Provided herein are methods of administering N-(5-tert-butyl-isoxazol-3-yl)-N′-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzothiazol-2-yl]phenyl}urea, or a pharmaceutically acceptable salt or solvate thereof, to human patients, including a specific patient population. Specifically, dosing, dosing schedules or dosing regimens are provided herein. Methods of treating proliferative diseases or FLT-3 mediated diseases in humans are also provided.

Fms-like tyrosine kinase 3 (FLT3), which is also known as FLK-2 (fetal liver kinase 2) and STK-1 (stem cell kinase 1), plays an important role in the proliferation and differentiation of hematopoietic stem cells. FLT3 receptor kinase is expressed in normal hematopoietic cells, placenta, gonads, and brain. However, this enzyme is expressed in acute myeloid leukemia cells in approximately 90% of acute myeloid leukemia (AML) patients and in acute lymphoblastic leukemia cells in a fraction of acute lymphoblastic leukemia (ALL) patients. This enzyme can also be found on cells from patients with chronic myeloid leukemia in lymphoid blast crisis.
It has been reported that FLT3 kinase is mutated in 30% of acute myeloid leukemia (AML) and in a subset of acute lymphoblastic leukemia (ALL) as well (Gilliland et al., Blood 2002, 100, 1532-1542; Stirewalt et al., Nat. Rev. Cancer 2003, 3, 650-665). The most common activating mutations in FLT3 are internal tandem duplications (ITD) found within the juxtamembrane region. The FLT3 ITD mutation has been associated with poor prognosis (Frohling et al., Blood 2002, 100, 4372-4380). The second most frequent activating mutation of FLT3 is the missense mutation in the tyrosine kinase domain, mainly at D835 within the activation loop of the tyrosine kinase domain (Yamamoto et al., Blood 2001, 97, 2434-2439). In addition, many non-mutated FLT3 patients show evidence of FLT3 activation. The association of FLT3 mutations with poor clinical outcome and the therapeutic effects observed in early stage clinical trials with first generation FLT3 inhibitors strongly implicate FLT3 as an important target for small molecule intervention in AML.
More than a dozen known FLT3 inhibitors are being developed and some have shown promising clinical effects against AML (Levis et al. Int. J. Hematol. 2005, 82, 100-107). It has been reported that some of small-molecule FLT3 inhibitors are effective in inducing apoptosis in cell lines with FLT3-activating mutations and prolonging survival of mice that express mutated FLT3 in their bone marrow cells (Levis et al., Blood 2002, 99, 3885-3891; Kelly et al., Cancer Cell 2002, 1, 421-432; Weisberg et al., Cancer Cell 2002, 1, 433-443; Yee et al., Blood 2002, 100, 2941-2949).
Despite the success in identification of small molecules that inhibit protein tyrosine kinases, there continues to be an effective method of using or administering such compounds, particularly to humans having AML and ALL, including compounds useful for the treatment of FLT-3 mediated diseases. Methods with improved therapeutic index, i.e, where adverse or unwanted effects of therapy are reduced while efficacy is maintained, are sought.


The invention relates to an apparatus for monitoring a field device for determining and/or monitoring a physical and/or chemical process parameter of a process medium with a first sealing stage facing toward the process and at least one housing with a predetermined interior volume. The housing is located on the side of the first sealing stage facing away from the process, wherein energy is transferable through the first sealing stage 4 in the direction of the process medium. This energy interacts with the process medium, wherein at least one detector unit is provided in the housing, which unit monitors at least one condition parameter of the interior volume of the housing. A control/evaluation device determines, on the basis of the energy interacting with the process medium, the physical and/or chemical process parameter, and wherein the control/evaluation unit and/or another monitoring unit recognizes and/or seals off and/or issues an alarm, on the basis of the monitored condition parameter in the interior volume of the housing, as soon as the monitored condition parameter in the interior volume of the housing a predetermined limit value.

For detecting the limit level of liquids or bulk materials in containers, capacitive measuring equipment or vibration systems are installed. In addition to these limit level detectors, which signal the attainment of a predetermined fill level as soon as they come into contact with the process medium, there are contactlessly working measuring systems, which, as measuring radiation, use ultrasonic waves, microwaves—or in especially critical applications—radioactive radiation. With the exception of the vibration systems, the aforementioned measuring devices are naturally also suited for the continuous measurement of the fill level of a process medium in a container.
The measuring devices are normally sealed against the process. Depending on the application, it may be necessary to securely and reliably encapsulate the measuring device against the process and/or from a remote control station. This sealing or encapsulation is especially important when the atmosphere in the container is an aggressive or explosive one. If, for example, an explosive gas mixture penetrates into the housing of the measuring device, then, through direct contact with the electrical or electronic components of the measuring device, an acute danger of explosion exists. Furthermore, a measuring device is normally connected to a remote control station by means of connecting lines. If the measuring device is not encapsulated, then it cannot be ruled out that the explosive, aggressive, or toxic gas mixture will escape through the lines into the remote control station and do harm there.


The present invention relates to the field of stereodefined phosphorothioate oligonucleotides and to stereodefining nucleoside monomers comprising an amine containing chiral auxiliary group, and methods of orthogonally protecting the nitrogen of chiral auxiliaries during oligonucleotide synthesis, preventing post elongation chain cleavage, increasing yield and purity of stereodefined phosphorothioate oligonucleotides.

The use of stereodefined phosphorothioate internucleoside linkages in oligonucleotides allow for the optimisation of the pharmacological profile of therapeutic oligonucleotides. However, the manufacture of stereodefined phosphorothioate oligonucleotides is at present comparatively inefficient as compared to non stereodefined phosphorothioate oligonucleotides. There is therefore a need to improve the efficiency of synthesis of stereodefined oligonucleotides.
Oka et al., J. AM. CHEM. SOC. 2008, 130, 16031-16037, reports on the solid phase synthesis of stereoregular DNA phosphorothioates using bicyclic oxazaphospholidine derivatives. In the Oka et al. process, the amine on the oxazaphospholidine chiral auxiliary is protected by trifluroacetylation.
EP 2 620 428A1 paragraph [0015] reports that the removal of the trifluoroacetyl group causes problems in the synthesis of long DNA strands or chemically unstable RNA strands, possibly due to decomposition of the strand or problems in complete removal of the group. EP 2 620 428A1 proposes the use of a different chiral auxiliary.
The present invention is based on the finding that the Oka et al., method results in significant premature chain termination, and that the use of a carbamate protection group rather than a triflouroacetyl protection group on the amine of the oxazaphospholidine chiral auxiliary allows for rapid and efficient deprotection and cleavage of the chiral auxiliary whilst avoiding premature chain termination.

Orthogonal protecting groups for the preparation of stereodefined phosphorothioate oligonucleotides


A linear guide device which comprises a track bed having a substantially rectangular section opened at one side and is provided at its inner surfaces with rolling surfaces for rolling members; and a bearing block which has load rolling surfaces cooperating with the rolling surfaces to hold the rolling members therebetween and moves in a hollow portion of the track bed in accordance with rotation of a feed screw shaft engaging the bearing block. The bearing block is formed of a block body, rolling aperture forming plates and covers which are jointed together to entirely form ball circulation paths through which no-load balls circulate. Therefore, a long bearing block can be facilely manufactured, and thus a number of the rolling members can be increased for achieving the linear guide device having a large maximum allowable load and a compact configuration.

