The present invention discloses a variety of methods and apparatus for providing patches within a computer operating system. A patch structure in accordance with one embodiment of the present invention includes a patch block which serves to link the patch structure into a patch chain, and a patch which contains the desired functionality of the patch structure. The patch chain includes a root patch structure and a final patch structure. The root patch structure has a root patch block and a given function which has the root functionality. One aspect of the present invention teaches a method for integrating patches into a computer operating system including the steps of obtaining a new patch to be associated with a patch chain for the given function, determining whether a patch chain is already created in the operating system for the given function and creating a root patch block pointing to the given function as the start of a new patch chain if a patch chain has not already been created for the given function, creating a new patch block for the new patch, and inserting data into the new patch block to cause the new patch block to point to the new patch.

Computer operating systems often allow application programs to install "patches" within the operating system code. As used herein, a "patch" is computer code which replaces or augments a function already implemented on the computer. Typically multiple patches may be installed thereby further enhancing the original function.
When a patch replaces a function, any client calls made to the given function are transparently (from the client's perspective) redirected to the patch. The patch, in turn, performs the requested service and, if necessary, returns any results of the call to the client. In a similar manner, when a patch augments a given function, any client calls made to the given function are redirected to the patch. The patch then performs any preprocessing and passes the call along to the given function. The given function will return results directly to the client, or return results to the patch. If desired, the patch may perform post-processing and, if necessary, return the results of the call to the client.
The prototypical patch function must have the same parameters as the given function which it patches and may perform both pre-processing and post-processing. In order to further elaborate, two versions of pseudo-code for a prototypical patch function will now be provided. As will be appreciated by those skilled in the art of computer programming, the following pseudo-code provides a rough outline for use in programming a typical patch function.
The first pseudo-code is suitable for use on a computer system implementing register calling conventions:
______________________________________ typedef ResultType(TheProcType) (Param1Type param1,...); ResultType MyPatch (Param1Type param1,...1) Param1Type innerParam1; ... ResultType innerResult, finalResult; DoPrefixStuff; //This is the "head patch" part// innerResult = (*(TheProcType)NextPatch) (innerParam1,...); DoPostfixStuff, //This is the "tail patch" part//; return finalResult; } ______________________________________
The second pseudo-code is suitable for use on a computer system implementing stack calling conventions:
__________________________________________________________________________ typedef ResultType(TheProcType) (int state, Param1Type param1,...); ResuItType MyPatch (int state, Param1Type param1,...) Param1Type innerParam1; ... ResuItType innerResult, finalResult; DoPrefixStuff; //This is the "head patch" part// innerResult = (*(TheProcType)NextPatch) (state, innerParam1,...); DoPostfixStuff; //This is the "tail patch" part//; return finalResult; } __________________________________________________________________________
With reference to FIG. 2, the well known 68K patching paradigm 100 will be described. By way of background, the 68K patching paradigm 100 is implemented by versions of the Macintosh.RTM. Operating system designed for the Motorola 68K series of microprocessors, which operating system is hereinafter referred to as the "68K operating system." The paradigm 100 is implemented on a computer system such as computer system 50 of FIG. 1, wherein a CPU 52 includes one of the Motorola 68K series microprocessors or microcontrollers as well as other components necessary to properly interface with and control other devices coupled with the CPU 52.
The system routines for the 68K operating system reside mainly in ROM. However, to provide flexibility for any subsequent development, application code written for execution within the 68K operating system must be kept free of any specific ROM addresses. For this reason, all calls to system routines are passed indirectly through a trap table resident in RAM. This indirect mechanism permits the ROM addressing of system routines to vary, or to be replaced by patch routines, without affecting the operation of applications which utilize the system routines.
The 68K patching paradigm 100 includes application code 102 having at least one ATRAP instruction 104, low memory locations 106, a trap dispatcher 108, a trap table 110, ROM 120 having system code 122, and RAM 130 including at least one patch code 132. While the operating system routines reside mainly in ROM 120 (in the original state), information regarding the locations of the operating system routines is encoded in compressed form within ROM 120. Upon system start up, this information is decompressed and the trap table 110 is formed in RAM 130.
The indirect calling mechanism of the 68K patching paradigm 100 is further implemented by utilizing a feature of the 68K series microprocessor called a trap. A "trap" is a kind of microprocessor exception which arises in response to the execution of certain machine language instructions. An "exception" is an error or abnormal condition detected by the processor during the course of execution. For example, any 68K machine language instruction whose first four bits has the hexadecimal value "A" will generate an exception (hence the name "ATRAP"). In the 68K operating system, the set of language instructions whose first four bits has the hexadecimal value "A" are specifically set aside by the operating system for use in implementing client calls to system routines.
During execution of application code 102, the 68K microprocessor will encounter and execute the ATRAP 104. In response, the microprocessor pushes some state onto the computer system's stack, the state including the address of the ATRAP instruction 104. Then, the microprocessor resumes execution at the address indicated in a low memory location, which is the address of the trap dispatcher 108. Once executing, the trap dispatcher 108 examines the bit pattern of the ATRAP instruction 104 to determine what operation it stands for, looks up the address of the corresponding system routine in the trap table 110, and then jumps to the corresponding system routine.
One example of the general execution path of a system routine which is not patched is symbolized by flow control lines 140, 142, 144, 146, and 148. Note that in certain cases the flow control lines may imply structure. For example, the flow control line 146 has its tail at address.sub.-- 1 in trap table 110 and its head at the beginning of the system routine within the system code 120: right to where address.sub.-- 1 points. However, the flow control lines in general are not intended to illustrate structure.
Flow control line 140 symbolizes the microprocessor pushing the address of the ATRAP instruction 104 onto the computer system's stack and beginning execution at the trap dispatcher 108. Flow control line 142 symbolizes the trap dispatcher 108 evaluating the ATRAP instruction 104 and flow control line 144 symbolizes the trap dispatcher looking up the corresponding system routine in the trap table 110. Flow control line 146 symbolizes jumping to a system routine 123 to which address.sub.-- 1 points and flow control line 148 symbolizes jumping back to the application code 102 once the system routine 123 has been executed.
Because the trap table 110 is resident in RAM 130, individual entries in the trap table 110 can be changed to point to addresses other than the original ROM addresses. This allows the system routines to be replaced or augmented by patches. At startup time the system can load new versions of individual routines (e.g. from the System file or from a floppy disk) into RAM and then patch the trap table in order to redirect any calls to the original system routine to the new versions. Additionally, when new applications are launched they too can load new versions of individual routines into RAM and then patch the trap table in order to redirect any calls to the original system routine to the new versions.
One example of a redirection to a patched system routine is symbolized in FIG. 2 by dashed flow control lines 150 and 152. Similar to the unpatched system routine described previously, an ATRAP instruction 104 calling a patched system routine will initiate a process in which the trap dispatcher 108 will look up the system routine corresponding to the ATRAP instruction 104. However, in the patched case, address.sub.-- 1 will point to patch code 132 located in RAM 130 rather than the original system routine. Thus dashed flow control line 150 illustrates jumping to the patch code 132 and dashed flow control line 152 illustrates jumping back to the application code 102 after the patch code 132 has finished executing.
Next, in reference to FIG. 3, one method for installing patches in the 68K operating system will be described. In an initial step 200, the computer boot process is started. Then, in a step 202, the ROM boot is performed. In ROM boot step 202, initialization procedures such as expanding the trap table from ROM into RAM are performed. Next, in a step 204, the disk operating system boot is performed. At this point any system patches are also installed.
As discussed previously, new versions of individual system routines may be loaded into RAM and the trap table patched in order to redirect any calls to the original system routine to the new versions. After this is complete, the operating system boot procedure is complete in a step 206. In a next step 208, the application "Finder" is launched. As will be appreciated by those skilled in the art, the Finder is the primal application which performs critical tasks such as displaying the Macintosh.RTM. desktop and launching other applications at the request of the user. Once the Finder is running, in a step 210 other applications may be launched and in turn any patches necessary for the other applications may be installed.
Turning now to FIG. 4, the well known PowerPC patching paradigm 300 will be described. By way of background, the PowerPC patching paradigm 300 is implemented by versions of the Macintosh.RTM. Operating system designed for the PowerPC series of microprocessors, which operating system is hereinafter referred to as the "PowerPC operating system." The paradigm 300 is implemented on a computer system such as computer system 50 of FIG. 1, wherein the CPU 52 includes one of the PowerPC series microprocessors as well as other components necessary to properly interface with and control the other devices.
The example PowerPC patching paradigm 300 includes a native PowerPC application 302, an emulated segment 304, an interface library 306, a native PowerPC system routine 308, and a routine descriptor 310. In the PowerPC native environment, a "fragment" is a block of executable PowerPC code and its associated data. As illustrated, the native PowerPC application 302 is a fragment having application code 320 and application data 322.
In the native PowerPC environment, rather than directly calling system routines, application code will have a call 324 to service glue 326. As will be appreciated by those skilled in the art, service glue 326 provides an indirection across dynamically linked library boundaries. The main function of the service glue is to save memory resources. That is, if the system routine were called more than once, the service glue 326 plus the multiple calls require less memory than duplicating service glue 326 in multiple locations. The service glue in turn uses a pointer 328 found in the application data 322 which points to the transition vector 330 of the interface library 306.
In explanation, a transition vector such as transition vector 330 is a data structure which has two pointers: a code pointer (which is the address of the code of the fragment being called) and a global pointer (which is the address of the called fragment's table of contents). A fragment's "table of contents" is a table containing a pointer to each routine or data item that is imported from some other fragment, as well as pointers to the fragment's own static data.
The interface library 306 is a fragment including interface library code 332 and interface library data 334. The interface library 306 serves a function similar to the trap dispatcher 108 of FIG. 2, as is described in the following. When the service glue 326 is called to execute a system routine, the interface library code 332 is invoked via the interface transition vector 330. Then the interface library 306 evaluates the call using a trap table 340 to determine the appropriate system routine to jump to. The trap table 340 is used in a manner similar to the trap table 110 of FIG. 2.
The appropriate system routine as determined by the interface library 306 may be written in 68K type code such as 68K code 344 or may be in native PowerPC code (i.e. dynamically linked library type code). In the case of 68K code, execution jumps directly from the trap table 340 to the 68K code 344. In the case of native PowerPC code, execution jumps first to a routine descriptor 310. As used herein, a "routine descriptor" is a data structure which contains mode information necessary for the operating system to properly execute the code. By way of explanation, the PowerPC operating system has an emulator which allows 68K code to be properly executed. In the case of 68K code, execution proceeds via the trap table 340, a mixed-mode manager, and an emulator to interpret and execute the 68K code 344. The routine descriptor is one component of this mechanism.
Patching in the PowerPC patching paradigm 300 is performed in a manner similar to the 68K patching paradigm 100 of FIG. 2. That is, a patch is added by changing an element in the trap table 340 to redirect any system calls to patch code residing in RAM. Thus the PowerPC patching paradigm 300 functions by emulating the appropriate elements of the 68K patching paradigm 100 of FIG. 2.
While the prior art patching systems provide the basic capability of patching system routines, these paradigms are neither resource efficient nor do they provide the flexibility and functionality required by modern computer systems. Each of the prior art patching paradigms result in costly (in terms of system resource utilization) system exceptions every time a system routine is called. For example, each ATRAP instruction executed generates a costly exception.
A further limitation of prior art patching paradigms is that only distinguished system routines (i.e. system routines called indirectly through the trap table) may be patched. Another limitation of prior art patching paradigms is that chaining of patches (i.e. multiple patches for a system routine) must be done manually. That is, each new patch must "capture" the preceding routine and manually chain through. Furthermore, the prior schemes do not allow patches to be inserted in or deleted from a patch chain, rather they can only be appended.

