A method for detecting a signal propagation time between a mobile radio terminal and a base station in a mobile radio network in a mobile radio terminal, particularly for the purpose of localizing the mobile radio terminal which inserts a propagation time detection information item into a channel request message in order to signal to the base station that no channel reservation is necessary, and that only the propagation time detection needs to be carried out, so as to achieve significantly reduced loading of network resources.

To set up a connection between a mobile radio terminal and a base station in a mobile radio network, it is necessary to ascertain the time delay for the signal transmission between the two. This signal propagation time is required in a GSM system, for example, in order to synchronize the uplink bursts from the terminal to the timeslot pattern in the base station.
To this end, the base station determines the signal propagation time from the access bursts transmitted by the mobile station. A channel request message in the GSM system is sent as an access burst of this type. The base station then instructs the mobile station to bring forward its transmission time as appropriate by transmitting the determined signal propagation time to the mobile station in a channel allocation message, in the GSM system the "Immediate Assignment message".
The signal propagation time is indicated in the GSM environment by the "timing advance value" (TA value). This is simultaneously a measure of the mobile station's distance from the respective base station. The TA value can thus be used as a basis for autolocation methods on the mobile station, for example.
The localization of a mobile radio terminal in a mobile radio network forms the prerequisite for providing the numerous "location services". These are services which use different methods to make use of information regarding the position of the terminal or of the equipment user. Besides automatic transmission of the position or of the location in the case of an emergency call, they include position-dependent charging, position-dependent connection setup methods and position tracking, for example as part of traffic monitoring or fleet management.
One localization method is based on determining the cell in which the terminal is located. This provides actually usable statements in the core areas of large towns, in which the cell radii are in ranges of several hundred meters. In rural areas with their large cells, accuracies in the region of several kilometers are not adequate, however.
More accurate methods require expensive additional devices for the terminal. In the case of OTD ("Observed Time Difference") methods, the mobile station has a complex design in order to determine the difference between the arrival times of particular signals that are emitted by a plurality of base stations. Also, a mobile station may be equipped with a GPS receiver, which increases the overall cost.
Other methods require additional devices in the mobile radio network, which likewise means high outlay. Thus, many ToA ("Time of Arrival") methods are based on measuring the arrival times of a signal emitted by the mobile station at a plurality of known locations. This requires that what are known as LMUs ("Location Measurement Units") be placed at numerous locations in the network.
By contrast, methods which use the signal propagation time between the terminal and the base station to determine the interval make it possible to dispense with expensive additional devices in the network. In this context, the mobile radio terminal is usually localized using three TA values ascertained by different base stations. However, these methods having drawbacks associated with their use.
One drawback is that the primary objective of the interchange of channel request and channel allocation messages outlined above is not to determine the signal propagation time and to transmit it to the mobile station, but rather to determine and reserve at least one radio channel for connection setup in the base station for the purpose of further interchange of messages. To this end, the channel allocation message is used to transmit the physical properties of the reserved channel (e.g. frequency, timeslot, subchannel number) to the mobile station.
A TA value is thus recorded in the base station in connection with the simultaneous setup of a connection via the air interface. The request for such a connection is setup with a reservation of at least one signaling channel (in the case of GSM: of a "Dedicated Control Channel") and possibly of a further channel, e.g. a voice channel.
However, there is no requirement for channel reservation if only the signal propagation time is intended to be detected in the mobile station, such as for a terminal-aided localization method. Following receipt of the channel allocation method with the value it contains for the signal propagation time, the aim of the procedure has been achieved from the point of view of the mobile radio terminal. In a GSM system, the mobile station then changes to the RR idle state; the channel reserved by the base station is not required.
The reserved channel is released no earlier than after a few seconds, namely after the base station has detected that the reserved channel is not being used. In a GSM system, a typical value before release is six seconds. For this time, the requested channel is not available to other mobile stations for connection setup. This practice therefore wastes network resources. This problem has been an obstacle to acceptance of the inherently simple localization method described above to date, and hence to the use of localization methods on the whole.

Method for detecting a signal propagation time between a mobile radio terminal and a base station


The present invention describes an improved pressing roller for a tire building machine. The roller comprises a cylindrical sleeve with each end attached to a housing. Inside the sleeve, and between the housings is a spring biased to separate the housings. A multiplicity of ring shaped inner bearings circumferentially surrounding the sleeve in a parallel arrangement and a multiplicity of ring shaped outer bearings circumferentially surrounding the inner bearings in parallel arrangement. The outer bearings are rotatable relative to the inner bearings. As the roller is moved into operating proximity of the tire the spring is displaced away from the rotating axis of the roller causing the outer bearings to press on the tire and provide the pressure necessary for a stitching operation.

The present invention relates to a device which is useful in building tires. Particularly, the present invention relates to an improved roller which is novel and which finds particular utility in stitching two elements of a tire together to form a layered structure.
The principle elements in the art of tire building are well known to include a stitching operation wherein an inner element, or carcass, is brought into intimate contact with an outer element, or tread. A cement is applied between the carcass and tread to adhere one to the other. Of utmost importance to this stitching operation is the application of pressure to insure an adequate bond between the carcass and tread and to eliminate any air that is entrapped between the tread and carcass. Air is usually excluded from the space by the use of pressure rollers as well known in the art. There are three main categories of pressure rollers taught in the art. These can be categorized as spiral rollers, sequential rollers and contouring rollers.
Spiral rollers typically comprise a multiplicity of wheels, or similar device, which travel around the tire in a spiral fashion beginning in the center of the tread and transiting towards the edges. Typically, a pair of wheels work in symmetrical tandem excluding air as both transit linearly towards the outer edge of the tire while the tire rotates on its axis. Exemplary examples include U.S. Pat. Nos. 5,312,502; 5,181,982; 4,341,584; 4,306,931; 4,276,105; 4,057,455; 3,850,719 and 3,850,728. Spiral roller mechanisms tend to compress and spread the tread which causes tread material to accumulate towards the edge of the tire. This is undesirable.
Sequential rollers typically comprise a multiplicity of wheels situated in pairs which are symmetrical about the center of the tread. The roller(s) closest to the center of the tread come into contact with the tread first to exclude air from between the center portion of the tread and carcass. After a suitable time a second set of rollers, displaced towards the edge, are brought into contact with the tread of the tire. Additional sets of rollers, each displaced outwardly relative to the previously contacting rollers, are brought into contact sequentially. Exemplary examples include U.S. Pat. Nos. 4,039,366; 4,004,961 and 3,819,449. The sequential rollers eliminate the problem of outward displacement of tread material but are lacking in their ability to easily conform to differing surface contours. If a change in tire style, or size is required the wheels are replace which is undesirable.
Contouring rollers, the class containing the present invention, typically comprise a multiplicity of independently moving disk around a central core. U.S. Pat. No. 4,052,246 and U.S. Pat. No. 5,330,609 are exemplary references teaching contouring rollers.
Both U.S. Pat. No. 4,052,246 and U.S. Pat. No. 5,330,609 comprise a multiplicity of parallel disk circumferentially surrounding an inflatable tube. The tube is inflated which, in turn, causes the disk to exert pressure on the surface of the tread. The amount of deflection available is limited to the size of the inflatable tube. The range of contour changes with which the existing contouring roller design can be operated is limited thereby diminishing their operating range.


Topical ophthalmic compositions comprising certain thiadiazoles are useful in the treatment of glaucoma and ocular hypertension. The thiadiazoles are slightly less potent than timolol; however, they have greatly reduced systemic side effects as compared to timolol.

This invention relates to topical ophthalmic compositions comprising certain 4-(3-substituted amino-2-hydroxypropoxy)-1,2,5-thiadiazoles. These compounds are .beta.-blockers which are effective at relatively low doses. Ophthalmic compositions comprising these compounds are useful in the treatment of glaucoma and ocular hypertension.
This class of compounds was originally disclosed in German Patent No. 1,925,956 (issued in 1969 to B. K. Wasson), which is equivalent to U.S. No. 3,655,663 (issued in 1972) and U.S. No. 3,729,469 (issued in 1973). It was later found that topical application of timolol, one of the most effective thiadiazoles disclosed and claimed in U.S. No. 3,655,663 (the '663 patent), was also useful to treat ocular hypertension. See, for example, Heel, et al., Drugs, 17:38-55 (1979). Although effective in decreasing intraocular pressure, there are often rather severe systemic side effects associated with the use of topical ophthalmic compositions of timolol. Because timolol was the most potent of the compounds tested, other compounds of the class disclosed in the '663 patent were thought to be unsuitable for the treatment of ocular hypertension, as the larger doses which would be needed would be intolerable due to the corresponding increase in systemic and ocular side effects.

Topical ophthalmic compositions comprising 4-(3-substituted amino-2-hydroxypropoxy)-1,2,5-thiadiazoles and methods for their use


Provided is a method for validating a predetermined digital certificate having a validation device, wherein the validation device stores approval information that specifies which digital certificates of a plurality of digital certificates are permissible digital certificates, and wherein the validation device further stores trust information which indicates a trust level of the permissible digital certificates. The method includes determining, while taking account of the approval information, whether the predetermined digital certificate is permissible for the planned use under the current conditions; and if it is determined that the predetermined digital certificate is permissible, determining the trust level of the predetermined digital certificate by taking into consideration the trust information for the planned use and the current conditions, is provided. A trust level can be determined for a digital certificate which indicates how trustworthy the digital certificate is for a planned use under the current conditions.

