A class of pyrido[2,3-d]pyridazine derivatives, possessing an optionally substituted cycloalkyl, phenyl or heteroaryl substituent at the 8-position, a substituted alkoxy moiety at the 2-position, and a range of substituents at the 3-position, are selective ligands for GABAA receptors, in particular having high affinity for the xcex12 and/or xcex13 and/or xcex15 subunit thereof, and are accordingly of benefit in the treatment and/or prevention of adverse conditions of the central nervous system, including anxiety, convulsions and cognitive disorders.

This application is a U.S. National Phase application under 35 U.S.C. 371 of PCT Application No. PCT/GB00/03353, filed Aug. 30, 2000, which claims priority under 35 U.S.C. 119 from GB Application No. 9921351.4, filed Sep. 9, 1999.
The present invention relates to a class of substituted pyrido-pyridazine derivatives and to their use in therapy. More particularly, this invention is concerned with substituted pyrido[2,3-d]pyridazine derivatives which are ligands for GABAA receptors and are therefore useful in the therapy of deleterious mental states.
Receptors for the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), are divided into two main classes: (1) GABAA receptors, which are members of the ligand-gated ion channel superfamily; and (2) GABAB receptors, which may be members of the G-protein linked receptor superfamily. Since the first cDNAs encoding individual GABAA receptor subunits were cloned the number of known members of the mammalian family has grown to include at least six xcex1 subunits, four xcex2 subunits, three xcex3 subunits, one xcex4 subunit, one xcex5 subunit and two xcfx81 subunits.
Although knowledge of the diversity of the GABAA receptor gene family represents a huge step forward in our understanding of this ligand-gated ion channel, insight into the extent of subtype diversity is still at an early stage. It has been indicated that an xcex1 subunit, a xcex2 subunit and a xcex3 subunit constitute the minimum requirement for forming a fully functional GABAA receptor expressed by transiently transfecting cDNAs into cells. As indicated above, xcex4, xcex5 and xcfx81 subunits also exist, but are present only to a minor extent in GABAA receptor populations.
Studies of receptor size and visualisation by electron microscopy conclude that, like other members of the ligand-gated ion channel family, the native GABAA receptor exists in pentameric form. The selection of at least one xcex1, one xcex2 and one xcex3 subunit from a repertoire of seventeen allows for the possible existence of more than 10,000 pentameric subunit combinations. Moreover, this calculation overlooks the additional permutations that would be possible if the arrangement of subunits around the ion channel had no constraints (i.e. there could be 120 possible variants for a receptor composed of five different subunits).
Receptor subtype assemblies which do exist include, amongst many others, xcex11xcex22xcex32, xcex12xcex22/3xcex32, xcex13xcex2xcex32/3, xcex12xcex2xcex31, xcex15xcex23xcex32/3, xcex16xcex2xcex32, xcex16xcex2xcex4 and xcex14xcex2xcex4. Subtype assemblies containing an al subunit are present in most areas of the brain and are thought to account for over 40% of GABAA receptors in the rat. Subtype assemblies containing xcex12 and xcex13 subunits respectively are thought to account for about 25% and 17% of GABAA receptors in the rat. Subtype assemblies containing an xcex15 subunit are expressed predominantly in the hippocampus and cortex and are thought to represent about 4% of GABAA receptors in the rat.
A characteristic property of all known GABAA receptors is the presence of a number of modulatory sites, one of which is the benzodiazepine (BZ) binding site. The BZ binding site is the most explored of the GABAA receptor modulatory sites, and is the site through which anxiolytic drugs such as diazepam and temazepam exert their effect. Before the cloning of the GABAA receptor gene family, the benzodiazepine binding site was historically subdivided into two subtypes, BZ1 and BZ2, on the basis of radioligand binding studies. The BZ1 subtype has been shown to be pharmacologically equivalent to a GABAA receptor comprising the xcex11 subunit in combination with a xcex2 subunit and xcex32. This is the most abundant GABAA receptor subtype, and is believed to represent almost half of all GABAA receptors in the brain.
Two other major populations are the xcex12xcex2xcex32 and xcex13xcex2xcex32/3 subtypes. Together these constitute approximately a further 35% of the total GABAA receptor repertoire. Pharmacologically this combination appears to be equivalent to the BZ2 subtype as defined previously by radioligand binding, although the BZ2 subtype may also include certain xcex15-containing subtype assemblies. The physiological role of these subtypes has hitherto been unclear because no sufficiently selective agonists or antagonists were known.
It is now believed that agents acting as BZ agonists at xcex11xcex2xcex32, xcex12xcex2xcex32 or xcex13xcex2xcex32 subtypes will possess desirable anxiolytic properties. Compounds which are modulators of the benzodiazepine binding site of the GABAA receptor by acting as BZ agonists are referred to hereinafter as xe2x80x9cGABAA receptor agonistsxe2x80x9d. The xcex11-selective GABAA receptor agonists alpidem and zolpidem are clinically prescribed as hypnotic agents, suggesting that at least some of the sedation associated with known anxiolytic drugs which act at the BZ1 binding site is mediated through GABAA receptors containing the xcex11 subunit. Accordingly, it is considered that GABAA receptor agonists which interact more favourably with the xcex12 and/or xcex13 subunit than with xcex11 will be effective in the treatment of anxiety with a reduced propensity to cause sedation. Moreover, agents which are inverse agonists of the xcex15 subunit are likely to be beneficial in enhancing cognition, for example in subjects suffering from dementing conditions such as Alzheimer""s disease. Also, agents which are antagonists or inverse agonists at xcex11 might be employed to reverse sedation or hypnosis caused by xcex11 agonists.
The compounds of the present invention, being selective ligands for GABAA receptors, are therefore of use in the treatment and/or prevention of a variety of disorders of the central nervous system. Such disorders include anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, animal and other phobias including social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic and acute stress disorder, and generalized or substance-induced anxiety disorder; neuroses; convulsions; migraine; depressive or bipolar disorders, for example single-episode or recurrent major depressive disorder, dysthymic disorder, bipolar I and bipolar II manic disorders, and cyclothymic disorder; psychotic disorders including schizophrenia; neurodegeneration arising from cerebral ischemia; attention deficit hyperactivity disorder; and disorders of circadian rhythm, e.g. in subjects suffering from the effects of jet lag or shift work.
Further disorders for which selective ligands for GABAA receptors may be of benefit include pain and nociception; emesis, including acute, delayed and anticipatory emesis, in particular emesis induced by chemotherapy or radiation, as well as post-operative nausea and vomiting; eating disorders including anorexia nervosa and bulimia nervosa; premenstrual syndrome; muscle spasm or spasticity, e.g. in paraplegic patients; and hearing loss. Selective ligands for GABAA receptors may be beneficial in enhancing cognition, for example in subjects suffering from dementing conditions such as Alzheimer""s disease; and may also be effective as pre-medication prior to anaesthesia or minor procedures such as endoscopy, including gastric endoscopy.
The present invention provides a class of pyrido-pyridazine derivatives which possess desirable binding properties at various GABAA receptor subtypes. The compounds in accordance with the present invention have good affinity as ligands for the xcex12 and/or xcex13 and/or xcex15 subunit of the human GABAA receptor. The compounds of this invention may interact more favourably with the xcex12 and/or xcex13 subunit than with the xcex11 subunit; and/or may interact more favourably with the xcex15 subunit than with the xcex11 subunit.
The compounds of the present invention are GABAA receptor subtype ligands having a binding affinity (Ki) for the xcex12 and/or xcex13 and/or xcex15 subunit of 100 nM or less, typically of 50 nM or less, and ideally of 10 nM or less. The compounds in accordance with this invention may possess at least a 2-fold, suitably at least a 5-fold, and advantageously at least a 10-fold, selective affinity for the xcex12 and/or xcex13 and/or xcex15 subunit relative to the xcex11 subunit. However, compounds which are not selective in terms of their binding affinity for the xcex12 and/or xcex13 and/or xcex15 subunit relative to the xcex11 subunit are also encompassed within the scope of the present invention; such compounds will desirably exhibit functional selectivity in terms of zero or weak (positive or negative) efficacy at the xcex11 subunit and (i) a full or partial agonist profile at the xcex12 and/or xcex13 subunit, and/or (ii) an inverse agonist profile at the xcex15 subunit.
The present invention provides a compound of formula I, or a salt or Prodrug thereof:
wherein
Z represents C1-6 alkyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C6-8 bicycloalkyl, aryl, C3-7 heterocycloalkyl, heteroaryl or di(C1-6)alkylamino, any of which groups may be optionally substituted;
R1 represents C3-7 cycloalkyl, phenyl, furyl, thienyl or pyridinyl, any of which groups may be optionally substituted; and
R2 represents C3-7 cycloalkyl(C1-6)alkyl, aryl(C1-6)alkyl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted.
The groups Z, R1 and R2 may be unsubstituted, or substituted by one or more, suitably by one or two, substituents. In general, the groups Z, R1 and R2 will be unsubstituted or monosubstituted. Examples of optional substituents on the groups Z, R1 and R2 include C1-6 alkyl, aryl(C1-6)alkyl, pyridyl(C1-6)alkyl, halogen, halo(C1-6)alkyl, cyano, cyano(C1-6)alkyl, hydroxy, hydroxymethyl, C1-6 alkoxy, C3-7 cycloalkyl(C1-6)alkoxy, C3-7 cycloalkoxy, amino(C1-6)alkyl, di(C1-6)alkylamino(C1-6)alkyl, di(C1-6)alkylaminocarbonyl(C1-6)alkyl, N-(C1-6)alkylpiperidinyl, pyrrolidinyl(C1-6)alkyl, piperazinyl(C1-6)alkyl, morpholinyl(C1-6)alkyl, di(C1-6)alkylmorpholinyl(C1-6)alkyl and imidazolyl(C1-6)alkyl. Representative substituents include C1-6 alkyl, aryl(C1-6)alkyl, halogen, cyano, hydroxy, hydroxymethyl, C1-6 alkoxy and C3-7 cycloalkyl(C1-6)alkoxy. Particular substituents include methyl and fluoro.
As used herein, the expression xe2x80x9cC1-6 alkylxe2x80x9d includes methyl and ethyl groups, and straight-chained or branched propyl, butyl, pentyl and hexyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl, tert-butyl and 1,1-dimethylpropyl. Derived expressions such as xe2x80x9cC1-6 alkoxyxe2x80x9d are to be construed accordingly.
Typical C3-7 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The expression xe2x80x9cC3-7 cycloalkyl(C1-6)alkylxe2x80x9d as used herein includes cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.
Typical C4-7 cycloalkenyl groups include cyclobutenyl, cyclopentenyl and cyclohexenyl.
Typical C6-8 bicycloalkyl groups include bicyclo[2.1.1]hexyl and bicyclo[2.2.1]heptyl.
Typical aryl groups include phenyl and naphthyl, preferably phenyl.
The expression xe2x80x9caryl(C1-6)alkylxe2x80x9d as used herein includes benzyl, phenylethyl, phenylpropyl and naphthylmethyl.
Suitable heterocycloalkyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl groups.
Suitable heteroaryl groups include pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl groups.
The expression xe2x80x9cheteroaryl(C1-6)alkylxe2x80x9d as used herein includes furylmethyl, furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl, oxazolylmethyl, oxazolylethyl, isoxazolylmethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl, oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl and quinoxalinylmethyl.
The term xe2x80x9chalogenxe2x80x9d as used herein includes fluorine, chlorine, bromine and iodine, especially fluorine or chlorine.
For use in medicine, the salts of the compounds of formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
The present invention includes within its scope prodrugs of the compounds of formula I above. In general, such prodrugs will be functional derivatives of the compounds of formula I which are readily convertible it vivo into the required compound of formula I. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
Where the compounds according to the invention have at least one asymmetric centre, they may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.