Method and apparatus for patching operating systems


A segmented photomultiplier tube having an electrode which, in its higher part acts as a focusing electrode for distributing photo-electrons on both sides of an axial plane, while in its lower part forming a collection cage, the photo-electrons undergo a first multiplication at the portions of the lateral walls, which are folded towards the axial plane. Apertures in a median plate of the electrode are covered by a highly transparent grid. The electrode is completed by a central partition which extends along the median plate just to the proximity of an input dynode of a laminated multiplier. A bar having a small cross-section may be provided, centered on the axial plane and receiving a potential near the potential across the photocathode. A plurality of these tubes can be arranged in a mosaic pattern for mapping luminous events.

1. Field of the Invention
The present invention relates to a segmented photomultiplier tube having at least two multiplication paths, including a sealed envelope having a front face on the inner surface of which a photocathode is provided, and from the latter, arranged one after the other, an electronic optical member providing a division of the photo-electrons in one of the multiplication paths according to their starting position from the photo-cathode, as well as an electron multiplier of the segmented type, having at least one input dynode.
2. Description of the Related Art
A photomultiplier of this type is disclosed in the document EP-A-428 215. This document has more specifically for its object a class of photomultipliers for which the number of paths is not so high and which are of a simple and cheap construction. A major application of this type of photomultipliers is the use as a contiguous mosaic arrangement for determining the positions in space of localized luminous radiation. In the majority of cases these radiations have their origin in scintillators placed in front of each tube. As far as the realization of a segmented photomultiplier (i.e. multi-way) tube remains rather cheap, it can be more economical to use this type of photomultipliers in such applications instead of conventional tubes. Moreover, if the basic photomultipliers of a segmented tube are small, the luminous event can be located with greater precision, provided the segmented tubes used have performances which are as uniform as possible from one tube to the other and from one path to the other. A further point to be taken into account consists in minimizing to the highest possible extent the diaphoty 1 between the paths of one and the same tube.
The segmented tube disclosed in the above-mentioned document, satisfies to a certain extent the structural simplicity looked for because it effects the distribution of the electrons over the different paths according to their starting position from the photo-cathode by means of an electronic optical means whose essential components are common to all the paths.

Segmented photomultiplier tube with at least two ways disposed on both sides of an axial plane


A method for the manufacture of polymer products from cyclic esters, according to which a catalyst and cyclic monomers are mixed in a mixing chamber and are optionally brought to a higher temperature, after which the mixture is injected, under pressure, into a cavity of a mold consisting of at least two parts and the mold is heated for some time at a temperature above the melting temperature of the monomers, after which the mold is opened and the product is removed from the mold. Polymer products manufactured by this method can be used in medical fields and particularly in reconstructive orthopedics.

Such a method is known from EP-B-0.108.635, according to which an amount of cyclic monomers and an amount of catalyst are transferred to a glass reactor under dry conditions, for example under a dry stream of N.sub.2. The reactor is sealed and the monomers and the catalyst are melted and mixed. The polymer is removed from the reactor on completion of the reaction.
In view of the fact that a polymerized polymer of cyclic esters is a rigid piece of material, it is usually only possible to remove the material from the reactor by breaking the glass wall of the reactor. This is a great drawback for applications on an industrial scale, characterized by the production of many pieces of material.
With a method according to EP-B-0.108.635 the material obtained has to be processed by milling or melting in order to obtain an object with a usable shape. Milling presents the drawback that a large amount of waste is obtained, which is economically and ecologically disadvantageous. Melting presents the drawback that the microscopic, molecular, structure of the material obtained immediately after polymerization, the so-called "as polymerized" material, is lost. Several publications state that the "as polymerized" structure presents advantages; see for example Makromol. Chemie, 188, pp. 1809-1814, 1987.
Moreover, a number of bonds in the polymer will be broken in melting and as a result the molecular weight of the polymer will decrease.
With a reactor without a separate mixing chamber as in the conventional method, in order to mix the monomer and catalyst composition the entire reactor is shaken or a magnetic stirring bar is used. Neither of these methods leads to a desirable degree of mixing of the catalyst and monomer. On the other hand, by mixing the catalyst and monomer in a specially designed mixing chamber, a much better mixing occurs. Furthermore, when a stirring bar is used, there is the undesirable result of having the stirring bar incorporated in the product.

Method for the manufacture of polymer products from cyclic esters


A method of printing with at least two printing plates, or their equivalent, characterized in that associated halftone dots belonging to two distinct pluralities, each of which is printed with one of said two printing plates, and each of which are interleaved with the other and printed in a color different from the other, are separated by a gap when printed in perfect register.