1. Field of the Invention
The present invention relates to a linear guide device used, for example, in a linear motion component of a machine tool or an industrial robot.
2. Description of the Related Art
A linear guide device of a type described above has been disclosed in Japanese Laid-Open Patent publication No. 62-200016. Specifically, as shown in FIG. 17, a bearing block (a) (which will be called merely a "block") is provided at its opposite side surfaces with load ball grooves (c) in which balls (b) rolls. A pair of track beds (d) is disposed with the block (a) therebetween. The beds (d) are provided with ball rolling grooves opposed to the load ball grooves (c). The balls (b) held between the load ball grooves (c) and the ball rolling grooves support the block (a) so that the block (a) may be movable along the track beds (d).
A screw shaft (f) of a feed screw mechanism is engaged with a central portion of the block (a), so that the screw shaft (f) may be rotated to move the block (a) along the track beds (d).
According to this linear guide device, since the bearing block for supporting a movable member such as the table is constructed integrally with the feed screw mechanism for applying a driving force for the linea motion to the movable member, a compact construction of the device can be achieved, and a height of the movable member can be minimized, which enables a stable motion.
However, with respect to the bearing block of the linear guide device described above, opposite ends of each load ball groove must be connected by a ball circulation path so as to guide or introduce the balls from a termination end of the load ball groove to a start end of the load ball groove again.
In the prior art, the ball circulation path is generally formed of a no-load ball rolling aperture, which is formed in the block to correspond to each load ball groove, and ball return paths, each of which connects an end of the ball load groove and an end of the no-load ball rolling aperture.
However, the no-load ball rolling aperture is a very small aperture having a diameter only slightly larger than that of the ball, and thus it is difficult to form a long no-load ball rolling aperture by drilling. Therefore, machining of the no-load rolling aperture restricts increase of a length of the block, and thus restricts the length of the load ball groove.
Generally, in a bearing which employs rolling members such as balls for bearing the motion between two objects, a maximum allowable load may be increased by 1 increasing sizes of the rolling members, or 2 increasing numbers of the rolling members which rolls on the load rolling groove. However, the latter can be hardly applied to practical products because the lengths of the load ball grooves are restricted due to the above described reason.
The present invention is devised in view of the above problems. It is an object of the invention to provide a linear guide devide, which allows easy formation of no-load rolling apertures for rolling members and has a large maximum allowable load and a small sizes.


The present invention provides a thin vehicle closure panel design that substantially reduces a thickness (panel gauge plus the perpendicular distance or depth between the panels) of a vehicle hood (5) and the impact effect on the head of a pedestrian struck by a motor vehicle. In one embodiment, the vehicle hood (5) includes a hood shell (15) including an outer panel (25) and an inner panel (20); a unitary foam core (100) positioned between and bonded to the outer (25) and/or the inner panel (20) of the hood shell (15); and at least one recess (10) that corresponds to an underhood component (42). In another aspect of the invention, a vehicle hood (5) is provided in which a latch attachment member (60) and/or hinge members (70) are attached to inner surface (50) of the inner panel (20) of the hood shell (15).

Accidents in which a motor vehicle strikes a pedestrian present a serious safety risk to pedestrians. One type of pedestrian/vehicle accident that is particularly harmful occurs when the vehicle's frontal portion impacts the pedestrian's knee, leg, and/or abdominal region. This frontal impact potentially harms the pedestrian's knee, leg, and/or abdominal region. Additionally, this frontal impact may also elevate and/or flip the pedestrian such that the pedestrian's head strikes the vehicle's hood or windshield. This impact may be fatal if the head suffers trauma.
Various regulatory bodies around the world have established standards that car manufacturers must meet to reduce this type of head injury to pedestrians. The European Union has developed a test standard referred to as EURONCAP EEVC WG17 [2] ACEA[1]. Another standard adopted in Japan is referred to as JNCAP. In one example, the standard requires that a head injury criteria number (HIC#) not exceed 1000. The HIC# is dependent on the force and duration of the impulse experienced by the human head against the vehicle hood in a pedestrian and vehicle impact. During a pedestrian impact the head may experience 80-150 g's (1 g=32 ft/sec2).

Pedestrian safe automotive hood having reinforcing foam


The invention relates to a method for producing a magnesium hot strip, in which a melt from a magnesium alloy is continuously cast to form a roughed strip with a thickness of maximum 50 mm, and in which the cast roughed strip is hot-rolled directly from the cast heat at a hot-rolling initial temperature of at least 250° C. and maximum 500° C. to form a hot strip with a final thickness of maximum 4 mm, whereby in the first hot-rolling pass a reduction in the thickness of at least 15% is achieved. With the method according to the invention, magnesium sheets with improved deformability can be produced with reduced manufacturing effort and expenditure.

The invention relates to a method for producing hot strip from magnesium wrought alloys. Magnesium is the metal with the lowest density, has strength characteristics similar to those of aluminium, and could substitute for this as a lightweight construction material. An important precondition for the progress of magnesium as a lightweight construction material, however, is the availability of economically-produced sheet materials. Magnesium sheets are at the present time only available on the market in small quantities and at high prices. This is explained by the substantial effort and expense which is required in hot-rolling sheets or strip of magnesium wrought alloys according to the present state of the art. This is described in detail in the Magnesium Taschenbuch (Aluminium-Verlag Düsseldorf, 2000, 1st edition, pp. 425 to 429). One basic problem with the hot-rolling of sheets of Mg wrought alloys lies in the fact that the conventional raw material from ingot casting or continuous casting solidifies in large grain and porous form, as well as containing pronounced segregations and coarse precipitations. The cast ingots are in many cases subjected to a homogenisation annealing process, and then hot-rolled at temperatures of between approx. 200 and 450° C. These procedures in most cases require in part repeated intermediate heating of the rolling stock, since otherwise wastage is incurred due to crack formation.
Attempts have been made to improve the deformability and the properties of a hot-rolled magnesium strip by the production of suitable raw materials, from which the hot strip is then rolled. Such a method is known, for example, from U.S. Pat. No. 5,316,598. According to the known method, magnesium powder compressed at temperatures from 150-275° C. solidifies rapidly. By extruding or forging, a raw material is produced from this ingot which is then rolled to form a sheet with a thickness of at least 0.5 mm. The rolling temperatures in this situation lie at between 200° C. and 300° C. The magnesium hot strip which is obtained in this way exhibits superplastic properties and at room temperature has high strength and good toughness in the rolling direction.
A disadvantage with the known method, however, is that for the manufacture of the raw material a magnesium powder is first produced, this powder is compressed, and an accelerated cooling process must then be carried out. The effort and expenditure in terms of apparatus and personnel associated with this leads to high manufacturing costs. In addition to this, it has been shown that the deformation of the raw material in the course of hot-rolling is difficult to master despite the elaborate production of the raw material.
In addition to the aforementioned state of the art, a method is known from JP 06293944 A for the manufacture of a magnesium sheet, in which a slab is first cast from a melt containing 0.5-1.5% REM, 0.1-0.6% zirconium, 2.0-4.0% zinc, and magnesium as the remainder. This slab is then hot-rolled in two stages, whereby in the second stage of the hot-rolling the rolling temperatures lie between 180-230° C., for preference 180-200° C., and a total deformation is achieved of 40-70%, for preference 40-60%. The strip obtained in this way is said to possess good deformability. The hot-rolling carried out in two stages, however, also makes the rolling process, and the temperature controlling which is to be maintained, elaborate and expensive and difficult to master.

Method for producing a magnesium hot strip


A lubricating oil comprising a major amount of base oil and a minor amount of an additive package comprising a friction modifier component selected from:                (A) one or more friction modifiers of the formulae I and II:

1. Field
The present disclosure is directed to lubricating oil compositions, such as engine oils, containing acyl N-methyl glycine derivatives. For example, it is directed to lubricating oil compositions containing acyl N-methyl glycine derivatives as friction modifiers for reducing one or both of thin film friction and boundary layer friction.
2. Description of the Related Technology
Lubricating oil compositions play an important role in ensuring smooth operation of machinery, like engines. These compositions may lubricate a variety of sliding parts in an engine including, for example, piston rings/cylinder liners, bearings of crankshafts and connecting rods, valve mechanisms including cams and valve lifters, and the like. Lubricating oil compositions may also play a role in cooling the inside of an engine and dispersing combustion products. Further possible functions of lubricating oil compositions may include preventing or reducing rust and corrosion.
There are several classes of lubricating compositions including engine oils, gear oils, tractor oils, multifunctional oils, and the like. Each type of lubricating composition may require customized properties for the particular application in which it is to be used.
The principle consideration for engine oils is to prevent wear and seizure of parts in the engine. Lubricated engine parts operate mostly in a state of hydrodynamic or full fluid lubrication, but valve systems and top and bottom dead centers of pistons/cylinder liner contact zones are likely to be in a state of thin-film (elastohydrodynamic) and/or boundary lubrication. The friction between these parts in the engine may result in significant energy losses and thereby reduce fuel efficiency. Many types of friction modifiers have been used in engine oils to decrease frictional energy losses.
Improved efficiency may be achieved when friction between moving parts is reduced. Thin-film friction is the friction generated by a fluid, such as a lubricant, moving between two surfaces, when the distance between the two surfaces is very small. It is known that some additives form films of different thicknesses, which can have an effect on thin-film friction. Some additives normally present in engine oils, such as zinc dialkyl dithiophosphate (ZDDP) are known to increase thin-film friction. Though such additives may be required for other reasons such as to protect engine parts, the increase in thin-film friction caused by such additives can reduce operating efficiency.
Reducing boundary layer friction in engines may also enhance fuel efficiency. The motion of contacting surfaces in an engine may be retarded by boundary layer friction. Non-nitrogen-containing, nitrogen-containing, and molybdenum-containing friction modifiers are sometimes used to reduce boundary layer friction.
In recent years there has been a growing desire to employ lower friction lubricating oils to provide higher energy efficiency, such as providing lower friction engine oils to improve fuel efficiency. The present disclosure provides an improved lubricating oil composition that may reduce one or both of thin film friction and boundary layer friction. The present disclosure is directed to lubricating oil compositions containing acyl N-methyl glycine derivatives as friction modifiers for reducing one or both of thin film friction and boundary layer friction.
U.S. Pat. No. 5,599,779 discloses a rust inhibitor composition consisting of a three component rust inhibitor package including a compound of the formula:
wherein R represents a C8-18-alkyl or alkenyl group;
a dicarboxylic acid of the formula:
wherein x is an integer from 4 to 46; and
an amine of the formula:
wherein R1, R2, and R3 are independently selected from hydrogen, hydrocarbyl having up to 14 carbon atoms, hydroxyalkyl, cycloalkyl or polyalkyleneoxy groups. The rust inhibitor package is described as advantageous for use in a grease, and may be formulated with oils and waxes into rust preventative compositions for use in automotive and other industries.
WO 2009/140108 discloses the use of variety of different rust inhibiting compounds for certain types of multifunctional oils. In the specification there is a brief mention of the possibility of using a compound of the formula:

wherein R and R1 are not defined. No further details are given as to the amounts that should be used, nor are any specific formulations including such compounds exemplified in the application.
GB 1235896 discloses multifunctional lubricants and includes an example of a wet brake formulation including oleoyl sarcosine. The exemplified composition also includes basic calcium sulphonate detergent (TBN=300), P2S5—polybutene barium phenate/sulphonate detergent, a dispersant that is a reaction product of polybutenyl succinic anhydride with an Mw=900 PIB group and tetraethylene pentamine, zinc dihexyl dithiophosphate, dioleoyl phosphite, sperm oil, and sulphurised polybutene.

This patent is subject to a terminal disclaimer.

Friction modifiers for use in lubricating oil compositions

Abstract: (B) two or more friction modifiers independently selected from the formulae III and IV:

Abstract: and                (C) at least one friction modifier of the formulae III and IV in combination with at least one friction modifier of the formulae I and II, and R, R1, R2, R3, X and n are as defined in the specification.


A multi-purpose holder with a flexible block having a guide surface for securement and for attachment to a variety of surfaces, including similar surfaces of others of the same multi-purpose holder and as a guide for a strap and an opposite gripping surface with a central, wide V-groove and parallel, narrow side V-grooves adjacent wings forming a continuation of the gripping surface of the block and having gripping surfaces thereon to engage an object positioned in the central, wide V-groove as the strap is tightened around the flexible block, the wings and the object.

This invention relates to devices to releasably secure objects of variable size and shape together and more particularly to hold an object to a flat or curved surface or such that held objects extend in either a selected parallel relationship or a selected transverse relationship.
In the past devices to secure object together have been proposed. U.S. Pat. No. 3,679,530, Perina, for example discloses a holder having an endless band of elastic material connected to a support member that is made of a semi-rigid material. Opposed marginal edges of the support member are deflected into engagement with an object being held within the endless band of material, while the central portion of the support member, containing rearwardly projecting hooking elements remains in a substantially flat planar condition to be attached to a loop element bonded to a wall or the like.
U.S. Pat. No. Des. 188,000, Shanok, et al. shows a design of a support for a flashlight or similar article that has a base from which arms with rolled pieces on the free ends thereof project to grasp a flashlight cylinder.
U.S. Pat. No. 2,716,284, O'Neil, discloses a handle shaped holder for a flashlight wherein an elastic band that passes over the flashlight barrel has opposite sides thereof releasably hooked to the handle.
None of the previously identified patents disclose a holder having a flexible base, wrap-around flexible arms projecting from the base and strap means to fit around the base and the arms to secure the arms around an object to be securely grasped by both the arms and the body. Consequently, the prior art devices, while possibly suitable for the specific purposes for which they are intended, do not provide the holding ability of the present invention for a wide ranging variety of devices.
Pairs of the prior art devices obviously can be connected to hold a pair of objects in a spaced relationship, even though such an arrangement may not be specifically disclosed by the prior art. U.S. Pat. No. Des. 293,206, Beaty, et al, U.S. Pat. No. Des. 298,739, Richards, and U.S. Pat. No. Des. 367,999, McCallum disclose holders for securing pairs of objects in spaced apart relationship using oppositely facing spring or resilient clips extending from a central base member. The holders shown in these prior art patents hold the interconnected objects in parallel extending relationships and are not disclosed as being alternatively able to hold the objects in a transversely extending relationship.
Another commercially available holder for a pair of objects comprises a flexible block with spaced apart, transversely extending slots passing therethrough. Straps having hook portions and loop portions are inserted through the slots and are locked around transversely extending objects held in cradles formed at opposite ends of the flexible block.


Methods for treating fibromyalgia by administering a therapeutically effective amount of a botulinum toxin to a patient with fibromyalgia.