Examples of suitable values for the substituent Z include methyl, ethyl, isopropyl, tert-butyl, 1,1-dimethylpropyl, methyl-cyclopropyl, cyclobutyl, methyl-cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl, cyclobutenyl, bicyclo[2.1.1]hex-1-yl, bicyclo[2.2.1]hept-1-yl, phenyl, pyrrolidinyl, methyl-pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyridinyl, furyl, thienyl, chloro-thienyl and diethylamino.
In a particular embodiment, the substituent Z represents C3-7 cycloalkyl, either unsubstituted or substituted by C1-6 alkyl, especially methyl. Favourably, Z represents cyclobutyl.
In another embodiment, Z represents tert-butyl.
In a further embodiment, Z represents phenyl.
Examples of typical optional substituents on the group R1 include methyl, fluoro and methoxy, especially fluoro.
Representative values of R1 include cyclopropyl, phenyl, methylphenyl, fluorophenyl, difluorophenyl, methoxyphenyl, furyl, thienyl, methyl-thienyl and pyridinyl. More particularly, R1 may represent unsubstituted, monosubstituted or disubstituted phenyl. Most particularly, R1 represents phenyl, fluorophenyl or difluorophenyl, especially phenyl.
Suitably, R2 represents aryl(C1-6)alkyl or heteroaryl(C1-6)alkyl, either of which groups may be optionally substituted.
Suitable values for the substituent R2 in the compounds according to the invention include cyclohexylmethyl, benzyl, pyrazolylmethyl, isoxazolylmethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, benzimidazolylmethyl, oxadiazolylmethyl, triazolylmethyl, tetrazolylmethyl, pyridinylmethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl and quinoxalinylmethyl, any of which groups may be optionally substituted by one or more substituents.
Suitably, R2 represents an optionally substituted triazolylmethyl group.
Examples of suitable optional substituents on the group R2 include C1-6 alkyl, aryl(C1-6)alkyl, pyridyl(C1-6)alkyl, halogen, halo(C1-6)alkyl, cyano, cyano(C1-6)alkyl, hydroxymethyl, C1-6 alkoxy, C3-7 cycloalkyl(C1-6)alkoxy, amino(C1-6)alkyl, di(C1-6)alkylamino(C1-6)alkyl, di(C1-6)alkylaminocarbonyl(C1-6)alkyl, N-(C1-6)alkylpiperidinyl, pyrrolidinyl(C1-6)alkyl, piperazinyl(C1-6)alkyl, morpholinyl(C1-6)alkyl and di(C1-6)alkylmorpholinyl(C1-6)alkyl.
Specific illustrations of particular substituents on the group R2 include methyl, ethyl, n-propyl, benzyl, pyridinylmethyl, chloro, chloromethyl, cyano, cyanomethyl, hydroxymethyl, ethoxy, cyclopropylmethoxy, dimethylaminomethyl, aminoethyl, dimethylaminoethyl, dimethylaminocarbonylmethyl, N-methylpiperidinyl, pyrrolidinylethyl, piperazinylethyl, morpholinylmethyl and dimethylmorpholinylmethyl, especially methyl.
Representative values of R2 include hydroxymethyl-cyclohexylmethyl, cyanobenzyl, hydroxymethyl-benzyl, pyrazolylmethyl, dimethyl-pyrazolylmethyl, methyl-isoxazolylmethyl, thiazolylmethyl, methyl-thiazolylmethyl, ethyl-thiazolylmethyl, methyl-thiazolylethyl, imidazolylmethyl, methyl-imidazolylmethyl, ethyl-imidazolylmethyl, benzyl-imidazolylmethyl, benzimidazolylmethyl, methyl-oxadiazolylmethyl, triazolylmethyl, methyl-triazolylmethyl, propyl-triazolylmethyl, benzyl-triazolylmethyl, pyridinylmethyl-triazolylmethyl, cyanomethyl-triazolylmethyl, dimethylaminomethyl-triazolylmethyl, aminoethyl-triazolylmethyl, dimethylaminoethyl-triazolylmethyl, dimethylaminocarbonylmethyl-triazolylmethyl, N-methylpiperidinyl-triazolylmethyl, pyrrolidinylethyl-triazolylmethyl, piperazinylethyl-triazolylmethyl, morpholinylethyl-triazolylmethyl, methyl-tetrazolylmethyl, pyridinylmethyl, methyl-pyridinylmethyl, dimethyl-pyridinylmethyl, ethoxy-pyridinylmethyl, cyclopropylmethoxy-pyridinylmethyl, pyridazinylmethyl, chloro-pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl and quinoxalinylmethyl.
A favoured value of R2 is methyl-triazolylmethyl.
A particular sub-class of compounds according to the invention is represented by the compounds of formula IIA, and salts and prodrugs thereof:
wherein
Z and R1 are as defined with reference to formula I above;
m is 1 or 2, preferably 1; and
R12 represents aryl or heteroaryl, either of which groups may be optionally substituted.
Suitably, R12 represents phenyl, pyrazolyl, isoxazolyl, thiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl or quinoxalinyl, any of which groups may be optionally substituted by one or more substituents.
A particular value of R12 is optionally substituted triazolyl.
Examples of typical substituents on the group R12 include C1-6 alkyl, aryl(C1-6)alkyl, pyridyl(C1-6)alkyl, halogen, cyano, cyano(C1-6)alkyl, hydroxymethyl, C1-6 alkoxy, C3-7 cycloalkyl(C1-6)alkoxy, di(C1-6)alkylamino(C1-6)alkyl, amino(C1-6)alkyl, di(C1-6)alkylaminocarbonyl(C1-6)alkyl, N-(C1-6)alkylpiperidinyl, pyrrolidinyl(C1-6)alkyl, piperazinyl(C1-6)alkyl and morpholinyl(C1-6)alkyl.
Illustrative values of specific substituents on the group R12 include methyl, ethyl, n-propyl, benzyl, pyridinylmethyl, chloro, cyano, cyanomethyl, hydroxymethyl, ethoxy, cyclopropylmethoxy, dimethylaminomethyl, aminoethyl, dimethylaminoethyl, dimethylaminocarbonylmethyl, N-methylpiperidinyl, pyrrolidinylethyl, piperazinylethyl and morpholinylmethyl, especially methyl.
Particular values of R12 include cyanophenyl, hydroxymethyl-phenyl, pyrazolyl, dimethyl-pyrazolyl, methyl-isoxazolyl, thiazolyl, methyl-thiazolyl, ethyl-thiazolyl, imidazolyl, methyl-imidazolyl, ethyl-imidazolyl, benzyl-imidazolyl, benzimidazolyl, methyl-oxadiazolyl, triazolyl, methyl-triazolyl, propyl-triazolyl, benzyl-triazolyl, pyridinylmethyl-triazolyl, cyanomethyl-triazolyl, dimethylaminomethyl-triazolyl, aminoethyl-triazolyl, dimethylaminoethyl-triazolyl, dimethylaminocarbonylmethyl-triazolyl, N-methylpiperidinyl-triazolyl, pyrrolidinylethyl-triazolyl, piperazinylethyl-triazolyl, morpholinylethyl-triazolyl, methyl-tetrazolyl, pyridinyl, methyl-pyridinyl, dimethyl-pyridinyl, ethoxy-pyridinyl, cyclopropylmethoxy-pyridinyl, pyridazinyl, chloro-pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl and quinoxalinyl.
A favoured value of R12 is methyl-triazolyl.
A particular subset of the compounds of formula IIA above is represented by the compounds of formula IIB, and pharmaceutically acceptable salts thereof:
wherein
R1 is as defined with reference to formula I above;
Q represents the residue of a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl ring;
R3 represents hydrogen, methyl or fluoro; and
R4 represents methyl or ethyl.
In relation to formula IIB above, R1 suitably represents phenyl, fluorophenyl or difluorophenyl, especially phenyl.
In a particular embodiment, Q suitably represents the residue of a cyclobutyl ring. In another embodiment, Q represents the residue of a phenyl ring.
Suitably, R3 represents hydrogen.
Suitably, R4 represents methyl.
Specific compounds within the scope of the present invention include:
3,8-diphenyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrido[2,3-d]pyridazine;
and salts and prodrugs thereof.
Also provided by the present invention is a method for the treatment and/or prevention of anxiety which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined above or a pharmaceutically acceptable salt thereof.
Further provided by the present invention is a method for the treatment and/or prevention of convulsions (e.g. in a patient suffering from epilepsy or a related disorder) which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined above or a pharmaceutically acceptable salt thereof.
The compounds according to the present invention may exhibit anxiolytic activity, as may be demonstrated by a positive response in the elevated plus maze and conditioned suppression of drinking tests (cf. Dawson et al., Psychopharmacology, 1995, 121, 109-117). Moreover, the compounds of the invention are likely to be substantially non-sedating, as may be confirmed by an appropriate result obtained from the response sensitivity (chain-pulling) test (cf. Bayley et al., J. Psychophamacol., 1996, 10, 206-213).
The compounds according to the present invention may also exhibit anticonvulsant activity. This can be demonstrated by the ability to block pentylenetetrazole-induced seizures in rats and mice, following a protocol analogous to that described by Bristow et al. in J. Pharmacol. Exp. Ther., 1996, 279, 492-501.
In another aspect, the present invention provides a method for the treatment and/or prevention of cognitive disorders, including dementing conditions such as Alzheimer""s disease, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined above or a pharmaceutically acceptable salt thereof.
Cognition enhancement can be shown by testing the compounds in the Morris watermaze as reported by McNamara and Skelton, Psychobiology, 21, 101-108.
Cognitive disorders for which the compounds of the present invention may be of benefit include delirium, dementia, amnestic disorders, and cognition deficits, including age-related memory deficits, due to traumatic injury, stroke, Parkinson""s disease and Down Syndrome. Any of these conditions may be attributable to substance abuse or withdrawal. Examples of dementia include dementia of the Alzheimer""s type with early or late onset, and vascular dementia, any of which may be uncomplicated or accompanied by delirium, delusions or depressed mood; and dementia due to HIV disease, head trauma, Parkinson""s disease or Creutzfeld-Jakob disease.
In order to elicit their behavioural effects, the compounds of the invention will ideally be brain-penetrant; in other words, these compounds will be capable of crossing the so-called xe2x80x9cblood-brain barrierxe2x80x9d. Preferably, the compounds of the invention will be capable of exerting their beneficial therapeutic action following administration by the oral route.
The invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Typical unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
In the treatment of neurological disorders, a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day.
The compounds of formula I as defined above may be prepared by a process which comprises reacting a compound of formula III (or its 2-hydroxypyrido[2,3-d]pyridazine tautomer) with a compound of formula IV:
wherein Z, R1 and R2 are as defined above, and L1 represents a suitable leaving group.
The leaving group L1 is suitably a halogen atom, typically chloro.
The reaction between compounds III and IV is conveniently effected by stirring the reactants in a suitable solvent, typically N,N-dimethylformamide, in the presence of a base such as cesium carbonate or potassium carbonate.
The intermediates of formula III above may be prepared by reacting a compound of formula V with a compound of formula VI:
wherein Z and R1 are as defined above, L2 represents a suitable leaving group, and Alk represents a C1-6 alkyl group, typically n-butyl; in the presence of a transition metal catalyst.
The leaving group L2 is suitably a halogen atom, e.g. bromo.
A suitable transition metal catalyst of use in the reaction between compounds V and VI is tris(dibenzylideneacetone)dipalladium(0), in which case the reaction is conveniently effected at an elevated temperature in a solvent such as N,N-dimethylformamide, typically in the presence of triphenylarsine.
The intermediates of formula IV above may be prepared by the procedures described in WO 98/04559, or by methods analogous thereto.
Where they are not commercially available, the starting materials of formula V and VI may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art.
It will be understood that any compound of formula I initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula I by techniques known from the art. For example, a compound of formula I initially obtained wherein R2 is unsubstituted may be converted into a corresponding compound wherein R2 is substituted, typically by standard alkylation procedures, for example by treatment with a haloalkyl derivative in the presence of sodium hydride and N,N-dimethylformamide, or with a hydroxyalkyl derivative in the presence of triphenylphosphine and diethyl azodicarboxylate. Furthermore, a compound of formula I initially obtained wherein the R2 substituent is substituted by a halogen atom, e.g. chloro, may be converted into the corresponding compound wherein the R2 substituent is substituted by a di(C1-6)alkylamino moiety by treatment with the appropriate di(C1-6)alkylamine, typically with heating in a solvent such as 1,4-dioxane in a sealed tube.
Where the above-described processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The novel compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The novel compounds may, for example, be resolved into their component enantiomers by standard techniques such as preparative HPLC, or the formation of diastereomeric pairs by salt formation with an optically active acid, such as (xe2x88x92)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base. The novel compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