1. Field of the Invention
The present invention relates to printing techniques in general and to what is known as halftone printing in particular. More particularly still, it relates to printing with more than a single printing plate. The preferred embodiment of the present invention is directed to printing on metal cans or the like, also known as metal decorating.
2. Description of the Prior Art
U.S. Pat. No. 3,948,171 granted Apr. 6, 1976 to Richard E. O'Connell and titled: Method For Printing Multicolor Halftone Images on Cylindrical Objects provides a novel method and apparatus for producing halftone effect printing using line-engraves press plates for printing cylindrical objects, particularly cans of the two-piece type. The patent, under the heading "Description of the Prior Art" provides a brief but useful discussion of problems in multicolor printing on two-piece cans at that time. Beginning at Column 1, line 36 the patent states:
"The printing techniques that have been developed for this so-called two-piece can construction are necessarily modified to provide for offset printing of multicolor images by direct application to the cylindrical surface. The methods employed include the formation of printing plates for each of several colors to be applied to the work. The traditional halftone lithograph effect by the use of printing mats prepared by the use of color separation, halftone dot or grid type screens and press plates, and overprinting have not been attainable in two-piece can printing since the problems of securing registry, proper printing pressure, angle of screen and plate, and the like to achieve the desired halftone effect attained by overprinting using halftone plates is, as a practical matter, difficult to accomplish. PA1 "The traditional grid or dot type screens used to form the halftone printing plates for multicolor printing produces a plate in which the printing surface is, in effect, a plurality of tiny raised dots or islands. The amount of color applied by each of the halftone plates was determined by the presence of and size of each of these dots, each of which, in turn, were formed photographically by traditional color separation and photoengraving techniques using appropriate filters and a halftone screen or grid. For each color, the grid and the resulting press plate is angled slightly to result in partial overprinting. The final composite multicolor shaded or toned printing product is achieved by overprinting and by optical blending, producing a visual effect of the desired tones or blends of color. Since each of the small dots formed in the press plate are fragile, the mechanical stress encountered in the application of each color to the offset surface or blanket results in smearing of the individual dots by the mechanical bending action encountered in the contact between the press plate and the surface of the offset blanket. This is especially true in the preparation of so-called flexible halftone press plates where the plate is formed by a chemical photoengraving method. In this procedure the plate is formed of a flexible, rubbery or polymeric material which has a photosensitive surface. On exposure to light, the photosensitive material is activated or hardened so that further treatment or etching, as by solvent, dissolves away the unexposed portions leaving a raised printing surface formed of a multitude of dots which corresponds to the particular color image applied to the plate. Since the base supporting the raised or printing portion is flexible, each printing operation flexes each dot and tends to smear the image and can also break the dots off. PA1 "Understandably, the quality of the images will deteriorate rapidly under these stresses, and such indeed is the experience in the can lithographing art. Likewise, the achievement of tone or color blend by traditional offset multicolor halftone techniques requires very accurate registry, careful angulation of the screens and press plates, accurate pressures, and more particularly, evenness of printing pressures. These desiderata were not attainable in the high speed printing techniques used for cylindrical objects or cans and required for economic operation in this industry. The result has been that halftone effects are not reproducible by any of the known standard multicolor offset or lithographic printing techniques which have been employed to date in the printing of two-piece cans. PA1 "Some of the prior art patents which deal with high speed can printing of two-piece metal cans include: Brigham, et al., U.S. Pat. No. 3,227,070; Brigham, U.S. Pat. Nos. 3,223,028 and 3,371,603; Freres, U.S. Pat. No. 3,385,209; and Maxin, U.S. Pat. No. 3,645,201. None of these patents, however, teach the successful use of a halftone color blend visual effect in high speed printing and all use solid color printing techniques." PA1 "forming a series of line-engraved press plates from said line screen transparencies wherein each press plate corresponds to one of the colors in the original art work and wherein the printed image from each of said press plates is separated from the color image of the other plates by the field color and the printing lines of the respective press plates are parallel to each other and run in the direction of printing." PA1 "Process for transferring overlayed multiple ink patterns from the surface of a release blanket to a receiving surface on a container or other formed article being printed. A substantially transparent film is first formed on the release blanket, with each ink pattern being printed sequentially over this release film. Proper printing on the release film without picking the release film or previously applied ink films is obtained when certain adhesive and cohesive relationships are maintained between the ink films and the release film. An adhesive film may be formed on the article to be printed, or it may be formed over the ink films and the release film on the release blanket. The receiving surface on the article to be printed is brought into contact with the films on the release blanket, with a resulting total transfer of the films on the blanket to the surface of the article." PA1 "A process of four-color halftone printing onto objects having a curved surface by means of dry offset printing which comprises transferring four images of yellow, magenta, cyan and black process inks having a difference of at least 1 in tackiness value from each other from four blocks onto two transfer areas provided on a blanket differently in the circumferential direction of a blanket cylinder in two layers two by two so that an image of an ink having the highest tackiness value and an image of an ink having the secondarily high tackiness value are transferred onto the first transfer area in that order and an image of an ink having the thirdly high tackiness value and an image of an ink having the lowest tackiness value are transferred onto the second transfer area in that order, and then transferring the images on the first transfer area and the images on the second transfer area in order onto the object having a curved surface in layers. Improved four-color halftone printing apparatus for objects having a curved surface is provided with a blanket cylinder having an effective printing surface of twice the size of the printing surface of the objects. The reproducibility of color and images is very excellent and the printing closely resembling the original can be obtained. PA1 "The individual one-color half-tone images print sequentially on the offset blanket cylinder, with the individual dots of sequential colors standing alone, overlapping or registering, as dictated by the color separation of the original photograph. At locations of dot overlap or registry, the colors blend. In this way, a four-color half-tone image, which is a reproduction of the originally photographed object, is obtained in a wet-form, suitable for printing onto a recipient surface, preferably a preformed article, such as, a plastic container."
The O'Connell solution to the above quoted problems is succinctly stated in clause d of claim 1 as:
U.S. Pat. No. 4,035,214 granted Jul. 12, 1977 to Laurence Verlan Shuppert et al and titled: Total Image Transfer Process teaches a radically different process from that of O'Connell as stated in the Abstract:
The Shupper patent also discusses the difficulties of applying conventional multi-color offset printing to formed containers and states that the necessity of precise registration of color patterns greatly slows the handling of the articles.
U.S. Pat. No. 4,241,657, granted Dec. 30, 1980 to Hikoichiro Fujimori and titled Four-Color Halftone Printing Process For Objects Having Curved Surface, provides yet another solution as stated in the Abstract:
U.S. Pat. No. 4,774,885, granted Oct. 4, 1988 to Reinhold Chmielnik and titled Printing Process Overlapping Multi-Color Dot Images provides a process whereby a multi-color halftone image of an original object is formed on preformed plastic containers or other recipient surface by printing such image while wet from an offset blanket cylinder on which the image is formed by overlying a plurality of one-color halftone images. In column 3, lines 7-16, it is stated that:

Printed product having adjacent or closely spaced multicolour halftone dots


A therapeutic or diagnostic system comprises a non-invasive brain stimulation device (such as a TMS stimulation device) or other neuromodulation device configured to stimulate a patient's brain or nervous system by emitting electromagnetic pulses according to stimulation parameters, such as a pulse frequency or burst repetition frequency or other parameters, that provides surprising improvements in responsiveness and/or may require only a relatively short train of pulses to achieve high efficacy. In particular, stimulation pulses may be delivered at a frequency of between 12 and 40 Hertz with a 3 to 5 ratio as compared with burst repetition frequency, or at other specific patterns within that range. The stimulation parameters may be pre-stored and customized to individual patients, being identified through an automated search routine during which patient feedback is monitored. A user interface may be provided to allow an operator to conveniently select the appropriate parameters for the desired treatment.