Fibromyalgia is a persistent muscle pain that can be accompanied by severe fatigue, insomnia, diarrhea, abdominal bloating, bladder irritation and headache. The criteria for a diagnosis of fibromyalgia can include widespread pain throughout the body accompanied by tenderness in 11 of 18 specific tender points (FIG. 1). Tenderness is determined by applying firm pressure over each designated area.
The underlying pathophysiology and pathology of fibromyalgia is not well understood. Radiographic and histological examinations of regions associated with tenderness reveal no abnormalities. Blood chemistries, CBC, erythrocyte sedimentation rate (ESR), as well as other immunologic manifestations commonly known for other diseases (i.e. autoantibodies in Lupus), are normally negative unless there is another underlying disorder.
The source of the pain in fibromyalgia is not clear. Nociceptors are present in the interstitial space between muscle fibers, in particular, on blood vessels. Studies have reported intramuscular microcirculation abnormalities as well as a decrease in energy-rich phosphates in fibromyalgia musculature, Raj et al, Pain Digest, 8(6), 357-363 (1998)). These abnormalities may be important for producing muscle associated pain since 1) impaired microcirculation results in insufficient delivery of oxygen to localized muscle regions which results in sub-optimal working capacity of the musculature which may lead to exhaustion of some motor units; and 2) reduced energy-rich phosphates (ATP and phosphorylcreatine) means that demands of working muscles are not met by the energy supply, which may cause localized muscular strain, weakness, fatigue and pain.
Fibromyalgia tender points are characterized by allodynia (a state where a normally non-painful stimulus elicits a painful perception). Muscular dysfunction, either mechanical or metabolic, can lead to a state of sensitization of the nociceptive sensory inputs into the spinal cord altering the neurochemical balance important for nociceptive control. The process of nociception may be accomplished by a controlled release of various pro-nociceptive and antinociceptive agents in the nervous system. These agents include excitatory amino acids, neuropeptides, biogenic amines, nitric oxide, and prostaglandins. One important pro-nociceptive mediator is the neuropeptide substance P, which is found to be consistently elevated in the cerebrospinal fluid of fibromyalgia patients. Substance P may be released by sensory afferents arising from the muscle into the dorsal horn of the spinal cord to interact with neurokinin-1 receptors. Activation of spinal neurons by substance P prepares the neurons for an inceptive pain signal, thereby facilitating nociceptive perception. Injection of substance P into animals causes allodynia by increasing the number of afferent neurons that are activated (e.g. discharge one or more action potentials) in response to a certain nociceptive stimulus and reducing the voltage threshold needed for their activation.
A recent finding of elevated nerve growth factor levels in cerebral spinal fluid of patients may exacerbate the condition by increasing the development of substance P-containing sensory neurons, which either contribute to or accentuate the painful symptoms brought about by an elevated level of substance P. Further, levels of anti-nociceptive substances such as the neuropeptide met-enkephalin and biogenic amine serotonin are found to be significantly reduced in fibromyalgia patients' cerebral spinal fluid.
Fibromyalgia tends to be chronic and often occurs after a stressful event suffered by the patient, either physical or psychological. Current treatments involve massages, exercise, changes in diet and anti-depressant medication. All of these forms of treatment are inadequate only providing some benefit to a small subset of patients.
What is needed are new effective methods to treat fibromyalgia, including pain associated with fibromyalgia. The present invention provides methods to treat the symptoms (including pain) of fibromyalgia by the injection of a Clostridial toxin, for example, a botulinum toxin, into a patient at a location that is not at or near a site (i.e. is anatomically distant) from which the patient perceives the pain to originate. It is hypothesized that botulinum toxin may interfere with a central pain pathway through routes not traditionally associated with the action of this neurotoxin, as may occur for example in the use of a botulinum toxin to treat a migraine headache. See e.g. U.S. Pat. No. 5,714,468.
Botulinum Toxin
The anaerobic, gram positive bacterium Clostridium botulinum produces a potent polypeptide neurotoxin, botulinum toxin, which causes a neuroparalytic illness in humans and animals referred to as botulism. The spores of Clostridium botulinum are found in soil and can grow in improperly sterilized and sealed food containers of home based canneries, which are the cause of many of the cases of botulism. The effects of botulism typically appear 18 to 36 hours after eating the foodstuffs infected with a Clostridium botulinum culture or spores. The botulinum toxin can apparently pass unattenuated through the lining of the gut and attack peripheral motor neurons. Symptoms of botulinum toxin intoxication can progress from difficulty walking, swallowing, and speaking to paralysis of the respiratory muscles and death.
Botulinum toxin type A ("BoNT/A") is the most lethal natural biological agent known to man. About 50 picograms of botulinum toxin (purified neurotoxin complex) serotype A is a LD50 in mice. One unit (U) of botulinum toxin is defined as the LD50 upon intraperitoneal injection into female Swiss Webster mice weighing 18-20 grams each. Seven immunologically distinct botulinum neurotoxins have been characterized, these being respectively botulinum neurotoxin serotypes A, B, C1, D, E, F and G each of which is distinguished by neutralization with serotype-specific antibodies. The different serotypes of botulinum toxin vary in the animal species that they affect and in the severity and duration of the paralysis they evoke. For example, it has been determined that BoNt/A is 500 times more potent, as measured by the rate of paralysis produced in the rat, than is botulinum toxin serotype B (BoNT/B). Additionally, botulinum toxin type B ("BoNt/B") has been determined to be non-toxic in primates at a dose of 480 U/kg which is about 12 times the primate LD50 for BoNt/A. Botulinum toxin apparently binds with high affinity to cholinergic motor neurons, is translocated into the neuron and blocks the release of acetylcholine.
Botulinum toxins have been used in clinical settings for the treatment of neuromuscular disorders characterized by hyperactive skeletal muscles. BoNt/A has been approved by the U.S. Food and Drug Administration for the treatment of blepharospasm, strabismus, hemifacial spasm and cervical dystonia. Additionally a botulinum toxin type B has been approved by the FDA for the treatment of cervical dystonia. Non-serotype A botulinum toxin serotypes apparently have a lower potency and/or a shorter duration of activity as compared to BoNt/A. Clinical effects of peripheral intramuscular BoNt/A are usually seen within one week of injection. The typical duration of symptomatic relief from a single intramuscular injection of BoNt/A averages about three months.
Although all the botulinum toxins serotypes apparently inhibit release of the neurotransmitter acetylcholine at the neuromuscular junction, they do so by affecting different neurosecretory proteins and/or cleaving these proteins at different sites. For example, botulinum serotypes A and E both cleave the 25 kiloDalton (kD) synaptosomal associated protein (SNAP-25), but they target different amino acid sequences within this protein. BoNT/B, D, F and G act on vesicle-associated protein (VAMP, also called synaptobrevin), with each serotype cleaving the protein at a different site. Finally, botulinum toxin serotype C1 (BoNT/C1) has been shown to cleave both syntaxin and SNAP-25. These differences in mechanism of action may affect the relative potency and/or duration of action of the various botulinum toxin serotypes.
Regardless of serotype, the molecular mechanism of toxin intoxication appears to be similar and to involve at least three steps or stages. In the first step of the process, the toxin binds to the presynaptic membrane of the target neuron through a specific interaction between the H chain and a cell surface receptor; the receptor is thought to be different for each serotype of botulinum toxin and for tetanus toxin. The carboxyl end segment of the H chain, HC, appears to be important for targeting of the toxin to the cell surface.
In the second step, the toxin crosses the plasma membrane of the poisoned cell. The toxin is first engulfed by the cell through receptor-mediated endocytosis, and an endosome containing the toxin is formed. The toxin then escapes the endosome into the cytoplasm of the cell. This last step is thought to be mediated by the amino end segment of the H chain, HN, which triggers a conformational change of the toxin in response to a pH of about 5.5 or lower. Endosomes are known to possess a proton pump which decreases intra endosomal pH. The conformational shift exposes hydrophobic residues in the toxin, which permits the toxin to embed itself in the endosomal membrane. The toxin then translocates through the endosomal membrane into the cytosol.