Pyrido-pyridazine derivatives as ligands for GABA receptors


Devices that include one or more functional semiconductor elements that are immersed in static electric fields (E-fields). In one embodiment, one or more electrets are placed proximate the one or more organic, inorganic, or hybrid semiconductor elements so that the static charge(s) of the electret(s) participate in creating the static E-field(s) that influences the semiconductor element(s). An externally applied electric field can be used, for example, to enhance charge-carrier mobility in the semiconductor element and/or to vary the width of the depletion region in the semiconductor material.

Trends in semiconductor-based electronics industries suggest that future displays, solar cells, and electronic products will be made on flexible/conformal substrates. This transition is seen as inevitable to service the ever-present need and desire to reduce the size, weight, and cost of the products we use without sacrificing their performance. A wide gamut of devices, from displays, electronics, solar cells, and sensors, to name a few, would benefit from methodologies that result in the mass production of ruggedized, light weight, portable, small form factor, less power hungry, and lower cost products. Furthermore, new and novel markets and opportunities could be addressed and opened up if these devices could be made flexible and/or conformal.
Future generation semiconductor technologies for flexible/conformal substrates will most likely utilize organic semiconductors, rather than the inorganic semiconductors that have largely dominated semiconductor device manufacturing into at least the early 2000s. Organic semiconductors typically require much lower processing temperatures than inorganic semiconductors, allowing them to be used with flexible substrates that cannot withstand the high-temperature processes used for inorganic materials. Inorganic semiconductors can be processed at lower temperatures. However, low temperature deposition of inorganic semiconductors used in industry typically yields amorphous and polycrystalline phases of the semiconductor, and these phases tend to have significantly lower carrier mobilities than can be realized in single-crystal variants of the same semiconductor.
For example, hydrogenated amorphous silicon is a ubiquitous material used in the liquid crystal display (LCD) industry and the emerging solar cell industry. However, electron carrier mobility in hydrogenated amorphous silicon is typically in the range of 0.3 cm2/Vs to 1.2 cm2/Vs, depending on deposition conditions. Amorphous silicon can be re-crystallized, post deposition, using a technique called "solid-phase crystallization." The resulting nano- and micro-grained polycrystalline material might have mobilities between 10 cm2/Vs to 250 cm2/Vs. However, this is still significantly below single crystal silicon mobilities of >450 cm2/Vs. A similar pattern of deteriorating electrical performance is found in most semiconductors as the material goes from the single-crystal to the poly-crystal to the amorphous phase.
The performance of some p-n-junction-based devices, such as solar cells, is based in part on the width of the depletion region within the device. For example, for an ideal solar cell, higher performance at longer wavelengths requires the width of the depletion region to be as wide as possible in order to obtain high photocurrent. This is due to the fact that typically the absorption coefficients of semiconductors are lower at higher wavelengths when compared to lower wavelengths. A wider depletion region can be achieved by reducing the dopant concentration. However, lower doping reduces the open-circuit voltage, Voc, of the solar cell. At lower wavelengths, the absorption coefficients tend to be high, and, therefore, the width of the depletion region must be made as small as possible so that the photons will be absorbed near the junction. However, a smaller depletion region will increase unwanted surface recombination thus the series resistance will increase. Consequently, the solar cell's efficiency is reduced. This means the solar cell efficiency is limited by the device and design parameters.