1. Field of the Invention
The field of the present invention relates to systems and methods for treating neurologic or psychiatric disorders or conditions relating to the central and peripheral nervous systems, and more specifically, to techniques and delivery apparatus for therapeutic stimulation of neurons.
2. Background
The human brain is a complex organ, with a high incidence of illness. For example, it is estimated that in the United States, about 46% of the population will suffer from a diagnosable psychiatric disorder during their lifetime. Estimated lifetime prevalence by illness categories is: 29% anxiety disorders, 21% mood disorders, 15% substance disorders, 15% personality disorders, 8% attention deficit hyperactivity disorders, 3% psychotic disorders, and 3% autism spectrum disorders.
Neurologic disorders are also highly prevalent in the population. For example, tinnitus (a condition in which the affected person perceives sound in the absence of an external sound source) afflicts about 10% of the population, with a significant percentage of those affected being so severely impaired as to be unable to work or socialize. Chronic pain is reported by a third of the population and one in seven people suffer daily. Chronic lower back pain, which accounts for a significant percentage of all physician office visits in the United States and hundreds of billions of dollars in annual treatment costs, is now also thought to have its origins in the brain.
Fortunately for the many people suffering from neuropsychiatric disorders, treatments are being developed that show a great deal of promise in treating such illnesses. Unfortunately, current treatments prescribed to patients suffering from nervous system disorders are merely palliative, at best, relieving pain but not the underlying cause of the ailment. For example, treatments for neurologic disorders, such as stroke, epilepsy and dementia, are often ineffective and do not address the root cause of the illness.
A. Chemical Treatments
Treatments offered for people suffering from neuropsychiatric disorders generally fall into one of two categories: chemical (psychopharmacologic) or neuromodulation (brain or peripheral nerve stimulation). The majority of psychiatric and neurologic illnesses are treated chemically, i.e., with pharmacologic agents. Neuropharmacologic and psychopharmacologic agents act at synaptic receptors to alter certain brain inputs in ways that reduce symptoms of mental and neurologic illness. However, chemical intervention has significant drawbacks. Often, the medication(s) must be taken for the rest of a patient's life to keep potentially disabling symptoms under control. If the medication regimen is stopped, the symptoms usually return, sometimes to a greater degree than were initially present, because the underlying pathologic neural wiring is not significantly altered. There are also potentially serious side effects, compliance problems, and widespread lack of efficacy (one-third of depressed and schizophrenic patients do not respond to known pharmacologic treatments) associated with medications.
B. Neuromodulation Treatments
In contrast to chemical treatments, neuromodulation involves modulation of the nervous system by electrically activating neurons in the body through stimulation. Neuromodulation treatments may also be neuroplastic. Neuroplasticity is the ability of the brain to rewire itself permanently in response to changing external or internal stimuli. The brain has a high degree of neuroplasticity in childhood, enabling children to learn in a highly efficient manner and heal from potentially devastating neural injuries. However, enhancement of neuroplastic properties for a particular brain area requires specific endogenous or artificial activation methods. Additionally, brain neuroplasticity tends to diminish rapidly with age. As such, age-related neuroplastic constraints can limit the effectiveness of most medical therapy of psychiatric or neurologic illnesses—at least for adults—to a slow, transient, or partial response.
Although still relatively undeveloped, neuromodulation techniques have shown promise in treating nervous system illnesses, including those that are refractory to chemical treatment methods. Neuromodulation techniques generally fall into one of two categories: peripheral nerve stimulation and central nerve stimulation. Central and peripheral neurons function similarly, using voltage-gated ion channels to transmit electrical impulses in the form of action potentials along nerve tracts leading directly or indirectly to specific regions in the brain or spinal cord. However, the two types of neurons differ in their locations; central neurons have cell bodies inside the dura mater enclosing the brain or spinal cord, while peripheral neurons have cell bodies outside the dura mater.
(1) Examples of Peripheral Neuromodulation
Peripheral nerve stimulation activates neurons having cell bodies outside the brain and spinal cord. An example of an invasive (penetrating the skin) peripheral nerve stimulation technique is vagus nerve stimulation ("VNS"). The vagus nerve is a peripheral cranial nerve important for homeostatic physiologic regulation (e.g., decreases heart rate, activates digestive tract), and generally extends from the brainstem to the abdomen, via various organs. VNS typically consists of surgically implanting an electronic stimulation device into the thoracic cavity and attaching linked electrodes. Stimulation of the vagus nerve transmits electrical impulses upward through the chest, neck, and skull base into the brainstem.
Another cranial nerve stimulation technique that is non-invasive is known as trigeminal nerve stimulation ("TNS"), which stimulates the superior branch of the trigeminal nerve. The axons of this nerve travel from the skin in the upper scalp, forehead and cranium to their extradural cell bodies inside the skull located the trigeminal nerve ganglion. Here, these neurons have synapses connecting them to various brain regions inside the dura mater. This is a relatively new and exciting technique, the effects of which are only now beginning to be explored.
(2) Example of Central Neuromodulation
In contrast to peripheral nerve stimulation, brain stimulation directly stimulates the brain or spinal cord. Transcranial magnetic stimulation ("TMS") is an example of brain stimulation. TMS is a non-invasive technique that typically involves placing an electromagnetic coil on or near the patient's head to depolarize or hyperpolarize neurons in specific brain areas. In particular, TMS uses electromagnetic induction to induce weak electrical currents using a rapidly changing magnetic field to increase or decrease activity in one or more brain regions.
TMS has diagnostic uses including determining the contribution of cortical networks to specific cognitive functions by disrupting activity in the focal brain region. TMS also has a number of therapeutic uses. For example, a variant of single pulse TMS is repetitive transcranial magnetic stimulation ("rTMS"). Repetitive TMS has been tested as a treatment tool for various neurological and psychiatric disorders including migraines, strokes, Parkinson's disease, dystonia, tinnitus, depression, and auditory hallucinations. The term repetitive transcranial magnetic stimulation is often used interchangeably with the term transcranial magnetic stimulation in the clinical domain. Likewise, the abbreviation rTMS is sometimes used interchangeably with TMS. For convenience, the term transcranial magnetic stimulation and abbreviation TMS will be used herein to encompass both single pulse and repetitive transcranial magnetic stimulation.
TMS techniques typically act on a volume of brain tissue that is approximately two to three centimeters in diameter. The localized nature of the intervention avoids systemic side effects that commonly plague current pharmacologic treatments. This type of approach also avoids adverse medication interactions and the difficulty of ascertaining compliance with treatment as the patient must be physically present for treatment to occur.
As with most any medical treatments, currently known TMS techniques also entail potential side effects or risks, including headache or local scalp discomfort, hypomania in bipolar patients, and in rare cases seizure activity. A patient's hearing may also be adversely affected, although there are not any reports of this occurring in humans. During treatment, rapid deformation of the TMS coil produces a loud clicking sound that increases with the stimulator intensity. Such clicking can theoretically affect hearing with sufficient exposure. Consequently, hearing protection is typically used during TMS treatment.
Recent advances have been made to neuromodulation treatments. For example, a novel therapeutic system comprising a brain stimulation device configured to stimulate a patient's brain by emitting an electromagnetic field based on certain stimulation parameters, a feedback device configured to measure data regarding brain activity, and a computer communicably connected to the feedback and stimulation devices has been.
While a substantial amount of research has shown that neuromodulation is safe and effective, questions remain about long-term efficacy and robustness. For example, current TMS techniques have not proven to be effective on all patients. In addition, significant relapse rates exist, requiring that the affected patient seek additional treatment possibly including additional TMS sessions.
(3) Comparison of Neuromodulation Techniques
Table 1 below compares some known electromagnetic neuromodulation techniques and illustrates certain characteristics of each. Only the last technique uses focused ultrasound to stimulate neurons; the remainder act electromagnetically. The laws of physics dictate that all electromagnetic fields have an electrical and a magnetic component, but neuromodulatory electromagnetic fields may act principally through their electrical component, their magnetic component, or a combination. Although neuromodulation techniques use different mechanisms of action, the end results are the same; hyperpolarization or depolarization of neural cell membranes is the final common pathway leading to therapeutic change. Similar pulse parameter sets applied using different neuromodulation techniques will likely have very similar effects due to the fact that neuromodulation is, by definition, a change in neural firing rates determined by the membrane potential of the associated target neurons. Therefore effective pulse parameter sets will likely have a universal value among the many forms of neuromodulation.
TABLE 1Comparison of Neuromodulation TechniquesNon-ExternalHome or Of-BrainStimulation TypeAbbrevMagneticInvasiveDevicefice ProcedureStimulationTranscutaneousTENSNOYESYESYESNOElectrical NerveStimulationTranscutaneoust-VNSNOYESYESYESNOVagal NerveStimulationTrigeminal NerveTNSNOYESYESYESNOStimulationPeripheral NervePNFSNONONOYESNOField StimulationPeripheral NervePNSNONONONONOStimulationVagus NerveVNSNONONONONOStimulationTranscranialTESNOYESYESYESYESElectrical Stimulation(Direct Current,tDCSAlternating Current,tACSRandom Noise)tRNSPaired AssociativePASYESYESYESYESYESStimulationTranscranialTMSYESYESYESYESYESMagnetic StimulationDeep TranscranialdTMSYESYESYESYESYESMagnetic StimulationMulti-CoilmTMSYESYESYESYESYESTranscranialMagnetic StimulationDeep BrainDBSNONONONOYESStimulationMagnetic SeizureMSTYESYESYESNOYESTherapyElectroconvulsiveECTNOYESYESNOYESTherapyFocused UltrasoundFUSNOYESYESYESYES
(4) TMS Delivery Techniques
Different techniques have been explored for delivering pulses in connection with TMS treatments. One particular TMS variant, known as Theta Burst Stimulation (TBS), involves the application of short bursts of relatively high-frequency (e.g., 50 Hz) pulses that may be applied continuously, or else repeated at a theta frequency (generally in the range of 4-8 Hz), upon the target site. Animal studies have long established that TBS can be an effective and safe method to induce changes in cortical excitability. Until relatively recently, it has only been applied to animals. However, in 2005, researchers reported safe and tolerable application of TBS in humans. See Huang, Y. Z., et al., Theta Burst Stimulation of the Human Motor Cortex, Neuron, 45(2), pp. 201206 (2005). In that study, TBS was applied as short bursts with three pulses/burst occurring at a pulse frequency of 50 Hz (i.e., separated by 20 millisecond intervals). These bursts were repeated at a burst frequency of 5 Hz (i.e., every 200 milliseconds). The TBS paradigm reported by Huang et al. was widely adopted by fellow researchers, who noted that TBS appeared to be superior to tonic stimulation in terms of inducing cortical excitability. There are other types of burst stimulation which may occur with burst frequencies in the delta range (0-4 Hz), alpha range (8-12 Hz), beta range (12-30 Hz) or gamma range (30-100 Hz), as generally described for example in De Ridder, D., et al., Theta, Alpha And Beta Burst Transcranial Magnetic Stimulation: Brain Modulation In Tinnitus, International Journal Of Medical Sciences, 4(5), 237 (2007).
Two kinds of theta burst stimulation have clinical relevance. The first type is referred to as "continuous" TBS (cTBS) and generally involves a continuous train of bursts applied to the target site, while the second type is referred to as "intermittent" TBS (iTBS) and generally involves a short train of bursts (typically 10 bursts) separated by an intertrain interval (typically several times longer than the duration of the train). iTBS and cTBS modulate human cortical excitability differently, with iTBS generally increasing it and cTBS generally decreasing it, according to past studies. When applied to motor cortex, TBS can cause long-term changes in motor-evoked potentials, with iTBS typically increasing the amplitude and cTBS typically decreasing the amplitude.
Several studies of human motor-evoked potential have indicated that TBS yields longer lasting post-stimulation effects on cortical activity than conventional TMS. These post-stimulation effects which outlast the stimulation interval are frequently referred to as long-term potentiation and long-term depression. Researchers have also found that long-term potentiation and long-term depression are not limited to motor cortex but occur in multiple brain regions. In addition, a few studies have noted that large pulse sequences of 1200 or more pulses divided into four sets of 300 pulses each delivered at increments of 15 minutes may increase the duration of the effect on motor-evoked potential.
(5) TBS Studies in Humans
TBS treatment has been considered for treatment of psychological disorders. Currently, however, there are only a handful of reported studies involving TBS for the treatment of depression. The most exhaustive of the three is an Israeli study assessing the effectiveness of a two-week TBS treatment using a burst frequency of 5 Hz and a pulse frequency of 50 Hz (TBS-50 Hz) on 32 patients diagnosed with depression. The results of this study were published in Chistyakov et al., Safety, Tolerability And Preliminary Evidence For Antidepressant Efficacy Of Theta-Burst Transcranial Magnetic Stimulation In Patients With Major Depression, International Journal of Neuropsychopharmacology, Vol. 13, No. 3, pp. 387-393 (2010). In this study, the patients were divided into two groups to assess laterality of treatment, as well as overall efficacy of theta 50 treatment. The first group received iTBS treatment applied as a 2 second train repeated every 10 seconds to the left dorsolateral prefrontal cortex (LDLPFC). The second group received cTBS applied as a single uninterrupted train to the right dorsolateral prefrontal cortex (RDLPFC). The patients were further divided into three sub-groups to evaluate dosage effect. The first group received 1200 stimuli per day, the second group received 1800 stimuli per day and the third group received 3600 stimuli per day. The results of this study showed an overall response rate (measured as 50% reduction of Hamilton Depression Rating Scale (HDRS) scores) of 56.3%. The results also indicated a dose effect since the increase of the number of stimuli added to the therapeutic effect.
The second study, conducted in Germany, also evaluated the therapeutic effect of TBS upon patients with depression, but limited the study to unilateral stimulation of the left dorsolateral prefrontal cortex (LDLPFC). The results of this study were published in Holzer et al, Intermittent Theta Burst Stimulation (iTBS) Ameliorates Therapy-Resistant Depression: A Case Series, Neuromodulation Vol. 3, Issue 3, pp. 181-183 (2010). In this study, seven treatment refractory patients received two daily sessions of TBS-50 Hz stimulation at 80% of resting motor threshold (rMT) over a three-week treatment period. Each iTBS sequence contained 600 pulses applied in an intermittent theta burst pattern with a 2 second stimulation interval and an 8 second intertrain interval. After the three weeks of treatment, Hamilton Depression Rating Scale (HDRS) scores dropped by 43% and Beck Depression Inventory (BDI) scores dropped by 49%. Three patients (42% remission rate) achieved remission and five patients (70% response rate) met the criteria for response.
A third study was reported in Wu et al, Continuous Theta Burst Stimulation Of Right Dorsolateral Prefrontal Cortex Induces Changes In Impulsivity Level, Brain Stimulation Vol. 3, Issue 3, pp. 170-176 (2010). In that study, researchers reported improvement in a patient with treatment-resistant obsessive-compulsive disorder and major depressive disorder. The treatment involved TBS-50 Hz applied sequentially to bilateral cortical targets, with 10 sessions of cTBS over patient's right dorsolateral prefrontal cortex (RDLPFC) followed by 10 sessions of two seconds stimulation, 8 second intertrain interval iTBS over his left dorsolateral prefrontal cortex (LDLPFC). After six weeks of this treatment, a significant reduction of the patient's symptoms was noted, including a 34 point drop (from 49 to 15) of his Hamilton Depression Rating Scale (HDRS) score.
Although the results of the above studies are of interest, the TBS protocols employed did not, or are not proven, to work universally on all patients. Further, the level of benefit varied from patient to patient. In other studies or clinical experience, performed by or under the direction of the inventor of the disclosed invention herein, some patients receiving a TBS treatment with a 50 Hz repetition rate did not experience a decrease in their depression symptoms. The results from the earlier studies are also unproven in terms of duration of relief, relapse rate, and overall safety and efficacy, including long-term effects, which have not been well studied.
TBS is more comfortable for patients because, contrary to tonic stimulation, it is generally administered at an intensity below motor threshold. TBS also can be advantageous over tonic stimulation because the pulses are more concentrated which shortens treatment times. For example, a patient whose treatment regimen is 3600 pulses over RDLPFC using tonic 1 Hz inhibitory stimulation requires an hour of treatment time. The same protocol using cTBS only requires a treatment period of four minutes. However, excitatory TBS may require a treatment period in the range of 15-20 minutes or more.
In sum, current neurologic and psychiatric treatments leave considerable room for improvement. It would therefore be advantageous to provide novel and effective systems and methods of treating neurologic or psychiatric disorders that are non-chemical, non-invasive, neuroplastic, and curative.
It would further be advantageous to provide more efficacious systems and methods for delivering therapeutic neuromodulatory stimulation to the brain. It would also be advantageous to provide systems and methods for neuromodulatory stimulation to the brain that yield results in a greater percentage of the population, that provide a greater reduction in adverse symptoms, provide longer lasting effects, and/or reduce the rate of relapse. It would also be advantageous to provide systems and methods for neuromodulatory stimulation to the brain that require less time to administer, without substantially sacrificing, or while improving, actual or potential efficacy.
In addition to the above, or alternatively, it would be advantageous to provide systems and methods for neuromodulatory stimulation to the brain that are safer to the patient, require shorter treatment times, and improve patient comfort during therapy, without substantially sacrificing, or while improving, actual or potential efficacy.
It would further be advantageous to provide systems and methods for conveniently determining and/or selecting parameters for neuromodulatory techniques. Likewise, it would be advantageous to provide systems and methods for electromagnetic stimulation to the brain that require less specialized knowledge or training, and are able to be administered by a wider population of medical or other personnel.