The last step of the mechanism of botulinum toxin activity appears to involve reduction of the disulfide bond joining the H and L chain. The entire toxic activity of botulinum and tetanus toxins is contained in the L chain of the holotoxin; the L chain is a zinc (Zn++) endopeptidase which selectively cleaves proteins essential for recognition and docking of neurotransmitter-containing vesicles with the cytoplasmic surface of the plasma membrane, and fusion of the vesicles with the plasma membrane. Tetanus neurotoxin, botulinum toxin/B/D,/F, and/G cause degradation of synaptobrevin (also called vesicle-associated membrane protein (VAMP)), a synaptosomal membrane protein. Most of the VAMP present at the cytosolic surface of the synaptic vesicle is removed as a result of any one of these cleavage events. Each toxin specifically cleaves a different bond.
The molecular weight of the botulinum toxin protein molecule, for all seven of the known botulinum toxin serotypes, is about 150 kD. Interestingly, the botulinum toxins are released by Clostridial bacterium as complexes comprising the 150 kD botulinum toxin protein molecule along with associated non-toxin proteins. Thus, the BoNt/A complex can be produced by Clostridial bacterium as 900 kD, 500 kD and 300 kD forms. BoNT/B and C1 are apparently produced as only a 500 kD complex. BoNT/D is produced as both 300 kD and 500 kD complexes. Finally, BoNT/E and F are produced as only approximately 300 kD complexes. The complexes (i.e. molecular weight greater than about 150 kD) are believed to contain a non-toxin hemaglutinin protein and a non-toxin and non-toxic nonhemaglutinin protein. These two non-toxin proteins (which along with the botulinum toxin molecule comprise the relevant neurotoxin complex) may act to provide stability against denaturation to the botulinum toxin molecule and protection against digestive acids when toxin is ingested. Additionally, it is possible that the larger (greater than about 150 kD molecular weight) botulinum toxin complexes may result in a slower rate of diffusion of the botulinum toxin away from a site of intramuscular injection of a botulinum toxin complex.
In vitro studies have indicated that botulinum toxin inhibits potassium cation induced release of both acetylcholine and norepinephrine from primary cell cultures of brainstem tissue. Additionally, it has been reported that botulinum toxin inhibits the evoked release of both glycine and glutamate in primary cultures of spinal cord neurons and that in brain synaptosome preparations botulinum toxin inhibits the release of each of the neurotransmitters acetylcholine, dopamine, norepinephrine, CGRP and glutamate.
BoNt/A can be obtained by establishing and growing cultures of Clostridium botulinum in a fermenter and then harvesting and purifying the fermented mixture in accordance with known procedures. All the botulinum toxin serotypes are initially synthesized as inactive single chain proteins which must be cleaved or nicked by proteases to become neuroactive. The bacterial strains that make botulinum toxin serotypes A and G possess endogenous proteases and serotypes A and G can therefore be recovered from bacterial cultures in predominantly their active form. In contrast, botulinum toxin serotypes C1, D and E are synthesized by nonproteolytic strains and are therefore typically unactivated when recovered from culture. Serotypes B and F are produced by both proteolytic and nonproteolytic strains and therefore can be recovered in either the active or inactive form. However, even the proteolytic strains that produce, for example, the BoNt/B serotype only cleave a portion of the toxin produced. The exact proportion of nicked to unnicked molecules depends on the length of incubation and the temperature of the culture. Therefore, a certain percentage of any preparation of, for example, the BoNt/B toxin is likely to be inactive, possibly accounting for the known significantly lower potency of BoNt/B as compared to BoNt/A. The presence of inactive botulinum toxin molecules in a clinical preparation will contribute to the overall protein load of the preparation, which has been linked to increased antigenicity, without contributing to its clinical efficacy. Additionally, it is known that BoNt/B has, upon intramuscular injection, a shorter duration of activity and is also less potent than BoNt/A at the same dose level.
It has been reported (as exemplary examples) that BoNt/A has been used clinically as follows:
(1) about 75-125 units of BOTOX®1 per intramuscular injection (multiple muscles) to treat cervical dystonia; 1Available from Allergan, Inc., of Irvine, Calif. under the tradename BOTOX®.
(2) 5-10 units of BOTOX® per intramuscular injection to treat glabellar lines (brow furrows) (5 units injected intramuscularly into the procerus muscle and 10 units injected intramuscularly into each corrugator supercilii muscle);
(3) about 30-80 units of BOTOX® to treat constipation by intrasphincter injection of the puborectalis muscle;
(4) about 1-5 units per muscle of intramuscularly injected BOTOX® to treat blepharospasm by injecting the lateral pre-tarsal orbicularis oculi muscle of the upper lid and the lateral pre-tarsal orbicularis oculi of the lower lid.
(5) to treat strabismus, extraocular muscles have been injected intramuscularly with between about 1-5 units of BOTOX®, the amount injected varying based upon both the size of the muscle to be injected and the extent of muscle paralysis desired (i.e. amount of diopter correction desired). (6) to treat upper limb spasticity following stroke by intramuscular injections of BOTOX® into five different upper limb flexor muscles, as follows:                (a) flexor digitorum profundus: 7.5 U to 30 U        (b) flexor digitorum sublimus: 7.5 U to 30 U        (c) flexor carpi ulnaris: 10 U to 40 U        (d) flexor carpi radialis: 15 U to 60 U        (e) biceps brachii: 50 U to 200 U. Each of the five indicated muscles has been injected at the same treatment session, so that the patient receives from 90 U to 360 U of upper limb flexor muscle BOTOX® by intramuscular injection at each treatment session.
The tetanus neurotoxin acts mainly in the central nervous system, while botulinum neurotoxin acts at the neuromuscular junction; both act by inhibiting acetylcholine release from the axon of the affected neuron into the synapse, resulting in paralysis. The effect of intoxication on the affected neuron is long-lasting and until recently has been thought to be irreversible. The tetanus neurotoxin is known to exist in one immunologically distinct serotype.
Acetylcholine
Typically only a single type of small molecule neurotransmitter is released by each type of neuron in the mammalian nervous system. The neurotransmitter acetylcholine is secreted by neurons in many areas of the brain, but specifically by the large pyramidal cells of the motor cortex, by several different neurons in the basal ganglia, by the motor neurons that innervate the skeletal muscles, by the preganglionic neurons of the autonomic nervous system (both sympathetic and parasympathetic), by the postganglionic neurons of the parasympathetic nervous system, and by some of the postganglionic neurons of the sympathetic nervous system. Essentially, only the postganglionic sympathetic nerve fibers to the sweat glands, the piloerector muscles and a few blood vessels are cholinergic and most of the postganglionic neurons of the sympathetic nervous system secret the neurotransmitter norepinephine. In most instances acetylcholine has an excitatory effect. However, acetylcholine is known to have inhibitory effects at some of the peripheral parasympathetic nerve endings, such as inhibition of the heart by the vagal nerve.
The efferent signals of the autonomic nervous system are transmitted to the body through either the sympathetic nervous system or the parasympathetic nervous system. The preganglionic neurons of the sympathetic nervous system extend from preganglionic sympathetic neuron cell bodies located in the intermediolateral horn of the spinal cord. The preganglionic sympathetic nerve fibers, extending from the cell body, synapse with postganglionic neurons located in either a paravertebral sympathetic ganglion or in a prevertebral ganglion. Since, the preganglionic neurons of both the sympathetic and parasympathetic nervous system are cholinergic, application of acetylcholine to the ganglia will excite both sympathetic and parasympathetic postganglionic neurons.
Acetylcholine activates two types of receptors, muscarinic and nicotinic receptors. The muscarinic receptors are found in all effector cells stimulated by the postganglionic neurons of the parasympathetic nervous system, as well as in those stimulated by the postganglionic cholinergic neurons of the sympathetic nervous system. The nicotinic receptors are found in the synapses between the preganglionic and postganglionic neurons of both the sympathetic and parasympathetic. The nicotinic receptors are also present in many membranes of skeletal muscle fibers at the neuromuscular junction.
Acetylcholine is released from cholinergic neurons when small, clear, intracellular vesicles fuse with the presynaptic neuronal cell membrane. A wide variety of non-neuronal secretory cells, such as, adrenal medulla (as well as the PC12 cell line) and pancreatic islet cells release catecholamines and insulin, respectively, from large dense-core vesicles. The PC12 cell line is a clone of rat pheochromocytoma cells extensively used as a tissue culture model for studies of sympathoadrenal development. Botulinum toxin inhibits the release of both types of compounds from both types of cells in vitro, permeabilized (as by electroporation) or by direct injection of the toxin into the denervated cell. Botulinum toxin is also known to block release of the neurotransmitter glutamate from cortical synaptosomes cell cultures.