Static-electrical-field-enhanced semiconductor-based devices and methods of enhancing semiconductor-based device performance


A wireless device includes a memory, a display unit configured to display a first image, a wireless communication unit configured to receive a mirroring image from an external device including a mobile display unit configured to display a second image, and a processor configured to control the display unit and the wireless communication unit. The processor is configured to automatically analyze a ratio of the second image based on the received mirroring image, and display a third image having the same ratio as that of the second image on the first image according to the analysis result.

The present invention relates to a wireless device and a wireless system, and more particularly, to a wireless device and a wireless system which are capable of automatically recognizing a screen ratio of a source device during screen mirroring.
With the recent development of information communication technologies, various wireless communication technologies are under development. Among them, a wireless local area network (WLAN) is a technology for wirelessly accessing Internet in homes, businesses, or specific service providing areas based on a wireless frequency technique by using portable terminals such as Personal Digital Assistants (PDAs), laptop computers, and Portable Multimedia Players (PMPs).
As a direct communication technology for allowing devices to be connected to each other easily without an access point (AP) that is required in a WLAN system, the introduction of Wi-Fi Direct or Wi-Fi peer-to-peer (P2P) is discussed. According to a Wi-Fi Direct standard technology, devices are connected without complex setting processes and in order to provide various services to users, data exchanging operations at a communication speed of a typical WLAN system can be supported.
Various Wi-Fi supporting devices have been used recently, and among them, the number of Wi-Fi Direct supporting devices for communication between Wi-Fi devices without requiring APs has been increasing. The Wi-Fi Alliance (WFA) discusses a technology for introducing a platform that supports various services using Wi-Fi Direct link (for example, send, play, display, and print). This can be referred to as Wi-Fi Direct Service (WFDS).
Display service in WFDS is a service for allowing screen sharing between P2P devices. The screen sharing service is also referred to as a screen mirroring technique in that a wireless device displays the same image through image transmission.
In an existing screen sharing service, when images are transmitted between P2P devices, the aspect ratios of the source devices that transmit the images are various. There is no way to determine the aspect ratio of the source device when the source device is not registered.
Therefore, the screen layout mode of the source device is not correctly recognized, or an image having a proper resolution cannot be provided.
In addition, in the existing screen sharing service, when the source device is in a portrait mode, there is no method that can distinguish between a black image of an active image transmitted from the source device and a letter box inserted for matching resolution.

Wireless device receiving a mirroring image from an external device and wireless system including wireless device and external device


The present disclosure provides a flow device including a body disposed in an extrusion apparatus. The body is defined along a plane and has a first side and a second side. The second side is disposed opposite the first side. The flow device also includes a first face formed at the first side and a second face formed at the second side. The body has a thickness defined between the first face and second face. A plurality of feedholes is defined in the body between the first side and the second side. In addition, at least a portion of the first face or second face forms a curvature that extends outwardly from the plane.

An extrusion process can create an object having a complex cross-section. In a conventional process, batch material is inserted into a chamber of an extruder barrel. Once inside the chamber, the material is pressurized by a pressure mechanism such as a pump, a piston, screws, or other conventional means. The pressure inside the chamber must be sufficiently high to overcome the material's resistance to flow, which is produced by a die disposed in the chamber. Once the resistance to flow is overcome, the pressure forces the material through the chamber from the inlet of the extruder barrel towards the die. The material can pass through openings or channels defined in plates disposed throughout the chamber between the inlet and die. As the material reaches the die, it is extruded through one or more feedholes and discharge slots defined in the die to form an extrudate having a desired geometry (e.g., a honeycomb body).
The conventional die is designed to produce a desired shape of the extrudate (e.g., the contour and cell pattern of the honeycomb body), but to do so, the die must also withstand the extreme pressure created within the extrusion chamber. Thin discharge slots required to form, e.g., thin wall honeycomb bodies, require high pressures within the extrusion chamber. If designed incorrectly, the die can deform or rupture due to plate bending from the pressure. Thus, the thickness of the die is often increased to withstand the high pressure built within the chamber. This is the same with other elements having restrictive openings that may be disposed in the chamber. As with any plate bending problem, as the diameter of the plate is increased the thickness of the plate must also be increased to stay within the yield limits of the material. As a consequence, the impedance and resistance to flow through openings in the die undesirably increase as the die thickness increases.
Thus, a need exists for an improved die that reduces the impedance and resistance to flow through the die. It is also desirable to increase throughput of the extrusion process while reducing the stress exerted on the die.


A printing apparatus includes: a main body; a cover; a pair of supporters including a movable supporter; a first urging member configured to urge the movable supporter in an approach direction; an engaging member movable between a separated position and an engaged position; and a second urging member configured to urge the engaging member toward the engaged position. When the cover is in an open state, the engaging member is located at the engaged position by an urging force of the second urging member so as to inhibit movement of the movable supporter in the approach direction. When the cover is in a closed state, the engaging member is located at the separated position against the urging force of the second urging member by contact of the cover with the engaging member so as not to inhibit the movement of the movable supporter in the approach direction.

The following disclosure relates to a printing apparatus.
There is known a printing apparatus configured to hold a roll of a printing medium in the printing apparatus and perform printing on the printing medium drawn from the roll. There is also known a roll-sheet support device configured to support a roll sheet (a roll paper) to be supplied to a printing device. The roll-sheet support device includes a shaft, two guides, and a guide limiter. The shaft extends in the axial direction of the roll sheet. The two guides are moved in the axial direction along the shaft to respectively guide side surfaces of the roll sheet. Coil springs mounted on the shaft urge the respective two guides in directions in which the two guides move closer to each other. The guide limiter is moved into moving paths of the two guides to hold the two guides in a state in which the distance between the two guides is greater than the greatest width of the roll sheet. In the case where the roll sheet is set, an outer circumferential surface of the roll sheet contacts and bends the guide limiter, so that the guide limiter is moved out of the moving paths of the two guides. The two guides are moved toward each other by the urging forces of the respective coil springs. As a result, the two guides are brought into contact with the respective side surfaces of the roll sheet to position the roll sheet.


An improved carrier apparatus for use by fire fighters to carry fire hose and to serve as a personnel carrier includes an elongate bottom, a first end wall connected to the bottom and first and second opposed and spaced apart side walls connected to the bottom and to the first end wall. A second fire hose retaining end wall is movably connected to the first side wall for removable connection to the second end wall. A gap is formed between a lower edge of the second end wall and the elongate bottom when the second end wall is removably fastened to the second side wall to permit water and debris to pass out through the gap while preventing the fire hose from falling out of the carrier prematurely.

This invention relates to a carrier apparatus and more particularly to a carrier apparatus for use by fire fighters both as a carrier for fire hose and as a carrier for a person.
It is often necessary for a fire fighter to carry a length of hose from the fire truck to a distant location, where the hose will be put in use. For example, where a fire occurs in a high-rise building, shopping mall, large department store, in subway stations and in parking garages, it is necessary to carry the hose into the structure, and to then connect it to a stand pipe, and to deploy it so that water may be directed at the fire. Other instances where the carrying of a fire hose is required are where the fire occurs in a rural location, and it is necessary to transport the fire hose to a suitable source of water, such as a pool, stream or pond.
It is highly desirable that minimum time be consumed between the arrival at the site of the fire by the firemen and the discharging of water on the fire, and so the fire hose must be readily carried, and a suitable length must be carried by a single fire fighter in many instances. Further, it is necessary that the hose be paid-out rapidly and without requiring the handling of the hose at the carrier by a second fire fighter, while one fire fighter is moving with the nozzle, connected to the fire hose, towards the fire.
Among the problems which face firemen in fighting fires is the necessity for removing victims from the site of the fire, and the most facile way of handling this problem has been the calling for a stretcher by the fireman who has located the victim. This is often time consuming, especially where the fire is at a remote location from the fire engine on which the stretcher is stored, thereby necessitating an additional trip for a hard-pressed fire fighter from the fire site to the fire engine to procure the stretcher. A delay can also occur while a separate part of the fire fighting crew is directed to bring a stretcher to the site where the victim is located.
Clemens, U.S. pat. Nos. 4,442,557 and 4,478,452 incorporated herein by reference, describe a carrier apparatus for use by fire fighters which are currently being used successfully by many fire departments. Although these carriers are serving the purpose for which they were designed, they have not proved entirely satisfactory under all conditions of service for several reasons. For example, the carrier described in those patents provides for an open end at the end opposite end wall 12. As a result, a fire hose can fall out of the carrier 10 prematurely. Also, having handles 24a, 24b, 26a and 26b only at the ends of carrier 10 makes it difficult for a single fireman to lift and move carrier 10 from one place to another. The absence of a pocket or sleeve on carrier 10 also has required a fireman to carry tools, such as elevator keys and hose spanners, on his person.
It is, therefore, an object of the present invention to provide a carrier apparatus for use by fire fighters which incorporates a movable end flap for retaining a hose within the carrier while enabling water and debris to pass out from the carrier through a gap between the movable flap and a bottom of the carrier.
Another object is to provide such a carrier apparatus which is designed to be carried by a single fire fighter by means of handles centrally positioned on the carrier apparatus.
A further object of the invention is the provision of such a carrier apparatus which includes a pocket or sleeve attached to an exterior surface of the carrier for receiving and storing support tools, such as elevator keys and a small hose spanner, so that the tools can be conveniently carried with the first-in equipment for fighting a high-rise building fire.
Still another object is to provide such a carrier apparatus which can be used as a carrier for fire hose and as a carrier for a fire victim.
A still further object is to provide such a carrier apparatus which is comprised of a flaccid material so that the carrier apparatus can be readily collapsed and folded for easy transportation and storage when not in use.
Still another object is to provide such a carrier apparatus which includes carrier handles at both ends of the apparatus to facilitate lifting and movement of the carrier by more than one fire fighter.
Additional objects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objects and advantages are realized and attained by means of the instrumentalities and combinations particularly pointed out in the appended claims.
To achieve these and other objects, the present invention provides carrier apparatus for use by fire fighters, the apparatus comprising: an elongate bottom, a first end wall connected to the bottom and first and second opposed and spaced apart side walls connected to the bottom and to the first end wall; a second end wall movably connected to the first side wall; first means in operative relationship with the second end wall and with the second side wall for removably fastening the second end wall to the second side wall; a plurality of handles connected to each of the first and second side walls for lifting and carrying the carrier apparatus and any load supported by the carrier apparatus; a plurality of straps connected to one of the side walls and extending to the other one of the side walls; and second means in operative relationship with the straps and with the other one of the side walls for releasably securing the straps to the other one of the side walls.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory but are not restrictive of the invention.