A digital certificate may be assigned to a certificate holder, for example a machine, a field device or a controller. The digital certificate of the certificate holder is used for example to encrypt data that are transmitted by a further device (user device) to the certificate holder, or to verify digital signatures of the certificate holder using a further device (user device). Before it is used by the user device, it is often necessary to validate the digital certificate of the certificate holder.
For this purpose, the user device may query a trust store. The trust store specifies in particular which certification authorities, in particular root certification authorities, issue digital certificates that are permissible or trustworthy from the point of view of the user device or indirectly certify the issuance through intermediate certification authorities. If the digital certificate to be validated was created by a certification authority that directly or indirectly creates trustworthy certificates according to the trust store, the digital certificate is able to be validated.
Document WO 2017/121602 A1 discloses a method for checking a security classification of a first device by way of an associated digital certificate. The method comprises the steps of: transmitting the digital certificate with an identifier of a security classification from the first device to a second device, checking the identifier of the security classification against a predefined security rule by way of the second device, and carrying out security measures according to the check result of the security rules.
Document WO 2008/130191 A1 discloses a method for using content taking into account security levels, in which a device security level is generated, contents are obtained, and the contents are used if the device security level is above a minimum permissible device security level.
Document U.S. Pat. No. 5,261,002 A comprises a method for issuing and revoking user authorization certificates in a cryptographic system.
Document US 2006/0294384 A1 discloses an information processing device for storing information that has an expiry date. The information is replaced with new information following the expiry date.
Against this background, one aspect of the embodiment of the present invention is to provide improved validation of a predetermined digital certificate.

Method and validation device for validating a digital certificate


An array of color filter elements may be formed over an array of photodiodes in an integrated circuit for an imaging device using a carrier substrate. The carrier substrate may have a planar surface with a release layer. A layer of color filter material may be applied to the release layer. The carrier substrate may then be flipped and the layer of color filter material may be bonded to the integrated circuit. Heat may be applied to activate the release layer and the carrier substrate may be removed at the interface between the release layer and the color filter material. The layer of color filter material may be patterned either before bonding the layer of color filter material or after the carrier substrate is removed. A layer of microlenses may be formed over the array of color filter elements using a carrier substrate.

This relates generally to imaging systems, and more particularly, to imaging systems with imaging device layers formed using carrier substrates.
Modern electronic device such as cellular telephones, cameras, and computers often use digital image sensors. Imagers (i.e., image sensors) often include a two-dimensional array of image sensing pixels. Each pixel typically includes a photosensor such as a photodiode that receives incident photons (light) and converts the photons into electrical signals. An image sensor contains an imaging device integrated circuit containing an array of photodiodes. An image sensor often also includes one or more imaging device layers over the array of photodiodes. For example, an imaging device layer such as a layer formed from color filter material is conventionally formed directly on the imaging device integrated circuit over the array of photodiodes using conventional spin coating techniques. However, the non-planar topography of the imaging device integrated circuit may result in the production of color filters arrays that do not meet desired performance criteria (for example, color filter arrays with streaks or waves due to non-uniform coating).
It would therefore be desirable to provide improved ways of forming imaging device layers over imaging device integrated circuits in imaging systems.

Methods of forming imaging device layers using carrier substrates

Semiconductor Components Industries, LLC


A method and means for converting a high resolution machine monitored phoiode array, comprising staircased linear sets of detectors operating in a time-delay-integration mode, to a low resolution visually monitored array, by delaying the output signal of odd sets in the staircase by the time required to scan one set and integrating the outputs of odd and even sets.

1. Field of the invention
The invention involves infrared imaging devices particularly imagers with focal plane arrays wherein rows of small infrared detectors are scanned in a Time Delay and Integration mode with an infrared image by means of a scanning mirror.
2. Prior Art
Infrared photoelectric imaging devices in the past have been developed chiefly for use by human observers. As the art of automatic target recognition (ATR) developed, it became clear that successful ATR devices require much more information than the human eye does to identify targets reliably. In other words, the resolution required by ATR devices is at least two times that required by simple navigation and surveillance type imaging systems. In systems where communication channels interconnect the imager with a remote display and/or a memory storage unit, this translates into a requirement for many wide band transmission elements and large banks of memory elements, when storage of the picture elements (pixels) is involved.
The primary object of the invention is to provide a method and means for using the same large focal plane detector arrays for both wide and narrow bandwidth applications.

Focal plane array for man and machine visions

The United States of America as represented by the Secretary of the Army


The present invention relates to Cardiac Targeting Peptides or CTPs that are able to transduce cardiomyocytes specifically in culture and in vivo, and to methods for using such peptides and their derivatives to deliver peptides, proteins or nucleic acids specifically to the heart. It is based, at least in part, on the discovery that the peptide APWHLSSQYSRT (SEQ ID NO:1) functioned as a cardiac-specific protein targeting peptide and was successful in delivering a number of different cargoes to cardiac muscle cells in vitro and in vivo.

Ischemic heart disease and occlusive coronary artery disease continue to be the number one killer in the developed world. There are an estimated 500,000 acute ST-elevation myocardial infarctions (MI) in the US alone each year [1], and this is becoming an increasingly significant problem in the developing world [2]. Current approaches for management of an acutely occluded coronary artery leading to an MI consist of anti-platelet and anti-thrombotic strategies with intervention aimed at opening the infarct-related artery in a timely fashion. Although this approach is able to protect cardiomyocytes from necrosis, with resulting decrease in morbidity and mortality, it necessitates exposing the heart to post-ischemic reperfusion injury. Limiting this reperfusion injury and decreasing apoptosis would ultimately lead to greater myocardial salvage and prevention of development of heart failure. Numerous animal studies have identified biological agents able to ameliorate this ischemia-reperfusion injury and reduce the ultimate infarct size [3, 4]. However, further development of these approaches is hindered by the inability to deliver the biologic agents to the myocardium in a tissue-specific, efficient and rapid manner. A protein transduction peptide specific for the heart would be able to deliver biologic agents in a timely fashion to the heart when given at the time of reperfusion for an infarction:
Protein transduction domains (PTD) are small cationic peptides that can cross cellular membranes, and are able to transport large, biologically active molecules into mammalian cells in culture as well as in vivo. The limitation of PTDs is the non-specific transduction of all tissue types with some tissues, such as liver and kidney, taking up the PTD much more avidly than heart tissue. Thus there is a need to identify peptides able to target cardiac tissue specifically for delivery of biologics of therapeutic potential.
Screening approaches using peptide phage display libraries are effective for identifying peptides able to bind to specific ligand targets as well as identifying peptides with novel properties. Phage display uses filamentous bacteriophage, such as M13, that are able to replicate in E. coli. The proteins or peptides to be displayed are fused to the N-terminus of phage coat protein pIII or pVIII and thus are present on the surface of the phage. Screening of peptide phage display libraries has been used in vivo to identify peptides able to target tumor vasculature [5], adipose tissue [6] and pancreatic islet cells [7]. In addition, it has been used to identify peptides able to facilitate internalization of intact, infectious phage into specific cell types such as synovial fibroblasts [8]. In vivo phage display also has been utilized to target atherosclerotic plaques [9], and to probe the heart vasculature for endothelial markers [10]. Although in vitro selection of a specific peptide sequence carrying phage resulted in increased targeting of cardiomyocytes by phage in vivo [11], it remains to be determined if the peptide can actually deliver "cargo" peptides or proteins of therapeutic potential to the heart. If such were indeed the case, it would open up new avenues of drug development, leading to delivery of therapeutics directly to the ischemic heart.

Cardiac-specific protein targeting domain

University of Pittsburgh—of the Commonwealth System of Higher Education


In accordance with embodiments disclosed herein, there are provided methods, systems, and apparatuses for enabling an agent interfacing with a pipelined backbone to locally handle transactions while obeying an ordering rule including, for example, receiving a transaction which requests access to a backbone; decoding routing destination information from the transaction received, in which the decoded routing destination information designates the transaction to be processed either locally or processed via the backbone; storing the decoded routing destination information and the transaction into a First-In-First-Out (FIFO) buffer; retrieving the decoded routing destination information and the transaction from the FIFO buffer; and processing the transaction locally or via the backbone based on the decoded routing destination information retrieved from the FIFO buffer with the transaction.

The subject matter discussed in the background section should not be assumed to be prior art merely as a result of its mention in the background section. Similarly, a problem mentioned in the background section or associated with the subject matter of the background section should not be assumed to have been previously recognized in the prior art. The subject matter in the background section merely represents different approaches, which in and of themselves may also correspond to disclosed embodiments.
In the field of computing, systems implement pipelined backbone protocols to separate issuance of transactions by an agent. Issued transactions are typically separated into two phases: (1) requests by agent, and (2) grant by backbone. Such pipelined backbone protocols allow an agent to present multiple requests to a backbone for the same request channel, regardless of whether or not previous requests have been granted by the backbone. Each phase (e.g., request or grant) is able to make forward progress independent of other phases, thus allowing for high speed transaction transmission. Grants by the backbone within the same request channel are typically required to follow the order of the request presented by the agent to the backbone. One exemplary pipelined backbone protocol is the Intel On-Chip System Fabric (IOSF).
However, such a model becomes problematic for transactions which are to be handled locally, either being discarded or consumed by the agent itself, as such local handling interferes with the ordering requirement for grants by the backbone.
The present state of the art may therefore benefit from systems, mechanisms, and methods for enabling an agent interfacing with a pipelined backbone to locally handle transactions while obeying an ordering rule as described herein.

