathcort et al., J. Leukocyte Biol. 38:341-50 (1985)). This process can be inhibited by the addition to the cell preparation of antioxidants such as butylated hydroxytoluene or vitamin E (Morel et al., Artheriosclerosis 4:357-64 (1984); Steinbrecher, et al., Arteriosclertosis 1:135-43 (1987)). LDL taken from patients treated with probucol, a cholesterol-lowering agent with lipid antioxidant properties, does not become oxidized in an endothelial preparation that does oxidize LDL from untreated patients (Parthasarathy et al., J. Clin. Invest. 77:641-44 (1986)). This in vitro data suggests that antioxidant therapy may reduce the rate of in vivo lipid oxidation. In addition, after controlling for its lipid-lowering effect, probucol reduced the rate of fatty-streak formation in Watanabe heritable hyperlipidemic rabbits (Carew et al., Proc. Natl. Acad. Sci. 84:7725-29 (1987)).

Beta-carotene vitamin E therapy for inhibition of major vascular events


In the course of regulating an electronically commutated d.c. motor as the drive motor of a winding device of a textile machine, the resolution of known angular rotation sensing systems is insufficient to assure a jerk-free drive of the drum at low rpm. It is therefore proposed by the invention to introduce a so-called Luenberger observer into the regulating circuit for regulating the motor rpm in which the signals of the angular rotation sensing system for the commutation of the motor are generated.

In bobbin winding machines, it is known, for example from German Patent Publication DE 43 36 312 A1, to drive the take-up bobbin by means of a friction roller, i.e., a so-called winding drum, which simultaneously also places the yarn onto the bobbin. In this apparatus the winding drum of each winding station has its own drive, which is triggered by the winding station computer. Often the winding drum drives are designed as electronically commutatable d.c. motors, since such drives are simple in construction and therefore relatively cost-effective. The commutation of the drive current of such d.c. motors is controlled by means of Hall sensors.
Similar Hall sensors are also employed for detecting the rpm of the winding drum drives. Specifically, a sensor system for recognizing the angular rotation of the winding drum provides information representing or indicative of the rpms of the winding drum, which is converted into predetermined winding drum rpm with the aid of known control methods, for example by using a PID regulating device.
However, with these known regulating systems, the regulation of the rotational speed (rpm) of the winding drum always becomes more difficult when the winding drum rotates at a low speed, which is the case in its start-up phase, for example. Because of their relatively coarse angular resolution below a defined rpm, these known sensor systems are no longer capable at low drum speeds (rpm) of providing sufficiently exact information regarding the angular position of the rotor of the drive motor, so that a smooth jerk-free winding drum rotation often is no longer provided. If, for example, a Hall sensor system with two Hall sensors, offset by 90 degrees, and a magnetic ring with, for example, 32 pairs of magnetic poles is available, an angular resolution, and therefore the detection of the rotating movement of the rotor of the drive motor, is only possible in steps of approximately 2.8 degrees.
As indicated by the curve a in FIG. 1, such a relatively coarse angular resolution is insufficient for the desired regulation of the current commutation of a drive motor in order to assure a uniform start-up as well as reverse running during the search for the yarn end of the dynamic system of the drive and winding drum. It can be seen from the curve a in FIG. 1 that the known regulating systems produce a step-by-step acceleration instead of a linear increase of the angular velocity. Such jerky running of the winding drum is disruptive, in particular during the start-up of the winding drum after a yarn splicing operation, since this leads to uneven yarn tension, which has a negative effect both on the yarn quality and the bobbin structure. Also, disruptions in the winding operation can occur in the course of slow running of the winding drum, for example during the search for the yarn preparatory to a splicing operation, because the non-uniform running of the winding drum leads to loop formation in the yarn running up on the cheese, for example.
Although it would be possible to prevent the non-uniform running of the drive motor, and therefore of the winding drum, at low rotational speeds (rpm) by the employment of a sensor system with an appropriately high angular resolution, the costs associated with such highly resolving systems is relatively large. Therefore these systems are quite expensive, wherein the costs greatly rise with the attainable accuracy of the angular resolution.

Winding drum drive of a cheese-producing textile machine


A flexible planar apparatus fabricated from polyvinylchloride has a matrix of foldable lines defining a plurality of quadrilateral tiles. Said tiles are configured to convey information, such as a multiplication table using numerals or Braille characters. The foldable lines allow a first fold of the apparatus to be manually effected followed by a second substantially orthogonal fold of said apparatus, thereby uniquely identifying one of the tiles, which may represent the product of multiplicands in a times table.

The representation of information in tabular form has been known for many years. An early introduction to this form of representation consists of a times table in which a matrix is defined in a 12.times.12 array, with first multiplicands 1 to 12 defined across the first row and second multiplicands 1 to 12 defined along a first column. The intersections of rows and columns then define the product of the two related multiplicands, thereby facilitating quick identification of the appropriate answer.
Tables of this form are also known in other applications, such as logarithmic tables, travel time tables and many other forms of charts, such as colour charts etc, where a resulting output property may be derived from the combination of two variable input properties. Thus, a particular shade of pink may be identified as being derived from a combination of saturated red with a proportion of added white. Thus, combined colour of this form may be specified in terms of its input proportions and a table may be used to facilitate the identification.
Tables are often used in computer systems such as data bases and spread sheets etc, therefore gaining a grasp of table use, along with a grasp of basic multiplication, is an important educational step and difficulties encountered at this stage may result in an inability to grasp more complex situations in later years.