A retractable marking device is provided having a casing in which a coil is tightly wound from which the marking device may be extended for use thereof. A housing may further be provided such that the casing is placed within the housing and the housing is attached to a device on which the marking device is most commonly implemented. The marking device may be a pen, pencil or other writing instrument or may also be, for example, a blunt-ended instrument for use as a pointing-type device. The tightly wound coil maintains the marking device in a retracted position so that the marking device is readily available for use. In addition, the marking device is replaceable with a substitute marking device or replaceable following depletion of, for example, ink contained therein.

The present invention generally relates to a marking device. More specifically, the present invention relates to a retractable marking device particularly for attachment to a computer or touch-type screen mechanism for use therewith. Further, the present invention relates to a combined marking device and holder. In addition, the present invention relates to a method for assisting of marking. Still further, the present invention relates to an anti-bacterial or anti-viral marking device or supplement to such a marking device that cleans the marking device or provides an anti-bacterial state for the marking device.
Computers, including computers with touch screens, have been used for a number of years. However, computer data is often generated that requires transposition or quick notes regarding the same to be written down by an individual who is working on or with the computer. Often, individuals have a notebook or some other type of note recording mechanism in which to jot down notes regarding that viewed on the screen or the like. Likewise, incoming telephone calls often require quick messages to be recorded or other notes taken while an individual is using a computer. However, this is also problematic as many desks are often cluttered, and a manner for recording such notes or messages can be difficult without the necessary equipment, such as paper, pens, pencils or the like readily available.
Still further, it is known to provide touch screens as a means to input information or data to a computer. This is particularly common in the restaurant industry wherein orders can be placed on a touch screen and subsequently sent to a kitchen for preparation of the order. Then, after the meal is completed, all items that have been consumed or otherwise purchased can be entered via the touch screen of the computer. Often, however, a marking device other than a user's finger is more convenient or less cumbersome to use in order to enter the data via a touch screen. However, a device readily available for use in assisting entry or marking of the screen is presently not available.
Moreover, it is often necessary for handicapped individuals, such as those individuals subjected to confinement in a wheelchair, to have ready access to a marking device, such as a pen. Such availability allows the handicapped individual to recognize the location and availability of a marking device when the same is necessary for use.
Another associated problem with marking devices that may be implemented particularly for public usage is the infection or bacterial and/or viral contaminants that may be carried on the marking device from continuous contact with the marking device by various users.
A need, therefore, exists for an improved marking device and combination marking device and mounted casing as well as a method for assisting in marking to overcome. the deficiencies of that which is presently available and/or implemented.

Recoiling, replaceable chain marking device with combination holder and a method for marking using same


A driving assistance system for a vehicle includes a processor of the vehicle operable to process data for the driving assistance system. The driving assistance system determines a priority for various processing tasks required by one or more systems of the vehicle. Responsive to the determination of the priority of various processing tasks required by one or more systems of the vehicle, the processor determines a task with a higher priority than other lower priority tasks and is operable to process the higher priority task and to shift processing of lower priority tasks to other processors within the vehicle.

Use of imaging sensors in vehicle imaging systems is common and known. Examples of such known systems are described in U.S. Pat. Nos. 5,949,331; 5,670,935 and/or 5,550,677, which are hereby incorporated herein by reference in their entireties. Image data captured by the cameras (and other data) is processed, such as for object detection or other machine vision functions.

Vehicle driving assist system with enhanced data processing


Apparatus for simulating corrosion activity of a process stream on equipment and transport lines. The apparatus includes a series of modular canisters coupled to a process stream source and a process stream discharge point. A cooling coil is positioned within each canister and the cooling coils are interconnected in series. The first cooling coil is coupled to a coolant source and the last cooling coil is connected to a coolant discharge. The process stream flows thorough the series of canisters and the coolant flows through the coils in counterflow to the process stream to cool and partially condense the process stream. Corrosion activity and temperature within the canister are monitored using corrosion probes and/or coupons. Modular construction of the canisters permits disassembly and reassembly to adapt the simulator to different simulation applications.

1. FIELD OF THE INVENTION
The present invention relates generally to an apparatus and method for simulating corrosion activity and, more particularly, to an apparatus and method for simulating corrosion activity of process streams on process machinery.
2. DESCRIPTION OF RELATED ART
Corrosion in industrial and process installations is a major and continuous problem, particularly in chemical plants and petroleum refineries. Corrosion activity occurs within process machinery and transport lines to varying degrees depending upon such factors as the corrosivity of the process stream and its condensates, the temperature of the process, process velocities, and the metallurgy of the equipment employed in the process. Such corrosion activity can adversely affect the performance of process equipment, reduce the useful life of equipment and lines, and necessitate costly maintenance, repair and replacement of system components. Consequently, corrosion reduction, or at least the mitigation of the effects of corrosion, is a continuing concern in industry.
The establishment of an effective corrosion control program in a particular industrial installation begins with information on the corrosion activity expected or actually occurring within the installation machinery. Such information typically relates to the source of the corrosion taking place, the location of the corrosion activity, the type and rate of the corrosion activity, and the process parameters affecting corrosion initiation and propagation. One important source of corrosion is process vapors and their condensates. Many process vapor streams contain corrosive components that initiate corrosion upon condensation. Aqueous condensation leads to much of this corrosion activity and occurs primarily in heat exchange units and transport lines. The effects of such corrosion can be mitigated through the implementation of a corrosion control program that may include the use of corrosion inhibiting chemicals. However, the design, implementation, and optimization of such a program usually requires information on the corrosion activity itself.
A number of methods are known for collecting information on the nature of corrosion activity caused by process vapors and vapor condensates and on the process parameters affecting the initiation and propagation of corrosion. It is known, for instance, to insert corrosion probes into a process stream by mounting the probes directly in the process machinery or lines. While this method may supply information on corrosion activity actually occurring at the precise point of insertion, the probe placement will rarely correspond to the actual point of the worst corrosion activity, which often changes over time depending upon variations in process parameters. In addition, direct placement of corrosion probes in process equipment generally does not provide a profile of corrosion activity as a function of temperature and aqueous condensation.
Another method for determining corrosion activity of process vapors and condensates is simulation. As used in the present context, simulation refers to physical testing and analysis. In known corrosion simulators, a slip stream of process vapor is diverted and passed through a simulator circuit consisting in a prepiped bank of condensing areas or chambers. Water cools the vapor stream and causes aqueous condensation within the simulator. Corrosion probes, weight loss coupons, and condensate samples are then used to evaluate the location, type, and rate of corrosion taking place in the simulator. This corrosion activity is then related to the corrosion actually occurring or expected in the actual process machinery from which the slip stream was taken.
In one existing corrosion simulator a slip stream of vapors is circulated through a cooling coil positioned in a water box. Cooling water circulated through the water box in counterflow to the vapor stream causes aqueous condensation within the cooling coil. Corrosion and temperature probes detect corrosion activity occurring within the cooling coil. While this arrangement does provide information on corrosion activity and can establish a corrosion profile related to temperature, it is susceptible to operational difficulties, particularly the maintenance of the desired cooling water level and flow within the water box. In addition, the prepiped arrangement of the cooling coil and water box limit the adaptability of the simulator to a particular simulation application.
In another known apparatus for simulating corrosion activity, process vapor is circulated through a prepiped bank of condensers including a primary condenser and several smaller condensers. Cooling coils located in each of the condensers cause aqueous condensation of the vapor stream to simulate conditions in heat exchange units. The cooling coils am piped in parallel and take flow of cooling water from a header. The cooling water flow through each of the cooling coils is controlled independently to cause condensation at desired locations in the simulator and to generate a corrosion profile. Temperature and corrosion probes positioned in the condensers monitor corrosion activity and temperature. However, this simulator has a number of drawbacks. The various flow rates of cooling water through each cooling coil are difficult to control and coordinate, making a clear corrosion profile difficult to obtain. In addition, the prepiped arrangement of the simulator does not provide the flexibility needed to adapt the simulator to different simulation conditions and applications.
The present invention is directed to overcoming or minimizing the drawbacks of the existing techniques set forth above.