Method and apparatus for agent interfacing with pipeline backbone to locally handle transactions while obeying ordering rule


A doped silicon layer is formed in a batch process chamber at low temperatures. The silicon precursor for the silicon layer formation is a polysilane, such as trisilane, and the dopant precursor is an n-type dopant, such as phosphine. The silicon precursor can be flowed into the process chamber with the flow of the dopant precursor or separately from the flow of the dopant precursor. Surprisingly, deposition rate is independent of dopant precursor flow, while dopant incorporation linearly increases with the dopant precursor flow.

Silicon and doped silicon films are frequently used in the semiconductor devices which form integrated circuits and other electronic devices. Typically, semiconductor devices are formed by depositing the silicon films by chemical vapor deposition (CVD) using silane (SiH4) as the silicon source gas.
For a variety of reasons, including the on-going miniaturization of semiconductor devices, there is a desire for ever thinner and ever smoother films. One method to increase film smoothness is to reduce deposition temperatures. The reduction of deposition temperatures results in the films being deposited in the amorphous state and having a smoother surface than films deposited at relatively high temperatures in the polycrystalline state. However, the deposition rate of the film strongly decreases with temperature and can fall to unacceptably low levels. In particular, the deposition rate can fall so low that the processing becomes uneconomical. Moreover, there exist limits to the extent that smoothness can be increased by lowering the deposition temperature.
This problem is particularly acute in the case of n-type doped films such as phosphorus doped films. A film can be doped as the film is being deposited, thereby forming "as-deposited" doped films. However, n-type dopants are known to poison deposition surfaces, thereby causing a strong reduction in deposition rate when a substrate is exposed to dopant during the deposition of the films. Thus, forming smooth n-type doped films at an acceptable deposition rate is problematic, since the combination of reducing deposition temperatures to deposit smoother films and the poisoning of the deposition surfaces can quickly lead to unacceptably low deposition rates and unacceptably low throughput.
Accordingly, there is a need for methods and apparatus to deposit n-type doped films which are smooth, while allowing for high throughput.

Low temperature doped silicon layer formation


A trailer driver for moving and supporting a trailer is disclosed. A frame provides a base for supporting two downwardly facing opposing arms. A fixed bearing extends upwardly from the base and supports a vertical hitch shaft that is rotatably engaged within the bearing. A trailer hitch clamp is removably fixed to the hitch shaft and is adapted for holding a trailer hitch. The hitch shaft engaging a cover and further provides a fixed steering sprocket coaxial with the hitch shaft. A drive wheel is rotatably mounted on a horizontal axle, which is positioned between the two arms of the frame, and engages a drive sprocket for rotating therewith on the axle. An electric motor is fixed to the frame and provides a driven sprocket interconnected with the drive sprocket by a first drive belt. A drive circuit drives the motor in either a forward or reverse direction. A steering assembly includes a rotatable steering shaft held in a fixed position by the cover and provides a rotatable steering sprocket at one end and a steering arm at the other end. The rotatable sprocket is interconnected by a second drive belt to a fixed steering sprocket. Rotation of the steering arm results in rotation of the frame and drive wheel with respect to the hitch shaft and the cover means, so as to enable the trailer driver to be steered. A dolly is further included for moving the trailer driver and for storing the trailer driver in an upright orientation.

Several motorized trailer drivers are found in the prior art. For example, U.S. Pat. No. 4,860,841 to Sacco on Aug. 29, 1989 teaches such a device, as to do U.S. Pat. Nos. 4,162,711 to Cornelius on Jul. 31, 1979; 3,861,482 to Stephens et al. on Jul. 21, 1975; 3,783,960 to Feliz on Jan. 8, 1974; and 3,770,070 to Smith on Nov. 6, 1973. Such devices have not found widespread acceptance in the market due to several drawbacks associated with such devices. Primarily, such prior art devices, particularly with large trailers, tend to be difficult to steer due to a lack of steering leverage. Further, while such devices are designed to aid in maneuvering a trailer, such devices are difficult to move and maneuver themselves when not connected to a trailer. Several of the prior art devices are designed for permanent attachment to the trailer, rendering them useless for moving other trailers. While there are several other prior art devices designed for removable use with trailers, such devices are not easily attached to or removed from the trailers, making their use difficult.
Clearly, then, there is a need for a trailer moving device that is relatively easy to steer while moving a trailer to which it is connected. Such a needed device would itself by easy to move and store, and would provided a simplified, easy-to-use attachment for attaching to the trailer. Such a needed device would further provide high traction with the ground. The present invention fulfills these needs and provides further related advantages.


This invention relates to encapsulation of drugs and other agents into liposomes.

Liposomes are microscopic particles that are made up of one or more lipid bilayers enclosing an internal compartment. Liposomes can be categorized into multilamellar vesicles, multivesicular liposomes, unilamellar vesicles and giant liposomes. Multilamellar liposomes (also known as multilamellar vesicles or "MLV") contain multiple concentric bilayers within each liposome particle, resembling the "layers of an onion". Multivesicular liposomes consist of lipid membranes enclosing multiple non-concentric aqueous chambers. Liposomes that enclose a single internal aqueous compartment include small unilamellar vesicles (SUVs) and large unilamellar vesicles (LUVs). LUVs and SLVs range in size from about 50 to 500 nm and 20 to 50 nm respectively. Giant liposomes typically range in size from 5000 nm to 50,000 nm and are used mainly for studying mechanochemical and interactive features of lipid bilayer vesicles in vitro (Needham et al., Colloids and Surfaces B: Biointerfaces (2000) 18: 183–195).
Liposomes have been widely studied and used as carriers for a variety of agents such as drugs, cosmetics, diagnostic reagents, and genetic material. Since liposomes consist of non-toxic lipids, they generally have low toxicity and therefore are useful in a variety of pharmaceutical applications. In particular, liposomes are useful for increasing the circulation lifetime of agents that have a short half-life in the bloodstream. Liposome-encapsulated drugs often have biodistributions and toxicities which differ greatly from those of free drug. For specific in vivo delivery, the sizes, charges and surface properties of these carriers can be changed by varying the preparation methods and by tailoring the lipid makeup of the carrier. For instance, liposomes may be made to release a drug more quickly by decreasing the acyl chain length of a lipid making up the carrier.
Liposomes containing metal ions encapsulated in the interior of the vesicle have been used in diagnostic applications. For example, liposomes have been used for delivery of contrast agents with the goal of accumulating a contrast agent at a desired site within the body of a subject. In the latter application, liposomes have mainly been used for delivery of diagnostic radionucleotides and paramagnetic metal ions in gamma and magnetic resonance imaging, respectively. This includes liposomal encapsulation of radionucleotides such as 111In, 99mTc and 67Ga and paramagnetic ions such as Gd, Mn and manganese oxide. Two methods are typically employed to prepare liposomes for imaging purposes. In the first method, the metal is converted to a soluble chelate and then introduced into the aqueous interior of a liposome. In the second method, a chelating agent derivatized with a lipophilic group is anchored to the liposome surface during or after liposome preparation.
Manganese and non-transition metal ions have also been involved in methods for encapsulation of ionizable agents into liposomes containing an ionophore inserted in the liposome membrane (see U.S. Pat. No. 5,837,282 and Fenske et al., Biochim. Biophys. Acta (1998) 1414: 188–204). In this method, the ionophore translocates the metal ion across the liposome membrane in exchange for protons, thereby establishing a pH gradient. The establishment of an appropriate pH gradient across the liposome bilayer allows the ionizable agent to be encapsulated since the agent can readily cross the liposomal bilayer in the neutral form and subsequently become encapsulated and trapped within the aqueous interior of the liposome due to conversion to the charged form (see Mayer et al., U.S. Pat. Nos. 6,083,530, 5,616,341, 5,795,589 and 5,744,158; Mayer et al., Biochimica et Biophysica Acta (1986) 857:123). This work arose from mechanistic studies completed by Deamer et al., (Biochimica et Biophysica Acta (1976) 455:269–271) who demonstrated that liposomes efficiently concentrated several catecholamines (dopamine, norepinephrine and epinephrine) in response to a transmembrane pH gradient).
The presence of an acidic liposomal interior and a basic to neutral exterior environment allows agents that are primarily in the neutral form at neutral to basic pH and primarily in the charged form at acidic pH to be readily entrapped within a liposome. Drugs containing ionizable moieties such as amine groups are readily encapsulated and retained in liposomes containing an acidic interior. This method, where an ionophore (A23187) is used to generate a pH gradient across a manganese-containing liposome, has been used to load topotecan into cholesterol-free liposomes comprising a PEG-lipid conjugate inserted in the membrane (see WO/0185131). However, successful loading and retention using a transmembrane pH gradient is realized while the internal pH of the liposome is maintained. Since the pH gradient can only be maintained for short periods of time, clinical formulation of drugs into liposomes requires the generation of a pH gradient in liposomes just prior to drug loading. A second disadvantage of this method results from instability of lipid, and some drugs, at acidic pH which prevents the need for long-term storage of the drug loaded liposome. Freezing of liposomal formulations slows the rate of hydrolysis but conventional liposomal formulations often aggregate and leak contents upon thawing unless appropriately selected cryoprotectants are used.
Complexes between drugs such as doxorubicin or ciprofloxacin and divalent metal ions such as Mn2+ have been reported (Bouma, J., et al. (1986) Pharm. Weekbl. Sci. Edn. 16:109–133; Riley, C. M., et al. (1993) J. Pharm. Biomed. Anal. 11:49–59; and, Fenske, D. B. (1998) Biochim. Biophys. Acta. 1414:188–204). Recently, it was reported that uptake of doxorubicin (but not ciprofloxacin) into sphingomyelin/cholesterol LUVs could be carried out with manganese in the internal loading medium without the presence of an ionophore (Cheung et al., Biochimica et Biophysica Acta (1998) 1414:205). It was suggested that a process involving both complex formation between doxorubicin and manganese ions and protonation of doxorubicin inside the liposome resulted in uptake of this particular drug in the presence of manganese ions. Stable entrapment of doxorubicin was reported but this work relied on the use of sphingomyelin/cholesterol liposomes, a formulation noted for optimal drug retention. The methodology reported by Cheung, et al., involving the use of MnSO4 in pH 7.4 HEPES buffer is not reproducible because the metal precipitates from such a buffer.
Various groups have investigated the interaction of metal ions with liposomes with the goal of evaluating the effects of metal cations on vesicle membranes (Steffan et al. (1994) Chem. Phys. Lipids 74(2): 141–150). Divalent metal cations such as Ca2+ have been implicated in the unfavourable formation of metal induced crosslinking of phosphatidylglycerol (PG) containing liposomes due to the negative charge of the liposome surface. Metal ions have also been implicated in increasing the phase transition temperature of negatively modeled membrane systems (Borle, et al., (1985) Chemistry and Physics of Lipids 36: 263–283; Jacobson, et al., (1975) Biochemistry 14(1): 152–161). These studies revealed that the addition of calcium to dipalmitoylphosphatidylglycerol (DPPG) membranes resulted in a phase transition temperature increase by about 50° C. These results indicate that the use of negatively charged lipids in conjunction with metal ions will result in liposomes that exhibit inferior characteristics for in vivo applications.