Botulinum toxin therapy for fibromyalgia


A method for the identification of unknown compounds based on a novel Retention Index System having a TAGs homologous series, wherein such identification is performed by means of liquid chromatography (LC), or liquid chromatography coupled with mass spectrometry (LC-MS) is disclosed.

Prior to the introduction of the retention index system, the qualitative chromatographic analysis relied on absolute retention time (tR) and/or relative retention time (tR(Rel)) as identification parameters.
Absolute retention time approach consists of comparing an analyte retention time with those of known compounds (e.g., listed tR of reference compounds): if the tR of a peak is the same as a reference, then a positive identification can be made.
However, such approach is reliable only under constant chromatographic conditions: even a slight difference may cause retention time deviations, making it very difficult, if not impossible, to identify analytes of interest. Therefore, due to the high variability of the absolute retention time, such an approach poses a problem of reproducibility.
In order to overcome this problem, the relative retention time approach (i.e. ratio between an analyte tR and an internal standard tR) can be used. In this way, due to the equal effect on both compounds, slight variations in analytical conditions can be compensated. The relative retention time approach, however, implies the challenging choice of one suitable standard. Therefore, due to the impossibility to fix a single standard close enough to all the analytes of interest, especially in a complex matrix, such an approach poses a problem of accuracy.
These limitations can mostly be overcome by using a retention index system.
The retention index system was first proposed by Kovàts who suggested the use of a homologous series of standard compounds (i.e. n-alkanes) to fix the gas-chromatographic (GC) retention behaviour of analytes eluting in the same region of the chromatogram. In said retention index system, a retention index value is arbitrarily attributed to each standard n-alkane according to the number of carbon atoms in the alkyl chain thereof. Conventionally, in order to avoid the use of a decimal fraction, the number of carbons atoms is multiplied by 100. The retention index of a given compound is equal to the number of carbons atoms (x 100) of a hypothetical n-alkane having the same adjusted retention time of said given compound. Thus, by way of example, a compound having a retention index equal to 1090 elutes between the alkanes C10 (I=1000) and C11 (I=1100).
According to Kovàts definition, the retention index (I) of a certain chemical compound is its retention time normalized to the retention times of adjacently eluting n-alkanes. Therefore, the retention index (I) calculation is performed according to the following equation:
                    I        =                  1                    0                                0                                      [                              z                +                                                                            log                                                                                t                                                  R                                                    i                                                ′                                                              -                                          log                                                                                t                                                  R                                                    z                                                ′                                                                                log                                                                                t                                                  R                                                                                (                                                          z                              +                              1                                                        )                                                                          ′                                                              -                                          log                                                                                t                                                  R                                                    z                                                ′                                                                                ]                                                          Eq        .                                          1
wherein,
t′Ri is the adjusted retention time of the unknown compound, t′Rz e t′R(z+1) are the adjusted retention times of the alkanes which elute, respectively, immediately before and immediately after the unknown compound i, and z represents the number of carbon atoms in the alkane chain (i.e. chain length).
The term "adjusted retention time" (t′R) means the time the analyte spends distributed into the stationary phase and corresponds to the analyte retention time (tR) minus the elution time of the unretained peak (tM) (i.e. also known as hold-up time):t′R=tR−tM
When isothermal GC conditions are applied, this homologous series elutes with retention times increasing exponentially along with the alkanes chain length. Therefore, a semi logarithmic relationship exists between the adjusted retention time and the retention index of the reference alkanes.
In temperature programmed GC, instead, due to the fact that the n-alkane series elutes in a linear mode, which means that a linear relationship exists between retention times and retention indices, retention indices are defined as linear retention indices (hereinafter also LRIs), and are calculated by means of the following equation:
                              L                    R                    I                =                  1                    0                                0                                      [                              z                +                                                                            t                                              R                                                i                                                              -                                          t                                              R                                                z                                                                                t                                              R                                                                          (                                                      z                            +                            1                                                    )                                                                                -                                          t                                              R                                                z                                                                                ]                                                          Eq        .                                          2
wherein,
tRi is the retention time of the unknown compound, tRz and tR(z+1) are the retention times of the alkanes which elute, respectively, immediately before and immediately after the unknown compound i, and z represents the number of carbon atoms in the alkane chain.
Such approach was proposed also by using polycyclic aromatic hydrocarbons as homologous series [M. L. Lee, D. L. Vassilaros, C. M. White, M. Novotny. Anal. Chem., v. 51, p. 768 (1979)]. In this paper, Lee et al. reported also that a retention index system based on closely related compounds as internal standards was more reliable for polycyclic aromatic hydrocarbons analysis. In other words, the reproducibility of the retention indices increases if the reference compounds have chemical-physical properties similar to those of the analytes to be determined.
Other retention index systems have been described in the literature. Among them, the one that employs the fatty acid methyl esters (FAMEs) with even carbon chain number as the homologous series was commonly employed for the characterization of fatty acids samples [F. P. Woodford, C. M. Van Gent. J. Lipid Res., v. 1, p. 188 (1960); T. K. Miwa, K. L. Mikolajcazak, F. R. Earle, I. A. Wolff. Anal. Chem., v. 32, p. 1739 (1960)]. In this case, as the difference of carbon atoms between two subsequent compounds of the homologous series is equal to two, Eq. 2 is modified as follows:
                                          L                        R                        I                    =                      1                        0                                      0                                            [                                  z                  +                                      2                                                                                t                                                      R                                                        i                                                                          -                                                  t                                                      R                                                        z                                                                                t                                                      R                                                                                (                                                              z                                +                                2                                                            )                                                                                -                                                  t                                                      R                                                        z                                                                                ]                                                    .                            Eq        .                                          3
Therefore, a generalization for LRI calculation can be performed according to Eq. 4:
                              L                    R                    I                =                  1                    0                                0                                      [                              z                +                                  n                                                                                t                                                  R                                                    i                                                                    -                                              t                                                  R                                                    z                                                                                t                                                  R                                                                                (                                                          z                              +                              n                                                        )                                                                                -                                              t                                                  R                                                    z                                                                                ]                                                          Eq        .                                          4
where,
z is an arbitrary number associated with the compound eluted immediately before the analyte and n represents the difference in z units between the reference compounds eluted immediately before and after the unknown analyte.
In GC, given the high reproducibility of both LRI and mass spectrometry (MS) data, the combination and complementarity of these parameters lead to an unequivocal identification. Moreover, the availability of commercial databases comprising thousands of MS spectra allows for a very fast and automatic identification process wherein LRIs are often used as a secondary filter (e.g., compounds with a high spectra matching but with a LRI value falling out from a selected range are automatically excluded from the list of possible candidates).
However, to date, an effective, reliable and high reproducible retention index system has not yet been established in liquid chromatography (LC).
Regarding the use of retention indices in liquid chromatography, several approaches have been proposed over the past years sometimes combined with UV spectral information, mainly for the identification of drugs in toxicology studies. The first attempt is ascribed to Baker and Ma [J. K. Baker, C-Y. Ma. J. Chromatogr. A, v. 169, p. 107 (1979)], who suggested the use of an alkan-2-one series (i.e. from acetone to 2-tricosanone) as homologous series reference mixture in isocratic conditions. Three years later Smith et al. [Smith, R. M. J. Chromatogr. A, v. 216, p. 313 (1982)] suggested the use of an alkyl aryl ketones homologous series, because of its higher UV absorption.
The influence of the stationary phase chemistry and packaging, as well as the mobile phase composition, was then evaluated leading to the conclusion that, due to the occurrence of significant tR deviations even under slightly different analytical conditions, a standardization of LC conditions was necessary to create a reliable identification method and a usable database in liquid chromatography.
In this regard, Bogusz et al. described the use of 1-nitroalkanes (i.e. from nitromethane to 1-nitrooctane) for retention index calculation, since, with respect to the alkyl aryl ketones series, they show a better coverage of the chromatographic space under common reversed phase (RP) conditions. Moreover, due to the fact that a gradient elution mode was employed, which is comparable to temperature program in GC, Eq. 2 was used for the retention indices calculation [M. Bogusz, R. Aderjan. J. Chromatogr. A, v. 435, p. 43 (1988)].
Nevertheless, nitroalkanes are neither affordable nor highly stable at high pH.
Moreover, as reported in WO2013/134862, retention index standards known in the art such as, for example, alkylphenones were designed mainly for LC with UV absorbance detection.
WO2013/134862 describes the use of a homologous series of 1-alkylpyridinesulfonic acids as retention indices standards for liquid chromatography, especially for LC-MS methods employing specifically electrospray (ESI) or atmospheric pressure chemical ionization (APCI) ionization systems.
In WO2013/134862, however, there is no hint about the identification of an unknown compound by means of other detectors, in particular, detectors which give no information regarding the structure of the compound such as, for example, an ELSD (evaporative light scattering detector) detector. The method described in WO2013/134862 is effective only if coupled with mass spectrometry, therefore it is not reliable in itself as identification tool in liquid chromatography. In addition, the compounds included in the homologue series have not yet been studied from a toxicological point of view and could present very high toxicity due to the presence of the pyridine ring. A further limitation of these compounds is related to their relatively limited availability in the market.
The limitations encountered by the use of each homologous series above described (such as low UV absorption, limited coverage of chromatographic space, high toxicity, poor affordability and chemical stability), and the low retention time reproducibility experimented by any change of the analytical parameters, instrumentation or even column packaging, hampered the widespread use of retention indices databases in liquid chromatography both at intra- and inter-laboratory levels.
Therefore, there is still the need for a homologous series effective as a reference mixture allowing it to establish a reliable and high reproducible method based on a novel Retention Index System for the identification of unknown compounds in liquid chromatography.