Corrosion simulator and method for simulating corrosion activity of a process stream


In a network game, player characters manipulated by individual players of video game apparatuses belong to the same party to battle with an opponent character. When a player character making a special move is not present in the party, the display screen of each video game apparatus becomes a screen focusing on the player character of the player who uses this video game apparatus. When one of the player characters makes a special move, not only the display screen of the video game apparatus corresponding to this player, but also the display screens of the video game apparatuses corresponding to the other player characters in the party become screens focusing on the player character which makes the special move.

1. Field of the Invention
The present invention relates to a network game in which a plurality of players participate to progress with the game, and, more particularly, to displaying of a screen showing the progress of a game on a terminal apparatus used by each player.
2. Description of the Related Art
The recent advancement on the network technology has made network games (online games) vivid in each of which a plurality of players participate to progress with the game. A system that executes a network game includes a server apparatus which is managed by one who runs the network game, and client devices of individual players which are connectable to the server apparatus over a network such as the Internet.
An RPG (Role Playing Game) among the network games progresses as multiple players participate in the game at the same time so that their player characters cooperate with one another to battle with an opponent character, or the players make their player characters battle with one another. Recently, an MMORPG (Massively Multiplayer Online RPG) which permits participation of more players is also provided.
In a network game, each client apparatus displays a game screen on its display device. The player of each client apparatus operates an input device to move his/her own player character. As disclosed in Japanese Patent Application Laid-Open Publication No. 2008-113696, the game screen to be displayed on each client apparatus is conventionally generated on the basis of the player character of the player using the client apparatus.
Among players who participate in a network game, there are quite a few players who want to stand out most (who want to make their own player characters standing out most) in the game. Since such a player generally tends to make his/her own player character perform a showy movement as compared to other players, the movement of this player often greatly influences the progress of the game.
However, when a player is attempting to participate in a network game and move his/her own player character, the screen displayed on each client apparatus in the network game is generated on the basis of the player character of the player's own player character, except for a case where the player is watching a movie which is displayed before a special event starts.
Accordingly, the player may not be able to see the movement of another player character which significantly influences the progress of the game. This brings about a problem that the lively feeling of the game is not enhanced. Even if a player makes his/her own player character make a showy movement which significantly influences the progress of the game, other players may not see the movement. In other words, the desire of a player who wants to stand out in a game may not be fulfilled in some cases.

This patent is subject to a terminal disclaimer.

Apparatus and method for displaying player character showing special movement state in network game


A circuit (10) for inserting a secondary video signal in a primary video signal. The primary and secondary video signals are combined forming a combined video signal having a primary video portion and a secondary video portion. The combined video signal is fed back to a feedback matching circuit (21) for measuring and comparing the phase, amplitude, and blanking level of a reference signal of the primary video portion and a reference signal of the secondary video portion of the combined video signal. The feedback matching circuit (21) makes an adjustment to the secondary video signal to reduce differences between the reference signals of the primary and secondary video portions of the combined video signal.

The present invention relates, in general, to television systems and, more particularly to, a picture-in-picture processing circuit for a television system.
A picture-in-picture (PIP) feature in televisions allows the viewer to see two or more channels simultaneously on the screen. The viewer selects a main primary channel to cover the majority of the screen and alternate channels which are inserted in small portions of the screen. The viewer may thus keep track of several channels at the same time.
The television typically includes a main signal processing path for the incoming video of the primary channel. To generate the PIP images, the other video channels are converted to a digital format and stored in RAM. The data for the PIP images is averaged or compressed to fit in a smaller area of the television screen. Once a complete image of the alternate channel is stored, it is off loaded from the RAM to a digital-to-analog converter. At the appropriate point in the horizontal sweep, a controller switches from the primary channel to the PIP-constructed secondary channel to insert the PIP image. The controller then switches back to the primary channel. The result is reduced size PIP images of the alternate channels inserted in small areas of the television screen with the primary channel filling the remaining areas of the screen.
A video signal contains different types of information which is processed by the receiver section of the television. Luminance and chroma information reside in the video signal. The luma data is amplitude modulated, where the higher amplitudes are white and lower amplitudes are black. The chroma data is superimposed as a 3.58 MHz sub-carrier on the luma signal. The chroma signal contains two chrominance components B-Y and R-Y modulated in quadrature on the sub-carrier. The amplitude and phase of the demodulated chroma signal relative to a 3.58 MHz reference burst introduced at the beginning of each horizontal scan determines the saturation and hue respectively.
The chroma components of the secondary channel are stored in RAM at a normalized level. To assure proper color rendition of the reconstructed secondary signal, the reconstruction must be done with reference to the phase and amplitude of the primary channel burst signal. Feed forward gain and phase control is one approach that has been used, but has performance limitations. Using feed forward usually requires factory adjustments to trim out error. For example, in prior art systems, the hue is matched by burst locking the reconstruction circuits to the primary channel burst; due to uncertain phase delays through this circuit, a factory adjustment is required. These uncertain phase delays take place at several points; static phase error in the phase detector, phase shifts in filters and amplifiers processing the signal, and propagation delays and rise times from the clock input to the D/A Converter output. For saturation or amplitude control, the primary burst amplitude is detected to produce a DC control signal proportional to the burst amplitude. This control signal then either modifies the level of the color difference signals going to the A/D Converter and on to the RAM, or modifies the gain of a D/A Converter reconstructing the chroma signal. Errors occur in this signal processing due to nonlinearity and sensitivity of the level detector and control mechanism. Trim adjustments are subject to initial setting errors as well as drift. Blanking level errors can occur due to clamping the primary and reconstructed secondary video to different levels before combining them together. Blanking errors also occur due to different offsets in amplifiers between the clamping point and the switching point. Furthermore, blanking level match is typically untrimmed. The quality of the blanking level match is typically a function of the circuitry used.
It would be of great benefit if a circuit could be developed which precisely compensated for the differences of two video signals thereby allowing one to be inserted with the other with minimal error. The circuit would eliminate the need for factory trimming and the manufacturing costs associated thereto and compensate for the effects of aging and temperature .

Video feedback matching circuit and method therefor


The present invention discloses use of butylidenephthalide (Bdph), a method of using the same, and a method for preparing a pharmaceutical composition containing the same. Because Bdph has the capability of promoting the hair growth and reducing the β-amyloid protein (Aβ) level in nerve cells, the efficacy of improving the health and appearance of a subject can be achieved by administrating an effective amount of Bdph to the subject. Specifically, the Bdph has the efficacy of preventing or treating neurodegenerative diseases such as Alzheimer's disease caused by excessive build up of Aβ in the cells, and as an active ingredient in a topical composition, the Bdph is effective in promoting the hair growth at the site where the Bdph is administered. Furthermore, the method for preparing a pharmaceutical composition containing Bdph comprises preparing the pharmaceutical composition through an organic synthesis reaction, wherein the Bdph is coated with a polymeric material such as F127 by covalent bonding of the polymeric material with the Bdph, thereby achieving the effect of reducing the cytotoxicity of the pharmaceutical composition for an organism.