A head for string trimmer machines uses fixed length segments of line including at least two line segments. The head includes a generally cylindrically shaped main housing member with at least two sets of first and second line entry holes on the housing member intermediate the first and second ends. At least two sets of first and second line exit openings also are found on the main housing member intermediate the first and second ends and spaced apart a greater distance than the distance between the first and second line entry holes. Arcuate guide channels are located between the respective entry holes and exit openings where the corresponding entry openings and exit openings of corresponding sets are located at different distances measured axially on the main housing member from the first end thereof.

Weed and grass trimmers have been developed which employ a rotatable hub with a short length of flexible nylon or other plastic line extending from the hub. When the hub is rotated (typically, at speeds from 6,000 RPM to 12,000 RPM), the tip of the line extending from the hub provides the cutting or trimmer action. Grass and weed trimmers using this principle of operation have become popular for their versatility of use and because the flexible trim line is safer to use that rigid rotating steel blades.
Various types of devices have been developed using such trim lines. Typically, rotating line trimmers or rotating string trimmers employ a trimmer line which generally has a circular cross section. The line, in many trimmers, is wound on a storage reel in the hub of the device, and is fed out of a hole or a plurality of holes in the hub in discrete amounts, as the end breaks off or wears off. Trimmers of this type sometimes are referred to as "bump and feed" trimmers. If the line breaks off, the bottom of the storage reel is bumped while the hub continues rotating to cause a spring release of the line within the trimmer. A short length of line then plays out through a hole in the hub by means of centrifugal force. Typically, the smaller (2½″ diameter to 3½″ diameter) head bump and feed string trimmers use relatively small diameter line, normally in the range of 0.65″ to 0.080″ diameter, since the smaller diameter flexible line functions better for the centrifugal feeding of such smaller diameter bump and feed heads.
A problem exists with all bump and feed trimmers, however, in that frequently the line which is wound on the storage reel in the hub tends to become stuck, either due to partial fusion of the line in the hub caused by high frequency vibration, or by successive turns of the line wound on the hub becoming somewhat entangled. As a result, feeding of the line from the hub when desired does not always take place. When this occurs, it is necessary to remove the hub from the string trimmer device and manually extract the desired length of line prior to re-attaching the hub of the device. This is a time consuming and frustrating experience for many users of flexible line string trimmers. It is particularly frustrating for commercial landscapers because of the amount of lost time required to remove the hub, extract the line, and then re-attach the hub before operation can resume.
Efforts to overcome the inherent disadvantages of bump and feed trimmers have included the development of heads designed to accept fixed lengths of line, which are inserted into the head and held in place by various techniques. Once such device is disclosed in the patent to U.S. Pat. No. 5,615,543 Caffey. This patent employs a cut length of line having an enlarged portion or flange at one end. A small entry hole is located in the periphery of the head adjacent a larger exit hole. The line is inserted from outside the periphery of the head into the insert hole, where the enlarged end or flange on the line meets an abutment and is held in place. The line then is grasped from the hollow interior of the head and pushed through the exit hole and pulled tight. The bottom of the head is open to allow this access to both the interior and exterior of the head. A disadvantage of this device is the requirement for the operator to insert the line from outside the periphery of the head, then turn the head over, and reinsert the line back through the exit hole each time a line is to be inserted into the machine. Removal of a line is the reverse of the order mentioned. It is necessary to have access to the head both from the exterior periphery and from the bottom in order to accomplish insertion and removal of line segments. Multiple line segments (two are shown in the patent) may be inserted on opposite sides of the head.
The U.S. Pat. No. 5,023,998 to Masciarella is another attempt at the design of a string trimmer cutting machine utilizing fixed lengths of line. In the Masciarella patent, line segments are inserted into the machine from the open bottom by manipulating the line around guide wedges in a generally serpentine path on opposite sides of the head. Two line segments, each extending diametrically across the head and crossing at 90° angles, may be used to allow the head to have four lengths or ends of line extending from it. When a new length of line needs to be inserted, the old line must be removed; and this requires manipulating the line past the wedges once again in order to permit the line to be taken out of the machine. A new line then must be guided into place around the wedges or guide surfaces. Because the guide surfaces are close together, it becomes difficult to install, and particularly to remove, sections of nylon line from a trimmer head having the design shown in the '998 patent. This difficulty results in excessive time being consumed for the removal and replacement of line segments.
The U.S. Pat. No. 6,035,618 to Fogle also is directed to a fixed line trimmer head using a single length of line extending from diametrically opposite sides of the trimmer head. The trimmer head of the Fogle '618 patent overcomes the disadvantages of the devices discussed above. The trimmer head of Fogle employs a pattern of pairs of entry and exit holes for inserting a fixed length of trimmer line through a pair of relatively closely spaced entry holes, and then extending each end of the line out through exit holes located in the head. The entry holes and exit holes are offset from one another in different planes perpendicular to the axis of the trimmer head, and securely hold the line in place during use of the trimmer. It is relatively easy to remove an expended section of line and replace it with a new section of line when necessary. The fixed line trimmer head of the Fogle '618 patent, however, does require the user to manually insert the opposite ends of the line through the two entry holes, and then again manually to insert each of the ends of the line segment into the exit holes in the head whenever line replacement is required. This is indicated somewhat in FIG. 9 of the Fogle patent. Because of the necessity to manually insert the ends of a line segment through separate entry and exit holes for each length of the line, the user is required to have access through the bottom of the hollow trimmer head in order to extend the ends of the line into the exit holes for use.
The U.S. Pat. No. 6,457,242 to Fogle eliminates the necessity for access to the interior of the head through the bottom while employing a single fixed length of trimmer line. In the Fogle '242 patent, a pair of entry holes are located on the exterior surface of the head in a similar manner to the position for the entry holes disclosed in the Fogle '618 patent. In the Fogle '242 patent, however, the two ends of the line inserted into the adjacent entry holes are internally guided through arcuate guide channels formed in an insert in the interior of the head to exit out of the line exit holes. Once the line has exited from the diametrically opposed exit holes, it is pulled tightly and the offset position axially of the entry holes with the exit holes, combined with the arcuate guide paths, firmly holds the line in place during use. Removal of the line is readily effected by grasping it from outside the housing at the loop between the two entry holes and pulling it out in the reverse direction from insertion. Consequently, removal and replacement of a line is greatly facilitated through the use of the Fogle '242 head. The Fogle '242 patent also discloses the use of two different sizes of entry holes located on opposite sides of the head to accommodate lines of smaller diameters on one side and lines of larger diameters on the other side. If a change from lines of one diameter set to a different diameter set is required, the arcuate guide insert is rotated 180° to accommodate the entry holes on the opposite side of the head. This requires removal and replacement of the insert carrying the guide channels whenever a change from one range of line sizes to a different range of sizes is desired.
It is desirable to provide a fixed length line trimmer head with greater versatility and ease of operation which overcomes the disadvantages of the prior art devices.