Identification of unknown compounds by using a novel retention index system in liquid chromatography


A mass positioning apparatus for use with seismic sensors is described. The seismic sensor includes axis mechanics including a pivotable boom with a defined null point. The mass positioning apparatus comprising: adjustment means for positioning the boom at the null point; actuator means for moving the adjustment means; and means for determining a position of the adjustment means relative to an operational range of travel.

A broadband seismometer typically requires an adjustable mass positioning apparatus operated by an electrical motor or a manually adjusted screw to position an inertial mass to a measurement null point to compensate for the inertial mass moving from the null point due to environmental changes or mis-calibration. Mass positioning apparatuses can be prone to jamming, and problems can be difficult to diagnose without disassembling the instrument to visually inspect the apparatus.
Mass positioning apparatuses operate within a defined range beyond which no further adjustment is possible, but such traditional apparatuses do not report position information of the apparatus relative to its operational range, and so the operator of the seismic sensor cannot readily know what further range of adjustment is available and whether the instrument is operating with sufficient margin to compensate for future expected environmental changes.
There is a need to provide mass positioning apparatuses that are more reliable, that report position information and other diagnostic information, and that can be realized relatively economically inside the seismic sensor without significantly increasing the volume of the sensor enclosure.

Mass positioning apparatus for a seismic sensor


A display apparatus with a brightness control function is provided, in which a camera portion generates a first detection signal in an image mode by capturing an image of an object by an image sensor according to a first control signal and generates a second detection signal in an illumination mode by detecting external illumination by the same image sensor according to a second control signal. The display displays an image signal, and a controller provides the first control signal to the camera portion in image detection mode, and provides the second control signal to the camera portion in illumination detection mode to control brightness of the display based on the second detection signal received from the camera portion. Only part of the pixels of the image sensor can be used in the illumination detection mode so that additional parts are not required to provide automatic illumination control.

1. Field of the Invention
The present invention generally relates to a display apparatus. More particularly, the present invention relates to brightness of a display apparatus with a camera portion.
2. Description of the Related Art
There is a variety of display apparatuses currently in use in devices such as portable phones, laptop and notebook computers, Portable Multimedia Players (PMPs), Digital Versatile Disks (DVDs), and MPEG Audio Layer 3 (MP3) players. In particular, the deployment of Digital Multimedia Broadcasting (DMB) is a driving force behind the proliferation of display apparatuses having a moving picture function.
With regard to such display apparatuses, image quality as well as functionality is often linked to the commercial success of the display apparatus, and/or the devices using the display apparatus. Among factors that determine the image quality, appropriate brightness is a significant factor. When brightness is automatically controlled according to external illumination, users' overall satisfaction is enhanced and power is typically saved versus displays that do not automatically adjust brightness.
Conventionally, brightness is typically fixed at a predetermined default level, or a user may set or change a level of desired brightness. Additionally, an illumination sensor is used. Such conventional devices and methods have the following shortcomings.
(1) In the case of having a fixed brightness, unnecessary power is wasted when the external illumination is high. On the other hand, the fixed brightness causes inconvenience in a dark area because sufficient brightness may not be available to comfortably view the display.
(2) When a user sets a desired brightness, it is not easy to set an appropriate brightness value unless he/she is skilled. Also, a user may not set the brightness level until there is an extreme situation, and setting the brightness at that time may actually degrade the viewability when the device is returned to more typical operating conditions and the user doesn't change it back, or does not remember exactly what the previous brightness values were.
(3) When an illumination sensor is additionally used, the cost is increased and the increase of parts in number makes the display apparatus bulky.
Accordingly, there exists a need for a display apparatus that automatically controls brightness according to external illumination without the aid of additional parts.

Display apparatus with brightness control function


A roll blind is provided which can guarantee a simple operation. The roll blind includes: a supporting frame disposed in a window frame; first and second winding bars rotatably disposed in the supporting frame; a winding driver rotationally driving one of the first and second winding bars; first and second screens coupled to the first and second winding bars, respectively; a weight bar to which the tower ends of the first and second screens are fixed; and a clutch unit binding and unbinding the first and second winding bars with respect to each other.

A roll blind serves to block light beams, block external sight, absorb sounds, protect against the hot, and protect against the cold by downward unwinding or winding a screen in a roll shape. In addition to the practical use, the roll blind also serves to soften the hardness of a wall or glass and improve an interior beautiful sight by combinations of colors.
On the other hand, the known roll blind cannot properly adjust the intensity of light input from the outside by downward unwinding or winding the screen, and it is thus difficult to adjust the brightness.
Accordingly, a roll blind that can easily adjust the brightness was suggested in recent years. Examples of such a roll blind having a brightness adjusting function are disclosed in Korean Utility Model Registration Nos. 20-365028 and 20-0279166.
In such roll blinds having the brightness adjusting function, a transparent portion and an opaque portion are alternately arranged on the surface of a screen, the transparent portion and the opaque portion are formed in a stripe pattern, and the front transparent portions and the rear opaque portions are made to overlap with each other to adjust the intensity of light input from the outside, thereby adjusting the brightness.
However, the known roll blinds having the brightness adjusting function take much time for unwinding or winding a screen and are troublesome in operation, thereby deteriorating the convenience of use.
The known roll blinds having the brightness adjusting function do not guarantee the straightness of the stripe lines of the transparent portions and the opaque portions. Accordingly, the stripe lines of the transparent portions and the opaque portions overlapping with each other may be inclined to one side or curved to both sides, thereby damaging the external appearance.


Methods and apparatus, including computer program products, implementing and using techniques for exchanging certificates, including generating a first container object including one or more of a sender's certificate and a request for a recipient's certificate, wherein the first container object has a recognizable container type, and transmitting the first container object to a recipient's address. Upon receipt of the first container object, it can be determined the first container object includes one or more of a certificate and a request for a certificate of the recipient. A request for a certificate can be responded to by generating a second container object including a certificate of the recipient, extracting a return address from the first container object, and transmitting the second container object to the return address.

The present invention relates to automated public key certificate transfer.
Public key cryptography uses public-private key pairs for electronic signatures, electronic signature verification and encryption and decryption of data for security during electronic transmission. In simple terms, a public key owned by an individual receiving the data (the "recipient") is used by a sender to encrypt the data. The recipient then uses the recipient's corresponding private key to decrypt the data. In order to encrypt the data, the sender must have access to the recipient's public key.
When electronically signing data, a sender signs the data using the sender's private key, an operation that can involve using the private key to encrypt a "cryptographic hash" of the data that is being signed, and then making available to the recipient the signed data and the encrypted hash (the "signature"). The recipient verifies the signature by computing a new hash over the data using the sender's public key, decrypting the encrypted hash of the signature and comparing the two hashes. If the hashes match, then the data integrity is proven.
Typically, a public key for another individual (the sender for example) is obtained by obtaining the individual's public key certificate directly or indirectly from that individual. A certificate is an electronic data object including a public key, and can be issued by a trusted third party, a certificate authority, that verifies the identity of the certificate holder. The certificate can also include the name of the certificate authority and the name of the individual or entity for whom the certificate is issued. The recipient of another individual's certificate should take steps to verify the trustworthiness or authenticity of the certificate, which can then be added to a personal certificate database for later use. The recipient of an electronically signed document can verify the identity of the sender (signer) by verifying the certificate of the sender.
Currently, there are a number of ways to obtain someone's certificate, some of which are covered by standards issued by the Internet Engineering Task Force public-key infrastructure (X.509) working group (IETF-PKIX). For instance, the certificate can be found in a searchable database on a server. Such a server would typically be provided and managed by a trusted party that undertakes to ensure the validity of the database's contents, including the certificates it contains.
A certificate owner can also manually include the certificate as an attachment to an e-mail message sent to a recipient. This requires the owner to place the certificate into a file that will be attached to the e-mail message, and the recipient must manually add the certificate to a personal certificate database for later use.