1. Field of the Invention
The present invention relates to use of a compound, particularly use of butylidenephthalide (Bdph), a method of using the same, and a method for preparing a pharmaceutical composition containing the same.
2. Description of the Related Art
Due to the increased survival time of modern people, more and more people face a variety of diseases affecting the health and also the problem of aging appearance with increased age and multiplied life stress. Specifically, Alzheimer's disease is the most prevalent neurodegenerative disease in the whole world, and the main pathological features comprise excessive deposition of β-amyloid protein (Aβ) forming the Aβ plaque in the brain (Glenner and Wong 1984; and Masters, C. L. et al., 1985) and intracellular neurofibrillary tangles (NFT) (Grundke-lqbal, I. et al., 1986; and Goedert, M. et al., 1988). The Aβ plaque is produced from amyloid protein precursor (APP) after cleavage by the β-site amyloid precursor protein cleaving enzyme (BACE) (Hussain, I. et al., 1999; and Vassar, R. et al., 1999) and the γ-secretase (Wolfe, M. S. et al., 1999; and Yu, G. et al., 2000), and consists essentially of Aβ40 and Aβ42 (Jarrett, J. T. et al., 1993). Large intra- and extracelluar accumulation of Aβ is a main cause of neuronal cell death.
The pathogenesis of Down's syndrome is uneven split of the 21th pair of chromosomes during meiosis, causing 1 additional chromosome to exist in the cell. The gene encoding the APP is located on the chromosome 21 (Rumble, B. et al., 1989; and Selkoe, D. J., 1996). It is generally accepted that the over-expression of APP leads to a symptom of early cognitive impairment in the patients with Down's syndrome (Burger, P. C. and F. S. Vogel, 1973). At present, many studies show that the Aβ plaque is found in the brain of patients with Down's syndrome (Masters, C. L. et al., 1985; Beyreuther, K. et al., 1992; Gyure, K. A. et al., 2001; and Mori, C. et al., 2002). Other studies show that the nerve cells produced by induced pluripotent stem cells (iPSCs) derived from patients with Down's syndrome can be used to reproduce the typical pathological features of Alzheimer's disease, for example, accumulation of Aβ42 and Aβ40, highly phosphorylated Tau protein, and others. Therefore, an iPSC differentiation system from patients with Down's syndrome can be used as a platform for screening drugs for treating or preventing Aβ-related neurodegenerative diseases.
The drugs for treating Alzheimer's disease currently available in clinic comprise cholinesterase inhibitors (Birks, J., 2006) and NMDA receptor antagonists (McShane, R. et al., 2006), both of which are suitable for improving the cognitive function of patients with Alzheimer's disease. However, the diseases derived from Alzheimer's disease, such as depression, insomnia, and so on, need to be treated with other suitable medications (Tariot, P. N. et al., 2004; Feldman, H. et al., 2006; and Howard, R. et al., 2012). Moreover, the two types of drugs can only ameliorate the symptoms, and cannot achieve the efficacy of curing Alzheimer's disease (Farlow, M. R. et al., 2010). Besides, in many studies, drugs for treating Alzheimer's disease are designed for reducing Aβ accumulation in the brain (Hong-Qi, Y. et al., 2012), and comprise specifically BACE inhibitors, for example, MK-8931 and ACI-91 (Mullard A., 2012), γ-secretase inhibitors, for example, LY450139 (Siemers, E. et al., 2005) and BMS-708163 (Tong, G. et al., 2012), or antibodies against Aβ by way of immunization.
Furthermore, although problems such as local alopecia, hair loss, or hypotrichosis do not adversely affect the health of an individual, they undeniably affect the appearance of the individual. Research suggests that those with hypotrichosis are prone to poor mood and unable to socialize, and may suffer from psychological problems such as social anxiety, insufficient self-confidence, and self-identity. Therefore, hypotrichosis or hair loss has become a problem received more and more attention at present.
In addition to the way to retarding the hair loss by changing the hair washing and dietary habits, there are many products for ameliorating the hair loss or promoting the hair growth available at present. The products are mainly divided into two classes, one class is vasodilators, and the other is prostaglandin-related derivatives. Further, among the vasodilators, the most well-known is "Regoine" (trade name minoxidil; Messenger A. G. et al., 2004), which is mainly composed of 2,4-diamino-6-piperidinopyrimidine 3-oxide. However, Regoine does not perform well for the hypotrichosis in each case, and the effect persists only when the product is used. Once the product is withdrawn, the newly grown hair will fall off again. It is reported that the prostaglandins F2α and E2 can be used to promote the eyelash and hair growth (Woodward, D. F. et al., 2013), but cause the side effects such as redness, irritation, pigmentation and the like to the user. Moreover, once the product is withdrawn, the newly grown hair will fall off too.
Butylidenephthalide (Bdph) is present in natural plants, for example, plants of the Apiaceae and Asteraceae family, and may be obtained by extraction with acetone and chloroform. Previous studies show that Bdph is useful in the treatment of spasm (Ko, W. C. et al., 1980) and inhibition of platelet aggregation (Teng, C. M. et al., 1987), and can suppress the cell growth and promote the cancer cell death. For example, the efficacy of inhibiting the tumor growth can be achieved by inhibiting the telomerase (Huang, M. H. et al., 2014; and Tsai, N. M. et al., 2006), and the efficacy of inhibiting the inflammatory response can be achieved by inhibiting NF-κB (Fu, R. H. et al., 2011). Furthermore, recent studies also show that Bdph can maintain the growth of embryonic stem cells and promote the formation of iPSCs by activating the Jak2/stat3 signaling pathway (Liu, S. P. et al., 2012).
The Wnt protein is a highly conserved secretary molecule, and an important factor for regulating the embryonic development and the stem cell maintenance. Wnt forms a ternary structure by binding to its receptor Frizzled (Frz) and LDL receptor-related proteins on the cell membrane, and acts on the Dishevelled (Dsh) in the cells.
Dsh binds to GSK-3β, the adenomatous polyposis coli protein and the Axin protein to inhibit the activity of GSK-3β, thereby inhibiting the β-catenin phosphorylation and the pathway of β-catenin degradation via ubiquitination. Activation of the Wnt signaling can induce the intracellular accumulation of β-catenin. After entering the nucleus, the β-catenin can activate other particular transcription factors, such as T-cell factors, lymphoid enhancer factors and Siamois, etc., to regulate the growth of cells and the development of an individual. Over or under activation of the Wnt signaling in the cells can cause damage to the organism, cause defects in early embryonic development, or cause tumor formation or dysfunction in late adulthood (Fodde, R. et al., 2007).
At present, many researches confirm that the efficacy of promoting the hair growth can be achieved with activation of Wnt by stimulating the replication of epidermal stem cells (Lim, X. et al., 2013). The epidermal stem cells are mostly present in hair follicle bulges, which are label-retaining cells, usually in a dormant state, and activated only when the epidermis is damaged or the tissue needs to be freshed. The Wnt/β-catenin pathway is an imoportant component in the maintenance of self-replication of epidermal stem cells. Activation of the Wnt signaling allows the dormant epidermal stem cells to enter a cell cycle for cell replication and differentiation into mature hair cells (Thompson, C. C. et al., 2006). Wnt7a expression can increase the number of hair follicles reproduced. Similarly, the β-catenin level in the nucleus can be increased by stabilizing the β-catenin against degradation via ubiquitination, thereby promoting the formation of new hair follicles (Gat, U. et al., 1998). On the contrary, inhibition of the Wnt signaling can prevent the formation of hair follicles caused by wounds (Ito, M. et al., 2007).
It can be known from the foregoing description that the prior art cannot provide an effective composition having no side effects for treating or preventing neurodegenerative diseases such as Alzheimer's disease; as well as for improving alopecia or promoting the hair growth. Therefore, it is the most important research topic at present to develop a novel composition effective in improvement or treatment of the above-mentioned symptoms.

Use of butylidenephthalide (Bdph), method of using the same, and method for preparing pharmaceutical composition containing the same


A stent system and method for use in the prostate gland. The stent is made of a shape memory alloy such as nitinol, and has a low temperature martensite state, with a martensite transition temperature below body temperature, and a high temperature austenite state, with an austenite transition temperature at or above body temperature, and a memorized shape in the high temperature austenite state which is a helical coil of diameter large enough to hold the prostatic urethra open. The stent is used to heat the prostate and is left in the prostatic urethra while the prostate heals. After the prostate is substantially healed, the stent is cooled to its martensite state and is easily removed from the urethra.

The inventions described below were developed to aid in the treatment of prostate enlargement and/or prostate cancer. Prostate enlargement, also known as benign prostate hyperplasia or benign prostate hypertrophy, is a common affliction among older men. The condition involves swelling of the prostate. The prostate surrounds the urethra, or urinary tract, and swelling of the prostate prevents passage of urine from the bladder. Benign prostate hyperplasia is uncomfortable because it makes urination difficult or impossible, The condition is also dangerous because it can lead to infection of the bladder and kidneys, and severe cases may lead to death.
Prostate cancer is also a common affliction among older men, and may lead to many of the same symptoms as benign prostate enlargement. Prostate cancer is more dangerous in that it may spread to other organs and is often fatal. Early treatment can reduce the risks of death due to prostate cancer.
A surgical cure for prostate enlargement is called resection. Resection can be accomplished by cutting away a large portion of the prostate gland. The operation can be performed by cutting through the skin to expose the prostate gland, and using scalpels to cut into the prostate. Preferably, resection is accomplished from inside the urethra, using a resectoscope inserted through the penis. The resectoscope includes an endoscope for visual observation and a resecting loop which a surgeon uses to scrape and gouge away the prostate gland from the inside.
Prostate enlargement can be treated with heat treatments such as hyperthermia or thermotherapy, cold treatment (hypothermia or cryotherapy), and ablation. It has long been known that heating a swollen prostate gland can lead to a decrease in swelling and eventual relief from the condition. Heat treatment denaturizes the proteins in the prostate tissue, like a slow cooking of the tissues. The biological effects of heat treatment and the appropriate thermal dosage are discussed in more detail in articles such as Terai, et al., Transurethral Microwave Thermotherapy For Benign Prostatic Hyperplasia, International Journal of Urology 24 (March 1995) and Pow-Sang, et al., Thermocoagulation Effect Of Diode Laser Radiation In The Human Prostate, 45 Urology 790 (May 1995), but it is sufficient for the purposes of this disclosure to understand that application of heat at sufficiently high temperature for sufficient lengths of time to destroy some or all cells in a portion of the prostate gland eventually produces a therapeutic effect.
Devices for heating the prostate are illustrated, for example, in Edwards, et al., Medical Probe Device and Method, U.S. Pat. No. 5,366,490 (Nov. 22, 1994), which shows a device for application of RF or microwave energy into the prostate while protecting the prostatic urethra from damage during the treatment. Hyperthermia treatment, as the term is generally used, is accomplished in the temperature range of 40-60.degree. C. Thermotherapy, as the term is generally used, is accomplished by heating the prostate above 60.degree. C. Both heat treatments have been beneficially used in the treatment of prostate enlargement.
After heat treatment, the prostate gland will be partially destroyed. Thermal necrosis, thermocoagulation, denaturization, and other such terms are used to describe the thermal damage done to the prostate gland. The prostatic urethra will also be partially destroyed. The prostate gland and the prostatic urethra swell in response to the burn caused by the heat treatment, and this immediately causes acute blockage of the urethra. The prostate gland and prostatic urethra eventually heal, over several weeks or months, typically about three months after heat treatment.
During the healing period, much of the prostate and prostatic urethra that were damaged by the heat treatment are re-absorbed by the body through the blood vessels supplying the area. However, significant portions near the urethra slough off the urethra wall and fall into the urethra. Sloughing causes acute blockage of the urethra. Thus, during the post-operative healing period, swelling and sloughing cause acute blockage of the urethra, leading to extreme discomfort and clinical danger to the patient. After healing, the prostate will be smaller than before heat treatment and will not force closure of the urethra. The condition of benign prostate hyperplasia is essentially cured. Prostate cancer can also be treated successfully with similar heat treatments, usually in combination with chemotherapy or radiation treatment.
It has recently been proposed to use stents to support the urethra and keep it open despite pressure from the swollen prostate. The Prostacoil.TM. temporary intraprostatic stent, marketed by Instent, Inc. of Eden Prairie, Minn., is an example of a stent adapted for use in the prostatic urethra. The stent includes an anchoring section and a prostatic section, and is placed with a delivery catheter shaft through the urethra. The stent is used long-term, for patients temporarily or permanently unfit for surgery.
A wide variety of stents have been proposed for use in various applications. Intravascular stents and coronary stents such as the Palmaz-Schatz stent illustrated in Palmaz, have been used to treat occlusions of blood vessels. A commonly suggested material for making stents is pseudoelastic and/or shape memory alloys such as Nitinol. For example, Sugita, Catheter, U.S. Pat. No. 4,969,890 (Nov. 13, 1990) proposes use of a shape memory alloy for an intravascular stent, and shows a device for percutaneous delivery of the stent to an occluded stenotic region of a blood vessel. Harada, et al, Method of Implanting a Stent Within a Tubular Organ of a Living Body and of removing Same, U.S. Pat. No. 5,037,427 (Aug. 4, 1991) proposes use of a two-way shape memory alloy stent in a blood vessel. Two-way shape memory is useful in a stent, according to Harada, to allow removal of the stent. AS explained in Harada, it is not possible to remove a one-way shape memory stent after implantation. Harada proposes use of two-way shape memory stent with a hot, large diameter shape which holds a blood vessel open and a cold, small diameter shape which can be moved within the vessel and removed. Harada also discloses a device for percutaneous placement of the stent. Dotter, Transluminally Placed Expandable Graft Prosthesis, U.S. Pat. No. 4,503,569 shows the use of shape memory alloy stent proposed for use in blood vessels. Each of these references use saline solution injected through a catheter to control the temperature of the stent, thereby controlling the shape of the stent.
Stents may be left in blood vessels permanently, and are usually implanted for permanent use. The risk of infection around the stent in a blood vessel, or movement of the stent within a blood vessel, are somewhat limited by the environment. In the urethra, however, the risk of infection is high, and movement within the urethra may be caused by urination or ejaculation, especially if the prostate gland shrinks in response to treatment. Thus, there is a limit to the amount of time a stent may be left implanted in the urethra before infection sets in or migration occurs.