Fixed line trimmer head with ease of loading


A photo detector which includes a wheel turned with a revolving shaft, the wheel having a plurality of light permeable portions and light tight portions alternatively arranged around the revolving shaft, a light source controlled to emit light onto the wheel, and a photo receiver element having a set of photo sensor chips adapted to receive light from the light source through the light permeable portions of the wheel, the photo receiver element having at least two sloping surface portions at a light receiving side thereof around each of the photo sensor chips for refracting proximity light to prevent an interference of proximity light.

The present invention relates to a photo detector for a data input device for example an optical mouse, and more particularly to such a photo detector which effectively eliminates interference of proximity light from photo sensor chips, so as to improve signal receiving accuracy.
A photo encoder used in a mouse, as shown in FIG. 1, is generally comprised of at least one encoding grid wheel 60 turned with a revolving shaft 50, the wheel 60 having light permeable portions 61 and light tight portions 62 alternatively arranged around the periphery, a light source 70, and a photo receiver element 80. The photo receiver element 80 comprises a set of photo sensor chips 81 adapted to receive light from the light source 70 through the light permeable portions 61 of the wheel 60. When the wheel 60 is turned with the revolving shaft 50, the light permeable portions 61 and the light tight portions 62 are moved to cut through light from the light source 70, causing working light beams to be produced. When the photo chips 81 receive a working light beam an energy is produced. When the wheel 60 is continuously turned, sine waves are obtained through a wave form monitor, and four signals (0,0);(0;1);(1;1);(1;0) are obtained through a rectifier circuit (see FIG. 2). However, because the light receiving side of the photo receiver element 80 and the light emitting side of the light source are of a planar design, a diffused light will be produced, thereby causing an interface. Referring to FIGS. 3 and 4, when the wheel 60 is turned, the photo sensor chips 81 are induced by working light beams from the light source 70 to produce sine waves A;B, causing a rectifier circuit to produce square waves A1;B1. When working light beams 71 enter the photo receiver element 80, diffused light C is produced, causing an interference to the photo sensor chips 81. Referring to FIG. 4A, the waveform B is theoretically a sine wave, however the photo sensor chips 81 are energized by diffused light to produce a sine wave X before arrival of working light beams 71. Because of the effect of diffused light C, the photo sensor chips 81 are induced to produce an energy before arrival of working light beams 71, and diffused light C causes the photo sensor chips 81 unable to release energy after leaving of working light beams 71. Because of the aforesaid problem, the wave form monitor cannot accurate obtain sine wave energy values from the sine waves A;B. and the rectifier circuit cannot produce square waves exactly same as the square waves A1;B1.


A tool holder includes a foldable plastic sheet being folded and configured to include a hanging end and a holding end. The hanging end and the holding end integrally form a one piece structure. The holding end having a first edge, a second edge, a first lateral edge, and a second lateral edge, with the first and second edges and the first and second lateral edges delimiting a circumferential periphery of a receiving space in which the first and second edges are opposite each other and the first and second lateral edges are opposite each other and respectively extend from two lateral sides of the first edge to two lateral sides of the second edge. A joint edge is distal the first lateral edge extending therefrom and adhered to the second lateral edge.

1. Field of the Invention
The present invention relates to a tool holder and the method of making thereof and, particularly to a tool holder having advantages of being produced quickly and at low cost and allowing a user to store and take out a tool conveniently and to hang it near the waist.
2. Description of the Related Art
Generally, a too box is too bulky for a worker to carry it in the working site conveniently, so the worker will use a portable and miniature tool holder to bring tools for a work and usually hang it near the waist to allow two hands available while working. Such tool holders are generally configured to receive various kinds of tools. However, these conventional tool holders not only take relatively long assembly time but are also expensive to make, and some tool receiving areas are not used all the time and become redundant.
The present invention is, therefore, intended to obviate or at least alleviate the problems encountered in the prior art.

Tool holder and the method of making thereof


A vehicle masking material and method of use. The masking material in one embodiment includes a dextrin, a plasticizer, and water. The masking material may additionally include a surfactant. The masking material is applied to a surface which is to be protected from paint overspray or other coating processes, allowed to dry, and the surface is coated (e.g. with paint). After drying of the paint, or other coating, the masking material is removed by water washing.

The present invention relates to the field of protective coatings to be used during coating operations of various surfaces including surfaces of vehicles or buildings. More specifically, in one embodiment the invention provides an improved method and composition for masking selected portions of a surface, in particular a vehicle surface, from paint.
It is well known that painting operations often require masking of certain portions of the surface of the painted object to prevent overspray. For example, it is often necessary to mask trim and windows on a vehicle from paint overspray. Also, building stucco must frequently be protected from paint or primer coats. On occasion, it is necessary to mask painted portions of a vehicle or building from paints of a different color and overspray of paints of the same color.
In practice, masking operations are often one of the most time consuming and, therefore, expensive parts of the painting process. In spite of attempts to develop suitable chemical masks for vehicle painting, vehicle painters continue to use primarily masking tape and paper to cover portions of a vehicle where paint is not desired. To mask the trim on a car, for example, will often require many hours of tedious labor. Furthermore, even when done carefully, defects in such paint masks allow paint to contact surfaces which are desired to be protected.
Chemical masking solutions have been proposed to the problem of protecting surfaces during coating processing operations. However, such techniques have often not found extensive use. Some of the proposed chemical masks have been unsuitable for application to portions of a vehicle or building because of damage which would potentially occur to the protected portions of the vehicle or building. Other compositions are not water soluble which increases the difficulty and expense of removal. In addition, masks that require solvents for removal are problematic in view of the increasing regulation of disposal of solvents as environmental regulation becomes stricter with time. Other compositions are difficult to apply, difficult to remove, excessively costly, or the like.
From the above it is seen that an improved masking that is easily applied and removed, that provides good surface protection, that is economical, and whose use entails little or no environmental impact is needed.

Protective coating compositions and methods of use thereof


A temozolomide compound according to formula (I)