Method and system for therapeutic brain stimulation using electromagnetic pulses


Methods for purifying 20(S)-camptothecin are described. The 20(S)-camptothecin in purified form is useful in the treatment of cancer.

20(S)-camptothecin (CPT) is a natural alkaloid product which is present as a component in a crude plant material isolated from the Chinese tree Camptotheca acuminata (Nyssaceae) (Wall, M.; Wani, M. C.; Cooke, C. E.; Palmer, K. H.; McPhail, A. T.; and Slim, G. A., "Plant antitumor agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata", J. Am. Chem. Soc. 88:3888-3890, 1966). CPT can also be isolated from the Indian tree Mappie foetida Miers (Govindachari, T. R. and Viswanathan, N., "Alkaloids of Mappia Foetida", Phytochemistry 11:3529-3531 (1972)). CPT has been determined to possess considerable antitumor activity (Wani, M. C. and Wall, M. E. "Plant Antitumor Agents. II. The Structure of Two New Alkaloids from Camptotheca acuminata", J. Org. Chem. 34(5):1364-1367 (1968) and has since been the focus of much scientific endeavor (See reviews: 1) Shamma, M.; St. Georgiev, V.; Journal of Pharmaceutical Sciences 63(2):163-183 (1974); 2) D'Arpa, P. and Liu, L. F. "Topoisomerases-targeting antitumor drugs" Biochimica et Biophysica Acta. 989:163177 (1989); 3) Corcoran, J. W. and Hahn, F. E. "Mechanism of Action of Antimicrobial and Antitumor Agents" Antibiotics, Vol. III, Springer-Verlag, New York, Heidelberg, Berlin, pp. 48-57 (1975); 4) Hutchinson, C. R. "Camptothecin: Chemistry, Biogenesis and Medicinal Chemistry", Tetrahedron 37:1047-1065 (1981): 5) Cai, J. C. and Hutchinson, C. R., "Camptothecin", The Alkaloids, Vol. XXV, pp. 101-137 (1983)). Recently, it was shown that CPT has high activity against human cancer xenografts in vivo (Giovanella, B. C.; Hinz, H. R.; Kozielski, A. J., Stehlin, Jr., J. S.; Silber, R. "Complete Growth Inhibition of Human Cancer Xenografts in Nude Mice by Treatment with 20(S)-camptothecin", Cancer Research, 51:3052-3055 (1991)), as well as in vitro (Pantazis, P.; Hinz, H. R.; Mendoza, J. T.; Kozielski, A. J.; Williams, Jr., L. J.; Stehlin, Jr., J. S.; Giovanella, B. C. "Complete Inhibition of Growth Followed by Death of Human Malignant Melanoma Cells In Vitro and Regression of Human Melanoma Xenografts in Immunodeficient Mice by Camptothecins," Cancer Research, 52:3980-3987 (1992)). It is of interest that a highly efficient method be developed for the purification of CPT since CPT is generally commercially available only as a plant extract.
The traditional methods of purifying CPT involve the use of conventional chromatography using a mixture of solvents, usually a nonpolar solvent in conjunction with a polar solvent to affect the separation of individual molecules from each other with silica gel, followed by crystallization from methanol-acetonitrile. (Wall, M. E., Fourth International Symposium on the Biochemistry and Physiology of Alkaloids, Halle, DDR, Jun. 25-28, 1969, pp. 77-87; Wall et al. 1966, supra.)

Methods for purifying camptothecin compounds

The Stehlin Foundation for Cancer Research


A method of treating a pathological condition of an internal organ in a patient which comprises topically applying capsaicin to the skin of the patient containing nerves which lead to the spinal cord segments corresponding to the internal organ without the need of systemic absorption of the capsaicin.