A system and method for stationary semantic zooming. Stationary semantic zooming allows selected non-spatial rendering attributes, such as level of detail, to be varied according to other specified non-spatial rendering attributes. Stationary semantic zooming allows low importance objects to be rendered with a lower level of detail than higher importance objects. A system and method for displaying network status and realty information using stationary semantic zooming are also disclosed.

1. Field of the Invention
This invention relates generally to the field of computer graphics and, more particularly, to software for rendering graphics data.
2. Description of the Related Art
As the pervasiveness of computers increases, the amount of information that applications and users need to display has also increased. The problem of displaying ever increasing amounts of information is exacerbated by the recent trend toward smaller displays. For example, personal digital assistants are becoming more popular because of their portability. However, this portability tends to require smaller displays. Thus, system designers are facing the difficult task of having to display increasing amounts of information on smaller screens.
Desktop personal computers and workstations are facing similar problems. With the processing power now available, it is possible to simultaneously run a large number of applications, each having multiples windows and/or documents open at the same time. Applications routinely manipulate very large databases of information, and the results tend to overflow current displays. Thus, even with increases in desktop screen size, displays are becoming even more crowded.
One common technique currently in use that allows a particular screen size or window to display more information is called "scrolling" or "zooming". In scrolling, the window displays only a portion of the entire image, and the user is able to shift which portion of the entire image is shown in the current window. In zooming, a portion of the image being displayed is magnified (usually to show more detail) at the expense of displaying other portions of the image. Scrolling and zooming are often combined to create an effective user interface. For example, mapping software may display a detailed map of an eastern section of a city. The user may "zoom out" to display the entire city (at a lower level of detail), scroll over to the western section of the city, and then "zoom in" on a final destination to see more detail.
Techniques such as scrolling and zooming have increased the amount of information that may be accessed using a given screen size. However, these techniques may not go far enough to allow large amounts of data to be viewed on a given screen size. Another class of techniques that attempt to address this problem allow users to vary non-positional (i.e., non-spatial) display attributes such as transparency and size. However, these techniques can be inefficient and sometimes distracting. Particularly when an object is drawn as small, highly transparent, or in an otherwise non-prominent state, it can be both computationally inefficient and a potential distraction to the user to create a highly detailed rendering of the object.
For at least these reasons, a system and method for efficiently displaying information on a computer display is desired.


For each of a plurality of music pieces, a storage device stores respective tone data of a plurality of fragments of the music piece and respective musical character values of the fragments. Similarity determination section calculates a similarity index value indicative of a degree of similarity between the character values of each of the fragments of a main music piece and the character values of each individual fragment of a plurality of sub music pieces. Each of the similarity index values calculated for the fragments of each of the sub music pieces can be adjusted in accordance with a user's control. Processing section processes the tone data of each of the fragments of the main music piece on the basis of the tone data of any one of the fragments of the sub music pieces of which the similarity index value indicates sufficient similarity.

The present invention relates to a technique for processing music pieces.
Disk jockeys (DJs), for example, reproduce a plurality of music pieces one after another while interconnecting the music pieces with no break therebetween. Japanese Patent Application Laid-open Publication No. 2003-108132 discloses a technique for realizing such music piece reproduction. The technique disclosed in the No. 2003-108132 publication allows a plurality of music pieces to be interconnected smoothly by controlling respective reproduction timing of the music pieces in such a manner that beat positions of successive ones of the music pieces agree with one another.
In order to organize a natural and refined music piece from a plurality music pieces, selection of proper music pieces as well as adjustment of reproduction timing of the music pieces becomes an important factor. Namely, even where beat positions of individual music pieces are merely adjusted as with the technique disclosed in the No. 2003-108132 publication, it would not be possible to organize an auditorily-natural music piece if the music pieces greatly differ from one another in musical characteristic.

Music-piece processing apparatus and method


A foot support device for use with a shoe has been invented, the foot support device, in one aspectc having two spaced-apart side posts, each having a bottom end connectible to a side of the shoe and a top end, a front member having a top end and a bottom end connectible to a top part of the shoe and spaced-apart from each of the side posts, and a cuff connected to the top end of the two sdie posts and to the top of the front member. In one aspect such a device has one or more upwardly projecting members that are releasably connectible to a knee brace to maintain the brace in a desired position with respect to a wearer's knee. Methods are also provided for using such devices.

1. Field of the Invention
This invention is directed to a foot support, an ankle support, and, in one particular aspect, to a support that supports a drop foot and inhibits both undesirable foot inversion and eversion.
2. Description of Related Art
The prior art discloses a wide variety of ankle braces, orthopedic shoes, and drop foot supports. Typically these devices attempt to address problems associated with drop foot, unwanted foot inversion or introversion (movement of the foot--or inward falling of ankle)--inwardly, or unwanted foot eversion (movement jig of the foot--or ankle--outwardly. Many of the prior art devices are complex, cumbersome, difficult to make and install, and uncomfortable to the wearer.
There has long been a need for a foot support that satisfactorily deals with the three problems stated above. There has long been a need for such a support that is easily made and easily installed. There has long been a need for such a support that is useful with a variety of commercially available footwear without requiring any change in the footwear. There has long been a need for such a support which is not unduly uncomfortable for the wearer. There has long been a need for such a support that can flex and have a range of motion to accommodate movement of the wearer's leg, ankle, and foot.