Temozolomide (TMZ) is a first-line chemotherapeutic indicated for treating patients diagnosed with glioblastoma. Administered orally, TMZ is a lipophilic, acid-stable DNA alkylating agent that efficiently crosses the blood-brain barrier and presents mild side effects. See, e.g., Adamson, C.; Kanu, O. O.; Mehta, A. I.; Di, C.; Lin, N.; Mattox, A. K.; Bigner, D. D. Glioblastoma Multiforme: A Review of Where We Have Been and Where We Are Going. Expert Opin. Investig. Drugs 2009, 18, 1061-1083. Serving as a small molecule prodrug, TMZ hydrolyzes spontaneously at physiologic pH liberating methyldiazonium cations that elicit antitumor activity by methylation of guanine and adenine nucleobases. See, e.g., Zhang, J.; Stevens, M. F. G.; Bradshaw, T. D. Temozolomide: Mechanisms of Action, Repair and Resistance. Curr. Mol. Pharmacol. 2012, 5, 102-114; Newlands, E. S.; Stevens, M. F. G.; Wedge, S. R.; Wheelhouse, R. T.; Brock, C. Temozolomide: A Review of Its Discovery, Chemical Properties, Pre-Clinical Development and Clinical Trials. Cancer Treat. Rev. 1997, 23, 35-61. Owing to the slightly alkaline microenvironment of brain tumors (see, e.g., Rottenberg, D. A.; Ginos, J. Z.; Kearfoot, K. J.; Junck, L.; Bigner, D. D. In Vivo Measurement of Regional Brain Tissue pH Using Positron Emission Tomography. Ann. Neurol. 1984, 15, S98-102) this pH-induced mechanism of action confers selective cytotoxicity for malignant versus healthy brain tissue (see, e.g., Zhang, J.; Stevens, M. F. G.; Bradshaw, T. D. Temozolomide: Mechanisms of Action, Repair and Resistance. Curr. Mol. Pharmacol. 2012, 5, 102-114) resulting in limited off-target toxicity. Unfortunately, in vivo decomposition and clearance of TMZ is rapid, and frequent dosing is required to retain antitumor activity. See, e.g., Stevens, M. F. G.; Hickman, J. A.; Langdon, S. P.; Chubb, D.; Vickers, L.; Stone, R.; Baig, G.; Goddard, C.; Gibson, N. W.; Slack, J. A.; Newton, C.; Lunt, E.; Fizames, C.; Lavelle, F. Antitumor Imidazo[5,1-d]-1,2,3,5-Tetrazin-4(3H)-One (CCRG 81045: M & B39831), a Novel Drug with Potential as an Alternative to Dacarbazine. Cancer Res. 1987, 47, 5846-5852. Moreover, efficacy is often hampered by chemoresistance primarily induced by O6-methylguanine-DNA methyltransferase (MGMT), a native enzyme that repairs damaged DNA following methylation. See, e.g., Newlands, E. S.; Stevens, M. F. G.; Wedge, S. R.; Wheelhouse, R. T.; Brock, C. Temozolomide: A Review of Its Discovery, Chemical Properties, Pre-Clinical Development and Clinical Trials. Cancer Treat. Rev. 1997, 23, 35-61. Clinical examination has shown that MGMT activity in glioblastoma tumors can be depleted by sustained TMZ exposure (see, e.g., Tolcher, A. W.; Gerson, S. L.; Denis, L.; Geyer, C.; Hammond, L A.; Patnaik, A.; Goetz, A. D.; Schwartz, G.; Edwards, T.; Reyderman, L.; Statkevich, P.; Cutler, D. L.; Rowinsky, E. K. Marked Inactivation of O6-Alkylguanine-DNA Alkyltransferase Activity with Protracted Temozolomide Schedules. Br. J. Cancer 2003, 88, 1004-1011), and that recurrent glioblastoma treated with protracted dosing schedules can improve tumor response. See, e.g., Wick, W.; Steinbach, J. P.; Kuker, W. M.; Dichgan, J.; Bamberg, M.; Weller, M. One week On/One Week Off: a Novel Active Regimen of Temozolomide for Recurrent Glioblastoma. Neurology 2004, 62, 2113-2115; Jauch, T.; Hau, P.; Bogdahn, U. Re-challenge with Temozolomide (TMZ) at Recurrence in High-Grade Gliomas (HGG). J. Clin. Onocol. 2007, 25, 2034; Wick, A.; Felsberg, J.; Steinbach, J. P.; Herrlinger, U.; Platten, M.; Blaschke, B.; Meyermann, R.; Reifenberger, G.; Weller, M.; Wick, W. Efficacy and Tolerability of Temozolomide in an Alternating Weekly Regimen in Patients with Recurrent Glioma. J. Clin. Oncol. 2007, 25, 3357-3361; Berrocal, A.; Perez Segura, P.; Gil, M.; Balanfa, C.; Garcia Lopez, J.; Yaya, R.; Rodriguez, J.; Reynes, G.; Gallego, O.; Iglesias, L.; GENOM Cooperative Group. Extended-Schedule Dose-Dense Temozolomide in Refractory Gliomas. J. Neurooncol. 2010, 96, 417-422. As these alternative regimens can increase occurrence of dose-limiting hematoxicity, an alternative therapeutic modality that extends TMZ circulation and masks drug-associated toxicity is desired.
Polymer-drug conjugation is effective for augmenting the antitumor efficacy of many small molecule chemotherapeutics, affording water-soluble prodrugs with improved pharmacokinetic behavior. See, e.g., Larson, N.; Ghandehari, H. Polymeric Conjugates for Drug Delivery. Chem. Mater. 2012, 24, 840-853; Fox, M. E.; Szoka, F. C.; Fréchet, J. M. J. Soluble Polymer Carriers for the Treatment of Cancer: The Importance of Molecular Architecture. Acc. Chem. Res. 2009, 42, 1141-1151. As a result of the leaky vasculature and poor lymphatic drainage of solid tumors, polymer therapeutic accumulation in malignant tissue is enhanced, leading to potentiated antitumor activity and reduced off-target toxicity. See, e.g., Maeda, H.; Nakamura, H.; Fang, J. The EPR Effect for Macromolecular Drug Delivery to Solid Tumors: Improvement of Tumor Uptake, Lowering of Systemic Toxicity, and Distinct Tumor Imaging In Vivo. Adv. Drug Delivery Rev. 2013, 65, 71-79.
Various delivery strategies have been explored for improving TMZ therapy, including encapsulation in nanoparticles and liposomes for systemic administration, as well as entrapment in hydrogels, degradable matrices, and microspheres for localized treatments (see, e.g., Fang, C.; Wang, K.; Stephen, Z. R.; Mu, Q.; Kievit, F. M.; Chiu, D. T.; Press, O. W.; Zhang, M. Temozolomide Nanoparticles for Targeted Glioblastoma Therapy. ACS Appl. Mater. Interfaces 2015, 7, 6674-6682; Kim, S-S.; Rait, A.; Kim, E.; DeMarco, J.; Pirollo, K. F.; Chang, E. H. Encapsulation of Temozolomide in a Tumor-Targeting Nanocomplex Enhances Anti-Cancer Efficacy and Reduces Toxicity in a Mouse Model of Glioblastoma. Cancer Lett. 2015, 369, 250-258; Dong, J.; Zhou, G.; Tang, D.; Chen, Y.; Cui, B.; Dai, X.; Zhang, J.; Lan, Q.; Huang, Q. Local Delivery of Slow-Releasing Temozolomide Microspheres Inhibits Intracranial Xenograft Glioma Growth. J. Cancer Res. Clin. Oncol. 2012, 138, 2079-2084; Fourniols, T.; Randolph, L. D.; Staub, A.; Vanvarenberg, K.; Leprince, J. G.; Préat, V.; des Rieux, A.; Danhier, F. Temozolomide-Loaded Photopolymerizable PEG-DMA-Based Hydrogel for the Treatment of Glioblastoma. J. Controlled Release 2015, 210, 95-104). To date, only one example of a polymer-TMZ therapeutic, prepared using metabolically-derived poly(β-L-malic acid), has been reported. See, e.g., Patil, R.; Portilla-Arias, J.; Ding, H.; Inoue, S.; Konda, B.; Hu, J.; Wawrowsky, K. A.; Shin, P. K.; Black, K. L.; Holler, E.; Ljubimova, J. Y. Temozolomide Delivery to Tumor Cells by a Multifunctional Nano Vehicle Based on Poly(β--malic acid). Pharm. Res. 2010, 27, 2317-2329. While this conjugate demonstrated in vitro activity against glioblastoma tumor cells, including a naturally chemoresistant cell line, chemical and physical characterization of the polymer prodrug was limited, and the synthetic strategy employed was not suitable for preparing well-defined structures with tunable drug content.
Glioblastoma is a cerebral neoplasm that represents the most prolific malignant central nervous system tumor diagnosed in the United States, with nearly 11,000 new cases presented annually. See, e.g., Ostrom, Q. T.; Gittleman, H.; Fulop, J.; Liu, M.; Blanda, R.; Kromer, C.; Wolinsky, Y.; Kruchko, C.; Barnholtz-Sloan, J. S. CBTRUS Statistical Report: Brain and Central Nervous System Tumors Diagnosed in the United States in 2008-2012. Neuro Oncol. 2015, 17, iv1-iv62. Characterized by substantial histologic and genetic heterogeneity, glioblastoma is an infiltrative astrocytoma with dismal patient prognosis. Even with early detection, median survival of only 12 to 15 months is expected following treatment. See, e.g., Omura, A.; DeAngelis, L. M. Glioblastoma and Other Malignant Gliomas. JAMA 2013, 310, 1842-1850; Wen, P. Y.; Kesari, S. Malignant Gliomas in Adults. N. Engl. J. Med. 2008, 359, 492-507. Standard of care for patients with newly diagnosed glioblastoma includes surgical debulking to resect maximal solid tumor tissue, followed by chemoradiotherapy and adjuvant chemotherapy with TMZ. Though therapeutic intervention can temporarily arrest disease progression, recurrence is generally inevitable.
Accordingly, there remains a continuing need for improved delivery systems for TMZ (e.g., polymer delivery systems), particularly for the treatment of cancer (e.g., glioblastoma).

This patent is subject to a terminal disclaimer.

Temozolomide compounds, polymers prepared therefrom, and method of treating a disease

Abstract: is described, wherein R1, L1, and X are defined herein. The temozolomide compound can be used to prepare polymers comprising temozolomide. Additionally, the polymers comprising temozolomide can be particularly useful in the treatment of certain diseases.


The present invention is directed to a guitar that has a detachable neck for ease of transport and storage. The body is attached to the neck in the preferred embodiment by means of a lever actuating clamp providing a clamping force substantially parallel with the longitudinal axis of the neck and body and the tensioned strings so that when reassembled the guitar strings regain their prior pre-assembled state of tune.

Conventional guitars comprise a body and neck with strings stretched and tensioned between the distal end of the neck and a bridge mounted in the body. The neck is usually integral with the body of the guitar. However, the size of the guitar makes the instrument difficult and awkward to transport or store. This problem is particularly relevant when guitars are transported by commercial carriers such as airlines where storage space is limited. On airlines, the guitar is usually too large for storage as hand luggage and must be stored in a well padded case to protect it from the rough handling often experienced by checked baggage.
As a consequence travel guitars have been developed. These include guitars with hinged necks that are able to fold back on themselves. An example of a guitar with a hinged neck is disclosed in U.S. Pat. No. 4,073,211, but in order for the neck to fold back the neck-hinge portion must be thin and the strings are overstretched. Thin necks provide flexibility which affects the pitch and tune of the guitar. Similarly overstretched strings change the tune and the guitar must be retuned prior to playing. To overcome the problem with overstretched strings, a guitar with a complex system of gears and rollers to relax the tension of the strings so the neck can be folded was developed and disclosed in U.S. Pat. No. 4,111,093. With another approach guitars such as the one disclosed in U.S. Pat. No. 4,686,882 were developed that were foldable with collapsible bodies.
In also addressing the problem, U.S. Pat. No. 5,353,672 discloses a guitar with a detachable neck. The guitar has a releasable latch mechanism comprising a neck plate fixed to the underside of the neck and a spring biased latch on the body and engageable with the neck. The latch mechanism holds the neck and body in position while releasable fasteners are used to tighten the neck plate and body together and relieve the latch from the forces pulling the neck away from the guitar body. The disadvantage with the disclosed guitar is that assembly is complicated by positioning the neck relative to the body with the latch mechanism and then using fasteners to secure the position. The reattachment is not reproducible as the fasteners can be fastened to varying degrees thereby affecting the sound produced by the guitar. As well the latch and latch lip may with time bend under the constant strain of the opposing forces and fail to reproducibly and accurately position the neck relative to the guitar body.