The traditional manner of using a medication to achieve an effect on an internal condition has been to use the non-invasive routes of oral, rectal, and nasal administration, and invasive routes of intravenous, subcutaneous and intramuscular administration. All of these routes depend on the medication entering the bloodstream, reaching effective levels and then exerting its effects on the internal organ or site. The medication could be introduced at any of the available sites in relation to the internal organ--there is no requirement of a specific site of application of the medication.
The cutaneous route of administration has also been used. All known cutaneous applications of medication to achieve their desired effects have been by one of two general mechanisms. One mechanism is the direct absorption of medication into the area of pathology to achieve a desired local effect. That is, the medication is placed directly over the site where it is expected to act. The medicine then absorbs through the skin to the site. Examples include the use of topical steroids (eg, the use of triamcinolone to treat eczema), and the use of topical capsaicin for the treatment of post-herpetic neuralgia. In this method, it makes no sense or utility to place capsaicin on the left arm when the Herpes zoster is on the right arm--the medicine must be placed directly on the site it is to effect. The other accepted mechanism is to use the skin as a means of delivering medication to the systemic circulation. The medication is absorbed through the skin and into the blood stream. The circulatory system then delivers the medicine to the site of pathology. Examples of that mechanism include the use of nitroglycerin ointment to treat angina pectoris of the heart, estrogen patches which act on the uterus and catapres patches for blood pressure control which act on the brain. The site of medication application to the skin is generally independent of the target site of action. That is, the medication may be placed, more or less, randomly on the skin. Another requirement is that the topical medication must be placed on the skin in large enough amounts to be absorbed into the blood stream and reach therapeutic levels. This is accomplished by higher concentrations of the medication in a reservoir, by the use of agents which enhance the absorption of medication present, and by delivery devices which control the rate of absorption such that overdose or dumping of the medicine does not occur. So, for a topical nitroglycerin patch to treat angina of the heart, an internal organ, the patch does not have to be placed over the heart. In fact the patch can be placed anywhere on the skin, no specific site is required. The only goal is to have as much of the medication as possible absorb through the skin and reach therapeutic blood levels at the heart.
The method of the present invention is distinctly different from all of the above methods and specifically different from the traditional methods of use of topical medications. None of the methods above require a specific site of application, or injection, to treat an internal organ condition. Our method requires a specific site of application to treat a distant internal organ. Whereas all of the above conditions require a systemic blood level to achieve its effect on an internal organ, our method does not require blood levels and, in fact, uses dosages of capsaicin which are far less than those used for systemic effects. Whereas our method requires specific topical application of capsaicin for effectiveness, that application is not directly on the site of its intended effect and is not directly on the site of pathology. All of these differences show the uniqueness of this invention.
Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), the pungent principle of red peppers, has been used cutaneously for the treatment of pain. Synthetic capsaicin (nonyl vanillylamide) acts in the same manner as capsaicin, and capsaicin (more properly capsaicinoids) is meant to include this substance for brevity. Capsaicin is believed to act on a subset of primary afferent nerves mostly of the C fiber type (polymodal, thin, unmyelinated), although some A delta (thin, myelinated) are also capsaicin sensitive. Capsaicin is believed to bind to a receptor at the nerve ending and cause a release of a variety of neuropeptides (e.g., substance P,CGRP and others) and results in afferent nerve conduction initially. There are two main phases of action, first an excitation and then a desensitization of the nerve to stimulation. The excitation results in the `hot` of hot pepper or the burning tingling sensation which can occur when capsaicin is applied to the skin. The desensitization results from the depletion of neuropeptides and interference with afferent conduction in a non-tetrodotoxin dependent manner. It has been demonstrated that topically (skin) applied capsaicin can deplete neuropeptides at the peripheral (cutaneous) and central (dorsal horn of spinal cord) endings of the peripheral cutaneous nerve. To date patents and articles have only described the use of capsaicin to treat cutaneous conditions (e.g., psoriasis or post-herpetic neuralgia), neuropathic conditions affecting the skin or subcutaneous area (e.g., postmastectomy neuroma or diabetic neuropathy) or direct subcutaneous conditions (e.g., osteoarthritis or rheumatoid arthritis). All of these treatments use the cutaneous application of the capsaicin to affect direct subcutaneous pathology (i.e., the local effect). These methods require direct application at the site of pathology (i.e., no internal conditions).
It is believed that no method of treatment has been described in the literature which employs the isolated topical application of capsaicin to the skin to achieve systemic effects for an internal condition distant from the site of application. Furthermore, no literature or available medicine was found which describes the treatment of an internal condition by topical application of that medication which did not require systemic absorption of the medication. Capsaicin has only been applied directly over the site of pathology for its therapeutic uses. The application of a medication at a specific skin site in amounts that cannot achieve significant systemic blood levels to treat a distant internal site of pathology has not been done--this invention is truly unique and unexpected.

Method of treating an internal condition by external application of capsaicin without the need for systemic absorption


Embodiments provide for a graphics processing apparatus including logic to receive data from an input buffer. The data can define a set of data points, where each data point includes one or more dimensions. The logic is configured to process the received data points to perform in-place construct a left-balanced and complete point k-d tree of the data points within the input buffer.

K-d trees are multi-dimensional (e.g., k-dimensional) search trees used for a large number of different applications in computer science. K-d trees are a special case of binary space partitioning trees and can be used for searches involving a multidimensional search key, such as range searches and nearest neighbor searches. Every non-leaf node of a k-d tree can be thought of as implicitly generating a splitting hyperplane that divides the space into two half-spaces. Points to the left of the splitting hyperplane are represented by the left sub-tree of that node. Points to the right of the hyperplane are represented by the right sub-tree. One key advantage of k-d trees is that in their "left-balanced and complete" form their entire topology can be encoded by simply arranging the points in the proper order, without requiring any memory for storing the tree topology.
A number of serial and parallel algorithms exist for building k-d trees, with proven optimal O(N log N) run time complexity. However, all algorithms known in the art require a temporary copy of the data to be stored in memory, which can be prohibitive for large data sets, which may include billions of data points. Existing techniques work by recursively finding the m-th median out of a list of points, while using a properly chosen m to ensure a balanced tree. The techniques then use that element as a sub-tree's root node, and recurse the list of points to the left and right of that point, respectively. These techniques require constant re-arranging of the as-yet-unprocessed particles, so existing techniques typically use two lists of particles: one list for the points that are not yet placed and one list for the final array of where nodes are written into as soon as their position is determined.

Method and apparatus for in-place construction of left-balanced and complete point K-D trees


An electroluminescent device includes a semiconductor layer (4) in the form of a thin dense polymer film comprising at least one conjugated polymer, a first contact layer (5) in contact with a first surface of the semiconductor layer, and a second contact layer (3) in contact with a second surface of the semiconductor layer. The polymer film (4) of the semiconductor layer has a sufficiently low concentration of extrinsic charge carriers that on applying an electric field between the first and second contact layers across the semiconductor layer so as to render the second contact layer positive relative to the first contact layer charge carriers are injected into the semiconductor layer and radiation is emitted from the semiconductor layer. The polymer film can be poly (p-phenyenevinylene) [PPV] of formula (I) wherein the phenylene ring may optionally carry one or more substituents each independently selected from alkyl (preferably methyl), alkoxy (preferably methoxy or ethoxy), halogen (preferably chlorine or bromine) or nitro. A method of manufacture of an electroluminescent device includes steps of depositing a thin layer of a precursor polymer onto a substrate and then heating the precursor polymer to a high temperature to form the conjugated polymer.

Electroluminescent (EL) devices are structures which emit light when subject to an applied electric field. The usual model for the physical process in a semiconductor used in this way is through the radiative combination of electron-hole pairs which are injected into the semiconductor from opposite electrodes. Common examples are light-emitting diodes based on GaP and similar III-V semiconductors. Though these devices are efficient and widely used, they are limited in size, and are not easily or economically used in large area displays. Alternative materials which can be prepared over large areas are known, and among the inorganic semiconductors most effort has been directed to ZnS. This system has considerable practical drawbacks, primarily poor reliability. The mechanism in ZnS is believed to be one where acceleration of one type of carrier through the semiconductor under a strong electric field causes local excitation of the semiconductor which relaxes through radiative emission.
Among organic materials, simple aromatic molecules such as anthracene, perylene and coronene are known to show electroluminescence. The practical difficulty with these materials is, as with ZnS, their poor reliability, together with difficulties in deposition of the organic layers and the current-injecting electrode layers. Techniques such as sublimation of the organic material suffer from the disadvantage that the resultant layer is soft, prone to recrystallisation, and unable to support high temperature deposition of top-contact layers. Techniques such as Langmuir-Blodgett film deposition of suitably-modified aromatics suffer from poor film quality, dilution of the active material, and high cost of fabrication.
An electroluminescent device utilising anthracene is disclosed in U.S. Pat. No. 3,621,321. This device suffers from high power consumption and low luminescence. In an attempt to provide an improved device, U.S. Pat. No. 4,672,265 describes an EL device having a double layer structure as its luminescent layer. However, the suggested materials for the double layer structure are organic materials which suffer from the disadvantages mentioned above.

Method of manufacturing of electrolumineschent devices


Identifying unvisited portions of visited information to visit includes receiving information to crawl, wherein the information is representative of one of web based information and non-web based information, computing a locality sensitive hash (LSH) value for the received information, and identifying a most similar information visited thus far. Identifying unvisited portions of visited information further includes determining whether the LSH of the received information is equivalent to most similar information visited thus far and, responsive to a determination that the LSH of the received information is not equivalent to most similar information visited thus far, identifying a visited portion of the received information using information for most similar information visited thus far and crawling only unvisited portions of the received information.