Urological stent therapy system and method


Simple compact apparatus for artificial resuscitation which avoids mouth-to-mouth contact. The apparatus enables a person to force exhaled air from his lungs into the lungs of a victim without mouth-to-mouth contact, the air flow being controlled by a flutter valve, so that air flows only from the person to the patient, with any fluid exhaled by the patient being by-passed around the valve and through appropriate outlets to the atmosphere.

A well known successful method for reactivating normal breathing in a person who has stopped breathing due to drowning, electrical shock, or various other reasons, is by mouth-to-mouth resuscitation, by which another person exhales air directly from his lungs at rhythmic intervals into the lungs of the victim placing his mouth in contact with the mount of the victim.
Such mouth-to-mouth resuscitation is currently widely practiced. However, a drawback to mouth-to-mouth resuscitation is the natural abhorrence by anyone to place his mouth against the mouth of another person, especially a stranger, an also the fear of contracting a disease from such a contact.
For that reason, a variety of devices have been proposed in the prior art for effectuating mouth-to-mouth resuscitation without actual contact with the mouth of the victim. However, for the most part such prior art devices have been unduly complex and awkward to use.
It is accordingly an objective of the present invention to provide a simple and compact apparatus which may be disposable, or which may be readily sterilized, and which may be used for effectuating mouth-to-mouth resuscitation without any actual mouth contact with the patient.


A rotor disk arrangement having a rotor disk which has, distributed around the outer circumference, a plurality of axially extending blade holding grooves and an encircling fastening protrusion and/or a plurality of fastening protrusions arranged in a circumferentially distributed manner, and having a plurality of sealing elements arranged in a circumferentially distributed manner, the sealing elements covering the blade holding grooves at least in portions on the end side and having, on the side facing the rotor axis, at least one fastening portion that bears against the underside of the fastening protrusion, wherein the fastening protrusion is embodied in an undercut manner, wherein the distance thereof from the rotor axis at the free end facing away from the rotor disk is less than in a region within the fastening protrusion.

In a rotor of a gas turbine, use is generally made of rotor disks which have, distributed around the outer circumference, a multiplicity of blade holding grooves in each of which a rotor blade is fastened by way of a blade holding profile. This makes it possible to replace the rotor blade in the event of wear. It is furthermore known that the blade holding grooves should be protected against the penetration of the hot gas flowing through the gas turbine. To this end, circumferentially distributed segmented sealing elements are used in a known manner in front of the end side of the rotor disk. Embodiments that are known in this regard are known for example from EP 1 804 338 A1, EP 1 944 471 A1 and from EP 2 399 004 A1. In these cases, the sealing elements generally have a flat shape and extend from an annular groove beneath the blade holding grooves to beyond the outer circumference of the rotor disk. Thus, the blade holding grooves are reliably covered by the sealing elements. The sealing elements are fastened to the rotor disk or to the rotor blades in different ways, wherein, to this end, the sealing elements are generally mounted on the inner circumference in an annular groove of the rotor disk. The sealing elements are likewise usually secured axially to the outer circumference in an annular groove which is formed by the circumferentially segmented mutually adjoining rotor blades.
Upon rotation of the rotor, the sealing elements are usually supported in the annular groove in the rotor blades. In this case, the centrifugal force on the sealing elements additionally stresses the in any case highly stressed rotor blades.

Rotor disk having an end-side sealing element


A film unit ejection and processing system for instant cameras having a spread roller pressure nip through which an exposed film unit is passed from the camera interior for processing and discharge to the camera exterior. The system includes an opaque feed web to frictionally engage each film unit and having a flight portion extending through the pressure nip to an end secured to a tray supported for reciprocation on the camera exterior. The tray carries guide rollers to support the feed web in a loop configuration so that the end of the web opposite from the tray connected end may be secured to the camera body without interference with film unit feeding by frictional engagement with the web flight portion extending from the pressure nip. The tray further operates a spring biased pick arrangement by which each film unit is advanced to present its leading edge at the pressure nip. Also, the web may be provided with frictional engagement augmenting means such as a roughened traction surface, a spread roller separating formation positioned to immediately precede the leading edge of a film unit into the pressure nip or traction nubs located to push the rear edge of the film unit through the pressure nip.

This invention relates to photographic equipment and more particularly, it concerns an improved system for processing and ejecting photographic film units of a type in which a film unit carried supply of processing fluid is spread over an area of exposed photosensitive materials as the unit is passed from the interior of a camera designed to handle such units.
Camera systems in which film units may be exposed and processed instantly on withdrawal or ejection of the exposed unit from a camera are now well known in the art. In general, such systems include a pair of spread rollers or equivalent means to establish a pressure nip through which each film unit is passed after exposure in order to rupture a unit carried pod of processing fluid and spread the fluid uniformly over the exposed photographic materials, usually lying at the interface of a pair of sheets in the unit, so that the latent image formed by exposure of such materials will be developed into a real or visual photographic image. In early systems, each film unit was provided or associated with some form of pull tab accessible at the camera exterior and which, when pulled manually, effected a withdrawal of the associated film unit through the aforementioned pressure nip. More recently, instant camera systems have become available in which improved film units are ejected from the camera, again through a processing fluid spreading pressure nip, by a motor-driven system. A principal advantage of the more recent of these systems is that they are "trash free"; that is, only the film unit is discharged from the camera with no pull tab or other discardable material accompanying the unit structure providing the final photograph.
Motor-driven processing fluid spreader systems for instant cameras possess several additional advantages which are important to film unit processing. For example, the speed at which the film unit is passed through the pressure nip can be controlled very accurately. This is important not only from the standpoint of assuring the uniform spread of processing fluid over the area of the exposed photographic materials contained in the unit, but also from the standpoint of controlling the length of time that infinitely successive increments of the film unit remain protected from light within the camera structure after processing fluid has been spread over such increments. In other words, the short duration of time between contact by the processing fluid and exit from the camera into ambient light permits the film to become insensitive to light before exiting from the camera. Equally as important as control over the rate of film unit feed through the pressure nip is that the driving force for feeding the unit is applied directly at the pressure nip by the rotatably driven rollers in a manner to avoid any film unit stresses which would interfere with uniform spreading of the processing fluid.
On the other hand, motor-driven processing fluid spreading systems for instant cameras suffer from such disadvantages as manufacturing costs, complexity of component packaging within the camera and need for a source of electrical energy of sufficient capacity to meet the power requirements of the motor drive. Additionally, it is necessary for at least one of the pressure nip defining rollers to be finished with a traction or friction surface so that rotation of the roller will be translated into linear movement of the film unit. Although all of these disadvantages have been overcome as is evidenced by instant camera systems available commercially at the present time, the success of the presently available systems has involved a measure of compromise in system costs. There is a need, therefore, for a manually actuated processing fluid spreader system for instant cameras by which costs incident to electric motor drives can be avoided but without compromise in the overall effectiveness of system operation.

Camera employing web for film ejection and processing