String instrument with a detachable neck


In one embodiment, a target alignment surface disposed on a target support mechanically engages a darkspace shield alignment surface disposed on a darkspace shield as the target is lodged into a chamber body. The respective alignment surfaces are shaped and positioned so that the darkspace shield is physically moved to a desired aligned position as the alignment surfaces engage each other. In this manner a darkspace shield may be directly aligned to a target within a semiconductor fabrication chamber to provide a suitable darkspace gap between the target and the darkspace shield.

1. Field of the Invention
The invention relates to physical vapor deposition, and more particularly, to a method and apparatus for controlling a darkspace gap within a physical vapor deposition chamber.
2. Description of the Related Art
Sputtering is a physical vapor deposition (PVD) process in which high-energy ions impact and erode a solid target and deposit the target material on the surface of a substrate such as a silicon wafer. In semiconductor fabrication the sputtering process is usually accomplished within a semiconductor fabrication chamber also known as a PVD process chamber or a sputtering chamber.
A typical semiconductor fabrication chamber has a disc-shaped target of solid metal or other material supported by a backing plate that holds the target. Material sputtered from the edges of the target may contribute to a non-uniform deposition of the material on the surface of a substrate within the PVD chamber. To promote uniform deposition, the PVD chamber may have an annular concentric metallic ring often called a darkspace shield which circumferentially surrounds the disc-shaped target. The gap between the inner surface of the darkspace shield and the circumferential surface of the target is typically referred to as the darkspace gap.
In many applications, it is preferred that the darkspace gap be kept large enough to inhibit or prevent electrical arcing between the target and the darkspace shield which are often at different electrical potentials. On the other hand, it is often preferred that the darkspace gap be kept small enough to prevent PVD plasma ignition within the gap and also to reduce the amount of sputtered material entering the darkspace gap and depositing onto the circumferential surface of the target. Such depositions on the target edge may cause particle contamination on processed silicon wafers or other workpieces. To provide a suitable darkspace gap around the complete periphery of the target, proper alignment of the target and the darkspace shield is often needed. In prior sputtering chambers, the target and the darkspace shield are typically each aligned to the chamber body in which the target and darkspace shield are installed.

Method and apparatus for controlling darkspace gap in a chamber


A reverse VSP system is provided and uses a frequency-controllable modulator of an MWD tool as a downhole seismic source. The modulator has a rotor and stator arranged to provide substantially sinusoidal outputs, and is controlled to provide a "Vibroseis"-type frequency sweep (preferably from 1 Hz to 50 Hz). With the bit of the MWD tool in contact with the bottom of the borehole, the force generated by the frequency-controllable modulator will generate measurable axial compressional (P-) waves. These waves which move through the formation are detected by an array of geophones on the formation surface, and a reference signal is obtained by a kelly-mounted accelerometer or strain gauge. The reference signal and signals obtained by the geophones are processed using known signal processing techniques. The disclosed downhole frequency-controllable seismic source provides many advantages including: good resolution due to the ability to output a sinusoidal wave at desired frequencies and the fact that the location of the source signal is well-defined (at the bit), the ability to image formations ahead of the bit, and the ability to conduct reverse VSP processing without adding downhole hardware equipment and without requiring trips out of the well.

1. Field of the Invention
The present invention relates to the profiling of geological formations. More particularly, the present invention relates to the use of a drilling tool as a frequency-controlled seismic source for the inverse or reverse vertical seismic profiling or imaging of a formation.
2. Description of the Related Art
Conventional reflection seismology utilizes surface sources and surface receivers to detect reflections from subsurface acoustic impedance contrasts; i.e., subsurface strata. The image and information obtained utilizing conventional reflection seismology is considered relatively poor due to long travel paths between the sources, reflectors, and receivers.
A technique known as vertical seismic profiling (VSP) has been used to provide more accurate information regarding the formation in the vicinity of a borehole. In VSP, seismic sources are located at the surface, and sensors (geophones) are suspended in the borehole with a wireline. When the sources are fired, the received data is recorded and processed for several borehole depths. VSP has the drawbacks, however, that each surface source is costly to apply, adds to acquisition time and rig inactivity, and generates multiple ghost images due to energy trapped in the surface layer. In addition, in drilling applications where the geophones would have to be added to an MWD (measurement while drilling) tool string, unless the downhole geophones could be decoupled from the drill string, they would only be capable of recording the relatively large first arrival event. Furthermore, downhole geophones are sensitive to tube wave events traveling up and down the borehole. Thus, to date, vertical seismic profiling has not been successful in MWD applications.
In order to overcome some of the problems relating to explosive sources used in conjunction with VSP, "Vibroseis" (a trademark of Conoco Incorporated) sources have been utilized. The "Vibroseis" source (described in U.S. Pat. No. 2,688,124) comprises vibrators which are carried on trucks which are coupled to the formation surface and which generate a frequency sweep from 10-90 Hz over a period of time. The trucks move to pre-designated source locations, lower their heavy baseplates, and start vibrating through the use of a hydraulic system. However, the "Vibroseis" source technique still suffers from several drawbacks. These include difficulty in correctly locating the trucks and in establishing good ground contact.
Long ago it was recognized that it might be possible to switch the location of the seismic source and the detectors; i.e., provide an "inverse" or "reverse" VSP (hereinafter referred to as "reverse VSP" or "RVSP"). A downhole source overcomes the logistical limitations inherent in using multiple surface sources, and permits simultaneous data acquisition at the surface with little cost.
Various different downhole source schemes have been proposed over the years. Some of the downhole source schemes utilize the drill bit as the source, while others use sources other than the drill bit. Of the former, U.S. Pat. No. 2,062,151 to Weatherby suggests using the drill bit as an impulse generator of seismic waves, while U.S. Pat. Nos. 4,363,112 and 4,365,322 to Widrow suggest using the continuous natural random vibrations of the drill bit to launch seismic waves. Techniques such as disclosed in U.S. Pat. No. 5,050,130 to Rector et al., can be useful in processing the information obtained from such a drill bit seismic source. Of the schemes which suggest using a source other than a drill bit, U.S. Pat. No. 3,909,776 to Broding et al. suggests using a fluid driven oscillator which changes emitted frequency as a function of time (much like a "Vibroseis" source), U.S. Pat. No. 3,881,168 to Farr et al. suggests using a monofrequency fluid oscillator, while U.S. Pat. No. 4,207,619 to Klaveness suggests using a pulse generator located in the drill string just above the drill bit. In addition, U.S. Pat. No. 4,033,429 to Farr suggests providing a seismic source in a drill string by modifying a section of a drill pipe to reduce it in diameter and provide a port, and providing a cylindrical sleeve surrounding the modified drill pipe section. The sleeve is provided with mud ports arranged in a helical path, with the spacing of the ports varying from a fifteen degree spacing at one end of the helix to a one hundred twenty degree spacing at the other end of the helix. To create a seismic signal, the entire drill string is lifted off of the hole bottom, and the drill pipe (and drill bit) is rotated and moves downward. The movement of the drill pipe port past the sleeve ports generates a series of pressure pulses in a siren-like fashion which change in frequency due to the spacing of the sleeve ports. The rotation rate of the drill pipe will therefore control the specific frequency range of the sweep.
While the idea of utilizing a "Vibroseis" type seismic source downhole is conceptually advantageous, the techniques proposed in the art for generating such a source have not been feasible. In particular, the fluid driven oscillator of Broding et al. will not provide a discrete point of signal excitation and will thereby "smear" the seismic image, and the oscillator must be inconveniently added to the drill string at extra expense. Additionally, in deviated wells, wellbore friction makes smooth rotation of the drill string impossible, causing variations in signal frequency. Finally, the drill string must be removed from the borehole each time the system is operated, forcing costly delays in the drilling process. With respect to U.S. Pat. No. 4,033,429 to Farr, the requirement to modify and rotate the drill pipe in order to effect a seismic source is disadvantageous for several reasons. First, in Farr, the drilling process and the seismic signal generation process are exclusive of each other, such that tripping out is required to move from drilling to seismic signal generation and vice versa. Second, the rotation of the drill pipe during seismic signal generation will cause banging on the side of the well which will generate undesirable noise. Third, because the seismic signal is being generated by a pressure differential across different orifices, the location where the pressure is being generated (i.e., the source signal location) will be undesirably uncertain.