Web-crawlers spider web sites in a methodical and automated way to analyze the web sites determining whether issues related to web vulnerabilities, accessibility, quality and a myriad of other purposes exist. Typically in web sites, the same web components or web information appear repeatedly across different pages of the site to facilitate site navigation. Crawling redundant components increases time and resources needed.
For example, a web crawler visits two web pages in which the pages have a common HTML form control. When the web crawler scans a second web page, the crawler detects the HTML form control was already scanned as part of a first page scan but skips the second page scan to avoid redundant processing only when the complete content of the web pages is similar.
A previous solution typically identifies two pages as the same when the pages are analyzed to be structurally similar. A similarity algorithm of the previous solution operates on a page level and assumes a repetitive consecutive sequence of HTML elements is redundant for analysis purposes. The technique can be applied in each sub-structure of a page, however the previous solution typically lacks scalability and efficiency. The previous solution generates an MD5 hash value as an identifier (ID) of a DOM or HTML elements. Accordingly a slightly different HTML can produce a completely different MD5 hash value and for each computed hash value of a page the crawler would need to search in a record repository comprising many records to determine whether a specific sub-tree or control was scanned previously.
In a similar solution, using similarity estimation, Gurmeet (Gurmeet S. Manku, Arvind Jain, Anish D. Sarma, (2007) "Detecting near duplicates for web crawling," Proceedings of the 16th international conference on World Wide Web, pp: 141-150) proposed a method to use a Locality Sensitive Hash (LSH) [Charikar (Moses Charikar, Similarity estimation techniques from rounding algorithms. In Proceedings of 34th Symposium on Theory of Computing (STOC) (2002), 380-388)] to detect near duplicate web pages. Benjamin Van (Benjamin Van Durme and Ashwin Lall, Online Generation of Locality Sensitive Hash Signatures, Proceedings of the ACL 2010 Conference Short Papers, pages 231-235, Uppsala, Sweden, 11-16 Jul. 2010. © Association for Computational Linguistics) revisited the work of Ravichandran (Deepak Ravichandran, Patrick Pantel, and Eduard Hovy. Randomized Algorithms and NLP: Using Locality Sensitive Hash Functions for High Speed Noun Clustering, Proceedings of the 43rd Annual Meeting of the ACL, pages 622-629, Ann Arbor, June 2005. © 2005 Association for Computational Linguistics) and Charikar (2002) in asserting that an online version of an LSH signature can be maintained. However, the work presented consisted of detecting complete content similarity (every character in an HTML page) of a web page. Other proposed similar solutions include those by Batkoa 2008 ("Scalability comparison of Peer-to-Peer similarity search structures" Michal Batkoa, David Novaka, Fabrizio Falchib, Pavel Zezulaa, Journal Future Generation Computer Systems archive Volume 24 Issue 8, October, 2008) and S. Asaduzzaman 2009 (A locality preserving routing overlay using geographic coordinates (S. Asaduzzaman and G. v. Bochmann) IEEE Intern. Conf on Internet Multimedia Systems Architecture and Application, Bangalore, India, December 2009).

This patent is subject to a terminal disclaimer.

INTERNATIONAL BUSINESS MACHINES CORPORATION


A hook latch mechanism for joining two members of an engine cowl or the like, with the hook latch mechanism carried on one member on a mounting bolt and a keeper carried on the other member, and with a keeper engaging hook spaced from the handle. The hook latch includes a body, a hook carried in the body for engagement with a keeper, a handle pivotally mounted on the body at a first pivot axis for movement between latched and unlatched positions, a catch carried on the handle for engagement with the body when the handle is in the latched position, and first, second and third links, with the first link pivotally connected at one end to the body at a second pivot axis, the second link pivotally connected to the handle at a third pivot axis, and the third link pivotally connected to the second link at a fourth pivot axis and pivotally connected to the first link at a fifth pivot axis, with the third link including a mounting bolt opening for pivotally receiving a mounting bolt, and the body including a slot for slidingly receiving the mounting bolt.

This invention relates to hook latch mechanisms for joining two members, typically portions of an aircraft cowling. A typical prior art latch mechanism is shown in U.S. Pat. No. 5,152,559. In such prior art designs, the hook and keeper are positioned at the members being joined, typically the two cowling panels, so that the load line through the keeper and hook of the latch is substantially at the surface of the structure.
In present day aircraft, the engine cowlings are quite large and substantial compression forces are required for compressing the seals between the members being joined. This results in undesirable bending moments in the surrounding aircraft structure.
It is an object of the present invention to provide a new and improved hook latch mechanism suitable for use in present day cowlings and capable of exerting the desired compression forces while reducing bending moments. It is a particular object of the invention to provide such a hook latch mechanism with the load line of the hook and keeper substantially spaced from the handle and outer surface of the structure, typically with the hook and keeper in the order of three inches between the handle and the latch load line. An additional object is to provide such a hook latch mechanism wherein the preload on the latch is easily adjusted.
Other objects, advantages, features and results will more fully appear in the course of the following description.


A shift-lever device includes a position plate integrated with a base plate and formed with a detent groove, a shift lever supported to the base plate to be swingable along the position plate and including a base arranged adjacent to the position plate, and a compression rod arranged through the shift lever to axially be movable by operation of a knob button. A detent protrusion is arranged with the compression rod at a lower end to be engageable with the detent groove. A guide integrated with the base of the shift lever holds part of the detent protrusion longitudinally with respect to a vehicle body.

The present invention relates generally to shift-lever devices for motor vehicles, and more particularly, to the shift-lever devices wherein when pressing a knob button arranged at the upper end of a shift lever, a compression rod arranged therethrough is moved to disengage a position pin arranged at the lower end from a detent groove of a detent or position plate, enabling shifting of the shift lever.
Conventionally, automatic transmission operating devices or shift-lever devices for motor vehicles include a shift lever comprising a pipe and longitudinally swingably supported to a housing fixed to a vehicle body, and a compression rod vertically movably arranged therethrough. When operating a knob button that is in slide contact with a taper surface formed at the upper end of the shift lever, the compression rod is moved against a biasing force to disengage a position pin arranged at the lower end from a detent groove of a detent or position plate arranged in the housing, making the shift lever swingable. Through a cable connected at the lower end of the shift lever, shifting of the shift lever is transmitted to operate an automatic transmission.
A known shift locking unit includes a lock lever for preventing movement of the shift lever by contacting it when the position pin is in the parking (P) range. The lock lever is rotated by a solenoid that operates when detecting actuation of a brake switch, etc., so that even when pressing the knob button, the position pin contacts the lock lever, obtaining no movement of the compression rod.
Regarding the known shift-lever devices, however, due to the fact that a pressing force applied to the knob button is input to the lock lever through the position pin, the lock lever needs to have a sufficient strength to resist this pressing force. This causes an increase not only in weight of the lock lever, but in size of the solenoid for actuating the lock lever, resulting in an increase in size and manufacturing cost of the shift locking unit.
It is, therefore, an object of the present invention to provide shift-lever devices for motor vehicles that contributes to a reduction in size and manufacturing cost of a shift locking unit.


The injection molding device of the present invention is provided with a supply pipe which supplies a heat medium to a mold, a discharge pipe which discharges the heat medium from the mold, a mold temperature adjustor to which the supply pipe and the discharge pipe are connected to adjust the temperature of the mold, and a discharge rate adjusting unit which is provided with a variable flow control valve installed on the discharge pipe to adjust a flow rate of the heat medium, a discharge pipe variable flow control valve bypass pipe for bypassing the variable flow control valve and a discharge pipe bypass on-off valve installed on the bypass pipe to change a flow rate of the heat medium and which is installed at a position upstream from the mold temperature adjustor on the discharge pipe.

There has been conventionally proposed an injection molding device which supplies a heat medium such as steam to heat a mold, thereby increasing the temperature thereof to a target temperature (refer to FIG. 1 in Patent Document 1). In this injection molding device, an ordinary discharge line 13 is connected to a heat medium discharge port of a mold 1, and a steam trap 12 is installed on the ordinary discharge line 13. There is also installed an outlet bypass line 15 which bypasses the steam trap 12 and is communicatively connected to the upstream side and the downstream side of the ordinary discharge line 13. The outlet bypass line 15 is installed so as to bypass the ordinary discharge line 13, and a transfer valve 14 is installed on the outlet bypass line 15. Here, a discharge rate adjusting unit which is constituted with the steam trap 12, the outlet bypass line 15 and the transfer valve 14 is mounted on a mold temperature adjustor which is separately provided from the mold 1.
Then, in the above-constituted conventional injection molding device, during the first half of a heating step of the mold 1, the transfer valve 14 is opened to distribute steam in a large quantity into the mold 1, thereby rapidly heating the mold. On the other hand, during the second half of the heating step, the transfer valve 14 is closed to keep the inside of the mold 1 high in pressure by causing the steam to pass through the steam trap 12. In addition, the steam is controlled for pressure to adjust the temperature of the mold with high accuracy.

Injection molding device and method for discharging heat medium for injection molding device

Mitsubishi Heavy Industries Plastic Technology Co., Ltd.


A hinge lock which during standstill of a primary control shaft, locks a driven shaft actuating a control element and connected by a gear drive to the control shaft. The arrangement is particularly adapted for control hinges of slats on large aircraft, in which a tangential key free-wheel lock is connected to the driven shaft with at least two tangential keys facing each other and locking in one direction of rotation. An engaging element driven by the primary control shaft, shifts a key release between the tangential keys, depending on the direction of rotation. A transmission is connected between the primary control shaft and the auxiliary shaft such that the speed of the auxiliary shaft is a multiple of the speed of the rotating body of the tangential key free-wheel lock.