Automated public key certificate transfer


In a communication apparatus has a line control unit that controls connection with a communication line network, a communication unit transmits/receives data through the communication line network. A detection circuit detects one of a line voltage value and a line current value when the communication apparatus is connected to the line network. A memory unit stores multiple voltage-current characteristic curves defining relationships of line voltage values with respect to line current values satisfying a predetermined standard. An adjusting unit adjusts the line voltage value and the line current value so as to satisfy the predetermined standard based on one of the voltage-current characteristic curves stored in the memory unit. A selecting unit selects another voltage-current characteristic curve different from the one of the voltage-current characteristic curves from among the multiple voltage-current characteristic curves stored in the memory unit. A re-adjusting unit adjusts one of the line voltage and a line current.

1. Technical Field
Aspects of the present invention relate to a communication apparatus and in particular to a communication apparatus that controls to suppress an oscillation in a line communication network when the communication apparatus is connected with a various kind of networks.
2. Description of Related Art
In order to maintain communication quality, a public line network is designed in accordance with predetermined standards. A communication apparatus connected to such a network is configured such that a line voltage or a line current is controlled so as to meet the standards, since a line resistance connected with an exchange installed in a telephone exchange station varies depending on the location of the communication apparatus.
For an example, Japanese Patent Provisional Publication P2004-112490A describes a communication apparatus that detects a line current and a line voltage, calculates line impedance, and adjusts the signal level of the modem based on the calculated impedance. Further, in order to control the line current and the line voltage which meet the standards of public line networks, etc., the apparatus adjusts a relation between the current and the voltage so as to satisfy the standards, based on a predetermined DC mask curve defining a relationship between the line current values and line voltage values. FIG. 10 is a graph showing an example of the DC mask curve used in a conventional communication apparatus.
In FIG. 10, a horizontal axis represents the line current value, while a vertical axis represents the line voltage. An area between two dotted lines represents line current values and line voltage values satisfying the public line standards.
A predetermined DC mask curve passing the above area is defined (indicated by solid line in FIG. 10), and by controlling the impedance of the line, the line current and the line voltage are adjusted.
For example, in FIG. 10, when initially a line current value and line voltage value are represented by point A, which is out of the area, point A is located below the DC mask curve and the values do not meet the standards. In such a case, the value of the line impedance is changed to a smaller value. Then, the line current value and the line voltage value are changed to values represented by point B. In this example shown in FIG. 10, point B is also out of the area (i.e., located above the DC mask curve). Therefore, the value of the line impedance is then changed to a larger value, and the line current value and the line voltage value are changed to point C. As shown in FIG. 10, still point C is out of the area (i.e., located below the DC mask curve), and the value of the line impedance is changed again to a smaller value. Then, the line current value and the line voltage value move to point D, which is substantially on the DC mask curve. The line current value and the line voltage value set in this way satisfy the standards.
However, when the line current value and the line voltage value are set in the way described above, an oscillation may occur as the network is in the resonant state with specific frequencies. The oscillation frequency is only within a frequency bandwidth from 20 kHz to 1 MHz, which is higher than an audio frequency range. However, the oscillation generated in the network would cause troubles such as generation of noises, malfunction in echo canceling while calling with a handset.


Method for preparing a mono-unsaturated alkene comprising contacting an aliphatic mono-unsaturated carboxylic acid with an Fdc1 polypeptide comprising an amino acid sequence with at least 21% sequence identity to SEQ ID NO: 1 and a Pad1 polypeptide comprising an amino acid sequence with at least 17% sequence identity to SEQ ID NO: 2.

With the diminishing supply of crude mineral oil, use of renewable energy sources is becoming increasingly important for the production of liquid fuels and/or chemicals. These fuels and/or chemicals from renewable energy sources are often referred to as biofuels. Biofuels and/or biochemicals derived from non-edible renewable energy sources are preferred as these do not compete with food production.
Hydrocarbons such as alkenes are important constituents in the production of fuels and/or chemicals. It would therefore be desirable to produce alkenes (sometimes also referred to as bio-alkenes) from non-edible renewable energy sources.


A monitor for controlling power-on and power-off of a host computer includes a switch device, a monitoring device and a transmission device. The host computer has a processing device. The switch device is used for changing a status thereof in response to an external force applied thereto. The monitoring device is electrically connected to the switch device for monitoring the change of the status of the switch device, and determines if a power management event is activated by the change of the status of the switch status. The transmission device is electrically connected to the monitoring device, and transmits a power management signal to the host computer according to the determination that the change of the status of the switching device activates a power management event, such that the processing device performs a startup power-on or a power-off operation on the host computer.

A power management system is widely used to save power consumption in a personal computer system. Advanced Configuration and Power Management Interface (ACPI), which was published by Intel, Microsoft and Toshiba in Dec. 22, 1996, is a specification defining standard interfaces for hardware configuration and power management of a power-saving system. According to the ACPI specification, the function of power management is integrated into the operation system to increase the efficiency of power management and the processing speed of the computer system.
According to the ACPI specification, the power management of the computer system is classified into six modes including S0 (a normal mode), S1˜S4 (suspended modes) and S5 (a power off mode) from low to high. Each of these different suspended modes S1˜S4 allows for different level of power saving and usage. A computer system in the S1 mode simply shuts down the hard drives and the monitor, but leaves everything else running normally. S2 mode offers slightly greater power saving than the S1 mode. A computer system in the S2 mode not only shuts down the monitor and hard drives, but also interrupts power to be supplied to the CPU and its cache. A computer system in the S3 mode shuts down almost everything except for the RAM and the power management controller. The S3 mode is also referred as a "suspend to RAM" mode to listen for a wake-up action. When the computer system comes into the S3 mode, the ACPI allows the RAM to store the last operation of the computer system. When the computer system is turned back on from the S3 mode, the computer system is quickly restored to the last operation based on the data stored in the RAM without normal booting. S4 mode is known as a hibernation mode in which the entire computer system is stopped and all of the system modes and contexts are stored to disk selected by the BIOS. The S4 mode is also referred as a "suspend to disk" mode.
On the other hand, the computer system principally comprises a host computer, a monitor and other peripheral devices. The monitor may be a cathode array tube (CRT) monitor or a liquid crystal display (LCD). Recently, the LCD monitors are becoming popular. The host computer transmits video signals to the monitor via signal lines. The peripheral devices are also electrically connected to the host computer. Generally, the host computer and the monitor are distant from each other. For example, the monitor is placed on a table, whereas the host computer is placed under the table. As such, when the host computer is to be started, the user needs to bend down to press the power button, which is not user-friendly. The common human-machine interfaces for the computer system include the monitor, the mouse, the keyboard, and the front panel of the host computer (which is used to turn on/off the host computer, draw out/insert disks or swap IEEE 1394 interface and USB devices, etc). However, among these the human-machine interfaces, the monitor, the mouse and the keyboard are frequently manipulated by a computer user when a computer system is used.
U.S. Patent Application Publication 2003/0107566, which is published in Jun. 12, 2003, describes the use of an external USB device such as a keyboard or a mouse to control the turning on/off state of the host computer. This technology provides a monitor having a USB hub in connection with external USB devices. In addition, a digital video interactive (DVI) cable is employed to connect the monitor with the power output port, the graphic card and the USB port of the host computer so as to transmit video signals from the host computer to the monitor for display. In the S3 mode of the power management system of the host computer, by operating the input/output device, for example, a USB keyboard or a mouse connected to the USB hub of the monitor, a USB controller inside the monitor will transmit a wake-up signal to the host computer via the USB cable to wake up the host computer from the power saving mode to the normal mode.
According to the above technology, the host computer can be woken up by employing a keyboard or a mouse. However, the external device should be connected to a monitor having a USB hub. Since the ordinary LCD monitor has no USB hub to connect the external USB device, this LCD monitor should be specifically designed. For example, an internal USB hub is provided in the LCD monitor as a connection medium of the external device. The fabrication cost of this LCD monitor having an internal USB hub is relatively high. After a triggering signal is asserted from the external device, the USB controller in the monitor will transmit a wake-up signal to the host computer to wake up the host computer from the suspended mode when the USB controller detects an input signal from the input/output device via the USB hub. However, such means of waking up the host computer by signal transmissions from the USB device to the LCD monitor and then from the LCD monitor to the host computer is inefficient. Furthermore, two power supply apparatuses are required by the LCD monitor to generate driving power for the USB controller and the USB hub, which is not cost effective.

Monitor and method for controlling power-on and power-off of host computer