Inverse vertical seismic profiling using a measurement while drilling tool as a seismic source


In an LC/MS analysis of a sample containing various compounds, additive supply pumps 164A and 164B in a post-column adding unit 16 draw and supply different kinds of additives A and B from containers 163A and 163B, respectively. The additives are mixed into an eluate through T-joints 162 and 161. A preferable combination of the additives is the combination of DMSO which produces the effect of gathering charge states and 2-propanol which produces the effect of promoting atomization or vaporization of droplets. By mixing the two additives into the eluate while mixing them at an appropriate flow-rate ratio according to a previously determined flow-rate program, the ionization efficiency can be nearly optimized for each compound during the process of generating ions by spraying electrically charged droplets of the eluate from an ESI spray 21. Consequently, the detection sensitivity becomes higher than conventional levels.

In a liquid chromatograph mass spectrometer (which may be hereinafter abbreviated as the "LC-MS"), a so-called "atmospheric pressure ionization (API) method", such as an electrospray ionization (ESI) method, atmospheric pressure chemical ionization (APCI) method or atmospheric pressure photoionization (APPI) method, is employed to ionize compounds in an eluate supplied from a column of a liquid chromatograph. In an atmospheric pressure ion source employing an atmospheric pressure ionization method, the eluate is sprayed through a spray nozzle into an ambience of substantially atmospheric pressure, and the compounds in the fine droplets produced by the spraying process are ionized to generate gaseous ions. Therefore, in order to improve the ionization efficiency, it is important to promote atomization and vaporization of the sprayed droplets.
The largest portion of the eluate introduced into the atmospheric pressure ion source is the mobile phase used in the liquid chromatograph. If the mobile phase is simply composed of water, alcohol, acetonitrile (ACN) or other basic substances, the characteristics of the mobile phase may not be suitable for performing satisfactory ionization in an atmospheric pressure ion source. Accordingly, for an LC-MS, an appropriate kind of reagent is often used as an additive to the mobile phase according to the characteristics of the sample, kind of mobile phase used, kind of ionization method and other related factors in order to improve the ionization efficiency (for example, see Non Patent Literature 1). Normally, such an additive is often mixed into the mobile phase. For an additive which may affect the separation characteristics of the column in the liquid chromatograph, the so-called "post-column" method is used, in which the reagent is mixed into the eluate exiting from the outlet of the column instead of being mixed into the mobile phase before the mobile phase is introduced into the column (for example, see Patent Literature 1).
In the case of adding a reagent by the post-column method, the compounds in the sample have already been separated at the point of the addition of the reagent. Accordingly, it is essential to appropriately determine not only the kind and amount of reagent to be added, but also the timing of the addition according to the compound, because the effectiveness of the reagent varies depending on the characteristics and concentration of the compound even when the same reagent is used. Besides, in the case of a gradient analysis, since the mixture ratio of the mobile phases changes with time, the effectiveness of the reagent may change with the mixture ratio even when the same reagent is used. Furthermore, in the case of the post-column method, an increase in the amount of addition of the reagent directly increases the amount of eluate introduced into the atmospheric pressure ion source. Therefore, for example, adding a highly volatile reagent in greater quantity does not always enhance the ionization efficiency.
However, in the case of performing a measurement on a sample containing various compounds with different characteristics, it is difficult to set the addition condition of the reagent so that a high level of ionization efficiency can be achieved for each of those various compounds. Accordingly, in conventional LC-MSs, the addition condition of the reagent is not always optimized for all various compounds to achieve the highest or nearly highest level of ionization efficiency. In some cases, the detection sensitivity in the mass spectrometer is sacrificed.

Method for liquid chromatographic mass spectrometry and liquid chromatograph mass spectrometer


A hand tool for removing roofing shingles and nails. The toll has a head attached to an elongated handle. The head has a wedge-shaped cross profile. The head is comprised of a plurality of identical, parallel blades, having a relatively flat, pointed leading edge adapted to being inserted underneath the exposed edge of a shingle to be removed. The blade leading edge rises in vertical height to a trailing edge. The trailing edge is connected to a handle. Spacers are attached between the blades to form spacing between blades sufficient to trap any roofing nails holding a shingle to an underlying roof sheath.

This invention relates to hand tools, and in particular, to a hand tool for simultaneously removing shingles and nails from a roof.
Roofs for many contemporary single family and multiple family dwelling structures utilize an outer roof covering consisting of fibrous shingles nailed to a plywood sheathing roof construction. The roofs are covered with a plurality of overlapping, horizontally aligned rows of shingles. The shingles may be made of asphalt or wood and are nailed or stapled to the underlying plywood sheathing. Generally, beginning with the bottom or lower-most edge of the roof, the shingles are nailed in place with successive layers or rows overlapping the top of the preceding below-mounted row. The shingles are generally attached to the roof sheathing by nails or staples.
Due to the inherent exposure to the elements, roofing materials have a limited effective life. This means that roofing materials must be replaced periodically during the useful life of the dwelling structure to ensure continued protection from weather. Replacement usually requires that all of the roofing materials be removed and replaced with new roofing materials. Since roofing materials are generally attached to a structure by fastening elements such as nails or staples, removal is difficult, tedious, and dangerous.
Various tools have heretofore been provided for removing old shingles preparatory to the installation of new roofing material. Designs heretofore provided either do not provide sufficient mechanical advantage for ease in removal of roofing nails or are not efficient for rapid removal. Nearly all prior art tools require a physical prying motion by the tool user. Typically, shingles are removed from a roof structure by using a chisel or pry bar type tool or spade fork leaving nails behind for a second operation with a claw hammer. The process involves inserting the chisel or pry bar underneath the uppermost shingle and then lifting the exposed end of the chisel or pry bar to push the uppermost shingle away from the underlying shingles. The process is time-consuming and relatively inefficient. Usually several back and forth motions of the chisel or pry bar are required to remove a given shingle from the roof surface.


A method of obtaining information that corresponds to the Rxe2x80x94R interval of electrocardiogram from the pulse-wave of a human body. The method is comprised of steps of detecting the pulse-wave of a human body in a predetermined period, differentiating the detected pulse-wave to provide a speed-pulse-wave, measuring intervals of peaks of the speed-pulse-wave, and substituting the intervals of peaks of the speed-pulse-wave for the Rxe2x80x94R interval of the electrocardiogram.

The present application is based on and claims priority from Japanese Patent Applications: Hei 11-242528, filed Aug. 30, 1999 and Hei 11-247264, filed Sep. 1, 1999, the contents of which are incorporated herein by reference.
1. Field of the Invention
The present invention relates to a method of obtaining information that corresponds to the Rxe2x80x94R interval of the electrocardiogram of a human body for medical and health examinations.
2. Description of the Related Art
The electrocardiogram has been used for medical and health examinations. Particularly, the Rxe2x80x94R intervals of the electrocardiogram have been frequently used to examine the heart beat rhythm and the automatic nervous system. The R-R intervals of the electrocardiogram are obtained from intervals of peak values of the R-wave that are most significantly observed in the QRS group, which is caused by depolarization of the ventricle.
On the other hand, it is considered to utilize the peak intervals between the pulse wavers peak values of the human-body as the information that corresponds to the Rxe2x80x94R intervals of the electrocardiogram.
Because the peak values of the pulse-waves are not so clear as the peak values of the R-wave, it has been difficult to accurately determine the peak intervals of the pulse-wave.
A commonly used pulse-wave sensor measures a pulse-wave of a human body by means of light absorbing characteristics of hemoglobin of the blood. Such a pulse-wave sensor includes a light-emitting element for emitting light to a finger and light sensing element for sensing the light reflected from the finger.
While such a pulse-wave sensor is attached to a human finger, the sensor always moves as the human body moves. This motion causes noises, which are included in the pulse-wave data. In particular, when a shoulder or an elbow moves, the quantity of the blood changes, thereby causing noises. It has been also difficult to eliminate, from such a pulse-wave sensor, noises caused by outside light such as sunshine or light of lamps.
Therefore, a main object of the invention is to provide an improved method of measuring pulse-waves that is effective to provide practically accurate information that can be substituted for the Rxe2x80x94R intervals of the electrocardiogram.
According to a main feature of the invention, a method of obtaining information that corresponds to the Rxe2x80x94R interval of electrocardiogram from the pulse-wave of a human body is comprised of differentiating the pulse-wave to provide a speed-pulse-wave (differentiated pulse-wave), and measuring the intervals of peaks of the speed-pulse-wave. The intervals of peaks of the speed-pulse-wave practically approximate the Rxe2x80x94R interval of the cardiogram.
In the meantime, the bottom interval of the pulse waves corresponds to the interval between consecutive times when the speed-pulse-wave changes from a negative to a positive. While, the peak interval of the pulse-waves corresponds to the interval between consecutive times when the speed-pulse-wave changes from a positive to a negative.
Another object of the invention is to provide a method of measuring a pulse-wave that can detect noises included in the pulse-wave data.
According to another feature of the invention, a method of measuring a pulse-wave is comprised of differentiating the pulse-wave to provide a speed-pulse-wave, detecting peak values of the speed-pulse-wave, calculating the dispersion of said peak values and comparing the dispersion with a predetermined value to determine whether a noise is included in the pulse-wave or not.

Method of obtaining information that corresponds to electrocardiogram of human body from pulse wave thereof