The present invention relates to a hinge lock which upon standstill of a primary control shaft blocks a driven shaft which actuates a control element and which is connected to the control shaft by a gear drive, particularly for the control hinges of slats on a giant aircraft.
The controllable slats on the leading edges of the wings of giant aircraft present, for safety reasons, the problem of instantly and absolutely rigidly blocking the controllable hinged arrangement of these slats in case of a break inside the hinge elements or in case of failure of the driving control force. This means that the control movement must proceed from the absolute fixation and rigidity of the hinges and must terminate instantly in rigidity upon ceasure of the control activity. It is necessary to consider the forces resulting from the high starting and landing speeds which are confronted by disproportionately lower control forces. The rotary speeds are such that the drive and control shafts with small torques perform a very slow fractional rotation, like the conventional servomotors. By interposing a gear reduction drive between drive shaft and the control shaft acting on the driven shaft, a suitable adaptation of the rotary speeds can be achieved.
Accordingly, it is an object of the present invention to provide a hinge lock of the preceding species with a tangential key free-wheel lock connected to the driven shaft, with at least two facing tangential keys locking in one rotary direction and an engaging element, driven by the primary control shaft; this engaging element moves a key release between the tangential keys into a release position.


There is provided a data processing device including an output port to transmit a request value to an interconnect arranged to implement a coherency protocol, to indicate a request to be subjected to the coherency protocol. An input port receives an acknowledgement value from the interconnect in response to the request value and coherency administration circuitry defines behavior rules for the data processing device in accordance with the coherency protocol and in dependence on the request value and the acknowledgement value. Storage circuitry administers data in accordance with the behavior rules. There is also provided an interconnect including an input port to receive a request value, issued by a data processing device having storage circuitry, to indicate a request for the data processing to be subjected to a coherency protocol. An output port transmits an acknowledgement value to the data processing device in response to the request value and coherency administration circuitry defines behavior rules for the interconnect in accordance with the coherency protocol and in dependence on the request value and the acknowledgement value.

A number of master devices may access a shared resource (also known as a slave device) such as memory via an interconnect. If some of the master devices have a local cache then it is possible that, after modifying data retrieved from memory, the modified version of that data can be stored in a local cache rather than being stored back to memory. However, this can cause problems if another master device needs to access the data. In particular if that master device accesses the version of the data stored in memory then the master device will be operating on out-of-date data, leading to a lack of coherency in the master device's view of the memory system. In order to reduce such problems, a coherency protocol may be implemented in order to dictate the behaviour of particular devices in a system such that all master devices have a coherent view of data.
A software controller, somewhere in the system, may take charge of the process of connecting to or disconnecting a master device from the system in such a way that the system remains coherent. Such a software controller may require the use of expensive communication between hardware and software components in order to complete the connection or disconnection process.

Hardware based coherency between a data processing device and interconnect


Embodiments include systems and methods for providing throughput increase and/or physical expansion of a data storage library. Some embodiments include multiple robotic assemblies, each having its own hand assembly, which are electrically and mechanically integrated for concurrent use in a single storage library environment for increased throughput. Other embodiments include an active vertical pass-through assembly that operates to ferry cartridges from one storage library environment to another, vertically adjacent storage library environment. Some such embodiments use existing robotic mechanisms of the libraries to exploit a shared slot through which vertical pass-through functionality can be realized. Other embodiments include an active horizontal pass-through assembly that operates to ferry cartridges from one storage library environment to another, horizontally adjacent storage library environment. Some such embodiments include a separate robotic mechanism that couples with each library and actively passes a cartridge among them and is adjustable to varying spans between the libraries.

Storage library systems are often used by enterprises and the like to efficiently store and retrieve data from storage media. In the case of some storage libraries, the media are data cartridges (e.g., tape cartridges) that are typically stored and indexed within a set of magazines. When particular data is requested, a specialized robotic mechanism finds the appropriate cartridge, removes the cartridge from its magazine, and carries the cartridge to a drive that is designed to receive the cartridge and read its contents. Some storage libraries have multiple drives that can operate concurrently to perform input/output (I/O) operations on multiple cartridges.
One limitation of some such storage library systems is that the throughput of the system (e.g., how quickly data can be accessed) is at least partly dependent on physical constraints relating to moving the robot, picking and placing cartridges, etc. For example, expanding the size of the library can effectively increase the distances traversed by the robot when performing pick and place operations, and the like, which can thereby increase access times and reduce throughput. Another limitation of some such storage library systems is that a fixed number of cartridges fit in the library. For example, if a library is intended to fit in half of a standard equipment rack, that overall footprint can drive the space available for cartridges, magazines, etc. To use more cartridges, customers typically purchase an additional library that operates independent of the other library.

Horizontal pass-through for a data storage library


Provided is a method for producing a temporary prosthesis that can be easily performed at a dental clinic and that at the same time enables fabrication of a temporary prosthesis that is less susceptible to wear and damage. The present invention is achieved by fabricating an occlusal surface with a dental composite resin that has higher strength compared to a conventional room temperature polymerization resin. The method includes fabricating a prosthesis model, using an impression material to take an impression of a prepared tooth model having the prosthesis model mounted thereon, applying a layer of dental composite resin material to a portion that is to become a crown within the impression that has been removed from the prepared tooth model and polymerizing the composite resin material, putting a powder-liquid mixture of a powder-liquid type room temperature polymerization resin into the impression, refitting the prepared tooth model to the impression, and curing the room temperature polymerization resin.

Conventionally, in cases where aesthetics resembling a natural tooth are desired in dental prostheses such as crowns and bridges, resin-faced cast crowns, porcelain-baked-faced cast crowns, resin-faced bridges, porcelain-baked bridges, all-ceramic crowns, and the like may be used, for example. Methods for producing such dental prostheses involve making an impression (counterdie of tooth) from the oral cavity of a patient subjected to formation of an abutment tooth, creating a model (replica of tooth) from the impression using resin or plaster, for example, and fabricating the dental prosthesis based on this model using the lost wax technique, for example. The lost wax technique involves, first preparing a wax pattern of a core portion by applying wax in an abutment tooth die, embedding the wax pattern with a refractory investment material, and after the investment material is hardened, placing the investment material in an electric furnace to burn out the wax pattern. Then, metal is cast into the resulting mold, and after retrieving the cast metal from the investment material, the cast metal is cut and polished to fabricate a metal prosthesis. Alternatively, a dental prosthesis may be fabricated by preparing a metal coping, and thereafter building up and polymerizing hard resin for a crown on the resulting metal coping portion, for example. In the case of fabricating an all-ceramic crown, a composite model is prepared using a refractory die material, and after building up and firing a porcelain material in the composite model, the porcelain material is removed from the composite model and is finished and polished.
Normally, the above procedures are performed by a dental technician, and it generally takes about 3 days to a week before the final prosthesis can be inserted into the mouth of the patient. Meanwhile, in cases where an abutment tooth formed by a dentist is needed, a temporary prosthesis is formed by a dentist, and such a temporary prosthesis is temporarily inserted until the final prosthesis can be inserted. Such a temporary prosthesis is inserted in order to prevent the abutment tooth from being exposed to physical impacts such as food hitting the abutment tooth during a meal, chemical impacts such as exposure to acid, and stimulation from the temperature of food, for example. A temporary prosthesis has other important functions such as maintaining the occlusal function and restoring aesthetics of the teeth, for example.
Conventional temporary prostheses are mainly fabricated using a room temperature polymerization resin (also referred to as "immediate polymerization resin") or a dedicated two-liquid mixture paste resin (see e.g. Patent Documents 1 and 2). The room temperature polymerization resin may be prepared by mixing a (meth)acrylic acid ester polymer powder and a (meth)acrylic acid ester monomer powder solution, for example, and the temporary prosthesis may be fabricated using a mold prepared in advance using the above mixture, for example. Alternatively, the temporary prosthesis may be fabricated directly in the oral cavity of the patient or on a model using the so-called brush-on technique, for example (see e.g. Patent Documents 3 and 4).
However, in general, temporary prostheses fabricated using room temperature polymerization resin or conventional paste resin contain filler at a relatively small ratio and therefore tend to wear easily and have relatively low strength. As such, temporary prostheses have been prone to wear due to occlusion pressure, for example, and cause occlusal problems even when they are used only for a short period of about several days to a week, for example. Also, depending on circumstances such as the schedule of the patient, there may be cases where temporary prostheses are used for up to a few months, and the above problems due to wear become even more conspicuous in such cases. Further, regardless of the use period, conventional temporary prostheses are susceptible to damage or breakage that may be caused by the consumption of tough solid food, for example, and as such, there is a demand for a temporary prosthesis having greater strength.
In recent years, prosthesis fabrication using CAD/CAM technology is becoming widespread, and by using such technology to fabricate a temporary prosthesis, the strength of the temporary prosthesis may be increased (see e.g. Patent Documents 5 and 6). However fabrication procedures using CAD/CAM tend to be more complicated compared to fabrication using room temperature polymerization resin, which can be prepared on site, and the time required for fabrication using CAD/CAM is not much different from fabrication using the lost wax technique.

Method for producing temporary prosthesis